WO1997016428A1 - Derives isoquinoleine et collections combinatoires d'isoquinoleines - Google Patents

Derives isoquinoleine et collections combinatoires d'isoquinoleines Download PDF

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WO1997016428A1
WO1997016428A1 PCT/US1996/016763 US9616763W WO9716428A1 WO 1997016428 A1 WO1997016428 A1 WO 1997016428A1 US 9616763 W US9616763 W US 9616763W WO 9716428 A1 WO9716428 A1 WO 9716428A1
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Prior art keywords
amino
phenyl
substituted
resin
methyl
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PCT/US1996/016763
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English (en)
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John S. Kiely
Michael C. Griffith
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Torrey Pines Institute For Molecular Studies
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Priority to KR1019980702842A priority Critical patent/KR19990064338A/ko
Priority to AU74571/96A priority patent/AU705066C/en
Priority to JP9517383A priority patent/JPH11514645A/ja
Priority to EP96936720A priority patent/EP0863877A4/fr
Publication of WO1997016428A1 publication Critical patent/WO1997016428A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/11—Compounds covalently bound to a solid support

Definitions

  • the present invention relates generally to the synthesis of heterocyclic compounds based on the isoquinoline ring. More specifically, the invention provides novel isoquinolines as well as novel libraries comprised of many such compounds, and methods of synthesizing the libraries.
  • the process of discovering new therapeutically active compounds for a given indication involves the screening of all compounds from available compound collections. From the compounds tested one or more structure (s) is selected as a promising lead. A large number of related analogs are then synthesized in order to develop a structure-activity relationship and select one or more optimal compounds. With traditional one-at-a-time synthesis and biological testing of analogs, this optimization process is long and labor intensive. Adding significant numbers of new structures to the compound collections used in the initial screening step of the discovery and optimization process cannot be accomplished with traditional one-at-a-time synthesis methods, except over a time frame of months or even years. Faster methods are needed that allow for the preparation of up to thousands of related compounds in a matter of days or a few weeks. This need is particularly evident when it comes to synthesizing more complex compounds, such as isoquinolines.
  • SCLs chemically synthesized combinatorial libraries
  • the preparation and use of synthetic peptide combinatorial libraries has been described, for example, by Dooley in U.S. Patent 5,367,053, Huebner in U.S. Patent 5,182,366, Appel et al . in WO PCT 92/09300, Geysen in published European Patent Application 0 138 855 and Pirrung in U.S. Patent 5,143,854.
  • SCLs provide the efficient synthesis of an extraordinary number of various peptides in such libraries and the rapid screening of the library which identifies lead pharmaceutical peptides.
  • organic libraries to the present, 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.
  • the present invention satisfies these needs and provides related advantages as well.
  • the present invention overcomes the known limitations to classical organic synthesis of isoquinolines as well as the shortcomings of combinatorial chemistry with heterocycles.
  • the present invention combines the techniques of solid-phase synthesis of heterocycles and the general techniques of synthesis of combinatorial libraries to prepare new isoquinoline compounds.
  • the present invention relates to novel isoquinoline compounds of the following formula, libraries containing such compounds, and to the generation of such combinatorial libraries composed of such compounds:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X and Y have the meanings provided below.
  • the present invention provides novel derivatives and libraries of novel derivatives of variously substituted isoquinoline compounds of Formula I:
  • i 1 is C : to C 6 alkyl, C x to C 6 substituted alkyl, C 2 to C 7 alkenyl, C 2 to C 7 substituted alkenyl, C 2 to C 7 alkynyl, C 2 to C 7 substituted alkynyl, C 3 to C 7 cycloalkyl, C 3 to C 7 substituted cycloalkyl, C 5 to C 7 cycloalkenyl, C 5 to C 7 substituted cycloalkenyl, phenyl, substituted phenyl, substituted naphthyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl or a group of the formula:
  • n and m are independently selected from a number 0 to 6; and Ar is an aryl group selected from the group consisting of phenyl, substituted phenyl, heteroaryl or substituted heteroaryl;
  • ?2 is hydrogen atom, C x to C 6 alkyl, C x to C 6 substituted alkyl, C 2 to C 7 alkenyl, C 2 to C 7 substituted alkenyl, C 2 to C 7 alkynyl, C 2 to C 7 substituted alkynyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, C 3 to C 7 cycloalkyl, C 3 to C 7 substituted cycloalkyl, C 7 to C 12 phenylalkyl, C 5 to C 7 cylcoalkenyl, C 5 to C 7 substituted cycloalkenyl, C 7 to C 12 substituted phenylalkyl or a heterocyclic ring;
  • R 4 , R 5 and R 6 are, independently, a hydrogen atom, halo, hydroxy, protected hydroxy, cyano, nitro, C x to C 6 alkyl, C 2 to C 7 alkenyl, C 2 to C 7 alkynyl, C x to C 6 substituted alkyl, C 2 to C 7 substituted alkenyl, C 2 to C 7 substituted alkynyl, C L to C 7 alkoxy, C to C 7 acyloxy, C x to C 7 acyl, C 3 to C 7 cycloalkyl, C 3 to C 7 substituted cycloalkyl, C 5 to C 7 cycloalkenyl, C 5 to C 7 substituted cycloalkenyl, a heterocyclic ring, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, cyclic C
  • X is hydroxy, protected carboxy, amino, protected amino, (monosubstituted)amino, (disubstituted)amino, an amino acid, aniline, substituted aniline or an amino- substituted heterocyclic ring;
  • Y is C0 2 H, SH, NHR 7 or C(0)NHR 7 , wherein R 7 is a hydrogen atom, C x to C 6 alkyl or C to C 6 substituted alkyl.
  • n and m are independently selected from a number 0 to 6.
  • n and m are independently selected from 0 to 4 and, more preferably, from 0 to 3.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R ⁇ X and Y are as defined above, with the exception that R 2 is other than a hydrogen atom and, therefore, R 2 is C j to C 6 alkyl, C, to C 6 substituted alkyl, C 2 to C 7 alkenyl, C 2 to C 7 substituted alkenyl, C 2 to C 7 alkynyl, C 2 to C 7 substituted alkynyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, C 3 to C 7 cycloalkyl, C 3 to C 7 substituted cycloalkyl, C 5 to C 7 cylcoalkenyl, C s to C 7 substituted cycloalkenyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl or a heterocyclic ring.
  • R 5 , R 6 , R 7 , X and Y are as defined for Formula I or as defined by any of the above-preferred embodiments, with the exception that R 5 is other than C x to C 7 alkoxy and, more preferably, is not methoxy, and even more preferably, when R 2 is a hydrogen atom, R 5 is other than C x to C 7 alkoxy.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X and Y are as defined for Formula I, with the exception that X is not amino or protected amino and is, therefore, hydroxy, protected carboxy, (monosubstituted) amino, (disubstituted) amino, an amino acid, aniline, substituted aniline or an amino-substituted heterocyclic ring.
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , X and Y are as defined above and R 2 is other than hydrogen or Cj . to C 6 alkyl and is, therefore:
  • R 2 is Ci to C 6 substituted alkyl, C 2 to C 7 alkenyl, C 2 to C 7 substituted alkenyl, C 2 to C 7 alkynyl, C 2 to C 7 substituted alkynyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, C 3 to C 7 cycloalkyl, C 3 to C 7 substituted cycloalkyl, C 5 to C 7 cylcoalkenyl, C 5 to C 7 substituted cycloalkenyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl or a heterocyclic ring.
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 and Y are as defined above and R 2 is other than hydrogen or C x to C 6 alkyl and is, therefore:
  • R 2 is Cj to C 6 substituted alkyl, C 2 to C 7 alkenyl, C 2 to C 7 substituted alkenyl, C 2 to C 7 alkynyl, C 2 to C 7 substituted alkynyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, C 3 to C 7 cycloalkyl, C 3 to C 7 substituted cycloalkyl, C 5 to C 7 cylcoalkenyl, C s to C 7 substituted cycloalkenyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl or a heterocyclic ring; and
  • X is hydroxy, protected carboxy, (monosubstituted) amino, (disubstituted) amino, an amino acid, aniline, substituted aniline or an amino-substituted heterocyclic ring.
  • the isoquinoline compounds have R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X and Y as defined above following Formula I, or as defined, in any of the above preferred embodiments, with the proviso that X is not a guanidinium group or, alternatively, with the proviso that when X is an amino acid it is other than the amino acid Lys, Arg, or a functional equivalent thereof containing a guanidium group.
  • the isoquinoline compounds are wherein:
  • R 1 is selected from the group consisting of methylene, 1,2-ethyl, 1,4-butyl, 1,6-hexyl, (s) -1- (amino) -1,2- ethyl, (s) -1- (amino) -1,5-pentyl, (r) - (1-methyl) -1,2- ethyl, (s) - (1- (methyl) -1,2- ethyl) ,
  • R 2 is selected from the group consisting of 1,4- benzodioxan-6-yl, l-methylindol-3-yl, 2,3- difluorophenyl, 2-bromophenyl, 2-chloro-5-nitrophenyl, 2-furyl, 2-imidazolyl, 2-naphthyl, 2-pyridinyl, 2- thiophenyl, 3, 4-dichlorophenyl, 3,5- bis (trifluoromethyl)phenyl, 3 , 5-dihydroxyphenyl, 3,5- dimethoxyphenyl, 3, 5-dimethyl-4-hydroxyphenyl, 3- (4- methoxyphenoxy)phenyl, 3-furyl, 3-hydroxyphenyl, 3- methyl-4-methoxyphenyl, 3-methylphenyl, 3-ni rophenyl, 3-pyridinyl, 3-thiophenyl, 4- (3-dimethylaminoprop-l- oxy)phenyl, 4- (dimethylamino
  • R 3 , R 4 , R 5 , R 6 are independently a hydrogen atom
  • X is selected from the group consisting of aminocyclopropyl, aminoisopropyl, 3-aminopropyl, aminoethanolyl, (aminomethyl) cyclopropyl, pyrrolidilyl, aminodiethyl, amino-2-methoxyethyl, aminocyclopentyl, piperidinyl, 1- (pyrrolidin-3-ol) , aminoamyl, amino- (2- (N,N-dimethyl) ) ethyl, azetidinyl, aminofurfuryl, aminodiallyl, 2-aminothiazolyl, 1-aminopiperidinyl, 1-methylpiperazinyl, 4-aminomorpholinyl, aminodiethanol,
  • Y is C(0)NH 2 .
  • R 1 is selected from the group consisting of methylene, 1, 2-ethyl, 1,4-butyl, 1,6-hexyl, (s) -1- (amino) -1, - ethyl, (s) -1- (amino) -1, 5-pentyl, (r) - (1-methyl) -1, 2- ethyl, (s) - (1- (methyl) -1,2-ethyl) ,
  • X is selected from the group consisting of anilinyl, 2- fluoroanilinyl, 3-fluoroanilinyl, 4-fluoroanilinyl, 2- chloroanilinyl, 3-chloroanilinyl, 4-chloroanilinyl, 2- bro oanilinyl, 3-bromoanilinyl, 4-bromoanilinyl, 2- methoxyanilinyl, 3-methoxyanilinyl, 4-methoxyanilinyl, 2-hydroxyanilinyl, 3-hydroxyanilinyl, 4- hydroxyanilinyl, 2-carboethoxyanilinyl, 3- carboethoxyanilinyl, 4-carboethoxyanilinyl, 2- trifluoromethylanilinyl, 3-trifluoromethylanilinyl, 4- trifluoromethylanilinyl, 2-dimethylaminoanilinyl, 3- dimethylaminoan
  • Y is C(0)NH 2.
  • R 1 is selected from the group consisting of methylene, 1, 2-ethyl, 1,3-propyl, 1,4-butyl, 1,5-pentyl, 1,6- hexyl, (S) -1-amino-l, 2-ethyl, (S) -1-amino-l, 5-pentyl, (R) -1-methyl-l, 2-ethyl, (S) -1-methyl-l, 2-ethyl,
  • phenyl is selected from the group consisting of phenyl, 2- bromophenyl, 2-cyanophenyl, 2-fluorophenyl, 2- hydroxyphenyl, 2-methoxyphenyl, 3-bromophenyl, 3- carboxyphenyl, 3-cyanophenyl, 3-fluorophenyl, 3- hydroxyphenyl, 3-methoxyphenyl, 3-methylphenyl, 3- nitrophenyl, 3- (trifluoromethyDphenyl, 4- acetamidophenyl, 4-bromopheny1, 4-carboxyphenyl, 4- cyanophenyl, 4- (3-dimethylaminopropoxy)phenyl, 4- fluorophenyl, 4- (dimethylamino)phenyl, 4- hydroxyphenyl, 4-isopropylphenyl, 4-methoxyphenyl, 4- methylphenyl, 4- (methylcarboxylate)phenyl, 4- methylsulphonylphenyl, 4-
  • R 3 , R 4 , R s , R 6 are independently a hydrogen atom
  • X is selected from the group consisting of pyridoxamino, 4- (dimethylamino)benzylamino , 2-chloro-4- fluoroanilino, 3-pyridylmethylamino, 4- (dimethylamino) anilino, 1-adamantanemethylamino, 4- isopropylanilino, 3 ,4-dichlorobenzylamino, N- benzylethanolamino, 4- ( ⁇ , , -trifluoro-m- tolyl)piperazino, 4-nitrobenzylamino, 5-indanylamino, cyclohexylamino, 4- (2-pyridyl)piperazino, 4- methoxyphenethylamino, 1-naphthalenemethylamino, 2,4- dimethoxybenzylamino, (+/-) -exo-2-norbornaneamino, 2- (2-chlorophenyl)ethylamin
  • Y is C(0)NH 2 .
  • the R ⁇ Y substituents are such that Y is always bonded to the 1-position of the R 1 radical. All naming hereinafter reflects this positioning between the two substituents.
  • the stereochemistry of chiral centers associated with the R 1 through R 7 groups can independently be in the R or S configuration, or a mixture of the two.
  • ⁇ 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 "Ci 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, propynyl, butynyl, pentynyl, hexynyl, heptynyl, as well as di- and tri-ynes of straight and branched chains.
  • C ⁇ to C 6 substituted alkyl denotes that the above C 2 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, oxo, protected oxo, cyclohexyl, naphthyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted) amino, guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, C x to C 7 alkoxy, C to C 7 acyl, C ⁇ to C 7 acyloxy, nitro, Cj to C 7 alkyl ester, carboxy, protected
  • Examples of the above substituted alkyl groups include the 2-oxo-prop-l-yl, 3-oxo-but-l-yl, cyanomethyl, nitromethyl, chloromethyl, hydroxymethyl, tetrahydropyranyloxymethyl, trityloxymethyl, propionyloxymethyl, amino, methylamino, aminomethyl, dimethylamino, carboxymethyl, allyloxycarbonylmethyl, allyloxycarbonylaminomethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4- dichloro(n-butyl) , 2-aminopropyl, chloroethyl, bromoethyl, fluoroethyl, iodoethyl, chloropropyl, bromopropyl, fluoropropyl, iod
  • Examples of the above substituted alkenyl groups include styrenyl, 3-chloro-propen-l-yl, 3-chloro- buten-1-yl, 3-methoxy-propen-2-yl, 3-phenyl-buten-2-yl, l-cyano-buten-3-yl and the like.
  • the geometrical isomerism is not critical, and all geometrical isomers for a given substituted alkenyl can be used.
  • Examples of the above substituted alkynyl groups include phenylacetylen-1-yl, 1-phenyl-2-propyn-1- yl and the like.
  • oxo denotes a carbon atom bonded to two additional carbon atoms substituted with an oxygen atom doubly bonded to the carbon atom, thereby forming a ketone moiety.
  • protected oxo denotes a carbon atom bonded to two additional carbon atoms substituted with two alkoxy groups or twice bonded to a substituted diol moiety, thereby forming an acyclic or cyclic ketal moiety.
  • ⁇ to C 7 alkoxy denotes groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups.
  • a preferred alkoxy is methoxy.
  • C x 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, pivaloyl, hexanoyl, heptanoyl, benzoyl and the like. Preferred acyl groups are acetyl and benzoyl.
  • the substituent term “C 3 to C 7 cycloalkyl” includes the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings.
  • C 3 to C 7 substituted cycloalkyl indicates the above cycloalkyl rings substituted by one or two halogen, hydroxy, protected hydroxy, C x to C 6 alkyl, C to C 7 alkoxy, oxo, protected oxo, (monosubstituted) amino, (disubstituted) amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, amino, or protected amino groups.
  • C 5 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 b to C 7 cycloalkenyl denotes the above C 5 to C 7 cycloalkenyl rings substituted by a C x to C 6 alkyl radical, halogen, hydroxy, protected hydroxy, C x to C 7 alkoxy, trifluoromethyl, carboxy, protected carboxy, oxo, protected oxo, (monosubstituted)amino, protected (monosubstituted) amino (disubstituted) amino, phenyl, substituted phenyl, 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 saturated, fully saturated or partially unsaturated, with fully saturated rings being preferred.
  • An "amino-substituted heterocyclic ring” means any one of the above-described heterocyclic rings is substituted with at least one amino group.
  • Preferred heterocyclic rings include morpholino, piperidinyl, piperazinyl, tetrahydrofurano, pyrrolo, and tetrahydrothiophen-yl .
  • Aryl groups which can be used with present invention include phenyl, substituted phenyl, as defined above, heteroaryl, and substituted heteroaryl.
  • heteroaryl means a heterocyclic aromatic derivative which is a five-membered or six-membered ring system having from 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.
  • heteroaryls include pyridinyl, pyrimidinyl, and pyrazinyl, pyridazinyl, pyrrolo, furano, oxazolo, isoxazolo, thiazolo and the like.
  • substituted heteroaryl means the above-described heteroaryl is substituted with, for example, one or more, and preferably one or two, substituents which are the same or different which substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, C x to C 6 alkyl, C x to C 7 alkoxy, C x to C 7 acyl, C x to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino,
  • C 7 to C 12 phenylalkyl denotes a C x 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-propyl) , 4-phenylhexyl, 3- phenyl (n-amyl) , 3-phenyl (sec-butyl) and the like.
  • Preferred C 7 to C 12 phenylalkyl groups are the benzyl and the phenylethyl groups .
  • C 7 to C 12 substituted phenylalkyl denotes a C 7 to C 12 phenylalkyl group substituted on the C x to C 6 alkyl portion with one or more, and preferably one or two, groups chosen from halogen, hydroxy, protected hydroxy, oxo, protected oxo, amino, protected amino, monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, guanidino, heterocyclic ring, substituted heterocyclic ring, C to C 7 alkoxy, C x to C 7 acyl, C x to C 7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N- ⁇ C x to C 6 alkyl) carboxamide, protected N- (C x to C 6 alkyl) carboxamide, N, N- (C x to C 6 dialkyl) carboxamide, cyan
  • C 7 to C 12 substituted phenylalkyl examples include groups such as 2-phenyl-l- chloroethyl, 2- (4-methoxyphenyl)ethyl, 4- (2,6-dihydroxy phenyl) -n-hexyl, 2- (5-cyano-3-methoxyphenyl) -n-pentyl, 3- (2, 6-dimethylphenyl) -n-propyl, 4-chloro-3-aminobenzyl, 6- (4-methoxyphenyl) -3-carboxy(n-hexyl) , 5- (4- aminomethylphenyl) -3- (aminomethyl) -n-pentyl, 5-phenyl-3- oxo-n-pent-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 x to C 7 alkoxy, C x to C 7 acyl, C x to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N- ( C x to C 6 alkyl) carboxamide, protected N- (C x to C 6 alkyl) carboxamide, N, N-di (C x to C 6 alkyl) carboxamide, trifluoromethyl, N- ( ⁇ C x to
  • substituted phenyl includes a mono- or di (halo)phenyl group such as 2, 3 or 4-chlorophenyl, 2, 6-dichlorophenyl, 2, 5-dichlorophenyl, 3,4-dichlorophenyl, 2, 3 or 4-bromophenyl, 3,4- dibromophenyl, 3-chloro-4-fluorophenyl, 2, 3 or 4- fluorophenyl and the like; a mono or di (hydroxy)phenyl group such as 2, 3 or 4-hydroxyphenyl, 2,4- dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 2, 3 or 4-nitrophenyl; a cyanophenyl group, for example, 2, 3 or 4-cyanophenyl; a mono- or di (alkyl)phenyl group such as 2, 3 or 4-methylphenyl, 2,4-dimethylphenyl, 2, 3 or 4- (iso-propyl
  • 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 aniline specifies an aniline 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 x to C 7 alkoxy, C x to C 7 acyl, C x to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(C X to C 6 alkyl)carboxamide, protected N- (C x to C 6 alkyl)carboxamide, N, N-difd to C 6 alkyl)carboxamide, trifluoromethyl, N- ( (C x to C 6 alkyl)sulf
  • substituted aniline includes, for example, 2-fluoroanilinyl, 3-fluoroanilinyl, 4- fluoroanilinyl, 2-chloroanilinyl, 3-chloroanilinyl, 4- chlorc .nilinyl, 2-bromoanilinyl, 3-bromoanilinyl, 4- bromoanilinyl, 2-methoxyanilinyl, 3-methoxyanilinyl, 4- methoxyanilinyl, 2-hydroxyanilinyl, 3-hydroxyanilinyl, 4- hydroxyanilinyl, 2-carboethoxyanilinyl, 3- carboethoxyanilinyl, 4-carboethoxyanilinyl, 2- trifluoromethylanilinyl, 3-trifluoromethylanilinyl, 4- trifluoromethylanilinyl, 2-dimethylaminoanilinyl, 3- dimethylaminoanilinyl,
  • substituted naphthyl specifies a naphthyl group substituted with one or more, and preferably one or two, moieties either on the same ring or on different rings chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C x to C 6 alkyl, C x to C 7 alkoxy, C x to C 7 acyl, C x to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino,
  • substituted naphthyl includes a mono or di (halo) naphthyl group such as 1, 2, 3, 4, 5, 6, 7 or 8-chloronaphthyl, 2, 6-dichloronaphthyl, 2, 5-dichloronaphthyl, 3, 4-dichloronaphthyl, 1, 2, 3, 4, 5, 6, 7 or 8-bromonaphthyl, 3, 4-dibromonaphthyl, 3- chloro-4-fluoronaphthyl, 1, 2, 3, 4, 5, 6, 7 or 8- fluoronaphthyl and the like; a mono or di (hydroxy) naphthyl group such as l, 2, 3, 4, 5, 6, 7 or 8-hydroxynaphthyl, 2, 4-dihydroxynaphthyl, the protected- hydroxy derivatives thereof and the like; a nitronaphthyl group such as 3- or 4-nitronaphthyl; a cyan
  • substituted naphthyl represents disubstituted naphthyl groups wherein the substituents are different, for example, 3-methyl-4-hydroxynaphth-1-yl, 3-chloro-4- hydroxynaphth-2-yl, 2-methoxy-4-bromonaphth-l-yl, 4- ethyl-2-hydroxynaphth-1-yl, 3-hydroxy-4-nitronaphth-2-yl, 2-hydroxy-4-chloronaphth-1-yl, 2-methoxy-7-bromonaphth-1- yl, 4-ethyl-5-hydroxynaphth-2-yl, 3-hydroxy-8- nitronaphth-2-yl, 2-hydroxy-5-chloronaphth-1-yl and the like.
  • halo and halogen refer to the fluoro, chloro, bromo or iodo groups. There can be one or more halogen, which are the same or different. Preferred halogens are chloro and fluoro.
  • (monosubstituted) amino refers to an amino group with one substituent chosen from the group consisting of phenyl, substituted phenyl, C x to C 6 alkyl, Ci to C 6 substituted alkyl, C x to C 7 acyl, C 2 to C 7 alkenyl, C 2 to C 7 substituted alkenyl, C 2 to C 7 alkynyl, C 2 to C, substitued alkynyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl and heterocyclic ring.
  • the (monosubstituted)amino can additionally have an amino- protecting group as encompassed by the term "protected (monosubstituted)amino.
  • (disubstituted)amino refers to amino groups with two substituents chosen from the group consisting of phenyl, substituted phenyl, C x to C 6 alkyl, Ci to C 6 substituted alkyl, Ci to C 7 acyl, C 2 to C 7 alkenyl, C 2 to C 7 alkynyl, C 7 to C 12 phenylalkyl, and C 7 to C 12 substituted phenylalkyl.
  • 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 of the molecule.
  • 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 on the carboxamide nitrogen.
  • 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-butoxycarbonyl ("Boc”), 2- (4-biphenylyl)propyl-2-oxycarbonyl ("Bpoc”), 2-phenylpropyl-2-oxycarbonyl ("Poc”), 2-(4- xenyl) isopropoxycarbonyl, 1, 1-diphenylethyl-l- oxycarbonyl, 1, 1-diphenylpropyl-l-oxycarbonyl, 2- (3,5- dimethoxyphenyl)propyl-2-oxycarbonyl (“Ddz”) , 2- (p- toluyl)propyl-2-oxycarbonyl, cyclopentanyloxycarbonyl,
  • 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, Cbz and Fmoc.
  • Further examples of amino-protecting groups embraced 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. Bodanzsky, "Principles of Peptide Synthesis," 1st and 2nd revised ed.
  • 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 t-butyl, 4-nitrobenzyl, 4-methoxybenzyl, 3,4- di ethoxybenzy1, 2,4-dimethoxybenzyl, 2,4,6- trimethoxybenzyl, 2,4, 6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4 ' -dimethoxytrityl, 4 ,4 ' , 4"-trimethoxytrityl, 2- phenylpropyl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2 , 2, 2-trichloroethyl, - (trimethylsilyl) ethyl, ⁇
  • 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, "Protective Groups in Organic Chemistry, " J.G.W. McOmie, Ed., Plenum Press, New York, NY, 1973, Chapter 5, and T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed. , John Wiley and Sons, New York, NY, 1991, Chapter 5, each of which is incorporated herein by reference. A related term is "protected carboxy, " which refers to a carboxy group substituted with one of the above carboxy-protecting groups.
  • hydroxy-protecting group refers to readily cleavable groups bonded to hydroxyl groups, such as the tetrahydropyranyl, 2-methoxypropyl, 1-ethoxyethyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4*- dimethoxytrityl, 4,4 ' ,4"-trimethoxytrityl, benzyl, allyl, trimethylsilyl, (t-butyl)dimethylsilyl, 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 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.
  • Ci to C 4 alkylthio refers to sulfide groups such as methylthio, ethylthio, n- propylthio, isopropylthio, n-butylthio, t-butylthio and like groups.
  • C x to C 4 alkylsulfoxide indicates sulfoxide groups such as methylsulfoxide, ethylsulfoxide, n-propylsulfoxide, isopropylsulfoxide, n- butylsulfoxide, sec-butylsulfoxide and the like.
  • C x to C 4 alkylsulfonyl encompasses groups such as methylsulfonyl, ethylsulfonyl, n- propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, t- butylsulfonyl and the like.
  • substituted phenylthio By “substituted phenylthio, " “substituted phenyl sulfoxide,” and “substituted phenylsulfonyl” is meant that the phenyl can be substituted as described above in relation to “substituted phenyl.”
  • cyclic C 2 to C 7 alkylene defines such a cyclic group bonded (“fused") to the phenyl radical resulting in a bicyclic ring system.
  • the cyclic group may be saturated or contain one or two double bonds.
  • the cyclic group may have one or two methylene or methine groups replaced by one or two oxygen, nitrogen or sulfur atoms which are the the cyclic C 2 to C 7 heteroalkylene.
  • the cyclic alkylene or heteroalkylene group may be substituted once or twice by the same or different substituents selected from the group consisting of the following moieties: hydroxy, protected hydroxy, carboxy, protected carboxy, oxo, protected oxo, C to C 4 acyloxy, formyl, Ci to C 7 acyl , C : to C 6 alkyl, carbamoyl, C x to C 7 alkoxy, Ci to C 4 alkylthio, C to C 4 alkylsulfoxide, C x to C 4 alkylsulfonyl, halo, amino, protected amino, (monosubstituted) amino, protected (monosubstitued) amino, (disubstituted) 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 three 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 indolyl .
  • fused cyclic groups which each contain one nitrogen atom and one or more double bond, preferably one or two double bonds, are when the phenyl is fused to a pyridino, pyrano, pyrrolo, pyridinyl, dihydropyrrolo, or dihydropyridinyl ring.
  • 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.
  • fused 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.
  • 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 or pyrazinyl.
  • salt encompasses those salts that form with the carboxylate anions and amine nitrogens and include salts formed with the organic and inorganic anions and 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, aluminum and calcium) ; ammonium and mono-, di- and tri-alkyl amines such as trimethylamine, cyclohexylamine; and the organic cations, such as dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis (2-hydroxyethyl) ammonium, phenylethylbenzylammonium, dibenzylethylenediammonium, and like cations.
  • 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 isoquinoline derivatives can be in the biologically active ester form, such as the non-toxic, metabolically-labile ester- form.
  • 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, isopropoxymethyl and the like; the - (C x to C 7 ) alkoxyethyl groups, for example methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl and the like; the 2-oxo-l,3-diooxlen-4-ylmethyl groups, such as 5-methyl-2-oxo-l,3-dioxolen-4-ylmethyl, 5-phenyl- 2-oxo-l,3-dioxolen-4-ylmethyl and the like; the C x to C 4 alkylthiomethyl groups, for example methylthiomethyl, ethylthiomethyl, iso-propylthiomethyl and the like; the acyloxymethyl groups, for example pivaloyloxymethyl, pivaloyloxyethyl,
  • amino acid includes any one of the twenty naturally-occurring amino acids or the D-form of any one of the naturally-occurring amino acids.
  • amino acid also includes other non-naturally occurring amino acids besides the D-amino acids, which are functional equivalents of the naturally- occurring amino acids.
  • non-naturally-occurring amino acids include, for example, norleucine ("Nle”), norvaline (“Nva”) , ⁇ -Alanine, L- or D-naphthalanine, ornithine ("Orn”), 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.
  • the compounds of Foimu a I and combinatorial libraries containing the same can be prepared as set forth in the Reaction Schemes below.
  • the substituents R 1 , R 2 , R 7 , X and Y in the Reaction Schemes have the same meaning as those described above.
  • homophthalic anhydride wherein each of R 3 , R 4 , R 5 , and R 6 are a hydrogen atom, is only an exemplary anhydride in the Reaction Schemes and that other anhydrides having the above-defined R 3 , R 4 , R 5 and R 6 substituents can alternatively be used.
  • the Y representation that Y is carboxamide is also exemplary and other Y groups can be used.
  • the isoquinoline compounds of the present invention can be prepared according to Reaction Scheme I.
  • a solid support resin- bound amine (1) (resin identified by ® ) is reacted, in situ, with an aldehyde (2) and, thereby, converted to the corresponding imine (3) .
  • Addition of a cyclic anhydride, such as homophthalic anhydride (3) yields isoquinoline (4) .
  • Deprotection is followed by the free amino group being condensed with an aldehyde to the individual or mixtures of resin-bound amino carboxylic acids using, an orthoformate such as trimethyl or triethyl orthoformate as a scavenger for water, in a polar solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidinone or the like for a period of 1 to 24 hrs, usually 3 to 5 hrs at 20 C C to 75°C and preferably at 25°C.
  • Aldehyde condensation is followed by reaction under standard conditions with cyclic anhydride, in the case of Reaction Scheme II, homophthalic anhydride, and an amine base (e.g.
  • a trialkylamine in an aprotic solvent such as chloroform, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone for 2 to 36 hrs and preferably 16 hrs at 20°C to 125°C, preferably at 20°C to 30°C to arrive at novel isoquinoline derivatives.
  • an aprotic solvent such as chloroform, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone
  • Resins which can serve as solid supports are well known in the art.
  • Such resins include, for example, 4-methylbenzhydrylamine-copoly(styrene-1% divinylbenzene) (MBHA) , 4-hydroxymethylphenoxymethyl-copoly(styrene-1% divinylbenzene) ,4-oxymethyl-phenylacetamido- copoly(styrene-1% divinylbenzene) (Wang) , and TentagelTM, from Rapp Polymere Gmbh, trialkoxy-diphenyl-methyl ester- copoly(styrene-1% divinylbenzene) (RINK) all of which are commercially available.
  • MBHA 4-methylbenzhydrylamine-copoly(styrene-1% divinylbenzene)
  • Wang 4-hydroxymethylphenoxymethyl-copoly(styrene-1% divinylbenzene)
  • Wang 4-oxymethyl-phenylacetamid
  • split resin approach Prepa nration of the combinatorial libraries can be by the "split resin approach."
  • the split resin approach is described by, for example, U.S. Patent 5,010,175 to Rutter, WO PCT 91/19735 to Simon, and Gallop et al . , J. Med. Chem.. 37:1233-1251 (1994), all of which are incorporated herein by reference.
  • Exemplary amino carboxylic acids used in the above Reaction Scheme II include 2-aminoethanoic acid, 3- aminopropionic acid, 5-aminopentanoic acid, 7- aminoheptanoic acid, (s) -2,3-diaminopropanoic acid, (s) - 2, 6-diaminohexanoic acid, (s) -3-amino-2-methylpropionic acid, (r) -3-amino-2-methylpropionic acid, 2- (2- aminoethoxyethoxy)acetic acid, trans-4- (aminomethyl) cyclohexanecarboxylic acid and 4- (aminomethyl)benzoic acid.
  • aldehydes used in the above Reaction Scheme II are 1, 4-benzodioxan-6-carboxaldehyde, 1- methylindole-3-carboxaldehyde, 2,3-difluorobenzaldehyde, 2-bromobenzaldehyde, 2-chloro-5-nitrobenzaldehyde, 2- furaldehyde, 2-imidazolecarboxaldehyde, 2-naphthaldehyde, 2-pyridinecarboxaldehyde, 2-thiophenecarboxaldehyde, 3,4- dichlorobenzaldehyde, 3, 5-bis (trifluoromethyl) benzaldehyde, 3, 5-dihydroxybenzaldehyde, 3,5- dimethoxybenzaldehyde, 3,5, -dimethyl-4- hydroxybenzaldehyde,
  • Isoquinoline 4-carboxylic acids can be converted to alternatively substituted compounds having an amide or ester, or other functionality as defined by X, following Reaction Schemes III and IV. Briefly, as shown in Reaction Scheme III, condensation of the isoquinoline 4-carboxylic acid prepared by the above
  • Reaction Schemes is condensed with an amine or alcohol (4) in an aprotic solvent such as DMF to furnish the substituted isoquinoline (5) .
  • the present invention also provides libraries and individual compounds which are the corresponding amines of the above-described isoquinoline amide derivatives.
  • the mixture can be further chemically transformed to extend the range and chemical diversity of the compounds.
  • libraries and compounds will have the following structure:
  • R 1 is selected from the group consisting of methylene, 1,2-ethyl, 1,3-propyl, 1,4-butyl, 1,5-pentyl, 1,6- hexyl, (S) -1-amino-l,2-ethyl, (S) -1-amino-l, 5-pentyl, (R) -1-methyl-l,2-ethyl, (S) -1-methyl-l,2-ethyl,
  • phenyl is selected from the group consisting of phenyl, 2- bromopheny1, 2-cyanopheny1, 2-fluorophenyl, 2- hydroxyphenyl, 2-methoxyphenyl, 3-bromophenyl, 3- (4- methoxybenzyl)phenyl, 3-cyanopheny1, 3-fluorophenyl, 3-hydroxyphenyl, 3-methoxyphenyl, 3-methylphenyl, 3- nitrophenyl, 3- (trifluoromethyl)phenyl, 4-(N- ethylamino) anilino, 4-bromophenyl, 4- (4- methoxybenzyl)phenyl, 4-cyanophenyl, 4- (3- dimethylaminopropoxy)phenyl, 4-fluorophenyl, 4- (dimethylamino)phenyl, 4-hydroxyphenyl, 4- isopropylphenyl, 4-methoxyphenyl, 4-methylphenyl, 4- methylsulphonylphenyl, 4- (
  • R 3 , R 4 , R 5 , R 6 are independently a hydrogen atom
  • X is selected from the group consisting of anilino, 2- fluoroanilino, 2-methoxyanilino, 2-chlorobenzylamino, 2-methoxybenzylamino, 2-trifluoromethylbenzylamino, 3- fluoroanilino, 3-methylanilino, 3- trifluoromethylanilino, 3- (methylmercapto) anilino, 3- trifluoromethylbenzylamino, 3-methylbenzylamino, 4- propylanilino, 4-pentylanilino, 4- (methylmercapto)anilino, 4-fluorobenzylamino, 4- methoxybenzylamino, 4-methylbenzylamino, 3-(l-(4- methoxyphenyl) ethyl) anilino, 4-chloroanilino, 2,3- dimethylanilino, 4-methoxyanilino, 2,5- dimethoxyanilino, 3-chloro-4-fluor
  • Y is selected from the group consisting of CH 2 OH, SH, NHR 7 and CH 2 NHR 7 , wherein R 7 is selected from the groups consisting of a hydrogen atom, C x to C 6 alkyl and C x to C 6 substituted alkyl.
  • the nonsupport-bound library mixtures were screened in solution in radio-receptor inhibition assays described in detail below. Deconvolution of highly active mixtures were carried out by iterative, and in one instance additionally, positional scanning methods. These techniques, the iterative approach or the positional scanning approach, can be utilized for finding other active compounds within the libraries of the present invention using any one of the below-described assays or others well known in the art.
  • a new sub-library with the first two variable positions defined is reacted again with all the other possibilities at the remaining undefined variable position.
  • the identity of the third variable position in the sub-library having the highest activity is determined. If more variables exist, this process is repeated for all variables, yielding the compound with each variable contributing to the highest desired activity in the screening process. Promising compounds from this process can then be synthesized on larger scale in traditional single-compound synthetic methods for further biological investigation.
  • the optimum substituent at that position is determined, pointing to the optimum or at least a series of compounds having a maximum of the desired biological activity.
  • the number of sublibraries for compounds with a single position defined will be the number of different substituents desired at that position, and the number of all the compounds in each sublibrary will be the product of the number of substituents at each of the other variables.
  • the new isoquinoline compounds of the present invention can be used for a variety of purposes and indications and as medicaments for any such purposes and indications.
  • isoquinolines are generally known to have antimicrobial activity.
  • the isoquinolines of the present invention can be used to treat infections.
  • the ability of the compounds to inhibit bacterial growth can be determined by methods well known in the art.
  • An exemplary in vi tro antimicrobial activity assay is described in Blondelle and Houghten, Biochemistry 30:4671-4678 (1991) , which is incorporated herein by reference.
  • Staphylococcus aureus ATCC 29213 (Rockville, MD) is grown overnight at 37°C in Mueller- Hinton broth, then re-inoculated and incubated at 37°C to reach the exponential phase of bacterial growth (i.e., a final bacterial suspension containing IO 5 to 5 x 10 s colony-forming units/ml) .
  • the concentration of cells is established by plating 100 ⁇ l of the culture solution using serial dilutions (e.g., IO" 2 , IO "3 and 10" 4 ) onto solid agar plates.
  • Isoquinolines are also known to be antiarrhythmic and cardioprotective agents as described, for example, in published European Patent Application 0 590 455 to Lai et al. , which is incorporated herein by reference. Therein is also described assays for assessing the antiarrhythmic and cardioprotective properties of isoquinolines, such as the reperfusion induced arrhythmias assay in isolated rat heart .
  • Additional assays can be, and have been, used to test the biological activity of the instant isoquinolines.
  • Such assays include a competitive enzyme- linked immunoabsorbent assay and, as described in
  • radio-receptor assays can be selective for any one of the ⁇ , K, or ⁇ opiate receptors and is, therefore, an indication of isoquinolines' analgesic properties as described, for example, in Dooley et al . , Proc. Natl. Acad. Sci.. 90:10811-10815 (1993) . Additionally, such compounds can, and have been as described in Example 47, tested in a ⁇ receptor assay.
  • Ligands for the ⁇ receptor can be useful as antipsychotic agents, as described in Abou-Gharbia et al. , Annual Reports in Medicinal Chemistry. 28:1-10 (1993) .
  • ELISA Competitive Enzyme-Linked Immunosorbent Assay
  • Radio-Receptor Assay Particulate membranes can be prepared using a modification of the method described in Pasternak et al. , Mol . Pharmacol . 11:340-351 (1975) , which is incorporated herein by reference.
  • Rat brains frozen in liquid nitrogen can be obtained from Rockland (Gilbertsville, PA) . The brains are thawed, the cerebella removed and the remaining tissue weighed. Each brain is individually homogenized in 40 ml Tris-HCl buffer (50 mM, pH 7.4, 4°C) and centrifuged (Sorvall * RC5C SA-600: Du Pont, Wilmington, DE) (16,000 rpm) for 10 mins.
  • the pellets are resuspended in fresh Tris-HCl buffer and incubated at 37°C for 40 mins. Following incubation, the suspensions are centrifuged as before, the resulting pellets resuspended in 100 volumes of Tris buffer and the suspensions combined. Membrane suspensions are prepared and used in the same day. Protein content of the crude homogenates generally range from 0.15-0.2 mg/ml as determined using the method described in M.M. Bradford, M.M. , Anal. Biochem. 72:248- 254 (1976), which is incorporated herein by reference.
  • the reaction is terminated by filtration through GF-B filters on a Tomtec harvester (Orange, CT) .
  • the filters are subsequently washed with 6 ml of Tris-HCl buffer, 4°C. Bound radioactivity is counted on a Pharmacia Biotech Betaplate Liquid Scintillation Counter
  • assays selective for K receptors can be carried out using [ 3 H]-U69,593 (3 nM, specific activity 62 Ci/mmol) as radioligand.
  • Assays selective for ⁇ opiate receptors can be carried out using tritiated DSLET ([D-Ser 2 , D-Leu 5 ] -threonine-enkephalin) as radioligand.
  • assays for the ⁇ receptor assay are the same as the ⁇ assay but use radiolabeled pentazocine as ligand.
  • the isoquinoline compounds of the present invention are generally in a pharmaceutical composition so as to be administered to a subject at dosage levels of from 0.7 to 7000 mg per day, and preferably 1 to 500 mg per day, for a normal human adult of approximately 70 kg of body weight, this translates into a dosage of from 0.01 to 100 mg/kg of body weight per day.
  • the specific dosages employed, however, can be varied depending upon the requirements of the patient, the severity of the condition being treated, and the activity of the compound being employed. The determination of optimum dosages for a particular situation is within the skill of the art.
  • inert, pharmaceutically acceptable carriers are used.
  • the pharmaceutical carrier can be either solid or liquid.
  • Solid form preparations include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances which can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
  • the carrier is generally a finely divided solid which is in a mixture with the finely divided active component.
  • the active compound is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient-sized molds and allowed to cool and solidify.
  • Powders and tablets preferably contain between about 5% to about 70% by weight of the active ingredient.
  • Suitable carriers include, for example, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter and the like.
  • compositions can include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the f active component (with or without other carriers) is surrounded by a carrier, which is thus in association with it.
  • a carrier which is thus in association with it.
  • cachets are also included.
  • Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
  • Liquid pharmaceutical compositions include, for example, solutions suitable for oral or parenteral administration, or suspensions, and emulsions suitable for oral administration.
  • Sterile water solutions of the active component or sterile solutions of the active component in solvents comprising water, ethanol, or propylene glycol are examples of liquid compositions suitable for parenteral administration.
  • Sterile solutions can be prepared by dissolving the active component in the desired solvent system, and then passing the resulting solution through a membrane filter to sterilize it or, alternatively, by dissolving the sterile compound in a previously sterilized solvent under sterile conditions.
  • Aqueous solutions for oral administration can be prepared by dissolving the active compound in water and adding suitable flavorants, coloring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical composition is in unit dosage form.
  • the composition is divided into unit doses containing appropriate quantities of the active isoquinoline.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
  • This Example provides a representative solid-phase combinatorial synthesis of a library which would contain approximately 525 derivatives of dihydroisoquinolines (DHQs) .
  • preparation of a library containing the DHQs involves the following steps. Briefly, first, thirty five diverse amino carboxylic acid, varying at R 1 , and including various amino-protected amino acids, are coupled to MBHA resin employing the tea-bag method of Houghten, et. al, as described, for example in U.S. Patent No. 4,631,211 to a?
  • the individual amino carboxylic acids which can be used to prepare a library of 525 DHQs include the following: Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Ser, Thr, Trp, Tyr, Val, D-Ala, D-Asp, D-Cys, D-Glu, D-Ile, D-Leu, D-Lys, D-Met, D-Phe, D-Ser, D-Thr, D-Tyr, and D-Val, ⁇ -alanine, and 4-aminobutyric acid. All are amino-protected with Fmoc or Boc and carry appropriate side chain protecting group as required.
  • aldehydes which can be employed are as follows: benzaldehyde, 4-methoxybenzaldehyde, 4-nitrobenzaldehyde, 4-chlorobenzaldehyde, 2-methoxybenzaldehyde, 2-nitrobenzaldehyde, 2-chlorobenzaldehyde, 4-phenylbenzaldehyde, furfuraldehyde, 2-propionaldehyde, 2-methyl-2-buten-l-al, cyclohexane carboxaldehyde, butanal, cinnamaldehyde, acetaldehyde.
  • Each resin packet is individually coupled overnight ( ⁇ 16 hrs except for Gly, 1 hr) by adding 10X amino acid in DCM (0.2 M) or amino carboxylic acid in DMF followed by 10X diisopropylcarbodiimide/DCM (0.2 M) for a final reagent concentration of 0.1 M DMF (5%) used to solubilize the Arg and Ser derivatives. Hydroxybenzotriazole (HOBt) (10X) is added to the amino carboxylic acids couplings. Following coupling completion, resin packets are washed with DCM (IX) , isopropanol (IPA) (2X) , and DCM (2X) .
  • DIX isopropanol
  • IPA isopropanol
  • Each packet is next shaken twice in 20% (v/v) piperidine/DMF (30 ml, 5 min, then 15 min) then washed with DMF (3 x 30 ml) and DCM (3 x 30 ml) .
  • a solution of the respective aldehyde (0.203 ml, 2 mmoles) and anhydrous trimethylorthoformate (0.438 ml, 4 mmoles) is prepared in DMF (7.5 ml) and added to the packet. After shaking for 3 hrs the packet is washed with dry ( ⁇ 0.03% water) DMF (5 x 30 ml) .
  • a solution of homophthalic anhydride (324 mg, 2 mmoles) and triethylamine (0.021 ml, 0.15 mmoles) is prepared in DMF (5 ml) and added to each packet. After heating at 80°C for 16 hrs the packets are then washed with DMF (3 x 30 ml) and DCM (3 x 30 ml) .
  • the packet was next shaken twice in 20% (v/v) piperidine/DMF (30 ml, 5 min, then 15 min) , then washed with DMF (3 x 30 ml) and DCM (3 x 30 ml) .
  • a solution of N- (9-fluorenylmethoxycarbonyl) glycine (149 mg, 0.5 mmoles) , HOBt (68 mg, 0.5 mmoles) , and DIC (0.094 ml, 0.6 mmoles) was prepared in DMF (5 ml) and added to the resin packet . After shaking for 2 hrs the packet was washed with DMF (3 x 30 ml) and DCM (3 x 30 ml) .
  • the packet was next shaken twice in 20% (v/v) piperidine/DMF (30 ml, 5 min, then 15 min) then washed with DMF (3 x 30 ml) and DCM (3 x 30 ml) .
  • a solution of benzaldehyde (0.203 ml, 2 mmoles) and anhydrous trimethylorthoformate (0.438 ml, 4 mmoles) was prepared in DMF (7.5 ml) and added to the packet. After shaking for 3 hrs the packet was washed with dry ( ⁇ 0.03% water) DMF (5 x 30 ml) .
  • a solution of homophthalic anhydride (324 mg, 2 mmoles) and triethylamine (0.021 ml, 0.15 mmoles) was prepared in DMF (5 ml) and added to the packet. After heating at 80°C for 16 hrs the packet was washed with DMF (3 x 30 ml) and DCM (3 x 30 ml) .
  • the isoquinolone was cleaved off of the resin by addition of a solution of 75/20/5 (v/v/v)
  • the crude oil was dissolved in DCM (20 ml and extracted with 1 N hydrochloric acid (HCl; 1 x 10 ml) .
  • the organic layer was next extracted with aqueous saturated sodium bicarbonate (NaHC0 3 ) (2 x 10 ml) .
  • NaHC0 3 aqueous saturated sodium bicarbonate
  • the NaHC0 3 layers were combined and the pH of the solution was brought to 1-2 by addition of 2 N HCl, followed by extraction with DCM (2 x 10 ml) .
  • the final organic layers were combined and the solvent was removed under reduced pressure, providing a quantitative yield of a clear oil which crystallized overnight into a white solid.
  • This Example provides the solid-phase synthesis of trans-N- (2-acetamidoyl) -3-phenyl-4-carboxy-3,4 -dihydro-1 (2H) -isoquinolone by condensing, on a polystyrene benzhydrylamine resin, glycine, benzaldehyde and homophthalic anhydride. The final product was cleaved from the resin using an HF procedure.
  • Polystyrene benzhydrylamine (BHA) resin (189 mg, 0.100 milliequivalents) was placed in a porous polypropylene packet.
  • the packet was placed in a 60 ml bottle and washed with 5% (v/v) DIEA/DCM(3 x 30 ml) followed by DCM (5 x 30 ml) .
  • a solution of N- (9-fluorenylmethoxycarbonyl) glycine 149 mg, 0.5 mmoles), HOBt (68 mg, 0.5 mmoles), and DIC (0.094 ml, 0.6 mmoles) was prepared in DMF (5 ml) and added to the resin packet .
  • the isoquinoline was cleaved off of the resin by treatment with HF (1) at -15°C for 2 hrs followed by warming to room temperature while removing HF (g) with a nitrogen stream.
  • HF HF
  • the packet and HF tube were washed with TFA (2 x 8 ml) and the two washes were transferred to a round bottom flask and concentrated to a clear oil under reduced pressure.
  • the crude oil was dissolved in DCM (20 ml and extracted with 1 N HCl (1 x 10 ml) .
  • the organic layer was next extracted with aqueous saturated NaHC0 3 (2 x 10 ml) .
  • the NaHC0 3 layers were combined and the pH of the solution was brought to 1-2 by addition of 2 N HCl, followed by extraction with DCM (2 x 10 ml) .
  • the final organic layers were combined and the solvent was removed under reduced pressure, providing a quantitative yield of a clear oil which upon lyophilization provided a white crystalline solid.
  • Spectral data was identical to the sample prepared in Example 2.
  • N- (t-Butyloxycarbonyl) -L-alanine attached to MBHA resin (0.05 mmoles) was sealed in a polypropylene packet.
  • the packet was shaken in 55% (v/v) TFA/DCM (30 ml, 30 min) then washed with DCM (1 x 30 ml) , isopropyl alcohol (2 x 30 ml), 5% (v/v) DIEA/DCM (3 x 30 ml, 2 min each), DCM (2 x 30 ml) , and anhydrous DMF (2 x 30 ml) .
  • a solution of benzaldehyde (10 mmoles) and anhydrous trimethylorthoformate (20 mmoles) was prepared in DMF (20 ml) and added to the packet. After shaking for 3.75 hrs the packet was washed with dry ( ⁇ 0.03% water) DMF (5 x 30 ml) .
  • a solution of homophthalic anhydride (7.5 mmoles) and triethylamine (225 mmoles) was prepared in chloroform (15 ml) and added to the packet.
  • This Example provides the solid-phase synthesis of trans-N- (3-propionamidoyl) -3-phenyl-4-carboxy- 3,4-dihydro-l (2H) -isoquinolone prepared by condensing, on a RINK linker derivatized TentaGelTM resin, aminopropionic acid, benzaldehyde and homophthalic anhydride. The final product was removed from the resin by TFA cleavage.
  • N- (9-Fluorenylmethoxycarbonyl) -3-aminopropionic acid was attached to RINK linker derivatized TentaGelTM resin as described in Example 2.
  • the packet was next shaken twice in 20% (v/v) piperidine/DMF (30 ml, 5 min, then 15 min) then washed with DMF (3 x 30 ml) and DCM (3 x 30 ml) .
  • a solution of benzaldehyde (0.203 ml, 2 mmoles) and anhydrous trimethylorthoformate (0.438 ml, 4 mmoles) was prepared in DMF (7.5 ml) and added to the packet. After shaking for 3 hrs the packet was washed with dry ( ⁇ 0.03% water) DMF (5 x 30 ml) followed by chloroform (3 90 x 30 ml) .
  • a solution of homophthalic anhydride (324 mg, 2 mmoles) and triethylamine (0.021 ml, 0.15 mmoles) was prepared in chloroform (5 ml) and added to the packet.
  • the isoquinolone was cleaved off of the resin by addition of a solution of 75/20/5 (v/v/v)
  • EXAMPLE 6 TO EXAMPLE 28 Synthesis of Additional Substituted Isoquinolines With the exception *oZf the amino carboxylic acid and aldehyde starting materials, Examples 6 to 28 were done using the procedures of Example 5. In place of the starting materials 3-aminopropionic acid and benzaldehyde of Example 5, Examples 6 to 28 provide all possible combinations of four different amino carboxylic acids and six unique benzaldehydes. The amino carboxylic acids and benzaldehydes used, along with the corresponding Example number is shown in TABLE I. As a reference, the compound prepared in Example 5 is shown in Table I at upper left.
  • N- (t-Butyloxycarbonyl)glycine attached to MBHA resin (0.05 mmoles) was sealed in a polypropylene packet.
  • the packet was shaken in 55% (v/v) TFA/DCM (30 ml, 30 min) then washed with DCM (1 x 30 ml) , isopropyl alcohol (2 x 30 ml) , 5% (v/v) DIEA/DCM (3 x 30 ml, 2 min each) , DCM (2 x 30 ml), and anhydrous DMF (2 x 30 ml) .
  • a solution of acetaldehyde (5 mmoles) and anhydrous trimethylorthoformate (10 mmoles) was prepared in DMF (10 ml) and added to the packet. After shaking for 3.75 hrs the packet was washed with dry ( ⁇ 0.03% water) DMF (5 x 30 ml) .
  • a solution of homophthalic anhydride (5 mmoles) and triethylamine (0.075 mmoles) was prepared in chloroform (10 ml) and added to the packet.
  • Trans-N- (2-Acetamidoyl) -3- (3, 5-dimethoxyphenyl) -4-carboxy-3,4-dihydro-1 (2H) -isoquinolone (0.05 mmoles) was prepared on MBHA polystyrene resin using the method described in Example 4 with the following changes: glycine was substituted for alanine, 3, 5-dimethoxybenzaldehyde was substituted for benzaldehyde, and the product was further modified before cleavage off resin.
  • the HATU treatment was repeated followed by decanting and addition of a second 1-propanol solution. This reaction was shaken at room temperature for 66 hrs. The bag was then washed with DMF (4 x 10 ml) , DCM (3 x 10 ml) , and allowed to dry.
  • This product was prepared as in Example 32 but with the substitution of (+/-) -3-aminoquinuclidine, bis HCl salt for 1-propanol; DIEA (200 mole % versus aminoquinuclidine) was also added to neutralize the HCl salt. Yield: 23 mg, 98%.
  • TentaGelTM S-NH2 resin (385 mg, 0.100 milliequivalents) derivatized with the protected RINK linker. Following the procedure provided in Example 2, one bag each was then coupled with one each of five different amino acids, N- (9-fluorenylmethoxycarbonyl)
  • N- (9-fluorenylmethoxycarbonyl) -4-aminobutyric acid N- (9-fluorenylmethoxycarbonyl) -6-aminohexanoic acid
  • N- (9-fluorenylmethoxycarbonyl) -glycine N- (9-fluorenylmethoxycarbonyl) -glycine.
  • the resin packets were dried at room temperature and cut open. The resin inside was pooled from all five bags and the res n was shaken in DCM (20 ml) for 75 min. The resin was filtered off and again dried before being divided into five equal portions and resealed in porous polystyrene packets. One packet was then reacted with first benzaldehyde and then homophthalic anhydride as in Example 5. The resin was cleaved and worked up as in Example 5, providing a clear oil, 11 mg, 61% yield based on average molecular weight) .
  • MALDI-TOF MS of the crude products after cleavage showed all five expected isoquinolines for each individual resin packet.
  • Analysis of the final extract by proton NMR and MALDI-TOF MS indicated that only four isoquinolines were now present with the 2, 6- (s) -diaminohexanoic acid based isoquinolone having been lost in the extraction procedure.
  • EXAMPLE 38 Solid-phase synthesis of a combinatorial library pool containing isoquinolines derived from five amino acids, 4-methoxybenzaldehyde and homophthalic anhydride
  • Eleven porous polypropylene tea-bags were prepared each containing polystyrene MBHA/resin (974 mg, 0.750 milliequivalents) .
  • One tea-bag was placed in a 60 ml bottle and washed with 5% (v/v) DIEA/DCM (3 x 30 ml) followed by DCM, 5 x 30 ml.
  • a solution of N- (t-butyloxycarbonyl)glycine (657 mg, 3.75 mmoles) , HOBt (507 mg, 3.75 mmoles), and DIC (0.705 ml, 4.5 mmoles) was prepared in DMF (37.5 ml) and added to the resin packet.
  • the remaining nine tea-bags were placed in one bottle and washed with DCM (150 ml, 15 min) and then treated with 55% (v/v) TFA/DCM (150 ml, 30 min) .
  • the bags were then washed with DCM (150 ml) , isopropyl alcohol (2 x 150 ml), DCM (2 x 150 ml) , 5% (v/v) DIEA/DCM (3 x 150 ml, 2 min each) and DCM (3 x 150 ml) .
  • the eleven tea-bags were cut open and the contents pooled in a bottle containing DCM (70 ml) . The bottle was shaken for 90 min to thoroughly mix the resin.
  • the DCM/resin slurry was then poured into a large (12 x 18 cm) tea-bag to separate the resin from the DCM and the resin was dried at 50°C.
  • the resulting 11.042 g of resin (8.25 mmoles total of mixed amino acids) was divided into 39 tea-bags containing 38 x 0.241 g resin (each 180 micromoles total of mixed amino acids) and 1 x 1.204 g (900 micromoles total of mixed amino acids) .
  • glycine control tea-bags 38 additional tea-bags each containing 23 mg (18 micromoles) of glycine (containing a free amino group) attached to MBHA resin (coupled and deprotected as in Example 1, subheading 1, hereinafter referred to as the "glycine control tea-bags" .
  • a solution of homophthalic anhydride (801 mg, 5 mmoles) and triethylamine (0.044 ml, 0.3 mmoles) was prepared in chloroform (10 ml) and added to the tea-bag. After shaking at room temperature for 15.5 hrs the packet was washed with DMF (6 x 30 ml) and DCM (4 x 30 ml) and dried at room temperature.
  • the 38 tea-bags containing mixed amino acid resin (now containing mixed isoquinolines after the anhydride condensation reaction) were cut open and the contents pooled in a bottle containing DCM (70 ml) . The bottle was shaken for 75 min to thoroughly mix the resin. The DCM/resin slurry was then poured into a large (12 x 18 cm) tea-bag to separate the resin from the DCM and the resin was dried at room temperature. The resulting 10.144 g of resin (6.84 mmoles total of mixed isoquinolines) was divided into 52 tea-bags each containing 0.178 g resin (120 micromoles total of mixed isoquinolines) .
  • a solution of HATU in anhydrous DMF 2.4 mmoles, 8 ml, 300 mM solution
  • the HATU solution was decanted off of the tea-bags and anhydrous DMF (6.9 ml) and cyclopropyl amine (0.52 ml, 7.5 mmoles) were added. After shaking for 1 hr the cyclopropyl amine solution was removed and the bags were washed with anhydrous DMF (2 x 8 ml) . The HATU treatment was repeated followed by decanting and addition of a second cyclopropyl amine solution. This reaction was shaken at room temperature for 24 hrs. The bags were then washed with DMF (3 x 8 ml), water (8 ml, 60 min) , DMF (3 x 8 ml) , DCM (3 x 8 ml) , and allowed to dry.
  • Each tea-bag prepared was cleaved separately via standard HF procedures with the addition of 0.2 ml anisole to each HF cleavage reaction as a scavenger and dissolved in an appropriate solvent and for testing in a variety of assays.
  • the control tea-bags were cleaved in the same manner and characterized by NMR or mass spectra. 9?
  • This example describes the identification of individual compounds contained within the synthetic combinatorial library of Example 43 which are selective inhibitors of the ⁇ and ⁇ -opioid ligands, [ 3 H] -DAMGO and [ 3 H] -U69, 593, respectively and the ⁇ receptor ligand, radiolabeled pentazocine. Compounds were identified using the iterative approach and radioreceptor assays as described above .
  • results of the screen provide evidence that there is selectivity of certain compounds for one opioid receptor over another. More importantly, the assays identify certain classes of compounds which are particularly active. For instance, those compounds made from cyclopentylamine for X (pool # 265) are particularly good inhibitors of the [ 3 H]-U69,593 ligand at the ⁇ -opioid receptor. Compounds made from 1-adamantanemethylamine at the X position (pool # 291) were identified as significant inhibitors of pentazocine ligand at the ⁇ receptor.
  • tea-bags each containing a mixture of 11 amino acids on resin (7 mg, 5 micromoles) were prepared as in Example 43.
  • Each tea-bag was reacted with a single aldehyde from the list: 1,4-benzodioxan-6-carboxaldehyde, 1-methylindole-3-carboxaldehyde, 2, 3-difluorobenzaldehyde, 2-bromobenzaldehyde, 2-chloro-5-nitrobenzaldehyde, 2-furaldehyde, 2-imidazolecarboxaldehyde, 2-naphthaldehyde, 2-pyridinecarboxaldehyde, 2-thiophenecarboxaldehyde, 3 ,4-dichlorobenzaldehyde, 3 , 5-bis (trifluoromethyl) benzaldehyde, 3, 5-dihydroxybenzaldehyde, 3, 5-dimethoxybenzaldehyde, 3, 5-dimethyl-4
  • the dried tea-bags were all placed in a 60 ml bottle and washed with anhydrous DMF (2 x 30 ml) .
  • Anhydrous DMF (30 ml) was then added to the tea-bags followed by HATU (3.5 g, 9.2 mmoles) and the tea-bags were shaken for 20 min.
  • the HATU solution was next decanted and the tea-bags were washed with anhydrous DMF
  • Example 43 After drying the tea-bags were cleaved as in Example 43, extracted into 1:1 water/acetonitrile, examined by mass spectrometry, and tested in the ⁇ receptor assay as described above. Table III provides the results of that assay and evidences that pool # M367, derived from 5-hydroxymethylfuraldehyde, are the most active compounds.
  • Example 43 Ten tea-bags each containing one amino acid on resin (75 micromoles) were prepared as in Example 43. As identified in Example 43, one amino acid was in a racemic mixture, therefor accounting for 11 different compounds in 10 bags. All of the tea-bags were placed in a 125 ml bottle and washed with anhydrous DMF (1 x 60 ml) . Added to the tea-bags were anhydrous DMF (27 ml) , 5- hydroxymethylfurfural (1.893 g, 15 mmoles), and anhydrous TMOF (3.282 ml, 30 mmoles) .
  • the tea-bags were washed with anhydrous DMF (3 x 50 ml) and anhydrous chloroform (1 x 50 ml) .
  • Next added to the tea-bags were anhydrous chloroform (30 ml) , homophthalic anhydride (2.432 g, 15 mmoles) , and triethylamine (0.133 ml, 1 mmole) .
  • the tea-bags were washed with DMF (5 x 50 ml) and DCM (4 x 50 ml) .
  • the tea-bags were next washed with anhydrous DMF (2 x 50 ml) .
  • tea-bags Added to the tea-bags were anhydrous DMF (48 ml) and HATU (5.47 g, 14.4 mmoles) . After shaking for 20 min., the HATU solution was decanted and the tea-bags were washed with anhydrous DMF (1 x 50 ml) . Anhydrous DMF (25 ml) was added to the tea-bags followed by 1- adamantanemethylamine (4.429 g, 25 mmoles) . After shaking for 1 hr, the tea-ba ⁇ gs were washed with anhydrous DMF (2 x 50 ml) and the HATU and 1-adamantanemethylamine treatments were repeated. After shaking for 18 hrs.
  • the tea-bags were washed with DMF (4 x 50 ml) , water (1 x 50 ml for 40 min., DMF (4 x 50 ml), and DCM (4 x 50 ml) . After drying the tea-bags were cleaved as in Example 43, extracted into 1:1 water/acetonitrile, examined by mass spectrometry, and screened in the ⁇ receptor assay, the results of which are shown in Table IV.
  • the most active compound from the library of Example 43 is one for which R 1 is 1,6-hexyl, R 2 is 5- (4 ' -methoxybenzyl) -furan-2-yl, R 3 through R 6 are, independently a hydrogen atom, X is 1- aminomethyladamantanyl, and Y is C(0)NH 2 .
  • Eleven porous polypropylene tea-bags are prepared each containing polystyrene MBHA/resin (974 mg, 0.750 milliequivalents).
  • One tea-bag is placed in a 60 ml bottle and washed with 5% (v/v) N,N, -diisopropylethylamine/dichloromethane (3 x 30 ml) followed by dichloromethane (DCM, 5 x 30 ml) .
  • a solution of N- (t-butyloxycarbonyl)glycine (657 mg, 3.75 mmoles), HOBt (507 mg, 3.75 mmoles), and DIC (0.705 ml, 4.5 mmoles) is prepared in DMF (37.5 ml) and added to the resin packet. After shaking for 16 hrs the tea-bag is washed with DMF (3 x 30 ml) and DCM (3 x 30 ml) .
  • a solution of homophthalic anhydride (801 mg, 5 mmoles) and triethylamine (0.044 ml, 0.3 mmoles) is prepared in chloroform (10 ml) and added to the tea-bag. After shaking at room temperature for 15.5 hrs the packet is washed with DMF (6 x 30 ml) and DCM (4 x 30 ml) and dried at room temperature.
  • the large tea-bag containing 1.204 g (900 micromoles total of mixed amino acids) of resin is reacted with 3,5-dimethoxybenzaldehyde in the same manner, but on a five times larger scale of all reagents and solvents and with no control tea-bag.
  • the 38 tea-bags containing mixed amino acid resin (now containing mixed isoquinolines after the above reaction) are cut open and the contents pooled in a bottle containing DCM (70 ml) . The bottle is shaken for 75 min to thoroughly mix the resin.
  • the DCM/resin slurry is then poured into a large (12 x 18 cm) tea-bag to separate the resin from the DCM and the resin is dried at room temperature.
  • the resulting 10.144 g of resin (6.84 mmoles total of mixed isoquinolines) is divided into 49 tea-bags each containing 0.178 g resin (120 micromoles total of mixed isoquinolines) .
  • HATU in anhydrous DMF (2.4 mmoles, 8 ml, 300 mM solution) and shaken for 20 min.
  • the HATU solution is decanted off of the tea-bags and anhydrous DMF (6.9 ml) and aniline (0.683 ml, 7.5 mmoles) are added. After shaking for 1 hr the aniline solution is removed and the bags are washed with anhydrous DMF (2 x 8 ml) .
  • the HATU treatment is repeated followed by decanting and addition of a second aniline solution. This reaction is shaken at room temperature for 24 hrs.
  • 3-trifluoromethylaniline 4-trifluoromethylaniline, 2-dimethylaminoaniline, 3-dimethylaminoaniline, 4-dimethylaminoaniline, 2-phenoxyaniline, 3-phenoxyaniline, 4-phenoxyaniline, 3,4-methylenedioxyaniline, 2, 3-methylenedioxyaniline, 2, 3-difluoroaniline, 3,4-difluoroaniline, 2, 3-dichloroaniline, 3,4-dichloroaniline, 2, 3-dibromoaniline, 3,4-dibromoaniline, 2, 3-dimethoxyaniline, 3,4-dimethoxyaniline, l-amino-5, 6,7, 8-tetrahydronaphthalelene,
  • tea-bag 1-amino-2-hydroxynaphthalene, 5-aminoindane, 1-aminofluorene, 2-aminofluorine, N-methylaniline.
  • the remaining tea-bag is left as the free carboxylic acid.
  • aniline in the same manner but on a 12.5 times larger scale are the 38 glycine control tea- bags as in Example 43.
  • the above procedures produced 50 tea-bags each containing a mixture of 418 isoquinoline amides or acids for a total library size of 20900 compounds.
  • Also prepared as a control for the aldehyde reaction are 38 single compounds from the building blocks: glycine, one of 38 aldehydes and aniline.
  • An additional control for the amine reaction is performed resulting in 49 pools of 11 isoquinolines each prepared from the following building blocks: a mixture of the eleven amino acids, 3, 5-dimethoxybenzaldehyde and, separately, each of the 49 amines.
  • Each tea-bag prepared is cleaved separately via standard HF procedures (Example 3) , dissolved in an appropriate solvent and tested in a variety of assays.
  • the control tea-bags are cleaved in the same manner and characterized by NMR or mass spectra.
  • Seventy-two porous polypropylene tea-bags were prepared each containing polystyrene MBHA/resin (l.lll g, 1.0 milliequivalents) .
  • Six tea-bags were placed in a 500 ml bottle.
  • a solution of N- (t-butyloxycarbonyl) -3- aminopropionic acid (beta alanine) (6.237 g, 33 mmoles) , HOBt (4.458 g, 33 mmoles), and DIC (6.2 ml, 39.6 mmoles) was prepared in DMF (275 ml) and added to the resin packet.
  • N,N- dimethylaminopyridine (164 mg, 1.3 mmoles) was added and the solution shaken for an additional 18 hrs.
  • the tea- bags were then washed with DMF (3 x 300 ml) and DCM (3 x 300 ml) .
  • the same coupling procedure was performed on the remaining 66 tea-bags in groups of six at a time, each six being reacted with a separate amino acid from the list: N- (t-butyloxycarbonyl)glycine, N- (t-butyloxycarbonyl) -5-aminopentanoic acid, N- (t-butyloxycarbonyl) -7-aminoheptanoic acid,
  • DIEA/DCM (3 x 900 ml, 2 min each set) and DCM (3 x 900 ml for each set) .
  • tea-bags each containing 49 mg (45 micromoles) of glycine (containing a free amino group) attached to MBHA resin (coupled and deprotected as described previously in this example) .
  • Placed in a 60 ml bottle were one of the library (0.673 g, 550 ⁇ moles of mixed amino acid resin) tea-bags and one of the control (45 micromoles of glycine) tea-bags.
  • the two tea-bags were treated with a solution of benzaldehyde (2.135 ml, 21 mmoles) and anhydrous trimethylorthoformate (4.6 ml, 42 mmoles) in anhydrous DMF (38 ml) . After shaking for 4 hrs the packets were washed with anhydrous DMF (3 x 20 ml) and anhydrous chloroform (1 x 20 ml) .
  • a solution of homophthalic anhydride (2.4 g, 15 mmoles) and triethylamine (0.132 ml, 0.9 mmoles) was prepared in chloroform (30 ml) and added to the tea-bag. After shaking at room temperature for 16 hrs the packets were washed with DMF (4 x 30 ml) followed by DCM (3 x 30 ml) and dried at room temperature.
  • the 90 tea-bags containing mixed amino acid resin (now containing mixed isoquinolines after the above reaction) were cut open and the contents pooled in a bottle containing DCM (400 ml) . The bottle was shaken for 70 min to thoroughly mix the resin. The DCM/resin slurry was then poured into a large (45 x 23 cm) tea-bag to separate the resin from the DCM and the resin was dried at room temperature.
  • Placed in a 20 ml bottle were one of the library (154 mg, 100 ⁇ moles of mixed isoquinoline resin) tea-bags and one of the second set of control tea-bags containing 72 mg of the isoquinoline prepared from glycine, homophthalic anhydride and benzaldehyde.
  • the two tea-bags were treated with a solution of HATU in anhydrous DMF (6 mmoles, 20 ml, 300 mM solution) and shaken for 20 min.
  • the HATU solution was decanted off of the tea-bags and anhydrous DMF (20 ml) and aniline (1.823 ml, 20 mmoles) were added.
  • Each tea-bag prepared was cleaved separately via standard HF procedures (Example 3 with the modification of an addition of 0.2 ml anisole to each HF cleavage reaction as a scavenger) , extracted into 45:45:10 water/acetonitrile/acetic acid, examined by HPLC coupled with mass spectrometry, and tested in a variety of assays.
  • the control tea-ba tgsi were cleaved in the same manner and characterized by NMR or HPLC and mass spectra.
  • This example describes an initial screen of libraries prepared according to Example 46 in the ⁇ - opioid receptor assay and the ⁇ receptor assay described above. The results of those screens are provided in ensuing Tables V and VI .
  • the tube After the solution is bubbling slows to a slight fizz the tube is capped tightly and heated at 65°C for 96 hrs. After cooling the borane solution is decanted and the bag washed with methanol (lx 25 ml) , tetrahydrofuran (1 x 25 ml) , and again with methanol (4 x 25 ml) . After drying the bag is returned to a 50 ml KIMAX glass tube, submerged completely in piperidine, sealed and heated at 65°C for 16 hrs.
  • EXAMPLE 49 Solid-phase synthesis of a library of 20,482 different isoquinoline aromatic amines Forty nine tea-bags are prepared as in Example 45 with each containing a mixture of 418 isoquinoline amides. While still attached to the resin the isoquinoline amides are reduced to the isoquinoline amines and cleaved off the resin as in Example 48, resulting in 49 pools of 418 isoquinoline amines for a total library size of 20,482.
  • Example 46 One-hundred seven tea-bags were prepared as in Example 46 but on two-fold larger scale (each bag containing 200 micromoles of resin) with each containing a mixture of isoquinoline amides or acids.
  • a subset of the amines used in Example 44 were used consisting of aniline, 2-fluoroaniline, 2-methoxyaniline, 2- chlorobenzylamine, 2-methoxybenzylamine, 2- trifluoromethylbenzylamine, 3-fluoroaniline, 3- methylaniline, 3-trifluoromethylaniline, 3- (methylmercapto) aniline, 3-trifluoromethylbenzylamine, 3- methylbenzylamine, 4-propylaniline, 4-pentylaniline, 4- (methylmercapto) aniline, 4-fluorobenzylamine, 4- methoxybenzylamine, 4-methylbenzylamine, 3-(l- hydroxyethyl) aniline, 4-chloroaniline, 2,3- dimethylaniline, 4-meth
  • the isoquinoline amides and acids were reduced to the isoquinoline amines and alcohols via the procedure of Cuervo et al. , supra, modified for solid-phase use.
  • One- half of the library tea-bags and one-half of the control tea-bags were placed in a 5 L glass reactor vessel under nitrogen gas containing boric acid (66.1 g, 1.07 moles) and anhydrous trimethyl borate (107 mL, 0.955 moles) .
  • boric acid 66.1 g, 1.07 moles
  • anhydrous trimethyl borate 107 mL, 0.955 moles
  • a IM solution of borane-tetrahydrofuran complex in tetrahydrofuran (3.2 L) was added slowly to the reaction. After sealing the reaction vessel was heated at 65°C for 96 hrs.
  • Example 48 extracted into 45:45:10 water/acetonitrile/acetic acid and examined by HPLC coupled with mass spectrometry.
  • the control tea-bags were cleaved in the same manner and characterized by NMR or HPLC and mass spectra.
  • the positional scan format as described above, is used to identify additional compounds which are significant inhibitors of the ⁇ receptor ligand, pentazocine.
  • Subsets of compounds were prepared as described below and screened in the ⁇ receptor assay.
  • the experimental procedure was as follows. Two 0.30 ⁇ mol bags each of either FMOC or BOC protected aminoacids were prepared using MBHA resin (0.90 ⁇ mol/g) as previously described (DIC, HOBt, DMF/DCM) .
  • the amino acids used were: N- (t-butyloxycarbonyl)glycine, N- (t-butyloxycarbonyl) -3-aminopropionic acid, N- (t-butyloxycarbonyl) -5-aminopentanoic acid, N- (t-butyloxycarbonyl) -7-aminoheptanoic acid, (s) -2-N- (t-butyloxycarbonyl) -3-N- (9-fluorenylmethoxy ⁇ carbonyl) -diaminopropionoic acid,
  • Subset 1 consisted of 11 bags containing 55 ⁇ mol of a mixture of all 11 the resin-aminoacids.
  • Subset 2 contained 11 bags of 240 ⁇ mol of the 11 resin- aminoacids mixture.
  • Subset 3 had each individual resin- aminoacid subdivided into 11x11 22 ⁇ mol bags for a total of 121 bags.
  • the bags from Subset 1,2 and 3 were divided into 11 groups.
  • the aldehydes used were benzaldehyde, 5-nitro-2-furaldehyde, 4- nitrobenzaldehyde, 5- (hydroxymethyl) -2-furaldehyde, 4- (dimethylamino) -benzaldehyde, 3-methylbenzaldehyde, 3,5- dimethoxybenzaldehyde, 2-pyridinecarboxaldehyde, 2- naphthaldehyde, 2-furaldehyde, and 2-bromobenzaldehyde.
  • Each group was composed of one bag each from Subset 1 and 2 and 11 bags of each individual resin-aminoacid from Subset 3 and at least one sibling bag (total 14 bags, 520 ⁇ mol) .
  • the formation of the imine intermediate was performed by placing a series of bags in 75 ml of a 0.5 M 1*3 solution (37.5 mmol) of the benzaldehyde.
  • the solution contained 8.2 ml (75 mmol) of trimethylorthoformate as a dehydrating agent.
  • the resin bags were shaken in the reaction solution for 3 to 3 1/2 hrs at room temperature then the solution decanted and bags quickly washed lx with 30 ml anhydrous DMF and lx 30 ml anhydrous CHC1 3 .
  • Subsets now contained the intermediate tetrahydroisoquinoline acids with a single benzaldehyde derived fragment in combination with either a mixture of all the 11 aminoacid derived fragment (Subset 1 and 2) or a single aminoacid derived fragment (Subset 3) .
  • Subset 1 all the resin-bound intermediates from original Subset 1, mixed into a single portion by combining the dry solids into a large (5cm x 5cm) resin bag and mixing for 30 min in DCM. After a MeOH wash and vacuum drying the mixed resin was divided into 12 equal portions to provide 50 ⁇ mol scale bags.
  • Subset 1 now represented mixtures from both the aminoacid and benzaldehyde building blocks.
  • Subset 2 each of the 240 ⁇ mol bags from original Subset 2 was divided into 12 equal portions of 20 ⁇ mol to create bags which were mixed aminoacid fragments but contained sets of individual benzaldehyde fragments.
  • Subset 3 for every individual If* resin-aminoacid set from original Subset 3 all the different benzaldehyde derived fragments were pooled into separate bags, mixed by treatment with DCM, then MeOH and dried under vacuum. These 11 new mixtures were subdivided into 12 equal portions to generate 20 ⁇ mol bags that contained a single aminoacid fragment and a mixture of the 11 benzaldehyde fragments.
  • the bags were once again separated into 11 groups which contained 1 bag from Subset 1, 11 bags from Subset 2, and 11 bags from Subset 3, and a sibling bag prepared from resin-glycine-3, 5-dimethoxybenzaldehyde.
  • the groups of bags were treated with 30 ml of a 0.3 M DMF stock solution of (O- (7-azabenzotriazol-l-yl) -1, 1, 3, 3- tetramethyluronium hexafluorophosphate (HATU: 79.84 g in 700 ml anhydrous DMF) by shaking for 30 min.
  • the HATU solution was decanted and the bags shaken for 2 hrs in 40 ml of a 1 M DMF solution of an amine (75 mmol in 75 ml) .
  • the amines used were 1- (2-aminoethyl)pyrrolidine, 1- adamantanemethylamine, 1- (2-hydroxyethyl)piperazine, piperidine, (aminomethyl) cyclohexane, 4-aminomorpholine, amylamine, aniline, cyclopentylamine, ethanolamine, and tryptamine.
  • the amine solution was decanted and the bags washed 2x 30 ml DMF.
  • Subset 1 The bags from Subset 1 contained mixtures from both the aminoac ifidfand benzaldehyde building blocks but had a single amine fragment . These 50 ⁇ mol bags were used directly in the HF cleavage step.
  • Subset 2 The 11 amine bags of the same resin- benzaldehyde-mixed amino acid fragments were combined into a bag in order to create a mixture of all the amines. After shaking for 30 min in DCM, then 30 min in MeOH, the resin was dried 3-4 hrs under vacuum. A 50 ⁇ mol sample bag was prepared from each of the fixed benzaldehyde mixtures for HF cleavage.
  • Subset 3 The 11 amine bags containing the same resin-aminoacid-mixed benzaldehyde were mixed with the DCM/MeOH/vacuum drying procedure. Fifty ⁇ mol sample bags were created from each of the mixtures with the fixed amino acid position.

Abstract

L'invention concerne la synthèse de composés hétérocycliques à base du noyau isoquinoléine. Plus particulièrement, l'invention concerne de nouvelles isoquinoléines ainsi que de nouvelles collections comprenant de nombreux composés de ce type, ainsi que des procédés pour constituer ces collections.
PCT/US1996/016763 1995-10-19 1996-10-18 Derives isoquinoleine et collections combinatoires d'isoquinoleines WO1997016428A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
KR1019980702842A KR19990064338A (ko) 1995-10-19 1996-10-18 이소퀴놀린 유도체 및 이소퀴놀린 조합 라이브러리
AU74571/96A AU705066C (en) 1995-10-19 1996-10-18 Isoquinoline derivatives and isoquinoline combinatorial libraries
JP9517383A JPH11514645A (ja) 1995-10-19 1996-10-18 イソキノリン誘導体およびイソキノリン組合せライブラリ
EP96936720A EP0863877A4 (fr) 1995-10-19 1996-10-18 Derives isoquinoleine et collections combinatoires d'isoquinoleines

Applications Claiming Priority (2)

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US54549395A 1995-10-19 1995-10-19
US08/545,493 1995-10-19

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WO (1) WO1997016428A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000050406A1 (fr) * 1999-02-22 2000-08-31 Lion Bioscience Ag Derives d'isoquinoleines et banques combinatoires d'isoquinoleines
EP1076649A1 (fr) * 1998-04-28 2001-02-21 Trega Biosciences, Inc. Composes a base d'isoquinoline tenant lieu de ligands de recepteurs de melanocortine et procedes d'utilisation
US6417195B1 (en) 1999-02-22 2002-07-09 Lion Bioscience Ag Isoquinoline derivatives and isoquinoline combinatorial libraries
WO2004004727A1 (fr) * 2002-07-03 2004-01-15 Axys Pharmaceuticals, Inc. Derives 3,4-dihydroisoquinolin-1-one, inducteurs d'apoptose
WO2010055164A2 (fr) * 2008-11-14 2010-05-20 Katholieke Universiteit Leuven, K.U.Leuven R&D Nouveaux inhibiteurs de la réplication de flavivirus
CN115197137A (zh) * 2022-07-07 2022-10-18 中国科学院成都生物研究所 异喹啉酮类化合物及其合成方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0590455A1 (fr) * 1992-09-28 1994-04-06 Hoechst Aktiengesellschaft 1 (2H) Isoquinoleines substituées à activité antiarrythmique et cardioprotective, procédé de préparation, médicaments les contenant et leur utilisation pour la préparation de médicaments pour traiter l'insuffisance cardiaque

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0590455A1 (fr) * 1992-09-28 1994-04-06 Hoechst Aktiengesellschaft 1 (2H) Isoquinoleines substituées à activité antiarrythmique et cardioprotective, procédé de préparation, médicaments les contenant et leur utilisation pour la préparation de médicaments pour traiter l'insuffisance cardiaque

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Title
CHEMICAL ABSTRACTS, Vol. 106, No. 3, 19 January 1987, (Columbus, Ohio, USA), page 584, Abstract No. 106:1833a, LEE et al., "Cycloaddition of Homophthalic Anhydrides to Azodicarboxylate and Alkylidenecarbamates"; & TAEHAN HWAHAKHOE CHI., 1986, 30(2), 243-7 (Eng). *
J. ORG. CHEM., Volume 60, No. 18, 08 September 1995, GOFF et al., "Solid-Phase Synthesis of Highly Sustituted Peptoid 1(2H)-Isoquinolinones", pages 5748-5749. *
See also references of EP0863877A4 *
TETRAHEDRON, 1977, Volume 33, HAIMOVA et al., "A Highly Stereoselective Synthesis of 3,4-Dihydro-1(2H)-Isoquinolinones and 8-Oxoberbines from Homophthalic Anhydrides and Azomethines", pages 331-336. *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1076649A1 (fr) * 1998-04-28 2001-02-21 Trega Biosciences, Inc. Composes a base d'isoquinoline tenant lieu de ligands de recepteurs de melanocortine et procedes d'utilisation
EP1076649A4 (fr) * 1998-04-28 2010-06-02 Trega Biosciences Inc Composes a base d'isoquinoline tenant lieu de ligands de recepteurs de melanocortine et procedes d'utilisation
WO2000050406A1 (fr) * 1999-02-22 2000-08-31 Lion Bioscience Ag Derives d'isoquinoleines et banques combinatoires d'isoquinoleines
US6417195B1 (en) 1999-02-22 2002-07-09 Lion Bioscience Ag Isoquinoline derivatives and isoquinoline combinatorial libraries
WO2004004727A1 (fr) * 2002-07-03 2004-01-15 Axys Pharmaceuticals, Inc. Derives 3,4-dihydroisoquinolin-1-one, inducteurs d'apoptose
WO2010055164A2 (fr) * 2008-11-14 2010-05-20 Katholieke Universiteit Leuven, K.U.Leuven R&D Nouveaux inhibiteurs de la réplication de flavivirus
WO2010055164A3 (fr) * 2008-11-14 2010-07-08 Katholieke Universiteit Leuven, K.U.Leuven R&D Nouveaux inhibiteurs de la réplication de flavivirus
CN115197137A (zh) * 2022-07-07 2022-10-18 中国科学院成都生物研究所 异喹啉酮类化合物及其合成方法
CN115197137B (zh) * 2022-07-07 2024-04-02 中国科学院成都生物研究所 异喹啉酮类化合物及其合成方法

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AU7457196A (en) 1997-05-22
EP0863877A4 (fr) 1999-07-21
AU705066B2 (en) 1999-05-13
CA2234058A1 (fr) 1997-05-09
JPH11514645A (ja) 1999-12-14
EP0863877A1 (fr) 1998-09-16
CN1202888A (zh) 1998-12-23
KR19990064338A (ko) 1999-07-26

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