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WO1997010221A1 - Synthese de banques de quinazolinones - Google Patents

Synthese de banques de quinazolinones Download PDF

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Publication number
WO1997010221A1
WO1997010221A1 PCT/US1996/000886 US9600886W WO9710221A1 WO 1997010221 A1 WO1997010221 A1 WO 1997010221A1 US 9600886 W US9600886 W US 9600886W WO 9710221 A1 WO9710221 A1 WO 9710221A1
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substituted
phenyl
protected
phenylalkyl
alkyl
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PCT/US1996/000886
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English (en)
Inventor
Richard A. Houghten
John M. Ostresh
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Torrey Pines Institute For Molecular Studies
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Priority to AU48585/96A priority Critical patent/AU4858596A/en
Publication of WO1997010221A1 publication Critical patent/WO1997010221A1/fr

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    • 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
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4

Definitions

  • the present invention relates generally to the field of synthetic combinatorial libraries and, more specifically, to the generation of libraries of small organic compounds based on the quinazolinone ring.
  • Quinazolinones and derivatives thereof are now known to have a wide variety of biological properties, including hypnotic, sedative, analgesic, anticonvulsant, antitussive and anti-inflammatory effects.
  • quinazolinones can be obtained by acid-catalyzed condensation of N-acylanthranilic acids with aromatic primary amines.
  • the current synthesis and study of quinazolinones is a slow process. Each quinazolinone must be individually synthesized and separately tested. There exists a need to more efficiently synthesize and test various quinazolinones.
  • SCLs chemically synthesized combinatorial libraries
  • the preparation and use of synthetic peptide combinatorial libraries has been described, for example, in Houghten et al., Nature 354. 84 (1991) .
  • Such SCLs provide the efficient synthesis of an extraordinary number of various peptides and screening of the library rapidly identifies lead pharmaceutical compounds.
  • Combinatorial approaches have recently been extended to "organic,” or non-peptidic libraries, as described, for example, in Gordon et al . , J. Med. Chem.. 37:1385-1401 (1994) .
  • organic libraries to present date are of limited diversity and generally relate to peptidomimetic compounds; in other words, organic molecules that retain peptide chain pharmacophore groups similar to those present in the corresponding peptide.
  • organic libraries are needed to prepare and screen quinazolinones and derivatives thereof. This invention satisfies these needs and provides related advantages as well.
  • the present invention relates to the generation of synthetic combinatorial libraries of organic compounds based on the quinazolinone ring of the formula:
  • the present invention provides a library of five or more variously substituted quinazolinones wherein each quinazolinone contained within the mixture has the basic ring structure of Formula I:
  • R 1 is a hydrogen atom, C x to C 6 alkyl; d to C 6 substituted alkyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, phenyl, substituted phenyl, C 3 to C 7 cycloalkyl, or C 3 to C 7 substituted cycloalkyl;
  • R 2 is a hydrogen atom, halo, hydroxy, protected hydroxy, cyano, nitro, C- to C 6 alkyl, C 2 to C 7 alkenyl, C 2 to C 7 alkynyl, C, to C 6 substituted alkyl, C 2 to C 7 substituted alkenyl, C 2 to C 7 substituted alkynyl, C x to C 4 alkoxy, C ⁇ to C 7 acyloxy, C- to C 7 acyl, C 3 to C 7 cycloalkyl, C 3 to C 7 substituted cycloalkyl, C 3 to C 7 cycloalkenyl, C 3 to C 7 substituted cycloalkenyl, a heterocyclic ring, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, phenyl, substituted phenyl, cyclic C 2 to C 10 alkylene, substituted cyclic C 2 to C 10 alkylene, cyclic
  • R 3 is C 2 to C 6 alkyl, C 2 to C 7 alkenyl, C 2 to C 7 alkynyl, C- to C 6 substituted alkyl, C 2 to C 7 substituted alkenyl, C 2 to C 7 substituted alkynyl, C 3 to C 7 cycloalkyl, C 3 to C 7 substituted cycloalkyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, phenyl, or substituted phenyl; and
  • Y may be absent and, if present, is carboxylic acid, carboxamide, protected carboxamide, an amino resin, or a hydroxy resin.
  • R 1 is n-prop-1,3-yl, n-prop-1,1-yl, n-pent-1,5-yl, n-hex-1,6-yl, p-benzyl, 2-chloro-p-phenyl, p-phenyl, 2-methyl-m-phenyl, 2-hydroxy-p-phenyl, and 2- (phenyl) -n-prop-1,3-yl, or the ⁇ -carbon and side chain of an amino acid and more preferably the ⁇ -carbon and side chain of an amino acid as provided in Table I.
  • R 2 is a hydrogen atom, 6, 8-dimethyl, 6-hydroxy, a 1,4-butadienyl moiety such that a naphthyl ring results, or halo, and more preferably 6,7-difluoro, 6,8-dichloro, or 6,8-dibromo;
  • R 3 is methyl; and Y may be present or absent and, if present, is selected from the group consisting of carboxylic acid, carboxamide, protected carboxamide, an amino resin, and a hydroxy resin.
  • the present invention also provides libraries of various quinazolinone derivatives.
  • the quinazolinone mixture can be further chemically transformed to extend the range and chemical diversity of the compounds.
  • various libraries of quinazolinone derivatives can be prepared by chemically altering the initial quinazolinone 1ibrary.
  • Such quinazolinone derivative libraries can be made by modifying the above described quinazolinone library in a variety of ways.
  • the above quinazolinone library can be modified to yield N-styryl derivatives of quinazolinones. Therefore, the present invention provides a mixture of five or more quinazolinone derivatives of the structure of Formula II:
  • R 1 , R 2 , and Y have the same meaning as provided above and R 4 is as follows:
  • R 4 is C- to C 6 alkyl; C- to C 6 substituted alkyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, or a heterocyclic ring.
  • R 1 is n-prop-1, 3-yl, n-prop- 1,1-yl, n-pent-1, 5-yl, n-hex-1, 6-yl, p-benzyl, 2-chloro- p-phenyl, p-phenyl, 2-methyl-m-phenyl, 2-hydroxy-p- phenyl, and 2- (phenyl) -n-prop-1, 3-yl, or the ⁇ -carbon and side chain of an amino acid and more preferably the ⁇ - carbon and side chain of an amino acid as provided in Table I above;
  • R 2 is a hydrogen atom, 6, 8-dimethyl, 6- hydroxy, 1,4-butadienyl moiety such that a naphthyl ring results, or halo, and more preferably 6, 7-difluoro, 6,8- dichloro, or 6,8-dibromo;
  • R 4 is phenyl, 2,
  • Y may be present or absent and, if present, is carboxylic acid, carboxamide, protected carboxamide, an amino resin, or a hydroxy resin.
  • Another library containing five or more quinazolinone derivatives provided by the present invention include 1,2-dihydro derivatives having the structure of Formula III:
  • R 1 , R 2 , and R 3 have the same meanings as provided above.
  • the basic ring nitrogen at position 1 can be alkylated using a variety of alkylating agents to prepare a mixture of five or more quinazolinone derivatives of the following Formula IV:
  • R 1 , R 2 , R 3 , and Y are as defined above, and R 5 is C x to C 6 alkyl; C x to C 6 substituted alkyl, C x to C 4 alkoxy, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, phenyl, or substituted phenyl.
  • R 6 is a hydrogen atom, C x to C 6 alkyl; Cj . to C 6 substituted alkyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, phenyl, substituted phenyl, C 3 to C 7 cycloalkyl, C 3 to C 7 substituted cycloalkyl, carboxylic acid, carboxamide, or protected carboxamide.
  • the stereochemistry of the chiral R 1 through R 6 groups can independently be in the R or S configuration, or a mixture of the two.
  • C- to C 6 alkyl denotes such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, amyl, tert- amyl, hexyl and the like.
  • the preferred "C- to C 6 alkyl” group is methyl.
  • C 2 to C 7 alkenyl denotes such radicals as vinyl, allyl, 2-butenyl, 3-butenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, as well as dienes and trienes of straight and branched chains.
  • C 2 to C 7 alkynyl denotes such radicals as ethynyl, propenyl, butynyl, pentynyl, hexynyl, heptynyl, as well as di- and tri-ynes.
  • Ci to C 6 substituted alkyl denotes that the above C ⁇ to C 6 alkyl groups and C 2 to C 7 alkenyl and alkynyl groups are substituted by one or more, and preferably one or two, halogen, hydroxy, protected hydroxy, cyclohexyl, naphthyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted)amino, guanidino, imidazolyl, indolyl, pyrolidinlyl, C to C 7 acyloxy, nitro, C to C 4 alkyl ester, carboxy, protected carboxy, carbamoyl, carbamoyloxy, carboxamide, protected carboxamide, cyano, methylsulfonylamino, sulfurhydryl, Cj to
  • Examples of the above substituted alkyl groups include the cyanomethyl, nitromethyl, chloromethyl, hydroxymethyl, tetrahydropyranyloxymethyl, trityloxy ethyl, propionyloxymethyl, aminomethyl, carboxymethyl, allyloxycarbonylmethyl, allylcaroxybonylaminomethyl, carbamoyloxymethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, 6- hydroxyhexyl, 2,4-dichloro (n-butyl) , 2-amino (iso-propyl) , 2-carbamoyloxyethyl chloroethyl, bromoethyl, fluoroethyl, iodoethyl, chloropropyl, bromopropyl, fluoropropyl, iodopropyl and the like.
  • C- to C 4 alkoxy denotes groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups.
  • a preferred C-, to C 4 alkoxy group is methoxy.
  • C ⁇ to C 7 acyloxy denotes herein groups such as formyloxy, acetoxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, and the like.
  • Ci to C 7 acyl encompasses groups such as formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like.
  • C 3 to C 7 cycloalkyl includes the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings.
  • the substituent term “C 3 to C 7 substituted cycloalkyl” indicates the above cycloalkyl rings substituted by a halogen, hydroxy, protected hydroxy, C x to C 6 alkyl, C- to C 4 alkoxy, carboxy, protected carboxy, amino, or protected amino.
  • C 3 to C 7 cycloalkenyl indicates a 1,2, or 3-cyclopentenyl ring, a 1,2,3 or 4- cyclohexenyl ring or a 1,2,3,4 or 5-cycloheptenyl ring
  • substituted C 3 to C 7 cycloalkenyl denotes the above C 3 to C 7 cycloalkenyl rings substituted by a C x to C 6 alkyl radical, halogen, hydroxy, protected hydroxy, Ci to C 4 alkoxy, carboxy, protected carboxy, amino, or protected amino.
  • heterocyclic ring denotes optionally substituted five-membered or six-membered rings that have 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms. These five-membered or six-membered rings may be fully unsaturated or partially unsaturated, with fully unsaturated rings being preferred.
  • Preferred heterocyclic rings include pyridino, pyrimidino, and pyrazino rings.
  • C 7 to C 12 phenylalkyl denotes a C- to C 6 alkyl group substituted at any position by a phenyl ring.
  • Examples of such a group include benzyl, 2- phenylethyl, 3-phenyl- (n-prop-1-yl) , 4-phenyl- (-hex-1- yl) , 3-phenyl- (n-am-2-yl) , 3-phenyl- (sec-butyl) , and the like.
  • a preferred group is the benzyl group.
  • C 7 to C 12 substituted phenylalkyl denotes a C 7 to C 12 arylalkyl group substituted on the C ⁇ to C 6 alkyl portion with one or more, and preferably one or two, groups chosen from halogen, hydroxy, protected hydroxy, keto, C 2 to C 3 cyclic ketal, amino, protected amino, Ci to C 7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carbamoyloxy, cyano, N- (methylsulfonylamino) or C- to C Pain alkoxy; and/or the phenyl group may be substituted with 1 or 2 groups chosen from halogen, hydroxy, protected hydroxy, nitro, C-, to C 6 to alkyl, C x to C 4 alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, a N- (methylsulfonylammo)
  • C 7 to C 12 substituted phenylalkyl examples include groups such as 2-phenyl-1- chloroethyl, 2- (4-methoxyphenyl)eth-1-yl, 2, 6-dihydroxy- 4-phenyl (n-hex-2-yl) , 5-cyano-3-methoxy-2-phenyl (n-pent- 3-yl) , 3- (2, 6-dimethylphenyl)n-prop-l-yl, 4-chloro-3- aminobenzyl, 6- (4-methoxyphenyl) -3-carboxy(n-hex-1-yl) , 5- (4-aminomethyl-phenyl) -3- (aminomethyl) (n-pent-2-yl) , 5- phenyl-3-keto- (n-pent-1-yl) , 4- (4-aminophenyl) -4- (1,4- oxetanyl) (n-but-1-yl) , and the like.
  • substituted phenyl specifies a phenyl group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C x to C 6 alkyl, C- to C 4 alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino trifluoromethyl, N- (methylsulfonylamino) , or phenyl, substituted or unsubstituted, such that, for example, a biphenyl results.
  • substituted phenyl includes a mono- or di (halo)phenyl group such as 4- chlorophenyl, 2, 6-dichlorophenyl, 2, 5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4- bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl and the like; a mono or di (hydroxy)phenyl groups such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4- dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 3-or 4- nitrophenyl; a cyanophenyl group for example, 4- cyanophenyl; a mono- or di (lower alkyl)phenyl group such as 4-methylphenyl, 2, 4-dimethylphenyl, 2-methylphenyl,
  • substituted phenyl represents disubstituted phenyl groups wherein the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4- hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2- hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy 4- chlorophenyl and the like.
  • substituted naphthyl specifies a naphthyl group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to C 6 alkyl, Ci to C 4 alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino trifluoromethyl or N- (methylsulfonylamino) .
  • halo and halogen refer to the fluoro, chloro, bromo or iodo groups.
  • (monosubstituted)amino refers to an amino group with one substituent chosen from the groups consisting of phenyl, substituted phenyl, C x to C 6 alkyl, and C 7 to C 12 arylalkyl, wherein the latter three substituent terms are as defined above.
  • (disubstituted)amino refers to amino groups with two substituents chosen from the group consisting of phenyl, substituted phenyl, C ⁇ to C 6 alkyl, and C 7 to C 12 arylalkyl wherein the latter three substituent terms are as described above.
  • the two substituents can be the same or different.
  • amino-protecting group refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the amine component.
  • protected (monosubstituted) amino means there is an amino-protecting group on the monosubstituted amino nitrogen atom.
  • protected carboxamide means there is an amino- protecting group replacing the proton so that there is no N-alkylation.
  • amino-protecting groups include the formyl ("For") group, the trityl group, the phthalimido group, the trichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups, urethane-type blocking groups, such as t-butoxy-carbonyl (“Boc”) , 2- (4-biphenylyl)propyl (2) oxycarbonyl ("Bpoc”) , 2-phenylpropyl (2)oxycarbonyl (“Poc”) , 2- (4- xenyl) isopropoxycarbonyl, 1, 1-diphenylethyl (1) - oxycarbonyl, 1, 1-diphenylpropyl (1) oxycarbonyl, 2- (3, 5- dimethoxyphenyl)propyl (2)oxycarbonyl (“Ddz”) , 2- (p- toluyl)propyl (2) oxycarbonyl, cyclopentanyloxycarbonyl, 1-
  • amino-protecting group employed is not critical so long as the derivatized amino group is stable to the conditions of the subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the compounds.
  • Preferred amino- protecting groups are Boc and Fmoc.
  • Further examples of amino-protecting groups embraced to by the above term are well known in organic synthesis and the peptide art and are described by, for example, T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed., John Wiley and Sons, New York, NY, 1991, Chapter 7, M.
  • carboxy-protecting group refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound.
  • carboxylic acid protecting groups include 4-nitrobenzyl, 4-methoxybenzyl, 3,4- dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6- trimethoxybenzyl, 2,4, 6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4, 4 ' -dimethoxytrityl, 4,4 ' ,4"-timethoxytrityl, 2- phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, 2,2, 2-trichloroethyl, ⁇ - (trimethylsilyl) ethyl, ⁇ - (di (n- butyl)methylsilyl
  • carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the conditions of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Further examples of these groups are found in E. Haslam,
  • hydroxy-protecting group refers to readily cleavable groups bonded to hydroxyl groups, such as the tetrahydropyranyl, 2-methoxyprop-2-yl, 1- ethoxyeth-1-yl, methoxymethyl, ⁇ -methoxyethoxymethyl, methylthiomethyl, t-butyl, t-amyl, trityl, 4- methoxytrityl, 4,4 ' -dimethoxytrityl, 4,4',4"- trimethoxytrityl, benzyl, allyl, trimethylsilyl, (t- butyl)dimethylsilyl and 2, 2,2-trichloroethoxycarbonyl groups and the like.
  • hydroxy-protecting groups are not critical so long as the derivatized hydroxyl group is stable to the conditions of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the quinazolinone molecule.
  • Further examples of hydroxy-protecting groups are described by CB. Reese and E. Haslam, "Protective Groups in Organic Chemistry,” J.G.W. McOmie, Ed., Plenum Press, New York, NY, 1973, Chapters 3 and 4, respectively, and T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed. , John Wiley and Sons, New York, NY, 1991, Chapters 2 and 3.
  • C- to C 4 alkylthio refers to sulfide groups such as methylthio, ethylthio, n- propylthio, iso-propylthio, n-butylthio, t-butylthio and like groups.
  • the substituent term "Ci to C 4 alkylsulfoxide” indicates sulfoxide groups such as methylsulfoxide, ethylsulfoxide, n-propylsulfoxide, iso-propylsulfoxide, n-butylsulfoxide, sec-butylsulfoxide, and the like.
  • C. to C 4 alkylsulfonyl encompasses groups such as methylsulfonyl, ethylsulfonyl, n- propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, t- butylsulfonyl, and the like.
  • Phenylthio, phenyl sulfoxide, and phenylsulfonyl compounds are known in the art and these terms have their art recognized definition.
  • substituted phenylthio substituted phenyl sulfoxide
  • substituted phenylsulfonyl is meant that the phenyl can be substituted as described above in relation to “substituted phenyl.”
  • cyclic C 2 to C 10 alkylene defines such a cyclic group bonded ("fused") to the phenyl radical.
  • the cyclic group may be saturated or contain one or two double bonds.
  • the cyclic group may have one or two methylene groups replaced by one or two oxygen, nitrogen or sulfur atoms.
  • the cyclic alkylene or heteroalkylene group may be substituted once or twice by substituents selected from the group consisting of the following moieties: hydroxy, protected hydroxy, carboxy, protected carboxy, keto, ketal, C. to C 4 alkoxycarbonyl, formyl, C 2 to C 4 alkanoyl, C- to C 6 alkyl, carbamoyl, C- to C 4 alkoxy, C x to C 4 alkylthio, C ⁇ to C 4 alkylsulfoxide, C x to C 4 alkylsulfonyl, halo, amino, protected amino, hydroxymethyl or a protected hydroxymethyl.
  • the cyclic alkylene or heteroalkylene group fused onto the benzene radical can contain two to ten ring members, but it preferably contains four to six members.
  • saturated cyclic groups are when the resultant bicyclic ring system is 2,3-dihydro- indanyl and a tetralin ring.
  • unsaturated examples occur when the resultant bicyclic ring system is a naphthyl ring or indanyl.
  • fused cyclic groups which each contain one oxygen atom and one or two double bonds are when the phenyl ring is fused to a furo, pyrano, dihydrofurano, or dihydropyrano ring.
  • Examples of cyclic groups which each have one nitrogen atom and contain one or two double more double bonds are when the phenyl is fused to a pyridino or pyrano ring.
  • Examples of cyclic groups which each have one sulfur atom and contain one or two double bonds are when the phenyl is fused to a thieno, thiopyrano, dihydrothieno or dihydrothiopyrano ring.
  • Examples of cyclic groups which contain two heteroatoms selected from sulfur and nitrogen and one or two double bonds are when the phenyl ring is fused to a thiazolo, isothiazolo, dihydrothiazolo or dihydroisothiazolo ring.
  • Examples of cyclic groups which contain two heteroatoms selected from oxygen and nitrogen and one or two double bonds are when the benzene ring is fused to an oxazolo, isoxazolo, dihydrooxazolo or dihydroisoxazolo ring.
  • Examples of cyclic groups which contain two nitrogen heteroatoms and one or two double bonds occur when the benzene ring is fused to a pyrazolo, imidazolo, dihydropyrazolo or dihydroimidazolo ring.
  • One or more of the quinazolinones or quinazolinone derivatives within a given library may be present as a pharmaceutically acceptable salt.
  • pharmaceutically-acceptable salt encompasses those salts that form with the carboxylate anions and amine nitrogens and include salts formed with the organic and inorganic cations discussed below. Furthermore, the term includes salts that form by standard acid-base reactions with basic groups (such as amino groups) and organic or inorganic acids.
  • Such acids include hydrochloric, sulfuric, phosphoric, acetic, succinic, citric lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D- glutamic, d-camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids.
  • organic or inorganic cation refers to counterions for the carboxylate anion of a carboxylate salt.
  • the counter-ions are chosen from the alkali and alkaline earth metals, (such as lithium, sodium, potassium, barium and calcium) ; ammonium; and the organic cations (such as dibenzylammonium, benzylammonium, 2- hydroxyethylammonium, bis(2-hydroxyethyl)ammonium, phenylethylbenzylammonium, dibebenzylethylenediammonium, and like cations) .
  • cations encompassed by the above term include the protonated form of procaine, quinine and N-methylglucosamine, and the protonated forms of basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine.
  • any zwitterionic form of the instant compounds formed by a carboxylic acid and an amino group is referred to by this term.
  • a cation for a carboxylate anion will exist when R 2 or Ri is substituted with a (quaternary ammonium)methyl group.
  • a preferred cation for the carboxylate anion is the sodium cation.
  • the compounds of the above Formulae can also exist as solvates and hydrates. Thus, these compounds may crystallize with, for example, waters of hydration, or one, a number of, or any fraction thereof of molecules of the mother liquor solvent.
  • the solvates and hydrates of such compounds are included within the scope of this invention.
  • One or more quinazolinones or quinazolinone derivatives can be in the biologically active ester form, such as the non-toxic, metabolically-labile ester-form. Such ester forms induce increased blood levels and prolong the efficacy of the corresponding non-esterified forms of the compounds.
  • Ester groups which can be used include the lower alkoxymethyl groups, for example, methoxymethyl, ethoxymethyl, iso-propoxymethyl and the like; the ⁇ - (C ⁇ to C 4 ) alkoxyethyl groups, for example methoxyethyl, ethoxyethyl, propxyethyl, iso-propoxyethyl, and the like; the 2-oxo-l, 3-diosolen-4-ylmethyl groups, such as 5-methyl-2-oxo-1, 3-dioxolen-4-ylmethyl, 5-phenyl- 2-oxo-l, 3-dioxolen-4-ylmethyl, and the like; the C- to C 3 alkylthiomethyl groups, for example methylthiomethyl, ethylthiomethyl, iso-propylthiomethyl, and the like; the acyloxymethyl groups, for example pivaloyloxymethyl, pivaloyloxyethyl,
  • the quinazolinone library of Formula I can be prepared, using either solution or solid-phase techniques, by combining and reacting an anthranilic acid and an amine component according to the general Reaction Scheme I :
  • the amino nitrogen of anthranilic acid can be, though need not be, acylated.
  • the amine component, H ⁇ -R ⁇ Y can be acylated as discussed in more detail below.
  • the anthranilic acid is acylated with any of the above defined R 3 groups.
  • anthranilic acids include, but are not limited to, N- (acetyl) anthranilic acid, 3 , 5-dichloro-N- (acetyl) - anthranilic acid, 3 , 5-dibromo-N- (acetyl)anthranilic acid, 4, 5-difluoro-N- (acetyl) -anthranilic acid, 3, 5-dimethyl-N- (acetyl) anthranilic acid, 4-nitro-N- (acetyl)anthranilic acid, and 5-hydroxy-N- (acetyl) anthranilic acid, 3-methoxy anthranilic acid and 3-ethoxyanthranilic acid.
  • the anthranilic acid is preferably acylated and, more preferably, acetylated (R 3 is methyl) .
  • Preferred acetylated anthranilic acids are N- (acetyl)anthranilic acid, 3 , 5-dichloro-N- (acetyl) -anthranilic acid, 3,5- dibromo-N- (acetyl) anthranilic acid, 4, 5-difluoro-N- (acetyl) -anthranilic acid, 3, 5-dimethyl-N- (acetyl) anthranilic acid, and 5-hydroxy-N- (acetyl) anthranilic acid.
  • Solid-phase techniques may be employed to condense anthranilic acid and the amine component, H ⁇ -R 1 - Y, of Reaction Scheme I whereby the anthranilic acid is resin bound.
  • the carboxylic acid functionality of an acylated anthranilic acid can be coupled to resin bound amines and subsequently condensed at 130°C with the amine component in xylene.
  • Various amino resins are discussed in greater detail below.
  • linkage of the compound to the solid support can be through the anthranilic acid component using aminoterephthalic acid and the like under condensing conditions similar to those discussed in further detail below.
  • quinazolinones where anthranilic acid derivatives are used in the preparation of quinazolinones as described above, the starting material, and hence the resulting quinazolinone, is based on a benzene ring.
  • quinazolinones can, alternatively, be based on other ring systems, and in particular on heterocyclic rings having the structure of Formula VI:
  • R 1 , R 2 , R 3 , and Y are as defined above and Z is a heteroaromatic ring having from two to six carbons and one or two heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen.
  • Z ring systems include pyridino, pyrimidino, pyrazino, and pyridazino.
  • Preferred alternative starting materials to anthranilic acid which provide different ring systems than phenyl include pyridine, such as 2-aminonicotinic acid, and pyrazine, such as 3-aminopyrazine-2-carboxylic acid.
  • the amine component H 2 N-R 1 -Y can be a variety of amines, including aniline derivatives, aliphatic amines, and amino carboxylic acids such as amino acids and aminophenyl carboxylic acids, each of which will be discussed in turn below.
  • Aniline compounds which can be used as the amine component include, for example, o-toluidine, 4-chloro-2- methylaniline and 2-chloroaniline, and others well known in the art which are readily available or which can easily be synthesized.
  • a solution phase reaction generally involves pyrolytically condensing the reactants at approximately 180-190 C C for about 15 minutes under inert atmosphere either as a melt or in any variety of polar aprotic solvents, such as sulfolane, dimethylformamide (DMF) , or 1-methyl-2-pyrolidinone (NMP) .
  • polar aprotic solvents such as sulfolane, dimethylformamide (DMF) , or 1-methyl-2-pyrolidinone (NMP) .
  • DMF dimethylformamide
  • NMP 1-methyl-2-pyrolidinone
  • reaction is carried out in solution phase, generally equimolar amounts or other defined amounts of reactants are use. Again, the reaction can done by solid-phase techniques as described above and in such instances excess reactants are used. In addition, condensation using various drying agents, such as phosphorus trichloride (PC1 3 ) , phosphorus oxychloride (POCl 3 ) , or phosphorus pentoxide (P 2 0 5 ) , in toluene can be done at lower temperatures.
  • drying agents such as phosphorus trichloride (PC1 3 ) , phosphorus oxychloride (POCl 3 ) , or phosphorus pentoxide (P 2 0 5 )
  • aniline can alternatively be acylated.
  • Acetanilide or N- (acetyl) - toluidine can be used.
  • the same reaction conditions as with non-acylated aniline apply, except that the reaction generally takes up to two hours.
  • the amine component, H 2 N-R 1 -Y, of Reaction Scheme I can be an aliphatic amine.
  • Aliphatic amines can be condensed with anthranilic acid under generally the same conditions as used when condensing the aniline compounds.
  • the amine component of Reaction Scheme I can also be an amino carboxylic acid, including amino acids and aminophenyl carboxylic acids.
  • the amino acid can be any one of the twenty naturally-occurring amino acids or the D-form of any one of the naturally-occurring amino acids.
  • the invention includes the use of non-naturally occurring amino acids, such as norleucine ("Nle”) , norvaline (“Nva”) , ⁇ -Ala, L- or D-naphthalanine, ornithine (“Om”), homoarginine (homoArg) and others well known in the peptide art, such as those described in M.
  • amino acids are indicated herein by either their full name or by the commonly known three letter code. Further, in the naming of amino acids, "D-" designates an amino acid having the "D" configuration, as opposed to the naturally occurring L-amino acids. Where no specific configuration is indicated, one skilled in the art would understand the amino acid to be an L-amino acid.
  • the amino acids can, however, also be in racemic mixtures of the D- and L-configuration.
  • any one of the twenty naturally-occurring amino acids means any one of the following: Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val.
  • the language "the D-form of a naturally-occurring amino acid” means the D-isomer of any one of these naturally-occurring amino acids, with the exception of Gly, which does not occur as D or L isomers.
  • Preferred amino acids are L- and D-Ala, L- and D-Phe, Gly, L- and D-Ile, L- and D-Leu, L- and D-Arg, L- and D-Ser, L- and D-Thr, L- and D-Val, L- and D-Tyr, L- Nle, L-Nva, ⁇ -Ala, L- and D-naphthylalanine.
  • R 1 is preferably the ⁇ - carbon and the side chain of these respective amino acid as provided above in Table I.
  • aminocarboxylic acids beside the above described amino acids include 7- aminoheptanoic acid, L- ⁇ -aminobutyric acid, ⁇ aminobutyric acid, e-aminocaproic acid, and aminophenyl carboxylic acids, such as 4-aminobenzoic acid, 4- aminophenylace ic acid, 4-aminophenylbutyric acid, 3- aminophenylacetic acid, 3-amino-2-methylbenzoic acid, 4- amino-2-chlorobenzoic acid, 4-aminosalicylic acid.
  • Such resins include 4- methylbenzhydrylamme (MBHA) , 4-methylbenzhydrylamme- copoly(styrene-1% divinylbenzene) , 4- (oxymethyl) - phenylacetamido methyl (Pam), 4- (oxymethyl) - phenylacetamido methyl-copoly(styrene-1% divinylbenzene), 4- (hydroxymethyl)phenoxymethyl-copoly(styrene-1% divinylbenzene) (Wang resin) , all of which are commercially available, or to p-nitrobenzophenone oxime polymer (oxime resin) , which can be synthesized as described by De Grado and Kaiser, J. Org. Chem.. 47:3258 (1982), which is incorporated herein by reference.
  • MBHA 4-methylbenzhydrylamme
  • oxime resin oxime resin
  • TentaGel a polyethylene-grafted cross-linked polystyrene resin termed TentaGel has been made commercially available by RappPolymere (Tubingen, Germany) , which resin can also be used with the present invention. These and other types of resins well known in the art can be used in the subject invention.
  • the amino carboxylic acid can be attached to the resin by coupling procedures well known in the art and as described in the ensuing Examples. During such attachment to the resin, at least the ⁇ -amino group of an amino acid, as well as the ⁇ -amino of other amino carboxylic acids, is protected with an amino-protecting group. However, with the relatively non-nucleophilic anilino group of an aminophenyl carboxylic acid, protection is not required. Where necessary, side chain functional groups of amino acids are also protected as is commonly done in the field.
  • the ⁇ -amino protecting group Prior to condensation of the amino carboxylic acid with anthranilic acid, at least the ⁇ -amino protecting group is removed with, for example, trifluoroacetic acid (TFA) for the removal of the Boc group and piperidine for the removal of the Fmoc group.
  • TFA trifluoroacetic acid
  • the condensation reaction can be done under the same conditions as those described above and as provided in Example II.
  • Styryl derivatives can be prepared by treating the quinazolinone product with a non-nucleophilic base under anhydrous condition with lithium t-butoxide in tetrahydrofuran (LiOtBu/THF) for approximately 15 min., followed by adding a non-enolizable aldehyde.
  • the aldehyde can be any one which results in R 4 as described above.
  • aldehydes include 2,4- dichlorobenzaldehyde, 4-hydroxybenzaldehyde, 2- naphthaldehyde, 2,5-dimethylbenzaldehyde, 3,4- difluorobenzaldehyde, 4-bromobenzaldehyde, 3- (4- methylphenoxy)benzaldehyde, para- (anisaldehyde) , 3- ethoxy-4-hydroxybenzaldehyde, 4-biphenylcarboxaldehyde, 4-nitrobenzaldehyde, benzaldehyde, 10-chloro-9- anthraldehyde, 6-methyl-2-pyridinecarboxaldehyde, 2- methoxy-1-naphthaldehyde, 2,4,5-trimethoxybenzaldehyde, 4- (dimethylamino)benzaldehyde, and 2-butylacrolein.
  • Preferred aldehydes are 2,4-dichlorobenzaldehyde, 2- naphthaldehyde, 2, 5-dimethylbenzaldehyde, 3,4- difluorobenzaldehyde, 4-bromobenzaldehyde, 3- (4- methylphenoxy)benzaldehyde, para- (anisaldehyde) , 4- biphenylcarboxaldehyde, benzaldehyde, 6-methyl-2- pyridinecarboxaldehyde, 2-methoxy-l-naphthaldehyde, 2,4,5-trimethoxybenzaldehyde, and 4- (dimethylamino)benzaldehyde.
  • the library of styrene derivatives itself can be further chemically altered.
  • the styrene derivatives can be epoxidized with peroxoacids, such as m-chloroperbenzoic acid.
  • the carbonyl can be reduced by standard procedures, for example, by reduction with lithium aluminum hydride (LiAlH 4 ) in THF.
  • the styrene compounds can be N-alkylated as described below.
  • the quinazolinone library can be reduced with, for example, a borohydride reagent under the usual conditions, to prepare a library five or more quinazolinone derivatives of Formula III:
  • the basic amine of the quinazolinones can be alkylated to prepare a library of compounds of Formula IV:
  • the amine is first reduced with a borohydride reagent, followed by alkylation with alkylating agents of the R 5 groups described above.
  • alkylating agents include R 5 groups derivatized with a bromo, iodo, triflate or methylsulfonate groups.
  • Other alkylating derivatives of the R 5 group are well known.
  • the compounds are reoxidized to obtain the quaternary amine using dichlorodicyanoquinone (DDQ) .
  • R 1 , R 2 , and R 6 are as defined above.
  • the substituent X is a leaving group, such as bromo, iodo, triflate, methylsulfonate, or phenylsulfonate.
  • the first amine component can be condensed with, for example, N- (bromoacetyl)anthranilic acid in sulfolane at 35 C C for one hour.
  • N- (bromoacetyl) anthranilic can be prepared by acylating anthranilic acid with bromoacetyl chloride.
  • the first amine component is protected with an amino-protecting group, such as Didyl .
  • the second amine component such as a second aniline, can be condensed in sulfolane at approximately 200°C for about two hours.
  • Example II the split synthesis approach was used to prepare a mixture of thirty five aminocarboxylic acids.
  • An alternative format is, preparing sublibraries in the 0 3 0 2 X ! format, wherein two positions on the compounds, 0 3 and 0 2 , are explicitly defined and a third position, ⁇ lf varies.
  • Such sublibraries can be conveniently prepared by the tea-bag technique, as is known in the art, and described, for example in U.S. Patent No. 4,631,211 to Houghten and Houghten et al. , Proc. Natl. Acad. Sci.. 82:5131-5135 (1985) , as well as described in Example II.
  • the iterative selection and enhancement process of screening and sublibrary resynthesis can be employed.
  • a sublibrary of various R 1 substituents can be screened to select the most active R 1 substituent.
  • the quinazolinone having the most active R 1 is then resynthesized and with the R 1 position being defined, a new R 2 position mixture library is prepared, screened, and the most active R 2 selected.
  • the above process can then be repeated to identify R 3 and the other most active R substituents on the quinazolinone ring.
  • the positional scanning technique only a single position is defined in a given sublibrary and the most preferred substituent at each position of the compound is identified.
  • SCLs synthetic combinatorial libraries
  • This Example provides a solution-phase combinatorial synthesis of a quinazolinone library.
  • N-acetyl anthranilic acids were condensed with aniline compounds to prepare a library of quinazolinones.
  • This Example provides a solid-phase combinatorial synthesis of a library containing approximately 3000 styryl derivatives of quinazolinones
  • R 1 , R 2 , R 3 , and R 4 are the respective R groups based on the starting materials provided in Table II below.
  • the P group is an amino- protecting group as defined above.
  • preparation of the library containing styryl derivatives of quinazolinones involved the following steps. Briefly, first, thirty five diverse amino carboxylic acids, varying at R 1 and including various Boc-protected amino acids (Boc-AAs) and differing aminophenyl carboxylic acids, were coupled to MBHA resin. The resins were then mixed, followed by condensation of seven acetylated anthranilic acids, each differing by their R 2 substituent, to the mixtures of resin bound amino carboxylic acids.
  • Boc-AAs Boc-protected amino acids
  • the resulting quinazolinone product was treated with LiOtBu/THF and thirteen different benzaldehydes having differing R 4 groups were added to arrive at a library of approximately 3000 styryl derivatives of quinazolinone. Finally, the compounds were cleaved from the MBHA resin and tested for biological activity.
  • the library was prepared in the 0 3 0 2 X ⁇ format in which there were 91 mixtures of 35 compounds.
  • the starting materials used are listed in Table II.
  • each anthranilic acid listed in Table II was first acetylated. Five to ten grams of each acetylated anthranilic acid was prepared by adding 1.5X neat acetic anhydride (Ac 2 0) to 0.2 M anthranilic acid/THF and allowing the reaction to proceed at room temperature for 1 hr. Following addition of an equal volume of IPA, the solution was evaporated to dryness on a rotary evaporator, redissolved and evaporated from IPA, followed by THF. Reaction completion was confirmed by RP-HPLC and MALDI-MS.
  • each of the resin-bound aminophenylcarboxlic acids was condensed with N- (acetyl) anthranilic acid. Products were removed from resin and analyzed. Using the same instruments and conditions as above, RP-HPLC and MALDI-MS of individual control compounds indicated that compounds of 60-95% purity were formed and in all cases the expected product was the major component.
  • the resin packets were then washed with DMF (IX) , DCM (2X) , followed by 5 alternating washes of DMF and MeOH.
  • the packets were dried under high vacuum, followed by treatment with hydrogen fluoride (5% anisole, 1 hr., 0°C) to cleave compounds from the MBHA resin.
  • Resins were made of each of the thirty five and aminocarboxylic acids used in the library. The resins were then condensed, first, with N- (Acetyl) anthranilic acid and then with 6-Methyl-2-pyridine carboxaldehyde. Upon cleavage from resin, products were analyzed by HPLC and MS.
  • Percent yields based upon starting resin substitution are listed in Table III.
  • Reference numbers (“REF. #”) in Table III first reference the aldehyde number provided in starting materials Table II, followed by the anthranilic acid derivative number also provided in Table II.
  • “1-1” hereinbelow in Table III means the yields for the reactants 2, 4-Dichlorobenz- aldehyde, N- (acetyl) anthranilic acid and each of the thirty five amino carboxylic acids of Table II.
  • reference number "6-3” means 4- Bromobenzaldehyde, 3, 5-Dichloroanthranilic acid and the thirty five amino carboxylic acids.

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Abstract

L'invention concerne des banques combinatoires synthétiques de composés organiques à base de noyau quinazolinone.
PCT/US1996/000886 1995-09-15 1996-01-18 Synthese de banques de quinazolinones WO1997010221A1 (fr)

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