WO1995022537A2 - 4-amino derivatives of 5-substituted mycophenolic acid - Google Patents

4-amino derivatives of 5-substituted mycophenolic acid Download PDF

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Publication number
WO1995022537A2
WO1995022537A2 PCT/US1995/001786 US9501786W WO9522537A2 WO 1995022537 A2 WO1995022537 A2 WO 1995022537A2 US 9501786 W US9501786 W US 9501786W WO 9522537 A2 WO9522537 A2 WO 9522537A2
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WIPO (PCT)
Prior art keywords
formula
compound
lower alkyl
methyl
hydrogen
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Application number
PCT/US1995/001786
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French (fr)
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WO1995022537A3 (en
Inventor
Dean R. Artis
Todd R. Elworthy
Ronald C. Hawley
David G. Loughhead
David J. Morgans, Jr.
Peter H. Nelson
John W. Patterson, Jr.
Eric B. Sjogren
David B. Smith
Ann Marie Waltos
Robert J. Weikert
Alicia C. Garcia
Mario F. Zertuche
Fidencio F. Andrade
Maria T. L. Hernandez
Fransisco X. T. Murra
Teresa A. T. Martin
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Syntex (U.S.A.) Inc.
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Publication date
Priority to JP7521867A priority Critical patent/JPH09509173A/en
Priority to MX9603484A priority patent/MX9603484A/en
Priority to BR9506838A priority patent/BR9506838A/en
Priority to EP95910983A priority patent/EP0745072B1/en
Priority to DE69502380T priority patent/DE69502380T2/en
Priority to AU18753/95A priority patent/AU1875395A/en
Application filed by Syntex (U.S.A.) Inc. filed Critical Syntex (U.S.A.) Inc.
Priority to DK95910983T priority patent/DK0745072T3/en
Priority to SI9530105T priority patent/SI0745072T1/en
Publication of WO1995022537A2 publication Critical patent/WO1995022537A2/en
Publication of WO1995022537A3 publication Critical patent/WO1995022537A3/en
Priority to FI963220A priority patent/FI963220A/en
Priority to HK98111768A priority patent/HK1010784A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to mycophenolic acid derivatives in which the 4-hydroxy group has been replaced by amino substituents.
  • the invention includes natural and derivative side chains at the 5 -position.
  • the invention is also directed to formulations and methods for treatment.
  • MPA Mycophenolic acid
  • MPA and certain related compounds having the following structure:
  • esters and derivatives of mycophenolic acid are useful in treating auto-immune related disorders, glomerulonephritis and hepatitis, and in preventing allograft rejection.
  • anti-inflammatory agents they are useful in treating rheumatoid arthritis.
  • anti-tumor agents they are useful in treating solid tumors and malignancies of lymphoreticular origins.
  • R 1 is hydrogen or lower alkyl
  • R 2 is hydrogen, lower alkyl, -C(O)R 3 , -C(O)NR 4 R 5 , -CO 2 R 6 , or -SO 2 R 3
  • R 3 is hydrogen, lower alkyl, halo lower alkyl or optionally
  • R 4 is hydrogen, lower alkyl or optionally substituted phenyl
  • R 5 is hydrogen, lower alkyl or optionally substituted phenyl
  • R 6 is lower alkyl or optionally substituted phenyl
  • Z is a side chain selected from Formulae ZA, ZB, ZC, ZD, ZE, ZF, ZG, and ZH:
  • Z 1 is H, lower alkyl, halo or CF 3 ;
  • Z 2 is H, lower alkyl, lower alkoxy, aryl, or -CH 2 Z 13 , where
  • Z 13 is aryl or heteroaryl
  • Z 3 is H, lower alkyl, lower alkenyl, lower alkoxy, phenyl, - P(O) (OCH 3 ) 2 , -P(O) (OH) (OCH 3 ), or -S(O) m Z 12 , where
  • Z 12 is lower alkyl
  • n 0, 1 or 2;
  • Z 4 is H, lower alkyl, or phenyl
  • n is an integer from 1 to 6
  • G 1 is H or lower alkyl
  • G 2 is H or lower alkyl
  • G 3 is lower alkylene of four to six carbon atoms, or lower alkylene of three to five carbon atoms plus one member that is -O-, -S-, or -N(G 4 )- where G 4 is H or lower alkyl;
  • Z 5 is H or lower alkyl
  • Z 8 is H or lower alkyl
  • D 1 and D 2 together with their adjacent carbon atoms form an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring of 3 to 7 atoms;
  • G is as defined above;
  • Z 5 , Z 8 , and G are as defined above; or
  • D 3 is -CH 2 - or -CH 2 CH 2 -;
  • G is as defined above;
  • Z 6 is H, lower alkyl , lower alkoxy, -COOH, -NH 2 or halo;
  • Z 7 is H, lower alkyl , lower alkoxy or halo
  • Z 5 and G are as defined above ;
  • D 4 is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -O-, or -OCH 2 - ;
  • the invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of Formula I admixed with at least one pharmaceutically acceptable excipient.
  • the invention relates to a method of treating immune, inflammatory, tumor, proliferative, viral and psoriatic disorders in a mammal by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • alkyl refers to a fully saturated monovalent radical of one to twelve carbon atoms containing only carbon and hydrogen, and which may be a cyclic, branched or straight chain radical. This term is further exemplified by radicals such as methyl, ethyl, t-butyl, pentyl, cyclopentyl, cyclohexyl, heptyl, cycloheptyl and
  • lower alkyl refers to a monovalent alkyl radical of one to six carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, t-butyl, i-butyl (or 2-methylpropyl), isoamyl, pentyl, cyclopentyl, i-pentyl, hexyl and cyclohexyl.
  • lower alkenyl refers to an unsaturated monovalent hydrocarbon radical of one to six carbon atoms. This term is further exemplified by such radicals as vinyl, prop-2-enyl, pent-3-enyl, and hex-5-enyl.
  • halo refers to fluoro and chloro, unless otherwise specified.
  • halo lower alkyl refers to a lower alkyl radical
  • halomethyl refers to a methyl radical substituted with one or more chlorine and/or fluorine atoms. This term is further exemplified by such radicals as trichloromethyl, trifluoromethyl, dichloromethyl, fluoromethyl and difluoro-chloromethyl.
  • lower alkylene refers to a divalent alkyl radical of one to six carbon atoms. This term is further exemplified by such radicals as methylene, ethylene, n-propylene, i-propylene, n-butylene, t-butylene, i-butylene (or 2-methylpropylene), isoamylene, pentylene, and n-hexylene.
  • alkoxy means the group -OR wherein R is lower alkyl.
  • lower alkanol means an alcohol of the formula ROH where R is a lower alkyl. This term is further exemplified by such alcohols as methanol, ethanol, n-propanol, i-propanol, n-butanol, t-butanol, i-butanol (or 2-methylpropanol), pentanol, n-hexanol.
  • ROH lower alkanol
  • This term is further exemplified by such alcohols as methanol, ethanol, n-propanol, i-propanol, n-butanol, t-butanol, i-butanol (or 2-methylpropanol), pentanol, n-hexanol.
  • optionally substituted phenyl refers to phenyl and mono-, di-, or tri-substituted phenyl, wherein the optional substituents are lower alkyl, lower alkoxy, hydroxy, trifluoromethyl, or halo.
  • This term is further exemplified by such radicals as 2-chlorophenyl, 2-trifluoromethylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 3,4-dimethoxyphenyl, 2-chloro-3,4-dimethoxyphenyl, 4-hydroxyphenyl,
  • aryl refers to a monovalent unsaturated aromatic
  • carbocyclic radical having a single ring (e.g., phenyl) or two condensed rings (e.g., naphthyl), which can optionally be mono-, di- or
  • heteroaryl refers to a monovalent aromatic carbocyclic radical having at least one heteroatom, such as N, O or S, within the ring, such as quinolyl, benzofuranyl, pyridyl, morpholinyl and indolyl, which can optionally be mono-, di- or tri-substituted, independently, with OH, COOH, lower alkyl, lower alkoxy, chloro, fluoro, trifluoromethyl and/or cyano.
  • X 1 , X 2 , X 3 , X 4 and X 5 can independently be -CHX a -, -C(O)-, -C(N-X b )-, -C(N-NX d X e ) -, -O-, -S-, -S(O)-, -S(O) 2 - or -NX c -, where
  • X a is H, lower alkyl or forms a double bond
  • X b is acyl, carbamoyl or ureido
  • X c is lower alkyl, C(O)X d , S(O) 2 X d or C(O)NX d X e ; and X d and X e are independently H or lower alkyl;
  • a sidechain of Formula ZB in which D 1 and D 2 together represent -CH 2 CH 2 CH 2 CH 2 - , and Z 5 and Z 8 are both hydrogen would be named as a 2-[(2-ethylidene)-2-cyclohex-1-yl]acetic acid derivative.
  • a sidechain of Formula ZB in which D 1 and D 2 together represent -CH 2 CH 2 OCH 2 -, and Z 5 and Z 8 are both hydrogen would be named as a 2-[(2-ethylidene)-4-tetrahydropyran-3-yl]acetic acid derivative.
  • a “pharmaceutically acceptable salt” may be any salt derived from an inorganic or organic acid or base. Salts may be derived from acids or bases.
  • the acid addition salts are derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid (giving the sulfate and bisulfate salts), nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, salicylic acid,
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid (giving the sulfate and bisulfate salts), nitric acid, phosphoric acid and the like
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, mal
  • the base addition salts are derived from inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonia, calcium hydroxide, magnesium hydroxide and the like.
  • Cations derived from organic bases include those formed from primary, secondary and tertiary amines, such as isopropylamine, diethylamine, trimethylamine, triethylamine, pyridine, cyclohexylamine, ethylene diamine, monoethanolamine,
  • inert organic solvent or “inert solvent” means a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran, diethyl ether, chloroform, methylene chloride, pyridine, xylene, dimethylformamide, 1,4-dioxane,
  • treatment means any treatment of a disease in a mammal, and includes:
  • the term "effective amount” means a dosage sufficient to provide treatment. This will vary depending on the patient and the treatment being effected.
  • Steps are isomers that differ only in the way the atoms are arranged in space.
  • Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “( ⁇ )” is used to designate a racemic mixture where appropriate.
  • Stereoisomers are stereoisomers that have at least two
  • stereochemistry at each chiral carbon may be specified by either RS or SR by reference to a single enantiomer of the racemate. In this manner relative stereochemistry is conveyed unambiguously.
  • the compounds of the invention may possess one or more asymmetric centers, and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers.
  • the number of stereoisomers present in any given compound of Formula I depends upon the number of asymmetric centers present (there are 2 n stereoisomers possible where n is the number of asymmetric centers).
  • the individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound of Formula I by conventional means.
  • Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures.
  • suitable separation and isolation procedures can be found by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can, of course, also be used.
  • the isobenzofuranyl nucleus of the compounds of Formula I is numbered as follows:
  • D represents -O-, -S(O) p -, -N(R 9 )-, and the like.
  • the compounds of Formula I are prepared from the lower alkyl 4- isocyanato esters of Formula 6, the structure of which is shown below: where Z a is a sidechain of Formula Z as defined in the Summary of the Invention in which G is lower alkoxy.
  • the compounds of Formula 6 are then converted to the compounds of Formula I by several different synthetic pathways, depending on the desired substitutions at the 4-position.
  • the compounds of Formula 1 may be prepared as described below in Reaction Schemes I to XXII. The preparation of such compounds is also described in more detail in co-pending Application Serial No. 08/???,???, Attorney Docket No. 27960, entitled "5-Substituted Derivatives of
  • Step 1 the phenolic hydroxyl group of a mycophenolic acid lower alkyl ester is protected.
  • a mycophenolic acid lower alkyl ester of Formula 101 in a solvent (such as ether, ethyl acetate, dimethylamide, or preferably
  • dichloromethane is reacted with an equimolar amount of a halogenated protecting group (such as: methoxyethoxymethyl chloride; a sulfonyl chloride, e.g., tosyl chloride, mesyl chloride; or a silyl chloride, e.g., trimethylsilyl chloride, diphenylmethylsilyl chloride, or preferably tert-butyldimethylsilyl chloride) in presence of an equimolar amount of an organic base (such as diisopropylethylamine, triethylamine, or imidazole).
  • a halogenated protecting group such as: methoxyethoxymethyl chloride; a sulfonyl chloride, e.g., tosyl chloride, mesyl chloride; or a silyl chloride, e.g., trimethylsilyl chloride, diphenylmethylsilyl chloride
  • Step 2 the side chain double bond of a protected mycophenolic acid lower alkyl ester is ozonized to yield an aldehyde.
  • a stream of ozonized oxygen is passed through a solution of a protected compound of Formula 102 in a solvent (such as an alcohol, a halocarbon, or preferably a mixture of methanol and dichloromethane).
  • a solvent such as an alcohol, a halocarbon, or preferably a mixture of methanol and dichloromethane.
  • the reaction takes place at -100 to -40°C (preferably at -80°C), and continues until the presence of excess ozone is detected by the development of a blue color.
  • the intermediate hydroperoxide thus formed is reduced without further purification, by the addition of a reducing agent (such as zinc and acetic acid, dimethyl sulfide, or preferably thiourea).
  • the reaction takes place at -80°C to 25°C (preferably 0°C) over a period of 12 to 24 hours (preferably 16 hours), to give the corresponding aldehyde of Formula 103.
  • Step 3 the aldehyde is converted to a carbinol by addition of an organometallic compound of
  • Formula 103a [where M is MgBr or lithium, preferably MgBr (a Grignard reagent); Z 1 is H, lower alkyl or CF 3 , and Z 2 is H or lower alkyl].
  • An organolithium reagent is formed by reaction of a halovinyl
  • halovinyl compound of Formula 103a is reacted with magnesium metal in an ethereal solvent (such as ether or preferably tetrahydrofuran).
  • an ethereal solvent such as ether or preferably tetrahydrofuran.
  • the reaction takes place at 30 to 60°C (preferably 40°C) over a period of 1 to 6 hours (preferably 2 hours).
  • the organometallic compound of Formula 103a where M is zinc or cadmium may be prepared by reaction of 103a where M is Li or MgBr with a zinc or cadmium halide, preferably chloride.
  • the compound of Formula 103a where M is tin may be prepared by reaction of 103a where M is Li or MgBr with a trialkyl chlorostannane, preferably tributyltin chloride.
  • the compound of Formula 103a where M is tin may also be prepared by reaction of 103a where M is trifluoromethanesulfonate by reaction with a compound of formula (R 3 Sn) 2 , where R is alkyl, preferably methyl, in the presence of a palladium catalyst, preferably tetrakis(triphenylphosphine)palladium.
  • the compound of Formula 103a where M is trifluoromethanesulfonate may be prepared from a ketone of the formula: by reaction with a strong base (such as sodium hydride or potassium hexamethyldisilazide), followed by reaction of the anion thus produced with trifluoromethanesulfonic anhydride.
  • the compound of Formula 103a where M is tin may be prepared by reacting a trialkyl tin hydride (preferably tributyl tin hydride) with an acetylene of the formula
  • One molar equivalent of the resultant organometallic reagent is added to a solution of an aldehyde of Formula 103 (in the same solvent system used to make the organometallic reagent).
  • the reaction takes place at -80 to 20°C (preferably 0°C) over a period of 5 to 60 minutes (preferably 10 minutes) to give the corresponding carbinol of Formula 104.
  • Formula 105 is formed by a Claisen ortho ester rearrangement reaction of a carbinol of Formula 104 and an orthoester of Formula 104a (where Z 3 is H, halo, lower alkyl, lower alkenyl, phenyl, alkoxy or -thio lower alkyl; and Z 4 is H or lower alkyl; or Z 3 and Z 4 taken together with the carbon to which they are attached form cycloalkyl).
  • a carbinol of Formula 104 is heated at 50 to 140°C (preferably about 130°C) with about 10 molar equivalents of an orthoester of Formula 104a, in the presence of from 0.05 to 0.25 molar equivalents (preferably 0.10 molar equivalents) of an organic acid catalyst (such as propionic, butyric, or preferably trimethylacetic acid).
  • an organic acid catalyst such as propionic, butyric, or preferably trimethylacetic acid.
  • One method of preparing individual enantiomers of compounds of Formula 1A is from chiral compounds of Formula 104b, the preparation of which is shown below in Reaction Scheme II.
  • Step 1 an aldehyde of Formula 103 is oxidized to the corresponding carboxylic acid of Formula 103f.
  • an oxidizing agent for example, chromic acid, silver oxide, bleach, or preferably sodium periodate
  • an inert solvent such as toluene, or preferably ethyl acetate
  • a catalytic amount for example, about 0.01 molar equivalents
  • a catalyst such as ruthenium oxide, or preferably ruthenium trichloride
  • Formula 103f is converted to the corresponding acyl halide of Formula 103g.
  • a carboxylic acid of Formula 103f is reacted with about one molar equivalent, preferably 1.1 molar equivalents, of an halogenating agent (for example, thionyl chloride, thionyl bromide, or preferably oxalyl chloride), in an inert solvent (such as dichloromethane, or preferably ethyl acetate), in the presence of a catalytic amount (for example, about 0.05 molar equivalents) of dimethylformamide.
  • the reaction takes place at 0 to 40°C (preferably 25°C) for 30 minutes to 8 hours (preferably 2 hours), to give the corresponding acyl halide of Formula 103g.
  • an acyl halide of Formula 103g is converted to the corresponding keto olefin of Formula 103h by addition of an organometallic compound of Formula 103a.
  • An acyl halide of Formula 103g is reacted with about one molar equivalent of a organometallic compound of Formula 103a (where M is cadmium, zinc, tin, or the like, prepared as shown in the preparation of compounds of Formula 104), in an inert solvent (such as dichloromethane, ether, or preferably tetrahydrofuran), optionally in the presence of a catalytic amount (for example, about 0.05 molar equivalents) of a palladium catalyst [preferably tetrakis(triphenylphosphine)palladium].
  • the reaction takes place at -10 to 20°C (preferably 0°C) for 30 minutes to 8 hours (preferably 4 hours), to give the corresponding keto olefin of Formula 103h.
  • Formula 103h is reduced stereospecifically to the corresponding carbinol of Formula 104b by reduction with borane methyl sulfide in the presence of a catalytic amount of (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo- [1,2-c][1,3,2]oxazaborole.
  • a keto olefin of Formula 103h is sterospecifically reduced with about one molar equivalent of borane methyl sulfide in the presence of a catalytic amount (0.05-0.3 molar equivalents) of (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2]oxazaborole in an inert solvent (preferably a mixture of toluene and dichloromethane).
  • the reaction takes place at -30 to 40°C (preferably -20°C) for 1-24 hours (preferably 12 hours), to give the corresponding carbinol of Formula 104b.
  • Step 1 an aldehyde of Formula 103 is transformed into an unsaturated aldehyde of Formula 106 by a Wittig reaction with an ylid of Formula 103b (where Z 1 is H or lower alkyl).
  • An aldehyde of Formula 103 is reacted with one molar equivalent of an ylid of Formula 103b, in an organic solvent (such as dichloromethane, dimethylformamide or preferably toluene).
  • the reaction takes place at 0 to 110°C (preferably 80°C) for 1 to 24 hours (preferably 8 hours) to give the corresponding unsaturated aldehyde of Formula 106.
  • an unsaturated aldehyde of Formula 106 is condensed with the anion of an ester of Formula 106a (where Z 3 is H, lower alkyl, lower alkenyl, or phenyl and Z 4 is H, lower alkyl, or phenyl) to give a beta-hydroxy ester of Formula 107.
  • An ester of Formula 106a is converted to an alkali metal salt by reacting a solution of the ester in an ethereal solvent (such as ether or preferably tetrahydrofuran) with an equimolar amount of an alkali metal hydride, hexamethyldisilazide or amide (preferably lithium
  • ester anion solution 1.0 to 1.5 molar equivalents, preferably 1.0 molar equivalents
  • the condensation reaction takes place at a temperature of -100°C to 0°C
  • Step 1 the beta-hydroxy group of an ester of Formula 107 is O-alkylated to give the corresponding beta-alkoxy ester (R b ) of Formula 108.
  • An ester of Formula 107 is reacted with 1 to 3 (preferably 1.5) molar equivalents of an alkyl halide (preferably an alkyl iodide, such as methyl iodide or n-butyl iodide, preferably methyl iodide) and 1 to 3 (preferably 1.25) molar equivalents of silver oxide, in a polar organic solvent (such as dioxane, dimethylformamide or preferably acetonitrile).
  • a polar organic solvent such as dioxane, dimethylformamide or preferably acetonitrile
  • Step 1 an alpha-halo alkyl ester of Formula 105 (where Z 1 is H, lower alkyl or CF 3 , Z 2 is H or lower alkyl, Z 3 is H, lower alkyl, lower alkenyl, or phenyl, and Z 4 is halo) is converted to an alpha-hydroxy acid of Formula 1A where Z 4 is hydroxy.
  • the reaction takes place by hydrolysis of an alpha-alkanoyloxy ester
  • alpha-halo (preferably chloro) ester of Formula 105 is reacted with 1 to 5 (preferably 3) molar equivalents of an alkali metal alkanoate (the metal preferably potassium and the alkanoate preferably acetate) in a polar organic solvent (such as acetonitrile or preferably
  • alpha-alkanoyloxy ester is then subjected to basic hydrolysis by reaction with 1 to 5 (preferably 2) molar equivalents of an alkali metal hydroxide (preferably sodium hydroxide) in a mixture of water and an organic solvent (such as methanol, dimethoxyethane or preferably
  • Step 1 an unsaturated aldehyde of Formula 106 is reduced and then converted to the corresponding compound of Formula 109 in which R b is a leaving group (a sulfonate or halide, preferably a bromide).
  • R b is a leaving group (a sulfonate or halide, preferably a bromide).
  • An unsaturated aldehyde of Formula 106 is reacted with from 0.5 to 2 (preferably 1) molar equivalents of a reducing agent (such as sodium cyanoborohydride or preferably sodium borohydride) in an alcoholic solvent (such as ethanol, isopropanol or preferably methanol).
  • a reducing agent such as sodium cyanoborohydride or preferably sodium borohydride
  • an alcoholic solvent such as ethanol, isopropanol or preferably methanol.
  • the allylic alcohol is reacted with from 1 to 1.5 (preferably 1.25) molar equivalents of a sulfonating agent (such as p-toluenesulfonyl chloride) and an organic base, or preferably reacted with a halogenating reagent (such as carbon tetrachloride/triphenylphosphine or preferably N-bromosuccinimide/triphenylphosphine) in an inert organic solvent (such as ether or preferably dichloromethane).
  • a sulfonating agent such as p-toluenesulfonyl chloride
  • a halogenating reagent such as carbon tetrachloride/triphenylphosphine or preferably N-bromosuccinimide/triphenylphosphine
  • an inert organic solvent such as ether or preferably dichloromethane
  • an allylic halide or sulfonate of Formula 109 is alkylated with a chiral 4-alkyl N-acyl oxazolidinone of Formula 109a to give the corresponding chiral substituted acyl oxazolidinone of Formula 110.
  • hexamethyldisilazide or dialkylamide preferably lithium diisopropylamide
  • an inert organic solvent such as ether or preferably tetrahydrofuran.
  • the reaction takes place at -100 to -20°C (preferably -80°C) for 5 to 120 minutes (preferably 30 minutes).
  • the solution of the salt (1 to 1.5, preferably 1.25 molar equivalents) is then added to a solution of an allylic compound of Formula 109 in the same solvent.
  • the alkylation reaction takes place at -100 to 0°C (preferably -80°C) for 30 minutes to 6 hours (preferably 1 hour) to afford the corresponding chiral substituted acyl oxazolidinone of Formula 110.
  • a chiral substituted acyl oxazolidinone of Formula 110 is hydrolyzed to the corresponding chiral acid of Formula 1A.
  • Use of an acyl oxazolidinone of Formula 109a having a 4-alkyl substituent of the opposite configuration in Reaction Scheme VI, Step 2, followed by hydrolysis as described in Step 3 results in the corresponding chiral acid where Z 3 has the opposite configuration .
  • An acyl oxazolidinone of Formula 110 is reacted with from 1.25 to 3.5 (preferably 3.0) molar equivalents of lithium hydroxide, in a mixture of water and a water-miscible organic solvent (such as dioxane or preferably tetrahydrofuran) containing from 6 to 10 (preferably 8) molar equivalents of 30% aqueous hydrogen peroxide.
  • the reaction takes place at -20 to 40°C (preferably 20°C) for 1 to 24 hours (preferably 12 hours) to afford the corresponding chiral acid of Formula 1A.
  • Step 1 an allylic compound of Formula 109 in which R b is a leaving group (a sulfonate or halide, preferably a bromide) is condensed with an ester of Formula 109b to give the mono- or di-alkyl ester of Formula 112 (where Z 3 is H, lower alkyl, lower alkenyl, or phenyl and Z 4 is H, lower alkyl, or phenyl).
  • R b is a leaving group (a sulfonate or halide, preferably a bromide)
  • An ester of Formula 109b is converted to an alkali metal salt by reaction with 1.05 to 1.25 (preferably 1.1) molar equivalents of an alkali metal amide (such as sodium hexamethyldisilazide, potassium
  • Step 1 a 2-(alkylthio)-4-hexenoic acid ester of Formula 1A (where Z 3 is S-lower alkyl, and Z 4 is H or lower alkyl) is oxidized to give the corresponding 2-(alkylsulfinyl)- or 2-(alkylsulfonyl)-4-hexenoic acid ester of Formula 1A where Z 3 is S(O)lower alkyl or S(O) 2 lower alkyl.
  • the reaction can be performed with an acid of Formula 1A where Z 3 is S-lower alkyl, to give the
  • An alkylthio-4 -hexenoic acid ester of Formula 1A is reacted with 1.0 to 1.25 (preferably 1.05) molar equivalents of an oxidizing agent (such as oxone ® ) optionally in the presence of an inert support (such as alumina), in a solvent (such as chloroform or preferably dichloromethane).
  • an oxidizing agent such as oxone ®
  • an inert support such as alumina
  • a solvent such as chloroform or preferably dichloromethane
  • a 2-(alkylsulfinyl)- or 2-(alkylsulfonyl)-4-hexenoic acid ester of Formula I-ZA-K is hydrolyzed to give the corresponding acid as described with reference to Reaction Scheme X, Step 2.
  • Step 1 a protected aldehyde of Formula 103 and a triphenylphosphoranylideneacetate of Formula 103c are combined in a Wittig reaction to give the corresponding alkyl-2-halobutenoate ester of Formula 114.
  • An aldehyde of Formula 103 is reacted with 1.0 to 1.5 (preferably
  • a 2-halo-4-aryl-2-butenoate ester of Formula 114 (preferably a t-butyl ester) is converted to the corresponding acid (preferably by dissolution in trifluoroacetic acid at room temperature for 1 to 2 hours).
  • the acid is isolated and purified by conventional means, then reacted with 0.5 to 3 (preferably 1.6) molar equivalents of a reducing agent (such as sodium cyanoborohydride, sodium borohydride, or preferably borane dimethyl disulfide complex) in an inert solvent (such as methanol, ethanol, isopropanol or preferably THF).
  • a reducing agent such as sodium cyanoborohydride, sodium borohydride, or preferably borane dimethyl disulfide complex
  • an inert solvent such as methanol, ethanol, isopropanol or preferably THF.
  • the reaction takes place at 0 to 50°C (preferably 25°C) for 1 to 48 hours (preferably 24 hours) to give
  • the allylic alcohol so-produced is reacted with from 1 to 1.5
  • a sulfonating agent such as p-toluenesulfonyl chloride
  • an organic base or preferably reacted with a halogenating reagent (such as carbon tetrachloride/triphenylphosphine or preferably N-bromosuccinimide/triphenylphosphine) in an inert organic solvent (such as ether or preferably dichloromethane).
  • a sulfonating agent such as p-toluenesulfonyl chloride
  • a halogenating reagent such as carbon tetrachloride/triphenylphosphine or preferably N-bromosuccinimide/triphenylphosphine
  • an inert organic solvent such as ether or preferably dichloromethane
  • Step 3 a protected 2-halo-4-aryl-2-butenyl bromide compound of Formula 115 is condensed with a dialkyl malonate of Formula 106b (substituted by Z 4 where Z 4 is hydrogen, lower alkyl, or phenyl), which is hydrolysed and decarboxylated to give the corresponding 4-halo-4-hexenoic acid derivative of Formula 1A where Z 1 is halo.
  • a malonic ester of Formula 106b (where Z 4 is H, lower alkyl, or phenyl) is converted to an alkali metal salt by reaction with 1.05 to 1.25 (preferably 1.1) molar equivalents of an alkali metal hydride (preferably sodium hydride) in an organic solvent (such as ether, dioxane or preferably tetrahydrofuran).
  • an alkali metal hydride preferably sodium hydride
  • organic solvent such as ether, dioxane or preferably tetrahydrofuran
  • the dialkyl ester thus produced is then hydrolysed conventionally, using a strong base, preferably aqueous sodium hydroxide, in a protic solvent, preferably ethanol, heating to reflux.
  • a strong base preferably aqueous sodium hydroxide
  • a protic solvent preferably ethanol
  • the dicarboxylic acid thus produced is separated conventionally, and then decarboxylated by heating, preferably in a high-boiling inert solvent, most preferably 1,2- dichlorobenzene, to give the corresponding 4-halo-4-hexenoic acid
  • Step 1 a protected phenol of Formula 117 (which can be any of the corresponding protected compounds of Reaction Schemes I to IX, such as Formulae 105, 107, 108, 112, and the like) is deprotected to give the corresponding alkyl ester of Formula 1A as an ester.
  • An alkyl ester of Formula 117 (having either an acetal-type or a silyl-type protecting group) is treated with from 0.05 to 0.2 molar equivalents (preferably 0.1 molar equivalents) of an aqueous mineral acid (such as sulfuric, perchloric, or preferably hydrochloric acid), in a water-miscible organic solvent (such as methanol, acetone, or preferably ethanol).
  • the reaction takes place at 0 to 50°C (preferably 25°C) over a period of 1 to 6 hours (preferably 2 hours) to give the corresponding free phenol of Formula 1A.
  • a compound of Formula 117 is treated with 0.05 to 0.25 molar equivalents (preferably 0.1 molar equivalents) of a Lewis acid (such as zinc chloride or preferably zinc bromide), in a solvent (such as benzene, chloroform, or preferably dichloromethane).
  • a Lewis acid such as zinc chloride or preferably zinc bromide
  • a solvent such as benzene, chloroform, or preferably dichloromethane
  • a compound of Formula 117 is reacted with 1.0 to 1.5 (preferably 1.25) moles of a tetraalkyl ammonium fluoride (preferably tetrabutylammonium fluoride) in an ethereal solvent (such as dioxane or preferably tetrahydrofuran).
  • a tetraalkyl ammonium fluoride preferably tetrabutylammonium fluoride
  • an ethereal solvent such as dioxane or preferably tetrahydrofuran
  • Step 2 a compound of Formula 1A as an ester (prepared as described above) is hydrolyzed to give the corresponding acid of Formula 1A as a carboxylic acid.
  • An alkyl ester of Formula 1A is reacted with from 1.5 to 4 molar equivalents (preferably 2 molar equivalents) of an inorganic hydroxide (such as potassium, sodium, or preferably lithium hydroxide) in a mixture of water and an organic solvent (such as tetrahydrofuran, methanol, or preferably dimethoxyethane).
  • an inorganic hydroxide such as potassium, sodium, or preferably lithium hydroxide
  • an organic solvent such as tetrahydrofuran, methanol, or preferably dimethoxyethane
  • the resulting anion is acidified with an aqueous mineral acid (such as hydrochloric acid).
  • the acidification takes place at 0 to 40°C (preferably 25°C) over a period of 1 to 10 minutes (preferably 2 minutes) to give the corresponding carboxylic acid of Formula 1A.
  • M Li or MgBr.
  • the aldehyde of Formula 103 is converted to a carbinol of Formula 202 by addition of an unsaturated cyclic organometallic compound of Formula 201 where M is Li or MgBr, prepared for example as described above with reference to Reaction Scheme I, Step 3.
  • One molar equivalent of the organometallic reagent 201 is added to a solution of an aldehyde of Formula 103 (in the same solvent system used to make the organometallic reagent).
  • the reaction takes place at -80 to -20°C (preferably -40°C) over a period of 5 to 60 minutes (preferably 15 minutes) to give the corresponding carbinol of Formula 202.
  • the racemic compound of Formula 202 may be separated into its two enantiomers by conventional means, for example by conversion into two diastereoisomers that are then separated by crystallization,
  • the carbinol is reacted with a chiral isocyanate to give a mixture of diastereoisomeric carbamates, which are separated by chromatography and cleaved to give the pure enantiomers.
  • a carbinol of Formula 202 is heated at 30 to 100°C (preferably about 60°C) with 2 to 6 molar equivalents (preferably 4 molar equivalents) of a chiral isocyanate in the presence of 1 to 1.5 molar equivalents (preferably 1.2 molar equivalents) of a strong organic base, for example
  • diastereoisomers are then separately cleaved by treatment with 1 to 1.5 molar equivalents (preferably 1.2 molar equivalents) of a trihalosilane, for example trichlorosilane, in the presence of an excess of a tertiary amine, for example triethylamine, in an inert solvent, for example toluene.
  • a trihalosilane for example trichlorosilane
  • a tertiary amine for example triethylamine
  • an inert solvent for example toluene.
  • the reaction takes place at a temperature of 90-120°C (preferably 110°C) over a period of 5 minutes to 2 hours (preferably 15 minutes) to give the corresponding enantiomer of the carbinol of Formula 202.
  • an alkyl ester of Formula 203 is formed by a Claisen ortho ester reaction of a carbinol of Formula 201 (or an enantiomer thereof) with an appropriately substituted orthoester.
  • a carbinol of Formula 202 is heated at 50 to 140°C (preferably 130°C) with a large excess of an orthoester of Formula 104a (see Reaction Scheme I, step 4), in the presence of from 0.05 to 0.25 molar equivalents
  • Step 1 an aldehyde of Formula 103 (prepared, for example as described above with reference to Reaction Scheme I, Steps 1 and 2) is transformed into an unsaturated aldehyde of Formula 302 by a Wittig reaction with an ylid of Formula 301 (where Z 5 is H or lower alkyl).
  • An aldehyde of Formula 103 is reacted with one molar equivalent of an ylid of Formula 301, in an organic solvent (such as dichloromethane, dimethylformamide or preferably toluene).
  • an organic solvent such as dichloromethane, dimethylformamide or preferably toluene.
  • the reaction takes place at 0 to 110°C (preferably 80°C) for 1 to 24 hours (preferably 8 hours) to give the corresponding unsaturated aldehyde of Formula 302.
  • an unsaturated aldehyde of Formula 302 is converted to the corresponding vinyl carbinol of Formula 303.
  • An aldehyde of Formula 302 is reacted with from 1.0 to 1.25
  • an organovinyl compound preferably vinylmagnesium bromide
  • a solvent such as ether or preferably
  • Step 3 a vinyl carbinol of Formula 303 is oxidized to give the corresponding dienone of Formula 304.
  • a vinyl carbinol of Formula 303 is reacted with 1.0 to 1.5
  • an oxidizing agent such as manganese dioxide, pyridinium chlorochromate or preferably pyridinium dichromate
  • a solvent such as pyridine or preferably dichloromethane
  • a dienone of Formula 304 is cyclized to give the corresponding cyclopentenone of Formula 305.
  • a dienone of Formula 304 reacted with 0.3 to 1.5 (preferably 1.0) molar equivalents of a Lewis acid (such as boron trichloride, tin (IV) chloride or preferably boron trifluoride etherate) in a solvent (such as tetrachloroethane or preferably dichloromethane).
  • a Lewis acid such as boron trichloride, tin (IV) chloride or preferably boron trifluoride etherate
  • a solvent such as tetrachloroethane or preferably dichloromethane
  • a cyclopentenone of Formula 305 is reacted with 1.0 to 1.5
  • a reducing agent such as lithium tri-tert-butoxyaluminium hydride or preferably sodium borohydride in the presence of an equimolar amount of cerium trichloride
  • cerium trichloride preferably tetrahydrofuran
  • Step 6 a cyclopentenol of Formula 306 is transformed to the corresponding vinyl ether of Formula 307.
  • a cyclopentenol of Formula 306 is reacted with from 10 to 100
  • a vinyl ether of Formula 307 is reacted with from 10 to 100
  • An acetaldehyde of Formula 308 is reacted with 1 to 3 (preferably 1.5) molar equivalents of a suitable oxidizing agent (such as silver oxide, Jones reagent or preferably sodium chlorite) in the presence of an oxidizing agent (such as silver oxide, Jones reagent or preferably sodium chlorite) in the presence of an oxidizing agent (such as silver oxide, Jones reagent or preferably sodium chlorite) in the presence of an oxidizing agent (such as silver oxide, Jones reagent or preferably sodium chlorite) in the presence of an oxidizing agent (such as silver oxide, Jones reagent or preferably sodium chlorite) in the presence of an oxidizing agent (such as silver oxide, Jones reagent or preferably sodium chlorite) in the presence of an oxidizing agent (such as silver oxide, Jones reagent or preferably sodium chlorite) in the presence of an oxidizing agent (such as silver oxide, Jones reagent or preferably sodium chlorite) in the presence of an oxidizing agent (
  • a phenol such as quinol or preferably resorcinol
  • the reaction is conducted in a mixture of water and a water-miscible organic solvent (such as tetrahydrofuran or preferably dioxane) at a pH of from 4 to 6 (preferably 5) at -10 to 25°C (preferably 0°C) for 10 minutes to 2 hours (preferably 30 minutes) to give the corresponding acid of
  • R a is a sulphonyloxy protecting group hydrolyzed under basic conditions, using from 1 to 5 (preferably 3) molar equivalents of an alkali metal hydroxide (preferably lithium hydroxide) in a mixture of water and a water-miscible organic solvent (such as dioxane or preferably methanol).
  • the reaction takes place at 40 to 100°C (preferably 60°C) for 1 to 48 hours (preferably 12 hours) to afford the corresponding cyclopentene carboxylic acid of Formula 1C.
  • an aldehyde of Formula 103 (where R a is a silyl protecting group) is converted to a carbinol by addition of an organometallic compound of Formula 103d (such as a
  • M is MgBr or Li
  • Z 2 is H or lower alkyl
  • TBS is a tert-butyldimethylsilyl protecting group
  • the aldehyde of Formula 103 is reacted with from 1.1 to 1.5
  • Formula 402 is formed by a Claisen ortho ester rearrangement reaction of a carbinol of Formula 401 and a trialkyl orthoacetate of Formula 104a.
  • a carbinol of Formula 401 is heated at 50 to 120°C (preferably about 100°C) with about 10 molar equivalents of an orthoester of Formula 104a, in the presence of from 0.05 to 0.25 (preferably 0.10) molar equivalents of an organic acid catalyst (such as propionic, butyric, or preferably
  • an alkyl ester of Formula 402 is reacted with a tetraalkylammonium fluoride and then halogenated to give a protected ester of Formula 403.
  • a compound of Formula 402 is reacted with from 2.0 to 3.0 (preferably 2.0) molar equivalents of a tetraalkylammonium (preferably
  • tetrabutylammonium fluoride in a solvent (such as dioxane,
  • a halogenating agent preferably a brominating agent, such as triphenylphosphine/carbon tetrabromide or preferably
  • triphenylphosphine/N-bromosuccinimide in a solvent such as ether or preferably dichloromethane.
  • the reaction takes place at from -40 to 0°C (preferably -10°C) for from 1 to 6 hours (preferably 4 hours) to give the corresponding halogenated ester of Formula 403.
  • a halogenated ester of Formula 403 is cyclized to give a cycloalkyl ester of Formula 1C.
  • a compound of Formula 403 is reacted with from 2.0 to 2.5 (preferably 2.25) molar equivalents of a strong base (such as lithium diisopropylamide, sodium hydride or preferably sodium hexamethyldisilazide) in an ethereal solvent (such as ether, dioxane or preferably tetrahydrofuran)
  • a strong base such as lithium diisopropylamide, sodium hydride or preferably sodium hexamethyldisilazide
  • an ethereal solvent such as ether, dioxane or preferably tetrahydrofuran
  • Step 1 the 2 -methyl group of an alkyl 2-methylbenzoate of Formula 501 (where Z 6 and Z 7 are selected from H, lower alkyl, lower alkoxy, lower alkoxycarbonyl, halo and nitro) is brominated to give the corresponding compound of Formula 502.
  • An ester of Formula 501 is reacted with 1.0 to 1.2 (preferably 1.05) molar equivalents of a brominating agent (such as N-bromoacetamide or preferably N-bromosuccinimide), optionally in the presence of an initiator (such as visible light) or from 0.001 to 0.01 (preferably 0.005) molar equivalents of a chemical initiator (such as azobisisobutyronitrile or preferably benzoyl peroxide) in a solvent (such as ethyl formate or preferably carbon tetrachloride).
  • a brominating agent such as N-bromoacetamide or preferably N-bromosuccinimide
  • an initiator such as visible light
  • a chemical initiator such as azobisisobutyronitrile or preferably benzoyl peroxide
  • solvent such as ethyl formate or preferably carbon tetrachloride
  • the reaction takes place at 40 to 80°C (preferably 75°C) for 30 minutes to to 6 hours (preferably 2 hours) to afford the corresponding alkyl 2-bromomethylbenzoate of Formula 502, which can be purified by conventional means or preferably used directly for the next step.
  • a 2-bromomethylbenzoate of Formula 502 is reacted with 1.0 to 1.25 (preferably 1.05) molar equivalents of a triaryl phosphine (preferably triphenyl phosphine) in a solvent (such as dimethylformamide or preferably acetonitrile).
  • a solvent such as dimethylformamide or preferably acetonitrile.
  • the reaction takes place at 25 to 90°C (preferably 50°C) for 1 to 24 hours (preferably 2 hours) to afford the corresponding phosphonium salt of Formula 503.
  • a phosphonium salt of Formula 503 is dissolved or suspended in a solvent (such as dioxane, ether or preferably dimethylformamide) and reacted with 1.0 to 1.25 (preferably 1.05) molar equivalents of a base (such as sodium hydride, triethylamine or preferably 1,5-diazabicyclo[4.3.0]non-5-ene).
  • a solvent such as dioxane, ether or preferably dimethylformamide
  • a base such as sodium hydride, triethylamine or preferably 1,5-diazabicyclo[4.3.0]non-5-ene.
  • the reaction takes place at 0 to 60°C (preferably 25°C) for 1 to 6 hours (preferably 2 hours) to afford the corresponding ylid of Formula 504, which can be isolated by conventional means or its solution can be used directly for the next step.
  • an ylid of Formula 504 and a protected aldehyde of Formula 103 are employed in a Wittig reaction to give the corresponding protected substituted benzoic acid alkyl ester of Formula 505 as a mixture of E and Z isomers, from which the desired E isomer of Formula 506 is isolated, as illustrated in Reaction Scheme XV, Step 5.
  • a solution of 0.8 to 1.0 (preferably 0.95) molar equivalents of a protected aldehyde of Formula 103 in a solvent (such as ether, dioxane or preferably dimethylformamide) is added to a solution of an ylid of Formula 504 in the same solvent.
  • the reaction takes place at 0 to 50°C (preferably 25°C) for 1 to 24 hours (preferably 12 hours) to afford the corresponding protected substituted benzoic acid alkyl ester of Formula 505 as a mixture of E and Z isomers, from which the desired E-isomer of Formula 506 can be isolated by conventional means (such as distillation, chromatography or preferably fractional crystallization).
  • Step 1 the alpha carbon of an alkyl 2-alkylbenzoate of Formula 507 (where Z 5 is H or lower alkyl, and Z 6 and Z 7 are selected from H, lower alkyl, lower alkoxy, lower
  • a compound of Formula 508 is reacted with from 5 to 20 (preferably 10) molar equivalents of a trialkyl phosphite (preferably triethyl phosphite). The reaction takes place at 100 to 200°C (preferably 150°C) for 1 to 24 hours (preferably 6 hours) to afford the corresponding phosphonate of Formula 509.
  • a trialkyl phosphite preferably triethyl phosphite
  • a phosphonate of Formula 509 is reacted with 1.0 to 1.5
  • a base such as sodium amide, potassium tert-butoxide or preferably sodium hydride
  • a solvent such as dioxane, dimethylformamide or preferably dimethoxyethane
  • the alkali metal salt is reacted with from 0.9 to 1.1 (preferably 1.0) molar equivalents of a protected aldehyde of Formula 103, dissolved in the same solvent.
  • the reaction takes place at 0 to 60°C (preferably 40°C) for 1 to 6 hours (preferably 2 hours) to afford the corresponding protected optionally substituted benzoic acid alkyl ester of Formula 510 as a mixture of E and Z isomers, from which the desired E-isomer of Formula 511 can be isolated by conventional means (such as distillation, chromatography or preferably fractional crystallization).
  • Step 1 a protected aldehyde of Formula 103 is converted to a trialkylsilylcarbinol of Formula 513 in a
  • a trialkylsilylalkyl-magnesium bromide such as trimethylsilylpropylmagnesium bromide, or preferably trimethylsilylmethylmagnesium bromide
  • an ethereal solvent such as ether, dimethoxyethane or preferably tetrahydrofuran
  • the reaction takes place at -40 to 40°C (preferably 0°C) for 30 minutes to
  • a carbinol of Formula 513 is reacted with from 1.0 to 1.5 (preferably 1.05) molar equivalents of a sulphonyl chloride (such as p-toluenesulphonyl chloride or preferably methanesulphonyl chloride) in the presence of the same molar proportion of a tertiary organic base (such as N-methylpyrrolidine or preferably triethylamine).
  • a sulphonyl chloride such as p-toluenesulphonyl chloride or preferably methanesulphonyl chloride
  • the reaction takes place at 0 to 40°C (preferably 15°C) for 30 minutes to 4 hours (preferably 2 hours) to afford the corresponding protected alkene of Formula 514 as a mixture of E and Z isomers, from which the desired Z-isomer of Formula 514 can be isolated by conventional means (such as distillation, chromatography or preferably fractional crystallization).
  • an alkene of Formula 514 where R" is a silyl protecting group is converted to an alkene of Formula 515 where R a is an acyl group.
  • An alkene of Formula 514 is heated at 50-130°C (preferably about 118°C) with a large excess of a mixture (preferably about equimolar) of a carboxylic acid of Formula ROH and an anhydride of Formula (R a ) 2 O (where R a is the desired acyl group), preferably a mixture of acetic acid and acetic anhydride.
  • the reaction takes place over a period of 6 to 48 hours
  • a protected alkene of Formula 515 is converted to a protected optionally substituted benzoic acid alkyl ester of Formula 511 in a Heck reaction with an alkyl-2-halo-benzoate of Formula 515.
  • An alkene of Formula 515 is reacted with 1.0 to 2.0 (preferably 1.25) molar equivalents of an alkyl 2-halobenzoate (such as an alkyl
  • the reaction is conducted in the presence of from 0.001 to 0.1 (preferably 0.05) molar equivalents of a palladium catalyst [such as tetrakis (tri-o-tolylphosphine) palladium, or tetrakis (triphenylphosphine)palladium or preferably palladium (II) acetate] optionally in the presence of from 1.0 to 1.25 (preferably 1.05) molar equivalents of a base (such silver carbonate, sodium bicarbonate or preferably triethylamine), in a solvent (such as acetonitrile or preferably dimethylformamide).
  • a palladium catalyst such as tetrakis (tri-o-tolylphosphine) palladium, or tetrakis (triphenylphosphine)palladium or preferably palladium (II) acetate
  • a base such silver carbonate, sodium bicarbonate or preferably triethylamine
  • solvent such as
  • the compounds of Formula 1E where Z 6 is nitro are employed as precursors to the corresponding compounds of Formula 1E where Z 6 is amino.
  • the nitro compounds are also active as IMPDH inhibitors when tested as described below.
  • a nitrobenzoic acid of Formula 1E (where Z 6 is nitro) is reacted with 1.0 to 3.0 (preferably 2.0) molar proportions of a reducing agent (such as sodium hydrosulfite or preferably tin (II) chloride) in hydrochloric acid solution, optionally in the presence of a water-miscible co-solvent (such as methanol or preferably acetic acid).
  • a reducing agent such as sodium hydrosulfite or preferably tin (II) chloride
  • hydrochloric acid solution optionally in the presence of a water-miscible co-solvent (such as methanol or preferably acetic acid).
  • a water-miscible co-solvent such as methanol or preferably acetic acid
  • Step 1 a phosphonate of Formula 509 undergoes a base catalyzed condensation (e.g., using 1 molar equivalent of sodium hydride) with tetrahydropyranyloxyacetaldehyde, in a solvent such as dimethylformamide.
  • the reaction takes place at 25°C over a period of 1 to 4 hours, to give E/Z mixture from which the desired product of Formula 517 can be isolated by conventional means, such as
  • tetrahydropyranyloxy group of a compound of Formula 517 is hydrolyzed in the presence of a catalytic amount of a dilute acid (e.g., HCl) in aqueous tetrahydrofuran.
  • a catalytic amount of a dilute acid e.g., HCl
  • the reaction takes place at 25°C over a period of 1 to 4 hours, to give the corresponding carbinol of Formula 518.
  • Step 3 a carbinol of Formula 518 is converted to the halo (e.g., chloro or bromo) derivative of Formula 519 using 1 molar equivalent of triphenylphosphine and either carbon tetrachloride or carbon tetrabromide, in dichloromethane.
  • the reaction takes place at 25°C over a period of 2 hours.
  • a halo derivative of Formula 519 undergoes a base-catalyzed ether formation with the indicated phenol, using 5 molar equivalents of potassium carbonate, in
  • an ether of Formula 520 is rearranged to give the corresponding ester of Formula IE by a thermal rearrangement catalysed by florisil.
  • the rearrangement takes place in toluene at 110°C over a period of one to four days.
  • Step 1 an aldehyde of Formula 601, prepared for example as shown in J. Org. Chem.. 1977, p3408, is reduced to a carbinol of Formula 602.
  • An aldehyde of Formula 601 is reacted with a reducing agent capable of selectively reducing an aldehyde in the presence of ester groups, preferably from 1 to 2 (preferably 1.5) molar equivalents of sodium borohydride in the presence of from 1 to 2 (preferably 1.5) molar
  • a carbinol of Formula 602 is reacted with an equimolar amount of a phenol of Formula 603 in the presence of from 1 to 3 (preferably 2) molar equivalents of a triarylphosphine, preferably triphenylphosphine, plus from 1 to 3 (preferably 1.5) molar equivalents of diethyl azodicarboxylate in an ethereal solvent (preferably tetrahydrofuran).
  • the reaction takes place at 0 to 40°C (preferably 25°C) for 1 to 10 hours (preferably 3 hours) to give the corresponding ether of Formula 604.
  • An ether of Formula 604 is heated in an inert solvent (preferably toluene) in the presence of about 10 parts by weight of an activated magnesium silicate, preferably Florisil ® .
  • the reaction takes place at reflux temperature for 1 to 10 days (preferably 4 days) to give the corresponding diester of Formula 605.
  • a diester of Formula 605 is reacted with an excess of an inorganic base, preferably about 50 molar equivalents of lithium hydroxide, in an aqueous solvent (preferably 5:1 methanol:water). The reaction takes place at 0 to 40°C (preferably 25°C) for 1 to 10 days (preferably 2 days) to give the corresponding dicarboxylic acid of Formula 606.
  • a dicarboxylic acid of Formula 606 is decarboxylated to give a monocarboxylic acid of Formula 1F.
  • a dicarboxylic acid of Formula 606 is heated (optionally in the presence of a high boiling inert solvent, for example tetramethylbenzene, but preferably in the absence of any solvent). The reaction takes place at 160 to 240°C (preferably 195°C) for about 5 minutes to give the
  • the phenol of Formula 701 is alkylated with 3-hydroxycyclohexene to give the corresponding ether of Formula 703, by means of the Mitsonobu reaction.
  • the Mitsonobu reaction takes place as described with reference to Reaction Scheme XIX, Step 2.
  • An alkylated phenol of Formula 704 is reacted with an equimolar amount of t-butyl dimethylsilyl chloride or p-toluenesulfonyl chloride, in the presence of an equimolar amount, respectively, of imidazole or 4-dimethylaminopyridine.
  • the reaction takes place in dichloromethane at a temperature of 25°C for 1 to 4 hours to give the corresponding protected phenol of Formula 705.
  • a protected phenol of Formula 705 is converted to the corresponding dialdehyde of Formula 706 by ozonolysis.
  • the ozonolysis reaction takes place as described with reference to Reaction Scheme I, Step 2.
  • an aldehyde of Formula 103 is converted to a carbinol by addition of an organometallic compound of Formula 103e (such as a substituted vinyl organolithium, or preferably a Grignard reagent, where M is MgBr; TBS is a tert-butyldimethylsilyl protecting group; and n is 3-5).
  • organometallic compound of Formula 103e such as a substituted vinyl organolithium, or preferably a Grignard reagent, where M is MgBr; TBS is a tert-butyldimethylsilyl protecting group; and n is 3-5).
  • a halovinyl (preferably bromovinyl) compound of Formula 103e (where M is halo) is reacted with magnesium metal in an ethereal solvent (such as ether or preferably tetrahydrofuran). The reaction takes place at 30 to
  • One molar equivalent of the resultant organometallic reagent is added to a solution of an aldehyde of Formula 103 (in the same solvent system used to make the organometallic reagent).
  • the reaction takes place at -80 to 20°C (preferably 0°C) over a period of 5 to 60 minutes (preferably 10 minutes) to give the corresponding silyl-protected carbinol of Formula 801.
  • Formula 802 is formed by a Claisen ortho ester rearrangement reaction of a carbinol of Formula 801 and an orthoester compound of Formula 104a (as illustrated in Reaction Scheme I, where Z 3 and Z 4 are H).
  • a silyl-protected carbinol of Formula 801 is heated at 50 to 120°C
  • a compound of Formula 803 is reacted with from 5 to 30 (preferably
  • a carbinol of Formula 803 is converted to a halide (preferably a bromide) of Formula 804, by means of a one-step or a two-step procedure.
  • a halide preferably a bromide
  • a carbinol of Formula 803 is reacted with from 1.0 to 1.3 (preferably 1.1) molar equivalents of a triaryl (preferably triphenyl) phosphine, and from 1.0 to 1.3 (preferably 1.1) molar
  • a halogen source such as N-bromosuccinimide or preferably carbon tetrabromide.
  • the reaction is conducted in an inert solvent (such as ether or preferably tetrahydrofuran). The reaction takes place at 0 to
  • a carbinol of Formula 803 is converted first into a sulphonate ester (such as a p-toluenesulphonate or preferably a methanesulphonate) by reaction with from 1.0 to 1.5 (preferably 1.3) molar equivalents a sulphonyl halide (preferably methanesulphonyl chloride) in the presence of an equimolar amount of a tertiary organic base (preferably diisopropylethylamine) in a solvent (such as chloroform or preferably dichloromethane).
  • a sulphonate ester such as a p-toluenesulphonate or preferably a methanesulphonate
  • a sulphonyl halide preferably methanesulphonyl chloride
  • a tertiary organic base preferably diisopropylethylamine
  • solvent such as chloroform or preferably dichloromethane
  • the so-obtained sulphonate ester is then reacted with from 5 to 20 (preferably 20) molar equivalents of an alkali metal halide (preferably lithium bromide) in a solvent (t-such as 2-butanone or preferably acetone).
  • a solvent such as 2-butanone or preferably acetone.
  • the reaction takes place at 0 to 56°C (preferably at reflux) for 30 to 180 minutes (preferably 90 minutes) to afford the corresponding halide of Formula 804.
  • a halogenated carbinol/alkyl ester of Formula 804 is deprotected at the phenolic group to give the corresponding halogenated carbinol/alkyl ester of Formula 805.
  • the deprotection reaction takes place as described above with reference to Reaction Scheme X, Step 1.
  • Step 6 a halogenated carbinol/alkyl ester of Formula 805 is subjected to a base-induced cyclization reaction to afford the product of Formula 1H.
  • a compound of Formula 805 is reacted with from 2.0 to 2.5 (preferably 2.3) molar equivalents of a strong base (such as lithium diisopropylamide, sodium hydride or preferably sodium hexamethyldisilazide) in a solvent (such as dioxane or preferably tetrahydrofuran).
  • a strong base such as lithium diisopropylamide, sodium hydride or preferably sodium hexamethyldisilazide
  • a solvent such as dioxane or preferably tetrahydrofuran
  • the cycloalkyl ester of Formula I-ZH-A1 may then be hydrolyzed to give the corresponding acid of Formula 1H.
  • the hydrolysis takes place as described above with reference to Reaction Scheme X, Step 2.
  • Formula 302 (where Z 5 is methyl) undergoes an aldol reaction with the bromo-alkyl oxazolidinone of Formula 806 (where q is 1 or 2), which can be prepared by analogy with the reactions described in J. Amer. Chem. Soc , 103, 2127 , 1981, to give the acyloxazolidinone of Formula 807.
  • An oxazolidinone of Formula 806 is reacted with an equimolar amount of a base (such as lithium diisopropylamide or preferably di-n-butylboryl trifluoromethane sulphonate/triethylamine), and then with an aldehyde of Formula 302.
  • a base such as lithium diisopropylamide or preferably di-n-butylboryl trifluoromethane sulphonate/triethylamine
  • an acyloxazolidinone of Formula 807 is hydrolyzed to the carboxylic acid of Formula 808.
  • An acyloxazolidinone of Formula 807 is reacted with 1-5 (preferably 3) molar equivalents of lithium hydroxide in 3 :1 tetrahydrofuran containing 5-20 (preferably 12) molar equivalents of hydrogen peroxide.
  • the reaction takes place at -10 to 25°C (preferably 0°) for 5 to 60 minutes (preferably 30 minutes) to give the corresponding carboxylic acid of Formula 808.
  • a phenol of Formula 809 is esterified to give the corresponding ester of Formula 810.
  • a phenol of Formula 809 is treated with methanol in the presence of 0.05 to 0.2 (preferably 0.1) molar equivalents of an acid catalyst
  • reaction takes place at 0 to
  • a methyl ester of Formula 810 undergoes an intramolecular cyclization reaction to give the corresponding cyclized ester of Formula 1H.
  • a methyl ester of Formula 810 is treated with 1.9 to 2.5 (preferably 2.0) molar equivalents of a strong base (such as lithium diisopropylamide or preferably sodium hydride) in tetrahydrofuran (or preferably
  • a strong base such as lithium diisopropylamide or preferably sodium hydride
  • reaction takes place at -10 to 25°C (preferably 0°) for 1-12 hours (preferably 2 hours) to give the corresponding cyclized ester of Formula IH, which may be hydrolyzed to give the corresponding acid of Formula IH, using the method described with respect to Reaction Scheme X, Step 2.
  • esters of Formula 1 can be prepared as described in U.S. Patents Nos. 4,727,069 and 4,753,935, incorporated herein by reference, by deprotection of a precursor (e.g., as described with reference to Reaction Scheme X, Steps 1) or as described below by attachment of a leaving group and its replacement by the desired ester.
  • the compound of Formula 1 may be prepared from the corresponding carboxylic acid by reaction with a large excess of an alcohol of the formula GH, where G is lower alkoxy, preferably methanol, with a catalytic amount of an acid catalyst, (such as methanesulfonic acid, sulfuric acid, hydrochloric acid and p-toluenesulfonic acid), preferably p-toluenesulfonic acid).
  • an acid catalyst such as methanesulfonic acid, sulfuric acid, hydrochloric acid and p-toluenesulfonic acid
  • the reaction is carried out in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 1 to 7 days, preferably about 24 hours.
  • the lower alkyl ester of Formula 1 is isolated and purified by conventional means.
  • a compound of Formula l is reacted in an organic solvent, preferably dichloromethane, with about 1 to 3 molar equivalents, preferably about 2 molar equivalents, of a base, preferably pyridine, and with a slight excess, preferably about 1.1 molar equivalents, of a sulfonic anhydride, (such as a halo lower alkyl sulfonic anhydride, halomethyl sulfonic anhydride, and halosulfonic anhydride, or preferably trifluoromethane- sulfonic anhydride or fluorosulfonic anhydride) or a sulfonyl halide, (such as trifluoromethylsulfonyl bromide, preferably trifluoromethylsulfonyl chloride).
  • a sulfonic anhydride such as a halo lower alkyl sulfonic anhydride, halomethyl sulfonic anhydride, and halos
  • the reaction is carried out in an inert solvent, preferably dichloromethane, in the temperature range from about -20°C to 20°C, preferably at about 0°C, for about 15 to 45 minutes, preferably about 30 minutes.
  • an inert solvent preferably dichloromethane
  • the trifluoromethylsulfonyl reaction product, a compound of Formula 2 is isolated and purified by conventional means.
  • a compound of Formula 2 is reacted with about 1 to 3 molar
  • Step 3 the cyano compound of Formula 3 is hydrolyzed to the carboxy compound of Formula 4.
  • a compound of Formula 3 is hydrolyzed by reacting it with about 1 to 10 molar equivalents, preferably about 4 molar equivalents, of an inorganic base (e.g., sodium hydroxide, lithium hydroxide, or potassium hydroxide, preferably sodium hydroxide,) in a large excess of organic solvent, preferably in about 3:2 water-.methanol solution.
  • the reaction is carried out in the temperature range from about 40°C to 130°C, preferably at about the reflux temperature of the 3:2 water/methanol solvent, for about 1 to 3 hours, preferably about 2 hours.
  • the reaction solution is distilled, and an additional of about 1 to 1.6 molar equivalents, preferably about 1.3 molar equivalents, of an inorganic base (e.g., sodium hydroxide, lithium hydroxide, or potassium hydroxide, preferably sodium hydroxide,) is added and the reaction is continued in the temperature range from about 40°C to 130°C, preferably at about the reflux temperature of the remaining solution, for about 1 to 3 days, preferably about 2 days.
  • an inorganic base e.g., sodium hydroxide, lithium hydroxide, or potassium hydroxide, preferably sodium hydroxide,
  • the reaction product, a compound of Formula 4 is isolated and purified by conventional means.
  • the compound of Formula 4 may be prepared by reacting a corresponding compound of Formula 2 with a catalytic amount of 1,1'-bis (diphenylphosphine)ferrocene palladium dichloride in a large excess of an alkanol (preferably methanol) in an organic solvent (preferably
  • reaction product which is a diester of a compound of Formula 4 is then hydrolyzed by reacting it with about 1 to 10 molar equivalents, preferably about 4 molar equivalents, of an inorganic base, preferably aqueous lithium hydroxide, in a large excess of an organic solvent, preferably 4:1 methanol/water solution.
  • the solution is heated to a temperature range from about 30°C to 80°C, preferably from about 50°C to 60°C, for about 1 to 10 hours, preferably for about 2 to 6 hours.
  • the reaction product, a compound of Formula 4 is isolated and purified by conventional means.
  • a carboxy derivative of Formula 4 is converted to the ester of Formula 5.
  • the compound of Formula 4 is reacted in a large excess of a compound of the formula GH, where G is lower alkoxy, preferably methanol, with catalytic amounts of an acid catalyst, preferably p-toluenesulfonic acid.
  • the reaction is carried out in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 4 hours to 3 days, preferably about 24 hours.
  • the reaction product, a 4 -carboxy derivative of Formula 5 is isolated and purified by conventional means.
  • a compound of Formula 5 is reacted with about 1 to 3 molar
  • an organic base preferably triethylamine
  • an organic solvent preferably dimethylformamide
  • chlorophosphate in the temperature range from about -20°C to 20°C, preferably at about 0°C, allowing it to warm to the temperature range from about 0°C to 40°C, preferably at about 20°C, allowing the reaction to proceed for about 0.5 to 2 hours, preferably about 1 hour.
  • the reaction mixture is recooled to the temperature range from about -20°C to 20°C, preferably at about 0°C, and a large excess of sodium azide is added and the reaction proceeds for about 10 to 30 hours, preferably about 18 hours.
  • the isocyanato reaction product, a compound of Formula 6, is isolated and purified by conventional means.
  • a compound of Formula 5 is reacted with about 1 to 3 molar equivalents, preferably about 2 molar equivalents, of an organic base, preferably triethylamine, in a large excess of an organic solvent, preferably dimethylformamide, and with a slight excess, preferably 1.2 molar equivalents, of a diphenyl or dialkyl phosphoroazide, preferably diphenyl phosphoroazide, in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 12 to 36 hours, preferably for about 24 hours.
  • the isocyanato reaction product, a compound of Formula 6, is isolated and purified by conventional means.
  • Z a represents a sidechain of Formula Z as defined in the Summary of the
  • Z a and Z b are as defined above.
  • a compound of Formula 6 is hydrolyzed with about 1 to 20 molar equivalents, preferably 10 molar equivalents, of an inorganic base, preferably lithium hydroxide monohydrate, in an inert organic solvent, preferably 3:10 water: 1,4-dioxane.
  • the reaction is carried out in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 1 to 3 hours, preferably about 2 hours.
  • the reaction product, a 4-amino compound of Formula IA where Z is Z b is isolated and purified by conventional means, preferably column chromatography.
  • a compound of Formula IA is esterified with a lower alkanol of formula GH, where G is lower alkoxy, as described in the preparation of a compound of Formula I as an ester.
  • a compound of Formula 6 is reacted with a large excess of an amine compound of the formula HNR 4 R 5 , where R 4 and R 5 are as defined in the Summary of Invention, for example, methylamine, dimethylamine, methylphenylamine, ammonia, and the like, in an inert organic solvent, preferably
  • reaction is carried out in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 30 minutes to 2 hours, preferably about 1 hour.
  • the reaction product, a 4-(optionally substituted ureido) ester of Formula 1B is isolated and purified by conventional means.
  • An ester of Formula IB is hydrolyzed by reacting with about 1 to 10 molar equivalents, preferably about 4 molar equivalents of an inorganic base, preferably aqueous lithium hydroxide, in a large excess of an organic solvent, preferably 4:1 methanol/water.
  • the solution is heated to a temperature range from about 30°C to 80°C, preferably from about 50°C to 60°C, for about 1 to 10 hours, preferably for about 2 to 6 hours.
  • the reaction product, a 4-(optionally substituted ureido) acid compound of Formula IB is isolated and purified by conventional means.
  • a compound of Formula IA is reacted in a large excess of an inert organic solvent, preferably dichloromethane, with about 1 to 6 molar equivalents, preferably about 2.5 molar equivalents, of an anhydride compound of the formula (R 3 C(O)) 2 O or of a acyl chloride of the formula R 3 C(O)Cl, where R 3 is as defined in the Summary of the Invention.
  • the reaction is carried out in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 30 minutes to 2 hours, preferably about 1 hour.
  • the reaction product, a carbamate ester of Formula IC is isolated and purified by conventional means, preferably by recrystallization.
  • a compound of Formula IC as an ester is hydrolyzed as described in the preparation of a compound of Formula 1B to give the corresponding compound of Formula IC as a carboxylic acid.
  • a compound of Formula IC is reacted with about 1 to 10 molar equivalents, preferably about 4.5 molar equivalents, of a weak base, preferably potassium carbonate, and with about 1 to 10 molar equivalents, preferably about 4 molar equivalents, of a lower alkyl bromide or iodide, preferably an iodide, in an inert organic solvent, preferably
  • the reaction is carried out in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 12 to 48 hours, preferably about 24 hours.
  • the organic layer is purified to give a carbamate ester of Formula ID where R 1 is lower alkyl and G is lower alkoxy.
  • a carbamate ester of Formula ID where R 1 is lower alkyl is hydrolyzed as described in the preparation of a compound of Formula IB to give the corresponding carboxylic acid of Formula ID where R 1 is lower alkyl.
  • An amido ester of Formula ID is hydrolyzed by reacting with about 1 to 10 molar equivalents, preferably about 4 molar equivalents of an inorganic base (for example sodium hydroxide, preferably lithium
  • the reaction takes place with (a) a reaction time of 20 to 120 hours, preferably 50 to 100 hours and most preferably 100 hours and (b) an initial pot temperature range of 114 to 120°C increasing to a final pot temperature range of 118 to 130°C, preferably an initial pot temperature range of 115 to 118°C increasing to a final pot temperature range of 118 to 125°C, each depending on solute concentration and atmospheric pressure, and most preferably an initial pot temperature of 116°C increasing to a final pot temperature of 121°C with a ratio of the acid compound of Formula I (where G is hydroxy) to toluene of lgm:2ml at one atmosphere of pressure.
  • Some of the compounds of Formula I may be converted to corresponding base addition salts by virtue of the presence of a carboxylic acid group.
  • the conversion is accomplished by treatment with a stoichiometric amount of an appropriate base, such as potassium carbonate, sodium bicarbonate, ammonia, ethylenediamine, monoethanolamine, diethanolamine, triethanolamine and the like.
  • an appropriate base such as potassium carbonate, sodium bicarbonate, ammonia, ethylenediamine, monoethanolamine, diethanolamine, triethanolamine and the like.
  • the free acid is dissolved in a polar organic solvent such as ethanol, methanol or ethyl acetate, and the base added in water, ethanol, methanol or isopropanol.
  • the temperature is maintained at about 0°C to 50°C.
  • the resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent.
  • the base addition salts of the compounds of Formula I may be decomposed to the corresponding free acids by treating with at least a stoichiometric amount of a suitable acid, such as hydrochloric acid or sulfuric acid, typically in the presence of aqueous solvent, and at a temperature of between about 0°C and 50°C.
  • a suitable acid such as hydrochloric acid or sulfuric acid
  • the free acid form is isolated by conventional means, such as extraction with an organic solvent.
  • some of the compounds of Formula I may be converted to the acid addition salts by the substitution of an organic or inorganic acid for the base in the above procedure.
  • the acid salts can be decomposed to the corresponding free bases by similar treatment with an appropriate base.
  • R 1 is hydrogen or lower alkyl
  • R 2 is hydrogen, lower alkyl, -C(O)R 3 , -C(O)NR 4 R 5 , -CO 2 R 6 , or -SO 2 R 3
  • R 3 is hydrogen, lower alkyl, halo lower alkyl or optionally substituted phenyl
  • R 4 is hydrogen, lower alkyl or optionally substituted phenyl
  • R 5 is hydrogen, lower alkyl or optionally substituted phenyl
  • R 6 is lower alkyl or optionally substituted phenyl
  • Z is a side chain selected from Formulae ZA, ZB, ZC, ZD, ZE, ZF, ZG, and ZH:
  • Z 1 is H, lower alkyl, halo or CF 3 ;
  • Z 2 is H, lower alkyl, lower alkoxy, aryl, or -CH 2 Z 13 , where
  • Z 13 is aryl or heteroaryl
  • Z 3 is H, lower alkyl, lower alkenyl, lower alkoxy, phenyl,
  • Z 12 is lower alkyl
  • n 0, 1 or 2;
  • Z 4 is H, lower alkyl, or phenyl,
  • n is an integer from 1 to 6
  • G 1 is H or lower alkyl
  • G 2 is H or lower alkyl
  • G 3 is lower alkylene of four to six carbon atoms, or lower alkylene of three to five carbon atoms plus one member that is -O-, -S-, or -N(G 4 )- where G 4 is H or lower alkyl;
  • Z 5 is H or lower alkyl
  • Z 8 is H or lower alkyl
  • D 1 and D 2 together with their adjacent carbon atoms form an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring of 3 to 7 atoms;
  • G is as defined above;
  • Z 5 , Z 8 , and G are as defined above; or
  • D 3 is -CH 2 - or -CHjCHz-; and G is as defined above; or
  • Z 6 is H, lower alkyl, lower alkoxy, -COOH, -NH 2 or halo;
  • Z 7 is H, lower alkyl, lower alkoxy or halo
  • D 4 is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - , -O-, or -OCH 2 -;
  • R 2 is -C(O)R 3 wherein R 3 is lower alkyl, halo lower alkyl or optionally substituted phenyl; or
  • R 2 is -C(O)R 3 , where R 3 is lower alkyl, halo lower alkyl or optionally substituted phenyl, and G is lower alkoxy, with a compound of the formula R 1 X, where R 1 is lower alkyl and X is iodine or bromine, to form a compound of Formula I wherein R 1 is lower alkyl; or
  • one preferred category includes the compounds where Z is a sidechain of Formula ZA.
  • a preferred group includes the compounds where Z 1 is hydrogen, especially where R 1 is hydrogen and R 2 is hydrogen or -C(O)R 3 .
  • a preferred subgroup includes the compounds where R 2 , Z 2 and Z 3 are all hydrogen, especially where Z 4 is methyl.
  • Another preferred subgroup includes the compounds where R 2 , Z 3 and Z 3 are all hydrogen, especially where Z 2 is methyl.
  • Another preferred category includes the compounds where Z is a sidechain of Formula ZB, especially where R 1 is hydrogen and R 2 is hydrogen or -C(O)R 3 .
  • a preferred group includes the compounds where D 1 and D 2 together with the their adjacent carbon atoms form a saturated carbocyclic ring of 5 or 6 carbon atoms.
  • a preferred subgroup includes the compounds where D 1 and D 2 together represent -CH 2 CH 2 CH 2 -, especially where Z 5 and Z 8 are both hydrogen.
  • a preferred class within this subgroup includes the compounds in which R 1 and R 2 are both hydrogen.
  • Another preferred subgroup includes the compounds where D 1 and D 2 together represent -CH 2 -CH 2 CH 2 CH 2 -, especially where Z 5 and Z 8 are both hydrogen.
  • a preferred class within this subgroup includes the compounds in which R 1 and R 2 are both hydrogen.
  • Yet another preferred subgroup includes the compounds where D 1 and D 2 together represent -CH 2 CH 2 OCH 2 -, especially where Z 5 and Z 8 are both
  • a preferred class within this subgroup includes the compounds in which R 1 and R 2 are both hydrogen.
  • the compounds are useful as immunosuppressive agents, anti-inflammatory agents, anti-tumor agents, anti-proliferative agents, anti-viral agents and anti-psoriatic agents in mammals, whether domestic (cattle, pigs, sheep, goats, horses), pets (cats, dogs), or preferably humans.
  • the compounds are inhibitors of inosine monophosphate dehydrogenase (IMPDH) and thus inhibit de novo purine synthesis; they have anti-proliferative effects (e.g., against smooth muscle cells and both B and T lymphocytes) and inhibit antibody formation and the glycosylation of cell adhesion molecules in lymphocytes and endothelial cells.
  • IMPDH inosine monophosphate dehydrogenase
  • the compounds are useful in treating auto-immune related disorders, for example: Type I Diabetes Mellitus;
  • Inflammatory Bowel Disease e.g., Crohn's Disease and ⁇ lcerative Colitis
  • Systemic Lupus Erythematosus Chronic Active Hepatitis; Multiple Sclerosis
  • Grave 's Disease Hashimoto's Thyroiditis
  • Behcet's Syndrome Myasthenia Gravis
  • Sjogren's Syndrome Pernicious Anemia
  • the compounds are also useful as therapeutic immunosuppressive agents in the treatment of Asthma, Immunohemolytic Anemia, Glomerulonephritis, and Hepatitis.
  • Preventative uses of the compounds as immunosuppressive agents include the treatment of allograft rejection, for example, in cardiac, lung, pancreatic, renal, liver, skin and corneal allografts, and prevention of Graft vs. Host Disease.
  • the compounds are useful for inhibiting proliferative responses to vascular injury, for example, stenosis following an insult to a blood vessel wall in post-angioplasty restenosis, and post-cardiac by-pass surgery restenosis.
  • the compounds are useful as anti-inflammatory agents, for example, in treating Rheumatoid Arthritis, Juvenile Rheumatoid Arthritis and Uveitis.
  • the compounds are useful in treating solid tumors and malignancies of lymphoreticular origin.
  • the compounds' utility for treatment of solid tumors includes: cancers of the head and neck, including squamous cell carcinoma; lung cancer, including small cell and non-small cell lung carcinoma; mediastinal tumors;
  • esophageal cancer including squamous cell carcinoma and adenocarcinoma; pancreatic cancer; cancer of the hepatobiliary system, including
  • hepatocellular carcinoma including cholangiocarcinoma, gall bladder carcinoma and biliary tract carcinoma; small intestinal carcinoma, including
  • adenocarcinoma adenocarcinoma, sarcoma, lymphoma and carcinoids
  • colorectal cancer including colon carcinoma and rectal carcinoma
  • metastatic carcinoma adenocarcinoma, sarcoma, lymphoma and carcinoids
  • cancers of the genitourinary system including ovarian cancer, uterine sarcoma, and renal cell, ureteral, bladder, prostate, urethral, penile, testicular, vulvar, vaginal, cervical, endometrial, and fallopian tube carcinoma; breast cancer; endocrine system cancer; soft tissue sarcomas; malignant mesotheliomas; skin cancer, including squamous cell carcinoma, basal cell carcinoma and melanoma; cancer of the central nervous system; malignant bone tumors; and plasma cell neoplasms.
  • lymphoreticular origin the compounds are useful in treating, for example: Lymphomas and Leukemias, including B, T and promonocyte cell line
  • Chronic Lymphocytic Leukemia Acute Lymphocytic Leukemia and Hairy Cell Leukemia.
  • the compounds are useful in treating, for example: retroviruses, including Human T-leukemia Viruses, Types I and II (HTLV-1 and HTLV-2) , Human Immuno Deficiency Viruses, Types I and II
  • Herpes Viruses including EBV infected B-lymphocytes, CMV infection, Herpes Virus Type 6, Herpes Simplex, Types 1 and 2, (HSV-1, HSV-2) and Herpes Zoster.
  • the compounds are useful in treating, for example, psoriasis and psoriatic arthritis.
  • IMPDH Inosine 5'-Monophosphate Dehydrogenase
  • Initial animal screening tests to determine anti-inflammatory activity potential include the adjuvant arthritis assay, e.g., according to the method of Pearson, Proc Soc Exp. Biol . Med. , 91:95-101 (1956). Also, in vitro tests, for example those using synovial explants from patients with rheumatoid arthritis, Dayer, et al., J. Exp. Med. , 145:1399-1404 (1977), are useful in determining whether compounds exhibit anti- inflammatory activity.
  • Autoimmune activity is determined, for example, utilizing
  • host disease are conducted, e.g., as described by Storb, Deeg, Whitehead, et al., "Methotrexate and cyclosporin compared with cyclosporin alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia.” New England J. Med. , 314:729-735 (1986).
  • Immunosuppressive activity is determined by both in vivo and in vitro procedures.
  • In vivo activity is determined, e.g., utilizing a modification of the Jerne hemolytic plaque assay, [Jerne, et al., "The agar plaque technique for recognizing antibody producing cells,” Cell -bound Antibodies, Amos, B. and Kaprowski, H. editors (Wistar Institute Press, Philadelphia) 1963, p. 109].
  • In vitro activity is determined, e.g., by an adaptation of the procedure described by Greaves, et al., "Activation of human T and B lymphocytes by polyclonal mitogens," Nature, 248:698-701 (1974).
  • Anti-viral activity is determined, for example, by the procedure described by Smee, et al. ["Anti-Herpesvirus Activity of the Acyclic
  • Anti-viral activity can likewise be determined by measurement of reverse transcriptase activity, for example, according to the method described by Chen et al., Biochem. Pharm. , 36:4361 (1987).
  • a large scale clinical trial can be conducted, e.g., as described by Volberding, P.A., et al. "Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD4 positive cells per cubic millimeter, " New England J. Med., 322(14):941-949 (1990).
  • a smaller scale (Phase I) clinical trial can be conducted, e.g., as described by Browne, et al., "2 ',3'-Didehydro-3'-deoxythymidine (d4T) in Patients with AIDS or AIDS-Related Complex:
  • Tests for systemic activity in psoriasis can be carried out, for example, as described by Spatz, et al., "Mycophenolic acid in psoriasis," Bri tish Journal of Dermatology, 98:429 (1978).
  • Tests for anti-tumor activity can be performed, for example, as described by Carter, et al. ["Mycophenolic acid: an anticancer compound with unusual properties,” Nature, 223:848 (1969)].
  • In vitro activity for treating stenosis is demonstrated, for example, by inhibiting the proliferation of smooth muscle cells, as established by the following human arterial smooth muscle cell proliferation assay.
  • Human smooth muscle cells are grown in culture.
  • a test group is treated with the test compound added at selected concentrations in fresh media. Both groups receive 2 ⁇ Ci tritiated thymidine ( 3 HTdR), a radioisotope label.
  • 3 HTdR 2 ⁇ Ci tritiated thymidine
  • the cells are harvested and the amount of label incorporated into DNA is counted by scintillation; this is compared for the test and control groups, the amount being proportional to cell proliferation.
  • Inhibition of smooth muscle proliferation is established when the test group has a lower radioisotope count than the control group.
  • the concentrations of test compound required to inhibit proliferation by 50% (the IC 50 ), and to inhibit proliferation by more than 95% are determined.
  • In vivo activity for treating stenosis is demonstrated, for example, in rat and pig models for arterial stenosis.
  • a test group is treated with the test compound, starting 6 days before and continuing for 14 days after injury to the left carotid artery; the test group is compared to a control group receiving vehicle without the test compound.
  • Injury is achieved by a gentle perfusion of air through a 10 mm long section of the left artery. The right artery is left intact.
  • Arterial cross-sections (10 ⁇ m) are taken from both the left and right arteries of each subject, and the area of the vessel wall (endothelium, intima, media) is measured, The amount of vascular proliferation is calculated by subtracting the mean area of the intact, right carotid artery from the mean area of the injured, left carotid artery. Reduction in vascular proliferation is established when the test group shows less proliferation than the control group.
  • the compounds of Formula I are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease states previously described.
  • Administration of the compounds of the invention or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities.
  • the compounds can be used both prophylactically (e.g., to prevent allograft rejection) and therapeutically.
  • a daily dose is from about 0.01 to 100.0 mg/kg of body weight, preferably about 0.1 to 64.3 mg/kg of body weight, and most preferably about 0.3 to 43.0 mg/kg of body weight.
  • the dosage range would be about 0.7 mg to 7 g per day, preferably about 7.0 mg to 4.5 g per day, and most preferably about 21 mg to 3.0 g per day.
  • the amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration (e.g., oral administration one day prior to cancer
  • any pharmaceutically acceptable mode of administration can be used.
  • the compounds of Formula I can be administered either alone or in combination with other pharmaceutically acceptable excipients, including solid, semi-solid, liquid or aerosol dosage forms, such as, for example, tablets, capsules, powders, liquids, injectables, suspensions, suppositories, aerosols or the like.
  • the compounds of Formula I can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for the prolonged administration of the compound at a predetermined rate, preferably in unit dosage forms suitable for single administration of precise dosages.
  • compositions will typically include a conventional pharmaceutical carrier or excipient and a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • these compositions may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc., such as multidrug resistance modifying agents, steroids, immunosuppressants such as
  • cyclosporine A azathioprene, rapamycin, FK-506, brequinar, leflunomide and vincrystine.
  • the pharmaceutically acceptable composition will contain about 0.1% to 90%, preferably about 0.5% to 50%, by weight of a compound or salt of Formula I, the remainder being suitable pharmaceutical excipients, carriers, etc.
  • One preferred manner of administration for the conditions detailed above is oral, using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
  • oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
  • a pharmaceutically acceptable composition is formed by the incorporation of any of the normally employed excipients, such as, for example, mannitol, lactose, starch, povidone, magnesium stearate, sodium saccharine, talcum, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate, and the like.
  • excipients such as, for example, mannitol, lactose, starch, povidone, magnesium stearate, sodium saccharine, talcum, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate, and the like.
  • Such compositions take the form of solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations and the like.
  • compositions will take the form of a pill or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; a disintegrant such as croscarmellose sodium or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose and derivatives thereof, and the like.
  • a diluent such as lactose, sucrose, dicalcium phosphate, or the like
  • a lubricant such as magnesium stearate or the like
  • a disintegrant such as croscarmellose sodium or the like
  • binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose and derivatives thereof, and the like.
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension.
  • a carrier such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like
  • the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, suspending agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, sodium acetate, sodium citrate, cyclodextrine derivatives, polyoxyethylene, sorbitan monolaurate or stearate, etc.
  • composition or formulation to be administered will, in any event, contain a quantity of the active compound in an amount effective to alleviate the symptoms of the subject being treated.
  • Dosage forms or compositions containing active ingredient in the range of 0.005% to 95% with the balance made up from pharmaceutically acceptable carrier may be prepared.
  • a pharmaceutically acceptable composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, povidone, cellulose derivatives, croscarmellose sodium, glucose, sucrose, magnesium carbonate, sodium saccharin, talcum and the like.
  • excipients such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, povidone, cellulose derivatives, croscarmellose sodium, glucose, sucrose, magnesium carbonate, sodium saccharin, talcum and the like.
  • Such compositions take the form of solutions, suspensions, tablets, capsules, powders, sustained release formulations and the like.
  • Such compositions may contain 0.01%-95% active ingredient, preferably 0.1-50%.
  • triglycerides is preferably encapsulated in a gelatin capsule.
  • ester solutions and the preparation and encapsulation thereof, are disclosed in U.S. Patents Nos. 4,328,245; 4,409,239; and 4,410,545.
  • the solution e.g. in a polyethylene glycol
  • a pharmaceutically acceptable liquid carrier e.g. water
  • liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g. propylene carbonate) and the like, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
  • Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously.
  • injectables can be prepared in conventional forms, either as liquid solutions or
  • compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, solubility enhancers, and the like, such as for example, sodium acetate, polyoxyethylene, sorbitan monolaurate, triethanolamine oleate, cyclodextrins, etc.
  • non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, solubility enhancers, and the like, such as for example, sodium acetate, polyoxyethylene, sorbitan monolaurate, triethanolamine oleate, cyclodextrins, etc.
  • a more recently devised approach for parenteral administration employs the implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained. See, e.g., U.S. Patent No. 3,710,795.
  • composition will comprise 0.2-2% of the active agent in solution.
  • Formulations of the active compound or a salt may also be
  • the particles of the formulation have diameters of less than 50 microns, preferably less than 10 microns.
  • R 1 is Methyl.
  • R 3 is -CF 3
  • Z is ZA, in which Z 1 is Methyl.
  • Z 2 , Z 3 , and Z 4 are Hydrogen, and G is Methoxy

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Abstract

The disclosed derivatives of mycophenolic acid of formula (IE) are therapeutic agens advantageous in the treatment of disease states indicated for mycophenolic acid and/or mycophenolate mofetil and other immunosuppressant agents. In said formula, Z is a side chain selected from formulae (ZA, ZB, ZC, ZD, ZE, ZF, ZG, and ZH).

Description

4-AMINO DERIVATIVES OP 5 -SUBSTITUTED MYCOPHENOLIC ACID Field of the Invention
The present invention relates to mycophenolic acid derivatives in which the 4-hydroxy group has been replaced by amino substituents. The invention includes natural and derivative side chains at the 5 -position. The invention is also directed to formulations and methods for treatment. Background Information and Related Disclosures
Mycophenolic acid ("MPA") is a weakly active antibiotic found in the fermentation broth of Penicillium brevicompactum, having the following structure.
Figure imgf000003_0002
MPA and certain related compounds, such as mycophenolate mofetil (the morpholinoethyl ester of MPA), having the following structure:
Figure imgf000003_0001
have more recently been described as having particularly advantageous properties as immunosuppressant drugs.
Various derivatives of mycophenolic acid, their synthesis and uses in the treatment of autoimmune disorders, psoriasis, inflammatory diseases, including, in particular, rheumatoid arthritis, tumors, viruses, and for treatment of allograft rejection, are described in U.S. Patents Nos.
4,686,234; 4,725,622; 4,727,069; 4,748,173; 4,753,935; 4,786,637;
4,808,592; 4,861,776; 4,868,153; 4,948,793; 4,952,579; 4,959,387;
4,992,467; 5,247,083; and U.S. Patent Application Serial No. 07/927,260, filed August 7, 1992.
As immunosuppressive agents, the previously described esters and derivatives of mycophenolic acid are useful in treating auto-immune related disorders, glomerulonephritis and hepatitis, and in preventing allograft rejection. As anti-inflammatory agents, they are useful in treating rheumatoid arthritis. As anti-tumor agents, they are useful in treating solid tumors and malignancies of lymphoreticular origins.
See also U.S. Patents No. 3,825,571 and 3,853,919; Japanese Pat. No. J 01290667; J. Wed. Chem., 33(2), 833-8 (1990); Austr. J. Chem. , 31(2), 353-64, (1978); and J. Antibiot., 29(3), 275-85, 286-91 (1976). The disclosed compounds are described as having anti-tumor, immunosuppressive, anti-viral, anti-arthritic and/or anti-psoriatic activities. The article by J.W. Patterson and G. Huang, Chemical Communications, 1579 (1991) describes synthetic methodology of interest with respect to such compounds.
The above-cited patents, publications, and the references/
publications referenced therein, are all incorporated herein by reference.
SUMMARY OF THE INVENTION
Derivatives of mycophenolic acid and their esters and the
pharmaceutically acceptable salts thereof, i.e. the compounds of Formula I:
wherein:
Figure imgf000004_0001
R1 is hydrogen or lower alkyl;
R2 is hydrogen, lower alkyl, -C(O)R3, -C(O)NR4R5, -CO2R6, or -SO2R3
where:
R3 is hydrogen, lower alkyl, halo lower alkyl or optionally
substituted phenyl;
R4 is hydrogen, lower alkyl or optionally substituted phenyl;
R5 is hydrogen, lower alkyl or optionally substituted phenyl;
R6 is lower alkyl or optionally substituted phenyl; and
Z is a side chain selected from Formulae ZA, ZB, ZC, ZD, ZE, ZF, ZG, and ZH:
Figure imgf000004_0002
wherein:
Z1 is H, lower alkyl, halo or CF3;
Z2 is H, lower alkyl, lower alkoxy, aryl, or -CH2Z13, where
Z13 is aryl or heteroaryl;
Z3 is H, lower alkyl, lower alkenyl, lower alkoxy, phenyl, - P(O) (OCH3)2, -P(O) (OH) (OCH3), or -S(O)mZ12, where
Z12 is lower alkyl, and
m is 0, 1 or 2;
Z4 is H, lower alkyl, or phenyl,
or Z3 and Z4 taken together with the carbon to which they are attached form cycloalkyl of three to five carbon atoms; and
G is OH, lower alkoxy, lower thioalkyl, -NG1G2, -O(CH2)nNG1G2, or - O(CH2)nN=G3, where
n is an integer from 1 to 6,
G1 is H or lower alkyl,
G2 is H or lower alkyl, and
=G3 is lower alkylene of four to six carbon atoms, or lower alkylene of three to five carbon atoms plus one member that is -O-, -S-, or -N(G4)- where G4 is H or lower alkyl;
provided that when Z1 is methyl, Z2, Z3 and Z4 are not all H; or
wherein:
Figure imgf000005_0001
Z5 is H or lower alkyl;
Z8 is H or lower alkyl;
D1 and D2 together with their adjacent carbon atoms form an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring of 3 to 7 atoms; and
G is as defined above; or
Figure imgf000005_0002
wherein :
Z5, Z8, and G are as defined above; or
Figure imgf000005_0003
wherein :
D3 is -CH2- or -CH2CH2-; and
G is as defined above; or
Figure imgf000006_0001
wherein:
Z6 is H, lower alkyl , lower alkoxy, -COOH, -NH2 or halo;
Z7 is H, lower alkyl , lower alkoxy or halo; and
Z5 and G are as defined above ; or
Figure imgf000006_0002
wherein:
Z1 and G are as defined above; or
Figure imgf000006_0003
wherein:
D3, Z2, Z3, Z4 and G are as defined above; or
Figure imgf000006_0004
wherein:
D4 is -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-, or -OCH2- ; and
Z1 and G are as defined above;
and the pharmaceutically acceptable salts thereof.
In still another aspect, the invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of Formula I admixed with at least one pharmaceutically acceptable excipient. In still another aspect, the invention relates to a method of treating immune, inflammatory, tumor, proliferative, viral and psoriatic disorders in a mammal by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
Definitions and General Parameters
The following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
As used herein, the term "alkyl" refers to a fully saturated monovalent radical of one to twelve carbon atoms containing only carbon and hydrogen, and which may be a cyclic, branched or straight chain radical. This term is further exemplified by radicals such as methyl, ethyl, t-butyl, pentyl, cyclopentyl, cyclohexyl, heptyl, cycloheptyl and
adamantyl.
The term "lower alkyl" refers to a monovalent alkyl radical of one to six carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, t-butyl, i-butyl (or 2-methylpropyl), isoamyl, pentyl, cyclopentyl, i-pentyl, hexyl and cyclohexyl.
The term "lower alkenyl" refers to an unsaturated monovalent hydrocarbon radical of one to six carbon atoms. This term is further exemplified by such radicals as vinyl, prop-2-enyl, pent-3-enyl, and hex-5-enyl.
The term "halo" refers to fluoro and chloro, unless otherwise specified.
The term "halo lower alkyl" refers to a lower alkyl radical
substituted with one or more chlorine or fluorine atoms. This term is further exemplified by such radicals as trichloromethyl, trifluoromethyl, dichloromethyl, fluoromethyl, difluoro-chloro-methyl, 3-chloropropyl and 4-trifluoro-2-chloro-butyl.
The term "halomethyl" refers to a methyl radical substituted with one or more chlorine and/or fluorine atoms. This term is further exemplified by such radicals as trichloromethyl, trifluoromethyl, dichloromethyl, fluoromethyl and difluoro-chloromethyl.
The term "lower alkylene" refers to a divalent alkyl radical of one to six carbon atoms. This term is further exemplified by such radicals as methylene, ethylene, n-propylene, i-propylene, n-butylene, t-butylene, i-butylene (or 2-methylpropylene), isoamylene, pentylene, and n-hexylene.
The term "alkoxy" means the group -OR wherein R is lower alkyl.
The term "lower alkanol" means an alcohol of the formula ROH where R is a lower alkyl. This term is further exemplified by such alcohols as methanol, ethanol, n-propanol, i-propanol, n-butanol, t-butanol, i-butanol (or 2-methylpropanol), pentanol, n-hexanol. The moiety "-N=G3" as defined represents a heterocycle radical such as pyrrolidino, piperidino, hexamethyleneimino, imidazolidino,
thiazolidino, morpholino, thiomorpholino, piperazino,
thiopentamethyleneimino, and the like.
The term "optionally substituted phenyl" refers to phenyl and mono-, di-, or tri-substituted phenyl, wherein the optional substituents are lower alkyl, lower alkoxy, hydroxy, trifluoromethyl, or halo. This term is further exemplified by such radicals as 2-chlorophenyl, 2-trifluoromethylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 3,4-dimethoxyphenyl, 2-chloro-3,4-dimethoxyphenyl, 4-hydroxyphenyl,
4-methylphenyl, 3-t-butylphenyl, and 4-hexylphenyl.
The term "aryl" refers to a monovalent unsaturated aromatic
carbocyclic radical having a single ring (e.g., phenyl) or two condensed rings (e.g., naphthyl), which can optionally be mono-, di- or
tri-substituted, independently, with OH, COOH, lower alkyl, lower alkoxy, chloro, fluoro, trifluoromethyl and/or cyano.
The term "heteroaryl" refers to a monovalent aromatic carbocyclic radical having at least one heteroatom, such as N, O or S, within the ring, such as quinolyl, benzofuranyl, pyridyl, morpholinyl and indolyl, which can optionally be mono-, di- or tri-substituted, independently, with OH, COOH, lower alkyl, lower alkoxy, chloro, fluoro, trifluoromethyl and/or cyano.
The term "optionally substituted, saturated or unsaturated
carbocyclic or heterocyclic ring of 3 to 7 atoms" as used with reference to a side chain of Formula ZB encompases side chains of the following structures:
Figure imgf000008_0001
Figure imgf000008_0002
Figure imgf000008_0003
Figure imgf000008_0004
where the line inside each respective ring indicates the optional presence of a double bond and X1, X2, X3, X4 and X5 can independently be -CHXa-, -C(O)-, -C(N-Xb)-, -C(N-NXdXe) -, -O-, -S-, -S(O)-, -S(O)2- or -NXc-, where
Xa is H, lower alkyl or forms a double bond;
Xb is acyl, carbamoyl or ureido;
Xc is lower alkyl, C(O)Xd, S(O)2Xd or C(O)NXdXe; and Xd and Xe are independently H or lower alkyl;
provided that if more than one heteroatom is present such heteroatoms are separated by at least one carbon atom. Thus, a sidechain of Formula ZB in which D1 and D2 together represent -CH2CH2CH2CH2- , and Z5 and Z8 are both hydrogen, would be named as a 2-[(2-ethylidene)-2-cyclohex-1-yl]acetic acid derivative. Likewise, a sidechain of Formula ZB in which D1 and D2 together represent -CH2CH2OCH2-, and Z5 and Z8 are both hydrogen, would be named as a 2-[(2-ethylidene)-4-tetrahydropyran-3-yl]acetic acid derivative.
The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances in which said event or circumstance occurs and instances in which it does not. For example, "optionally substituted phenyl" means that the phenyl may or may not be substituted and that the description includes both unsubstituted phenyl and phenyl wherein there is substitution: "optionally" followed by "converting the free base to the acid addition salt" means that such conversion may or may not be carried out in order for the process described to fall within the invention, and the invention includes those processes wherein the free base is converted to the acid addition salt and those processes in which it is not.
A "pharmaceutically acceptable salt" may be any salt derived from an inorganic or organic acid or base. Salts may be derived from acids or bases.
The acid addition salts are derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid (giving the sulfate and bisulfate salts), nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, salicylic acid,
p-toluenesulfonic acid, and the like.
The base addition salts are derived from inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonia, calcium hydroxide, magnesium hydroxide and the like. Cations derived from organic bases include those formed from primary, secondary and tertiary amines, such as isopropylamine, diethylamine, trimethylamine, triethylamine, pyridine, cyclohexylamine, ethylene diamine, monoethanolamine,
diethanolamine, triethanolamine, and the like.
As used herein, the term "inert organic solvent" or "inert solvent" means a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran, diethyl ether, chloroform, methylene chloride, pyridine, xylene, dimethylformamide, 1,4-dioxane,
dichloromethane, and the like).
As used herein, the term "treatment" or "treating" means any treatment of a disease in a mammal, and includes:
(i) preventing the disease, that is, causing the clinical symptoms of the disease not to develop;
(ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or
(iii) relieving the disease, that is, causing the regression of clinical symptoms.
As used herein, the term "effective amount" means a dosage sufficient to provide treatment. This will vary depending on the patient and the treatment being effected.
"Isomers" are different compounds that have the same molecular formula.
"Stereoisomers" are isomers that differ only in the way the atoms are arranged in space.
"Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to designate a racemic mixture where appropriate.
"Diastereoisomers" are stereoisomers that have at least two
asymmetric atoms, but which are not mirror-images of each other.
The absolute stereochemistry is specified according to the
Cahn-Ingold-Prelog R-S system. When the compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S . Resolved compounds whose absolute configuration is unknown are designated (+) or (-) depending on the direction (dextro- or laevorotary) which they rotate the plane of polarized light at the wavelength of the sodium D line .
When a compound is a racemic mixture the stereochemistry at each chiral carbon may be specified by either RS or SR by reference to a single enantiomer of the racemate. In this manner relative stereochemistry is conveyed unambiguously.
The compounds of the invention may possess one or more asymmetric centers, and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of Formula I depends upon the number of asymmetric centers present (there are 2n stereoisomers possible where n is the number of asymmetric centers). The individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound of Formula I by conventional means. The individual stereoisomers (including individual enantiomers and diastereoisomers) as well as racemic and non-racemic mixtures of stereoisomers are encompassed within the scope of the present invention, all of which are intended to be depicted by the structures of this specification unless otherwise specifically indicated. Specific examples of the separation of isomers are set forth in the
Examples. Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about -20°C to about 100°C, more preferably from about 10°C to about 50°C, and most preferably at about room temperature.
Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be found by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can, of course, also be used.
Nomenclature
The compounds of Formula I will be named using the numbering system illustrated below.
The isobenzofuranyl nucleus of the compounds of Formula I is numbered as follows:
Figure imgf000011_0001
Following are examples of how some representative compounds of Formula I are named.
Sidechains of Formula ZA are numbered as shown below:
Figure imgf000011_0002
Representative compounds of Formula I where the sidechain is ZA are as follows:
Figure imgf000012_0002
Sidechains of Formula ZB in which D1 and D2 do not contain a hetero atom are numbered as shown below:
Figure imgf000012_0001
Representative compounds of Formula I where the sidechain is ZB in which D2 does not include a hetero atom are as follows:
Figure imgf000012_0003
Figure imgf000013_0003
Sidechains of Formula ZB that include a heteroatom are numbered differently, depending upon the position of the heteroatom(s) in the ring. For example, a sidechain of Formula ZB in which D1 and D2 together with their adjacent carbon atoms form a saturated heterocyclic ring of 6 atoms is numbered as shown below:
Figure imgf000013_0001
where D represents -O-, -S(O)p-, -N(R9)-, and the like.
Representative compounds of Formula I where the sidechain is ZB includin a hetero atom are as follows:
Figure imgf000013_0002
Sidechains of Formula ZC are numbered as shown below:
Figure imgf000014_0001
Representative compounds of Formula I where the sidechain is ZC are as follows:
Figure imgf000014_0004
Sidechains of Formula ZD are numbered as shown below: or
Figure imgf000014_0002
Figure imgf000014_0003
where D3 is CH2 where D3 is CH2CH2
Representative compounds of Formula I where the sidechain is ZD are as follows:
Figure imgf000015_0002
Sidechains of Formula ZE are numbered as shown below:
Figure imgf000015_0001
Representative compounds of Formula I where the sidechain is ZE are as follows:
Figure imgf000015_0003
Sidechains of Formula ZF are numbered as shown below:
Figure imgf000016_0001
Representative compounds of Formula I where the sidechain is ZF are as follows:
Figure imgf000016_0003
Sidechains of Formula ZG are numbered as shown below:
Figure imgf000016_0002
Representative compounds of Formula I where the sidechain is ZG are as follows:
Figure imgf000016_0004
yl) cyclopent-1-en-1-yl]-3-methyl-2-phenyl propionic acid.
Sidechains of Formula ZH are numbered as shown below:
Figure imgf000017_0001
Representative compounds of Formula I where the sidechain is ZH are as follows:
Figure imgf000017_0002
Compounds of Formula I where the side chain is ZH, in which D4 is a heteroatom, are numbered differently, in that the heteroatom is designated as position 1 of the ring. For example, the compound where D4 is oxygen, and R1 and R2 are both hydrogen, Z1 is methyl, and G is hydroxy, is named as follows:
(E)-2-[3-(4-amino-l,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran- 5-yl)-1-methylprop-1-en-1-yl]tetrahydrofuran-3-carboxylic acid.
PREPARATION OF COMPOUNDS OF FORMULA I
The compounds of Formula I are prepared from the lower alkyl 4- isocyanato esters of Formula 6, the structure of which is shown below:
Figure imgf000018_0002
where Za is a sidechain of Formula Z as defined in the Summary of the Invention in which G is lower alkoxy.
The compounds of Formula 6 are then converted to the compounds of Formula I by several different synthetic pathways, depending on the desired substitutions at the 4-position.
Many of the esterification routes and/or final esterification steps for the esters of the 4-substituted derivatives of mycophenolic acid are described in U.S. Patent Nos. 4,686,234; 4,725,622; 4,727,069; 4,748,173; 4,753,935; 4,861,776; and the pending application entitled "Direct
Esterification of Mycophenolic Acid", Serial No. 07/911635, filed July 10, 1992 (by inventors working in the same research organization as that of the present applicants, and subject to an obligation of assignment to the same assignee as in the present application) all previously incorporated herein by reference. By substituting the acids of Formula I for mycophenolic acid or its acid derivatives as described in the above references, the
esterification routes and/or final steps described may likewise be used. Starting Materials
The intermediates of Formula 6 are prepared starting from compounds of Formula 1, the structure of which is shown below:
Figure imgf000018_0001
where Z is as defined in the Summary of the Invention.
The compounds of Formula 1 may be prepared as described below in Reaction Schemes I to XXII. The preparation of such compounds is also described in more detail in co-pending Application Serial No. 08/???,???, Attorney Docket No. 27960, entitled "5-Substituted Derivatives of
Mycophenolic Acid", filed contemporaneously herewith, which is hereby incorporated by reference in its entirety.
Preparation of Compounds of Formula 1 where Z is Sidechain ZA One method of preparing compounds of Formula 1 where Z is the sidechain of Formula ZA, illustrated as compounds of Formula 1A, is shown below in Reaction Schemes I to X .
Figure imgf000019_0001
Figure imgf000020_0001
Preparation of Formula 102
As illustrated in Reaction Scheme I, Step 1, the phenolic hydroxyl group of a mycophenolic acid lower alkyl ester is protected.
A mycophenolic acid lower alkyl ester of Formula 101, in a solvent (such as ether, ethyl acetate, dimethylamide, or preferably
dichloromethane), is reacted with an equimolar amount of a halogenated protecting group (such as: methoxyethoxymethyl chloride; a sulfonyl chloride, e.g., tosyl chloride, mesyl chloride; or a silyl chloride, e.g., trimethylsilyl chloride, diphenylmethylsilyl chloride, or preferably tert-butyldimethylsilyl chloride) in presence of an equimolar amount of an organic base (such as diisopropylethylamine, triethylamine, or imidazole). The reaction takes place at -20 to 35°C (preferably at 25°C) for 1 to 24 hours (preferably 16 hours) to give the corresponding compound of Formula 102 (where Ra is the protecting group).
Preparation of Formula 103
As illustrated in Reaction Scheme I, Step 2, the side chain double bond of a protected mycophenolic acid lower alkyl ester is ozonized to yield an aldehyde.
A stream of ozonized oxygen is passed through a solution of a protected compound of Formula 102 in a solvent (such as an alcohol, a halocarbon, or preferably a mixture of methanol and dichloromethane). The reaction takes place at -100 to -40°C (preferably at -80°C), and continues until the presence of excess ozone is detected by the development of a blue color. The intermediate hydroperoxide thus formed is reduced without further purification, by the addition of a reducing agent (such as zinc and acetic acid, dimethyl sulfide, or preferably thiourea). The reaction takes place at -80°C to 25°C (preferably 0°C) over a period of 12 to 24 hours (preferably 16 hours), to give the corresponding aldehyde of Formula 103. Preparation of Formula 104
As illustrated in Reaction Scheme I, Step 3, the aldehyde is converted to a carbinol by addition of an organometallic compound of
Formula 103a [where M is MgBr or lithium, preferably MgBr (a Grignard reagent); Z1 is H, lower alkyl or CF3, and Z2 is H or lower alkyl].
An organolithium reagent is formed by reaction of a halovinyl
(preferably bromovinyl) compound of Formula 103a (where M is halo) with an alkyllithium (preferably n-butyllithium) in an ethereal solvent (such as ether, or preferably tetrahydrofuran). The reaction takes place at -100 to 0°C (preferably -40°C) over a period of 0.5 to 5 hours (preferably 1 hour) .
Alternatively the halovinyl compound of Formula 103a is reacted with magnesium metal in an ethereal solvent (such as ether or preferably tetrahydrofuran). The reaction takes place at 30 to 60°C (preferably 40°C) over a period of 1 to 6 hours (preferably 2 hours).
The organometallic compound of Formula 103a where M is zinc or cadmium may be prepared by reaction of 103a where M is Li or MgBr with a zinc or cadmium halide, preferably chloride. The compound of Formula 103a where M is tin may be prepared by reaction of 103a where M is Li or MgBr with a trialkyl chlorostannane, preferably tributyltin chloride. The compound of Formula 103a where M is tin may also be prepared by reaction of 103a where M is trifluoromethanesulfonate by reaction with a compound of formula (R3Sn)2, where R is alkyl, preferably methyl, in the presence of a palladium catalyst, preferably tetrakis(triphenylphosphine)palladium. The compound of Formula 103a where M is trifluoromethanesulfonate may be prepared from a ketone of the formula:
Figure imgf000021_0001
by reaction with a strong base (such as sodium hydride or potassium hexamethyldisilazide), followed by reaction of the anion thus produced with trifluoromethanesulfonic anhydride. Alternatively, the compound of Formula 103a where M is tin may be prepared by reacting a trialkyl tin hydride (preferably tributyl tin hydride) with an acetylene of the formula
Z1-C≡C-Z2.
One molar equivalent of the resultant organometallic reagent is added to a solution of an aldehyde of Formula 103 (in the same solvent system used to make the organometallic reagent). The reaction takes place at -80 to 20°C (preferably 0°C) over a period of 5 to 60 minutes (preferably 10 minutes) to give the corresponding carbinol of Formula 104.
Preparation of Formula 105
As illustrated in Reaction Scheme I, Step 4, an alkyl ester of
Formula 105 is formed by a Claisen ortho ester rearrangement reaction of a carbinol of Formula 104 and an orthoester of Formula 104a (where Z3 is H, halo, lower alkyl, lower alkenyl, phenyl, alkoxy or -thio lower alkyl; and Z4 is H or lower alkyl; or Z3 and Z4 taken together with the carbon to which they are attached form cycloalkyl).
A carbinol of Formula 104 is heated at 50 to 140°C (preferably about 130°C) with about 10 molar equivalents of an orthoester of Formula 104a, in the presence of from 0.05 to 0.25 molar equivalents (preferably 0.10 molar equivalents) of an organic acid catalyst (such as propionic, butyric, or preferably trimethylacetic acid). The reaction takes place over a period of 1 to 48 hours (preferably 3 hours) to give the corresponding alkyl ester of Formula 105.
Preparation of Formula 1A
Compounds of Formula 1A are prepared as esters by deprotection of compounds of Formula 105 as described below with reference to Reaction Scheme X, Step 1; they are hydrolyzed to the corresponding carboxylic acid as described below with reference to Reaction Scheme X, Step 2.
Preparation of Enantiomers of Formula 1A where Z2 is Lower Alkyl
One method of preparing individual enantiomers of compounds of Formula 1A is from chiral compounds of Formula 104b, the preparation of which is shown below in Reaction Scheme II.
Figure imgf000022_0001
where Y is chloro or bromo .
Figure imgf000022_0002
Figure imgf000023_0001
Preparation of Formula 103f
As illustrated in Reaction Scheme II, Step 1, an aldehyde of Formula 103 is oxidized to the corresponding carboxylic acid of Formula 103f.
An aldehyde of Formula 103 is reacted with about two molar
equivalents of an oxidizing agent (for example, chromic acid, silver oxide, bleach, or preferably sodium periodate), in an inert solvent (such as toluene, or preferably ethyl acetate), in the presence of water and a catalytic amount (for example, about 0.01 molar equivalents) of a catalyst (such as ruthenium oxide, or preferably ruthenium trichloride). The reaction takes place at 0 to 40°C (preferably 25°C) for 30 minutes to 8 hours (preferably 2 hours), to give the corresponding carboxylic acid of Formula 103f.
Preparation of Formula 103g
As illustrated in Reaction Scheme II, Step 2, a carboxylic acid of
Formula 103f is converted to the corresponding acyl halide of Formula 103g.
A carboxylic acid of Formula 103f is reacted with about one molar equivalent, preferably 1.1 molar equivalents, of an halogenating agent (for example, thionyl chloride, thionyl bromide, or preferably oxalyl chloride), in an inert solvent (such as dichloromethane, or preferably ethyl acetate), in the presence of a catalytic amount (for example, about 0.05 molar equivalents) of dimethylformamide. The reaction takes place at 0 to 40°C (preferably 25°C) for 30 minutes to 8 hours (preferably 2 hours), to give the corresponding acyl halide of Formula 103g.
Preparation of Formula 103h
As illustrated in Reaction Scheme II, Step 3, an acyl halide of Formula 103g is converted to the corresponding keto olefin of Formula 103h by addition of an organometallic compound of Formula 103a.
An acyl halide of Formula 103g is reacted with about one molar equivalent of a organometallic compound of Formula 103a (where M is cadmium, zinc, tin, or the like, prepared as shown in the preparation of compounds of Formula 104), in an inert solvent (such as dichloromethane, ether, or preferably tetrahydrofuran), optionally in the presence of a catalytic amount (for example, about 0.05 molar equivalents) of a palladium catalyst [preferably tetrakis(triphenylphosphine)palladium]. The reaction takes place at -10 to 20°C (preferably 0°C) for 30 minutes to 8 hours (preferably 4 hours), to give the corresponding keto olefin of Formula 103h.
Preparation of Formula 104b
As illustrated in Reaction Scheme II, Step 4, a keto olefin of
Formula 103h is reduced stereospecifically to the corresponding carbinol of Formula 104b by reduction with borane methyl sulfide in the presence of a catalytic amount of (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo- [1,2-c][1,3,2]oxazaborole.
A keto olefin of Formula 103h is sterospecifically reduced with about one molar equivalent of borane methyl sulfide in the presence of a catalytic amount (0.05-0.3 molar equivalents) of (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2]oxazaborole in an inert solvent (preferably a mixture of toluene and dichloromethane). The reaction takes place at -30 to 40°C (preferably -20°C) for 1-24 hours (preferably 12 hours), to give the corresponding carbinol of Formula 104b.
Preparation of Enantiomers of Compounds of Formula 1A
The chiral carbinol of Formula 104b is then converted to an
enantiomer of a compound of Formula 1A in the same manner as shown above in Reaction Scheme I (conversion of compounds of Formula 104 to 105 to 1A).
Preparation of Compounds of Formula 1A where Z2 is Lower Alkoxy Compounds of Formula 1A where Z2 is lower alkoxyare prepared from the corresponding hydroxy compounds as shown below in Reaction Scheme III.
Figure imgf000024_0001
Preparation of Formula 106
As illustrated in Reaction Scheme III, Step 1, an aldehyde of Formula 103 is transformed into an unsaturated aldehyde of Formula 106 by a Wittig reaction with an ylid of Formula 103b (where Z1 is H or lower alkyl).
An aldehyde of Formula 103 is reacted with one molar equivalent of an ylid of Formula 103b, in an organic solvent (such as dichloromethane, dimethylformamide or preferably toluene). The reaction takes place at 0 to 110°C (preferably 80°C) for 1 to 24 hours (preferably 8 hours) to give the corresponding unsaturated aldehyde of Formula 106.
Preparation of Formula 107
As illustrated in Reaction Scheme III, Step 2, an unsaturated aldehyde of Formula 106 is condensed with the anion of an ester of Formula 106a (where Z3 is H, lower alkyl, lower alkenyl, or phenyl and Z4 is H, lower alkyl, or phenyl) to give a beta-hydroxy ester of Formula 107.
An ester of Formula 106a is converted to an alkali metal salt by reacting a solution of the ester in an ethereal solvent (such as ether or preferably tetrahydrofuran) with an equimolar amount of an alkali metal hydride, hexamethyldisilazide or amide (preferably lithium
diisopropylamide) at a temperature of -100 to 0°C (preferably -80°C), for 30 minutes to 2 hours (preferably 30 minutes) to give a solution of the corresponding ester anion. The ester anion solution (1.0 to 1.5 molar equivalents, preferably 1.0 molar equivalents) is added to a solution of an unsaturated aldehyde of Formula 106 in the same ethereal solvent. The condensation reaction takes place at a temperature of -100°C to 0°C
(preferably -80°C) for 1 to 6 hours (preferably 2 hours) to give the corresponding beta-hydroxy ester of Formula 107.
Preparation of Compounds of Formula 1A where Z2 is Lower Alkoxy
Compounds of Formula 1A where Z2 is lower alkoxy are prepared from compounds of Formula 107 as shown below in Reaction Scheme IV.
Figure imgf000025_0001
Preparation of Formula 108
As illustrated in Reaction Scheme IV, Step 1, the beta-hydroxy group of an ester of Formula 107 is O-alkylated to give the corresponding beta-alkoxy ester (Rb) of Formula 108.
An ester of Formula 107 is reacted with 1 to 3 (preferably 1.5) molar equivalents of an alkyl halide (preferably an alkyl iodide, such as methyl iodide or n-butyl iodide, preferably methyl iodide) and 1 to 3 (preferably 1.25) molar equivalents of silver oxide, in a polar organic solvent (such as dioxane, dimethylformamide or preferably acetonitrile). The reaction takes place at 25 to 100°C (preferably 70°C) for 1 to 24 hours (preferably 4 hours) to give the corresponding beta-alkoxy ester of Formula 108.
Preparation of Compounds of Formula 1A where Z4 is Hydroxy Compounds of Formula 1A where Z4 is hydroxy are prepared as shown below in Reaction Scheme V.
Figure imgf000026_0001
Preparation of Formula 1A where Z4 is Hydroxy
As illustrated in Reaction Scheme V, Step 1, an alpha-halo alkyl ester of Formula 105 (where Z1 is H, lower alkyl or CF3, Z2 is H or lower alkyl, Z3 is H, lower alkyl, lower alkenyl, or phenyl, and Z4 is halo) is converted to an alpha-hydroxy acid of Formula 1A where Z4 is hydroxy. The reaction takes place by hydrolysis of an alpha-alkanoyloxy ester
intermediate, formed by displacement of the alpha-halo group with an alkali metal alkanoate.
An alpha-halo (preferably chloro) ester of Formula 105 is reacted with 1 to 5 (preferably 3) molar equivalents of an alkali metal alkanoate (the metal preferably potassium and the alkanoate preferably acetate) in a polar organic solvent (such as acetonitrile or preferably
dimethylformamide) The reaction takes place at 40 to 100°C (preferably 75°C) for 1 to 24 hours (preferably 12 hours) to give the corresponding alpha-alkanoyloxy ester intermediate (not shown), which is employed without isolation or further purification.
The alpha-alkanoyloxy ester is then subjected to basic hydrolysis by reaction with 1 to 5 (preferably 2) molar equivalents of an alkali metal hydroxide (preferably sodium hydroxide) in a mixture of water and an organic solvent (such as methanol, dimethoxyethane or preferably
tetrahydrofuran). The reaction takes place at 0 to 60°C (preferably 40°C) for 1 to 12 hours (preferably 4 hours), to afford the corresponding alpha-hydroxy acid of Formula 1A. As illustrated in Reaction Scheme V, when Ra of Formula 105 is a silyl protecting group, the hydrolysis conditions are also effective for deprotection to restore the phenolic hydroxyl group. Alternatively, for example when R* is methoxymethylethyl, the deprotection and hydrolysis procedures described with reference to Reaction Scheme X, can be employed. Preparation of Chiral Compounds of Formula 1A
One method of preparing chiral compounds of Formula 1A is shown below in Reaction Scheme VI.
Figure imgf000027_0001
Preparation of Formula 109
As illustrated in Reaction Scheme VI, Step 1, an unsaturated aldehyde of Formula 106 is reduced and then converted to the corresponding compound of Formula 109 in which Rb is a leaving group (a sulfonate or halide, preferably a bromide).
An unsaturated aldehyde of Formula 106 is reacted with from 0.5 to 2 (preferably 1) molar equivalents of a reducing agent (such as sodium cyanoborohydride or preferably sodium borohydride) in an alcoholic solvent (such as ethanol, isopropanol or preferably methanol). The reaction takes place at 0 to 50°C (preferably 25°C) for 1 to 12 hours (preferably 2 hours) to give the corresponding allylic alcohol (not shown) which is used without isolation or further purification.
The allylic alcohol is reacted with from 1 to 1.5 (preferably 1.25) molar equivalents of a sulfonating agent (such as p-toluenesulfonyl chloride) and an organic base, or preferably reacted with a halogenating reagent (such as carbon tetrachloride/triphenylphosphine or preferably N-bromosuccinimide/triphenylphosphine) in an inert organic solvent (such as ether or preferably dichloromethane). The reaction takes place at a temperature of -40 to 40°C (preferably -10°C) for 1 to 12 hours (preferably 2 hours) to afford the corresponding compound of Formula 109.
Preparation of Formula 110
As illustrated in Reaction Scheme VI, Step 2, an allylic halide or sulfonate of Formula 109 is alkylated with a chiral 4-alkyl N-acyl oxazolidinone of Formula 109a to give the corresponding chiral substituted acyl oxazolidinone of Formula 110.
An alkali metal (preferably lithium) salt of a chiral 4-alkyl N-acyl oxazolidinone of Formula 109a (the alkyl group preferably being 4-isopropyl) by reaction of the N-acyl oxazolidinone with 1 to 1.25
(preferably 1.05) molar equivalents of an alkali metal hydride,
hexamethyldisilazide or dialkylamide (preferably lithium diisopropylamide) in an inert organic solvent (such as ether or preferably tetrahydrofuran). The reaction takes place at -100 to -20°C (preferably -80°C) for 5 to 120 minutes (preferably 30 minutes). The solution of the salt (1 to 1.5, preferably 1.25 molar equivalents) is then added to a solution of an allylic compound of Formula 109 in the same solvent. The alkylation reaction takes place at -100 to 0°C (preferably -80°C) for 30 minutes to 6 hours (preferably 1 hour) to afford the corresponding chiral substituted acyl oxazolidinone of Formula 110.
Preparation of Chiral Formula 1A
As illustrated in Reaction Scheme VT, Step 3, a chiral substituted acyl oxazolidinone of Formula 110 is hydrolyzed to the corresponding chiral acid of Formula 1A. Use of an acyl oxazolidinone of Formula 109a having a 4-alkyl substituent of the opposite configuration in Reaction Scheme VI, Step 2, followed by hydrolysis as described in Step 3 results in the corresponding chiral acid where Z3 has the opposite configuration .
An acyl oxazolidinone of Formula 110 is reacted with from 1.25 to 3.5 (preferably 3.0) molar equivalents of lithium hydroxide, in a mixture of water and a water-miscible organic solvent (such as dioxane or preferably tetrahydrofuran) containing from 6 to 10 (preferably 8) molar equivalents of 30% aqueous hydrogen peroxide. The reaction takes place at -20 to 40°C (preferably 20°C) for 1 to 24 hours (preferably 12 hours) to afford the corresponding chiral acid of Formula 1A.
Alternative Preparation of Compounds of Formula 1A An alternative preparation of compounds of Formula 1A is shown below in Reaction Scheme VII.
Figure imgf000029_0001
Preparation of Formula 112
As illustrated in Reaction Scheme VII, Step 1, an allylic compound of Formula 109 in which Rb is a leaving group (a sulfonate or halide, preferably a bromide) is condensed with an ester of Formula 109b to give the mono- or di-alkyl ester of Formula 112 (where Z3 is H, lower alkyl, lower alkenyl, or phenyl and Z4 is H, lower alkyl, or phenyl).
An ester of Formula 109b is converted to an alkali metal salt by reaction with 1.05 to 1.25 (preferably 1.1) molar equivalents of an alkali metal amide (such as sodium hexamethyldisilazide, potassium
tetramethylpiperidide or preferably lithium diisopropylamide) in an organic solvent (such as ether, dioxane or preferably tetrahydrofuran). The reaction takes place at -40 to 30°C (preferably 0°C) for 15 minutes to 3 hours (preferably 30 minutes). Without isolation or further purification, the resulting solution of the alkali metal salt of the ester of Formula 109b (1.2 to 1.6, preferably about 1.3 molar equivalents) is then reacted with an allylic compound of Formula 109, in the same solvent, optionally in the presence of from 2% to 10% (preferably about 5%) by volume of
hexamethyl phosphoric triamide. The reaction takes place at -100 to -40°C (preferably -80°C) for 30 minutes to 6 hours (preferably 1 hour) to afford the corresponding alkyl ester of Formula 112.
Preparation of Formula 1A
Compound of Formula 1A are then obtained as esters by deprotection of compounds of Formula 105 as described below with reference to Reaction
Scheme X, Step 1; they are hydrolyzed to the corresponding carboxylic acid as described below with reference to Reaction Scheme X, Step 2.
Preparation of Compounds of Formula 1A where Z3 is S(O)malkyl
Compounds of Formula 1A where Z3 is S(O)malkyl are prepared as shown below in Reaction Scheme VIII.
Figure imgf000030_0001
Preparation of Formula 1A where Z3 is S(O)malkyl
As illustrated in Reaction Scheme VIII, Step 1, a 2-(alkylthio)-4-hexenoic acid ester of Formula 1A (where Z3 is S-lower alkyl, and Z4 is H or lower alkyl) is oxidized to give the corresponding 2-(alkylsulfinyl)- or 2-(alkylsulfonyl)-4-hexenoic acid ester of Formula 1A where Z3 is S(O)lower alkyl or S(O)2lower alkyl. Alternatively, the reaction can be performed with an acid of Formula 1A where Z3 is S-lower alkyl, to give the
corresponding acid where Z3 is 2-(alkylsulfinyl) or 2-(alkylsulfonyl).
An alkylthio-4 -hexenoic acid ester of Formula 1A is reacted with 1.0 to 1.25 (preferably 1.05) molar equivalents of an oxidizing agent (such as oxone®) optionally in the presence of an inert support (such as alumina), in a solvent (such as chloroform or preferably dichloromethane). The reaction takes place at 0 to 55°C (preferably 35°C) for 1 to 10 hours (preferably 2 hours) to afford the corresponding 2-(alkylsulfinyl)-4-hexenoic acid ester of Formula 1A where Z3 is S (O) lower alkyl.
By repeating the foregoing procedure under the same conditions
[starting with the 2-(alkylsulfinyl)-4-hexenoic acid ester so-produced], or by conducting the reaction with the 2-(alkylthio)-4-hexenoic acid ester starting material [and using 2.0 to 2.5 (preferably 2.25) molar equivalents of oxone] the corresponding 2-alkylsulfonyl-4-hexenoic acid esters are produced.
A 2-(alkylsulfinyl)- or 2-(alkylsulfonyl)-4-hexenoic acid ester of Formula I-ZA-K is hydrolyzed to give the corresponding acid as described with reference to Reaction Scheme X, Step 2.
Preparation of Compounds of Formula 1A where Z1 is Halo
Compounds of Formula 1A where Z1 is halo are prepared as shown below in Reaction Scheme IX.
Figure imgf000031_0001
Preparation of Formula 114
As illustrated in Reaction Scheme IX, Step 1, a protected aldehyde of Formula 103 and a triphenylphosphoranylideneacetate of Formula 103c are combined in a Wittig reaction to give the corresponding alkyl-2-halobutenoate ester of Formula 114.
An aldehyde of Formula 103 is reacted with 1.0 to 1.5 (preferably
1.1) molar equivalents of an alkyl 2-halo-2-triphenylphosphoranylideneacetate of Formula 103c (the halo group preferably being chloro) in an organic solvent (such as acetonitrile, or preferably toluene) . The reaction takes place at 50 to 120°C (preferably 110°C) for 4 to 48 hours (preferably 24 hours) to afford the corresponding alkyl 2-halo-4-aryl-2-butenoate ester of Formula 114.
Preparation of Formula 115
As illustrated in Reaction Scheme IX, Step 2, a protected alkyl 2-halo-4-aryl-2-butenoate ester of Formula 114 is converted to the
corresponding bromide of Formula 115 after reduction to the corresponding alcohol (not shown).
A 2-halo-4-aryl-2-butenoate ester of Formula 114 (preferably a t-butyl ester) is converted to the corresponding acid (preferably by dissolution in trifluoroacetic acid at room temperature for 1 to 2 hours). The acid is isolated and purified by conventional means, then reacted with 0.5 to 3 (preferably 1.6) molar equivalents of a reducing agent (such as sodium cyanoborohydride, sodium borohydride, or preferably borane dimethyl disulfide complex) in an inert solvent (such as methanol, ethanol, isopropanol or preferably THF). The reaction takes place at 0 to 50°C (preferably 25°C) for 1 to 48 hours (preferably 24 hours) to give the corresponding alcohol (not shown) which is used after purification.
The allylic alcohol so-produced is reacted with from 1 to 1.5
(preferably 1.25) molar equivalents of a sulfonating agent (such as p-toluenesulfonyl chloride) and an organic base, or preferably reacted with a halogenating reagent (such as carbon tetrachloride/triphenylphosphine or preferably N-bromosuccinimide/triphenylphosphine) in an inert organic solvent (such as ether or preferably dichloromethane). The reaction takes place at a temperature of -40 to 40°C (preferably -10°C) for 1 to 12 hours (preferably 2 hours) to afford the corresponding 2-halo-4-aryl-2-butenyl bromide compound of Formula 115.
Preparation of Formula 1A where Z1 is Halo
As illustrated in Reaction Scheme IX, Step 3, a protected 2-halo-4-aryl-2-butenyl bromide compound of Formula 115 is condensed with a dialkyl malonate of Formula 106b (substituted by Z4 where Z4 is hydrogen, lower alkyl, or phenyl), which is hydrolysed and decarboxylated to give the corresponding 4-halo-4-hexenoic acid derivative of Formula 1A where Z1 is halo.
A malonic ester of Formula 106b (where Z4 is H, lower alkyl, or phenyl) is converted to an alkali metal salt by reaction with 1.05 to 1.25 (preferably 1.1) molar equivalents of an alkali metal hydride (preferably sodium hydride) in an organic solvent (such as ether, dioxane or preferably tetrahydrofuran). The reaction takes place at -40 to 30°C (preferably 0°C) for 15 minutes to 3 hours (preferably 30 minutes). Without isolation or further purification, the resulting solution of the alkali metal salt of the ester of Formula 106b (1.2 to 1.6, preferably about 1.3 molar
equivalents) is then reacted with an allylic bromo compound of Formula 115 in the same solvent. The reaction takes place at -20 to 50°C (preferably 25°C) for 30 minutes to 6 hours (preferably 2 hours) to afford the corresponding dialkyl ester derivative.
The dialkyl ester thus produced is then hydrolysed conventionally, using a strong base, preferably aqueous sodium hydroxide, in a protic solvent, preferably ethanol, heating to reflux. The dicarboxylic acid thus produced is separated conventionally, and then decarboxylated by heating, preferably in a high-boiling inert solvent, most preferably 1,2- dichlorobenzene, to give the corresponding 4-halo-4-hexenoic acid
derivative of Formula 1A where Z1 is halo.
Preparation of Compounds of Formula 1A
Compounds of Formula 1A as esters and carboxylic acids are obtained by deprotection and hydrolysis as shown below in Reaction Scheme X.
Figure imgf000033_0001
Preparation of Formula 1A as an Ester
As illustrated in Reaction Scheme X, Step 1, a protected phenol of Formula 117 (which can be any of the corresponding protected compounds of Reaction Schemes I to IX, such as Formulae 105, 107, 108, 112, and the like) is deprotected to give the corresponding alkyl ester of Formula 1A as an ester.
An alkyl ester of Formula 117 (having either an acetal-type or a silyl-type protecting group) is treated with from 0.05 to 0.2 molar equivalents (preferably 0.1 molar equivalents) of an aqueous mineral acid (such as sulfuric, perchloric, or preferably hydrochloric acid), in a water-miscible organic solvent (such as methanol, acetone, or preferably ethanol). The reaction takes place at 0 to 50°C (preferably 25°C) over a period of 1 to 6 hours (preferably 2 hours) to give the corresponding free phenol of Formula 1A.
Alternatively, to remove acetal-type protecting groups (such as MEM) a compound of Formula 117 is treated with 0.05 to 0.25 molar equivalents (preferably 0.1 molar equivalents) of a Lewis acid (such as zinc chloride or preferably zinc bromide), in a solvent (such as benzene, chloroform, or preferably dichloromethane). The reaction takes place at 0 to 50°C
(preferably 25°C) over a period of 1 to 12 hours (preferably 3 hours) to give the corresponding free phenol of Formula 1A. Alternatively, to remove silyl-type protecting groups (such as t-butyldimethylsilyl) a compound of Formula 117 is reacted with 1.0 to 1.5 (preferably 1.25) moles of a tetraalkyl ammonium fluoride (preferably tetrabutylammonium fluoride) in an ethereal solvent (such as dioxane or preferably tetrahydrofuran). The reaction takes place at -10 to 25°C (preferably 0°C) over a period of 0.1 to 2 hours (preferably 0.5 hours) to give the corresponding free phenol of Formula 1A.
Preparation of Formula 1A as a Carboxylic Acid
As illustrated in Reaction Scheme X, Step 2, a compound of Formula 1A as an ester (prepared as described above) is hydrolyzed to give the corresponding acid of Formula 1A as a carboxylic acid.
An alkyl ester of Formula 1A is reacted with from 1.5 to 4 molar equivalents (preferably 2 molar equivalents) of an inorganic hydroxide (such as potassium, sodium, or preferably lithium hydroxide) in a mixture of water and an organic solvent (such as tetrahydrofuran, methanol, or preferably dimethoxyethane). The reaction takes place at 0 to 60°C
(preferably 40°C) over a period of 1 to 12 hours (preferably 3 hours). The resulting anion is acidified with an aqueous mineral acid (such as hydrochloric acid). The acidification takes place at 0 to 40°C (preferably 25°C) over a period of 1 to 10 minutes (preferably 2 minutes) to give the corresponding carboxylic acid of Formula 1A.
Preparation of Compounds of Formula 1B
One method of preparing compounds of Formula 1 where Z is a sidechain of Formula ZB, illustrated as compounds of Formula 1B, is shown below in Reaction Schemes XI and XII.
.
Figure imgf000034_0001
where M is Li or MgBr.
Figure imgf000034_0002
Figure imgf000035_0001
Preparation of Formula 202
As illustrated in Reaction Scheme XI, Step 1, the aldehyde of Formula 103 is converted to a carbinol of Formula 202 by addition of an unsaturated cyclic organometallic compound of Formula 201 where M is Li or MgBr, prepared for example as described above with reference to Reaction Scheme I, Step 3.
One molar equivalent of the organometallic reagent 201 is added to a solution of an aldehyde of Formula 103 (in the same solvent system used to make the organometallic reagent). The reaction takes place at -80 to -20°C (preferably -40°C) over a period of 5 to 60 minutes (preferably 15 minutes) to give the corresponding carbinol of Formula 202.
Resolution of Formula 202
The racemic compound of Formula 202 may be separated into its two enantiomers by conventional means, for example by conversion into two diastereoisomers that are then separated by crystallization,
chromatography, or by any conventional separation technique. Preferably, the carbinol is reacted with a chiral isocyanate to give a mixture of diastereoisomeric carbamates, which are separated by chromatography and cleaved to give the pure enantiomers.
A carbinol of Formula 202 is heated at 30 to 100°C (preferably about 60°C) with 2 to 6 molar equivalents (preferably 4 molar equivalents) of a chiral isocyanate in the presence of 1 to 1.5 molar equivalents (preferably 1.2 molar equivalents) of a strong organic base, for example
4-dimethylaminopyridine, in a hindered tertiary amine (for example diisopropylethylamine) as a solvent. The reaction takes place over a period of 1 to 24 hours (preferably 7 hours) to give the corresponding carbamate as a mixture of diastereoisomers.
The mixture of diastereoisomeric carbamates is separated by
conventional means, preferably chromatography. The individual
diastereoisomers are then separately cleaved by treatment with 1 to 1.5 molar equivalents (preferably 1.2 molar equivalents) of a trihalosilane, for example trichlorosilane, in the presence of an excess of a tertiary amine, for example triethylamine, in an inert solvent, for example toluene. The reaction takes place at a temperature of 90-120°C (preferably 110°C) over a period of 5 minutes to 2 hours (preferably 15 minutes) to give the corresponding enantiomer of the carbinol of Formula 202. Preparation of Formula 203
As illustrated in Reaction Scheme XI, Step 2, an alkyl ester of Formula 203 is formed by a Claisen ortho ester reaction of a carbinol of Formula 201 (or an enantiomer thereof) with an appropriately substituted orthoester.
A carbinol of Formula 202 is heated at 50 to 140°C (preferably 130°C) with a large excess of an orthoester of Formula 104a (see Reaction Scheme I, step 4), in the presence of from 0.05 to 0.25 molar equivalents
(preferably 0.10 molar equivalents) of an organic acid catalyst (such as propionic, butyric, or trimethylacetic acid, preferably trimethylacetic acid). The reaction takes place over a period of 1 to 24 hours (preferably 2.5 hours) to give the corresponding alkyl ester of Formula 203.
Preparation of Formula 1B
Compounds of Formula 1B are prepared as described with reference to Reaction Scheme X, Step 1 (deprotection to afford the corresponding alkyl ester of Formula 1B), and Step 2 (hydrolysis to afford the corresponding acid of Formula 1B).
Alternative Preparation of Enantiomers of Compounds of Formula 1B
Another method of preparing individual enantiomers of compounds of Formula 1 where Z is sidechain ZB, illustrated as compounds of Formula 1B, is from chiral compounds of Formula 202b, the preparation of which is shown below in Reaction Scheme XII.
Figure imgf000036_0001
Preparation of Formula 202a
Compounds of Formula 202a are prepared as described above with reference to Reaction Scheme II, Step 3 (conversion of 103g to 103h). Preparation of Formula 202b
Compounds of Formula 202b are prepared as described above with reference to Reaction Scheme II, Step 4 (conversion of 103h to 104b).
Preparation of Enantiomers of Compounds of Formula 1B
The chiral carbinol of Formula 202b is then converted to an
enantiomer of a compound of Formula 1B in the same manner as shown above in Reaction Scheme XI (conversion of compounds of Formula 202 to 203 to 1B).
Preparation of Compounds of Formula IC
One method of preparing compounds of Formula 1 where Z is a sidechain of Formula ZC, illustrated as compounds of Formula IC, is shown below in Reaction Scheme XIII.
Figure imgf000037_0001
Figure imgf000038_0001
Preparation of Formula 302
As illustrated in Reaction Scheme XIII, Step 1, an aldehyde of Formula 103 (prepared, for example as described above with reference to Reaction Scheme I, Steps 1 and 2) is transformed into an unsaturated aldehyde of Formula 302 by a Wittig reaction with an ylid of Formula 301 (where Z5 is H or lower alkyl).
An aldehyde of Formula 103 is reacted with one molar equivalent of an ylid of Formula 301, in an organic solvent (such as dichloromethane, dimethylformamide or preferably toluene). The reaction takes place at 0 to 110°C (preferably 80°C) for 1 to 24 hours (preferably 8 hours) to give the corresponding unsaturated aldehyde of Formula 302.
Preparation of Formula 303
As illustrated in Reaction Scheme XIII, Step 2, an unsaturated aldehyde of Formula 302 is converted to the corresponding vinyl carbinol of Formula 303.
An aldehyde of Formula 302 is reacted with from 1.0 to 1.25
(preferably 1.1) molar equivalents of an organovinyl compound (preferably vinylmagnesium bromide) in a solvent (such as ether or preferably
tetrahydrofuran). The reaction takes place at -30 to 20°C (preferably at 0°C) for 0.1 to 4 hours (preferably 0.5 hours) to give the corresponding vinyl carbinol of Formula 303.
Preparation of Formula 304
As illustrated in Reaction Scheme XIII, Step 3, a vinyl carbinol of Formula 303 is oxidized to give the corresponding dienone of Formula 304.
A vinyl carbinol of Formula 303 is reacted with 1.0 to 1.5
(preferably 1.1) molar equivalents of an oxidizing agent (such as manganese dioxide, pyridinium chlorochromate or preferably pyridinium dichromate) in a solvent (such as pyridine or preferably dichloromethane). The reaction takes place at 0 to 30°C (preferably 25°C) for 30 minutes to 4 hours
(preferably 1 hour) to give the corresponding dienone of Formula 304.
Preparation of Formula 305
As illustrated in Reaction Scheme XIII, Step 4, a dienone of Formula 304 is cyclized to give the corresponding cyclopentenone of Formula 305.
A dienone of Formula 304 reacted with 0.3 to 1.5 (preferably 1.0) molar equivalents of a Lewis acid (such as boron trichloride, tin (IV) chloride or preferably boron trifluoride etherate) in a solvent (such as tetrachloroethane or preferably dichloromethane). The reaction takes place at 0 to 30°C (preferably 25°C) for 1 to 6 hours (preferably 2 hours) to give the corresponding cyclopentenone of Formula 305.
Preparation of Formula 306
As illustrated in Reaction Scheme XIII, Step 5, a cyclopentenone of Formula 305 is reduced to give the corresponding cyclopentenol of Formula 306.
A cyclopentenone of Formula 305 is reacted with 1.0 to 1.5
(preferably 1.1) molar equivalents of a reducing agent (such as lithium tri-tert-butoxyaluminium hydride or preferably sodium borohydride in the presence of an equimolar amount of cerium trichloride) in a mixture of an ethereal solvent (preferably tetrahydrofuran) and a lower alkanol
(preferably methanol). The reaction takes place at 0 to 40°C (preferably at 25°C) for 1 to 6 hours (preferably 2 hours) to give the cyclopentenol of Formula 306.
Preparation of Formula 307
As illustrated in Reaction Scheme XIII, Step 6, a cyclopentenol of Formula 306 is transformed to the corresponding vinyl ether of Formula 307.
A cyclopentenol of Formula 306 is reacted with from 10 to 100
(preferably 50) molar equivalents of a 1-alkenyl ether, optionally in the presence of a co-solvent (such as ether or tetrahydrofuran), in the presence of from 0.1 to 0.5 (preferably 0.3) molar equivalents of a mercury (II) salt (preferably mercury (II) acetate). The reaction takes place at 0 to 50°C (preferably 25°C) for 1 to 5 days (preferably 2 days) to give the corresponding vinyl ether of Formula 307.
Preparation of Formula 308
As illustrated in Reaction Scheme XIII, Step 7, a vinyl ether of Formula 307 is rearranged to the corresponding acetaldehyde of Formula 308.
A vinyl ether of Formula 307 is reacted with from 10 to 100
(preferably 50) molar equivalents of a lithium salt (such as the
tetrafluoroborate or preferably the perchlorate) in a solvent (such as tetrahydrofuran or preferably ether). The reaction takes place at 0 to 35°C (preferably 25°C) for 0.1 to 2 hours (preferably 0.5 hours) to give the corresponding acetaldehyde of Formula 308.
Preparation of Formula 309
As illustrated in Reaction Scheme XIII, Step 8, an acetaldehyde of Formula 308 is oxidized to give the corresponding acid of Formula 309.
An acetaldehyde of Formula 308 is reacted with 1 to 3 (preferably 1.5) molar equivalents of a suitable oxidizing agent (such as silver oxide, Jones reagent or preferably sodium chlorite) in the presence of an
equimolar amount of a phenol (such as quinol or preferably resorcinol). The reaction is conducted in a mixture of water and a water-miscible organic solvent (such as tetrahydrofuran or preferably dioxane) at a pH of from 4 to 6 (preferably 5) at -10 to 25°C (preferably 0°C) for 10 minutes to 2 hours (preferably 30 minutes) to give the corresponding acid of
Formula 309.
Preparation of Formula 1C
As illustrated in Reaction Scheme XIII, Step 9, an acid of Formula 309 is deprotected to give the corresponding acid of Formula 1C.
An acid of Formula 309 where Ra is a sulphonyloxy protecting group hydrolyzed under basic conditions, using from 1 to 5 (preferably 3) molar equivalents of an alkali metal hydroxide (preferably lithium hydroxide) in a mixture of water and a water-miscible organic solvent (such as dioxane or preferably methanol). The reaction takes place at 40 to 100°C (preferably 60°C) for 1 to 48 hours (preferably 12 hours) to afford the corresponding cyclopentene carboxylic acid of Formula 1C.
Alternatively, for other protecting groups, the deprotection reaction takes place as described above with reference to Reaction Scheme X, Step 1. Preparation of Compounds of Formula 1D
One method of preparing compounds of Formula 1 where Z is a sidechain of Formula ZD, illustrated as compounds of Formula 1D, is shown below in Reaction Scheme XIV.
Figure imgf000041_0001
Preparation of Formula 401
As illustrated in Reaction Scheme XIV, Step 1, an aldehyde of Formula 103 (where Ra is a silyl protecting group) is converted to a carbinol by addition of an organometallic compound of Formula 103d (such as a
substituted vinyl organolithium, or preferably a Grignard reagent where: M is MgBr or Li; Z2 is H or lower alkyl; and TBS is a tert-butyldimethylsilyl protecting group).
The aldehyde of Formula 103 is reacted with from 1.1 to 1.5
(preferably 1.25) molar equivalents of an organometallic, preferably organolithium, derivative of a protected 2-halo (preferably 2-bromo) but-1-en-4-ol. The reaction is performed at from -100 to -40°C (preferably at -78°C) for from 30 minutes to 6 hours (preferably 1 hour) to afford the corresponding compound of Formula 401.
Preparation of Formula 402
As illustrated in Reaction Scheme XIV, Step 2, an alkyl ester of
Formula 402 is formed by a Claisen ortho ester rearrangement reaction of a carbinol of Formula 401 and a trialkyl orthoacetate of Formula 104a.
A carbinol of Formula 401 is heated at 50 to 120°C (preferably about 100°C) with about 10 molar equivalents of an orthoester of Formula 104a, in the presence of from 0.05 to 0.25 (preferably 0.10) molar equivalents of an organic acid catalyst (such as propionic, butyric, or preferably
trimethylacetic acid). The reaction takes place over a period of 1 to 48 hours (preferably 8 hours) to give the corresponding alkyl ester of
Formula 402.
Preparation of Formula 403
As illustrated in Reaction Scheme XIV, Step 3, an alkyl ester of Formula 402 is reacted with a tetraalkylammonium fluoride and then halogenated to give a protected ester of Formula 403.
A compound of Formula 402 is reacted with from 2.0 to 3.0 (preferably 2.0) molar equivalents of a tetraalkylammonium (preferably
tetrabutylammonium) fluoride, in a solvent (such as dioxane,
tetrahydrofuran, or preferably methylene chloride) at from 0 to 25°C
(preferably 10°C), for from 30 minutes to 4 hours (preferably 1 hour). The product so obtained is reacted with from 1.0 to 1.5 (preferably 1.25) molar equivalents of a halogenating agent (preferably a brominating agent, such as triphenylphosphine/carbon tetrabromide or preferably
triphenylphosphine/N-bromosuccinimide) in a solvent such as ether or preferably dichloromethane. The reaction takes place at from -40 to 0°C (preferably -10°C) for from 1 to 6 hours (preferably 4 hours) to give the corresponding halogenated ester of Formula 403.
Preparation of Formula 1D
As illustrated in Reaction Scheme XIV, Step 4, a halogenated ester of Formula 403 is cyclized to give a cycloalkyl ester of Formula 1C.
A compound of Formula 403 is reacted with from 2.0 to 2.5 (preferably 2.25) molar equivalents of a strong base (such as lithium diisopropylamide, sodium hydride or preferably sodium hexamethyldisilazide) in an ethereal solvent (such as ether, dioxane or preferably tetrahydrofuran) The reaction takes place at from -100 to -60°C (preferably -78°C) for 1 to 12 hours (preferably 4 hours) to give the cycloalkyl ester of Formula 1D, which may be hydrolyzed to the carboxylic acid of Formula 1D as described above with reference to Reaction Scheme X, Step 2.
Preparation of Compounds of Formula 1E
Methods of preparing compounds of Formula 1 where Z is sidechain of Formula ZE, illustrated as compounds of Formula 1E, is shown below in Reaction Schemes XV to XVII.
Figure imgf000043_0001
Preparation of Formula 502
As illustrated in Reaction Scheme XV, Step 1, the 2 -methyl group of an alkyl 2-methylbenzoate of Formula 501 (where Z6 and Z7 are selected from H, lower alkyl, lower alkoxy, lower alkoxycarbonyl, halo and nitro) is brominated to give the corresponding compound of Formula 502.
An ester of Formula 501 is reacted with 1.0 to 1.2 (preferably 1.05) molar equivalents of a brominating agent (such as N-bromoacetamide or preferably N-bromosuccinimide), optionally in the presence of an initiator (such as visible light) or from 0.001 to 0.01 (preferably 0.005) molar equivalents of a chemical initiator (such as azobisisobutyronitrile or preferably benzoyl peroxide) in a solvent (such as ethyl formate or preferably carbon tetrachloride). The reaction takes place at 40 to 80°C (preferably 75°C) for 30 minutes to to 6 hours (preferably 2 hours) to afford the corresponding alkyl 2-bromomethylbenzoate of Formula 502, which can be purified by conventional means or preferably used directly for the next step.
Preparation of Formula 503
As illustrated in Reaction Scheme XV, Step 2, a 2-bromomethyl group of Formula 502 is converted to the corresponding phosphonium salt of
Formula 503.
A 2-bromomethylbenzoate of Formula 502 is reacted with 1.0 to 1.25 (preferably 1.05) molar equivalents of a triaryl phosphine (preferably triphenyl phosphine) in a solvent (such as dimethylformamide or preferably acetonitrile). The reaction takes place at 25 to 90°C (preferably 50°C) for 1 to 24 hours (preferably 2 hours) to afford the corresponding phosphonium salt of Formula 503.
Preparation of Formula 504
As illustrated in Reaction Scheme XV, Step 3, a phosphonium salt of Formula 503 is converted to the corresponding substituted
benzylidenetriphenylphosphorane ylid of Formula 504.
A phosphonium salt of Formula 503 is dissolved or suspended in a solvent (such as dioxane, ether or preferably dimethylformamide) and reacted with 1.0 to 1.25 (preferably 1.05) molar equivalents of a base (such as sodium hydride, triethylamine or preferably 1,5-diazabicyclo[4.3.0]non-5-ene). The reaction takes place at 0 to 60°C (preferably 25°C) for 1 to 6 hours (preferably 2 hours) to afford the corresponding ylid of Formula 504, which can be isolated by conventional means or its solution can be used directly for the next step.
Preparation of Formulae 505 and 506
As illustrated in Reaction Scheme XV, Step 4, an ylid of Formula 504 and a protected aldehyde of Formula 103 (prepared, for example, as described in connection with Reaction Scheme ZA-A, Step 2) are employed in a Wittig reaction to give the corresponding protected substituted benzoic acid alkyl ester of Formula 505 as a mixture of E and Z isomers, from which the desired E isomer of Formula 506 is isolated, as illustrated in Reaction Scheme XV, Step 5.
A solution of 0.8 to 1.0 (preferably 0.95) molar equivalents of a protected aldehyde of Formula 103 in a solvent (such as ether, dioxane or preferably dimethylformamide) is added to a solution of an ylid of Formula 504 in the same solvent. The reaction takes place at 0 to 50°C (preferably 25°C) for 1 to 24 hours (preferably 12 hours) to afford the corresponding protected substituted benzoic acid alkyl ester of Formula 505 as a mixture of E and Z isomers, from which the desired E-isomer of Formula 506 can be isolated by conventional means (such as distillation, chromatography or preferably fractional crystallization).
Figure imgf000045_0001
Preparation of Formula 508
As illustrated in Reaction Scheme XVI, Step 1, the alpha carbon of an alkyl 2-alkylbenzoate of Formula 507 (where Z 5 is H or lower alkyl, and Z6 and Z7 are selected from H, lower alkyl, lower alkoxy, lower
alkoxycarbonyl, halo and nitro) is brominated to give the corresponding compound of Formula 508. The reaction takes place under the conditions described with reference to Reaction Scheme XV, Step 1.
Preparation of Formula 509
As illustrated in Reaction Scheme XVI, Step 2, an alkyl 2-bromo- alkylbenzoate of Formula 508 and a trialkyl phosphite are combined in an Arbuzov reaction to give the corresponding phosphonate of Formula 509.
A compound of Formula 508 is reacted with from 5 to 20 (preferably 10) molar equivalents of a trialkyl phosphite (preferably triethyl phosphite). The reaction takes place at 100 to 200°C (preferably 150°C) for 1 to 24 hours (preferably 6 hours) to afford the corresponding phosphonate of Formula 509.
Preparation of Formulae 510 and 511
As illustrated in Reaction Scheme XVI, Step 3, a phosphonate of Formula 509 and a protected aldehyde of Formula 103 (prepared, for example, as described in connection with Reaction Scheme I, Step 2) are reacted to give the corresponding protected substituted benzoic acid alkyl ester of Formula 510 as a mixture of E and Z isomers, from which the desired E isomer of Formula 511 is isolated, as illustrated in Reaction Scheme XV, Step 4.
A phosphonate of Formula 509 is reacted with 1.0 to 1.5
(preferably 1.1) molar equivalents of a base such (as sodium amide, potassium tert-butoxide or preferably sodium hydride) for from 1 to 4 hours (preferably 2 hours) at 0 to 50°C (preferably 25°C) in a solvent (such as dioxane, dimethylformamide or preferably dimethoxyethane), to give a solution or suspension of the corresponding alkali metal salt of Formula 509, which is employed without isolation or further purification. The alkali metal salt is reacted with from 0.9 to 1.1 (preferably 1.0) molar equivalents of a protected aldehyde of Formula 103, dissolved in the same solvent. The reaction takes place at 0 to 60°C (preferably 40°C) for 1 to 6 hours (preferably 2 hours) to afford the corresponding protected optionally substituted benzoic acid alkyl ester of Formula 510 as a mixture of E and Z isomers, from which the desired E-isomer of Formula 511 can be isolated by conventional means (such as distillation, chromatography or preferably fractional crystallization).
Figure imgf000046_0001
Figure imgf000047_0001
Preparation of Formula 513
As illustrated in Reaction Scheme XVII, Step 1, a protected aldehyde of Formula 103 is converted to a trialkylsilylcarbinol of Formula 513 in a
Grignard reaction.
An aldehyde of Formula 103 is reacted with from 1.0 to 1.25
(preferably 1.1) molar equivalents of a trialkylsilylalkyl-magnesium bromide (such as trimethylsilylpropylmagnesium bromide, or preferably trimethylsilylmethylmagnesium bromide) of Formula 512, in an ethereal solvent (such as ether, dimethoxyethane or preferably tetrahydrofuran).
The reaction takes place at -40 to 40°C (preferably 0°C) for 30 minutes to
4 hours (preferably 1 hour) to give the corresponding trialkylsilylcarbinol of Formula 513.
Preparation of Formula 514
As illustrated in Reaction Scheme XVII, Step 2, a protected
trialkylsilylcarbinol of Formula 513 is dehydrated to give the
corresponding protected alkene as a mixture of E and Z isomers, from which the desired Z isomer of Formula 514 is isolated.
A carbinol of Formula 513 is reacted with from 1.0 to 1.5 (preferably 1.05) molar equivalents of a sulphonyl chloride (such as p-toluenesulphonyl chloride or preferably methanesulphonyl chloride) in the presence of the same molar proportion of a tertiary organic base (such as N-methylpyrrolidine or preferably triethylamine). The reaction takes place at 0 to 40°C (preferably 15°C) for 30 minutes to 4 hours (preferably 2 hours) to afford the corresponding protected alkene of Formula 514 as a mixture of E and Z isomers, from which the desired Z-isomer of Formula 514 can be isolated by conventional means (such as distillation, chromatography or preferably fractional crystallization).
Preparation of Formula 515
As illustrated in Reaction Scheme XVII, Step 3, an alkene of Formula 514 where R" is a silyl protecting group is converted to an alkene of Formula 515 where Ra is an acyl group.
An alkene of Formula 514 is heated at 50-130°C (preferably about 118°C) with a large excess of a mixture (preferably about equimolar) of a carboxylic acid of Formula ROH and an anhydride of Formula (Ra)2O (where Ra is the desired acyl group), preferably a mixture of acetic acid and acetic anhydride. The reaction takes place over a period of 6 to 48 hours
(preferably 18 hours) to give the corresponding alkene of Formula 515 where Ra is the acyl group.
Preparation of Formula 511
As illustrated in Reaction Scheme XVII, Step 4, a protected alkene of Formula 515 is converted to a protected optionally substituted benzoic acid alkyl ester of Formula 511 in a Heck reaction with an alkyl-2-halo-benzoate of Formula 515.
An alkene of Formula 515 is reacted with 1.0 to 2.0 (preferably 1.25) molar equivalents of an alkyl 2-halobenzoate (such as an alkyl
2-bromobenzoate or preferably 2-iodobenzoate). The reaction is conducted in the presence of from 0.001 to 0.1 (preferably 0.05) molar equivalents of a palladium catalyst [such as tetrakis (tri-o-tolylphosphine) palladium, or tetrakis (triphenylphosphine)palladium or preferably palladium (II) acetate] optionally in the presence of from 1.0 to 1.25 (preferably 1.05) molar equivalents of a base (such silver carbonate, sodium bicarbonate or preferably triethylamine), in a solvent (such as acetonitrile or preferably dimethylformamide). The reaction is conducted at from 0 to 120°C
(preferably 60°C) for 1 to 48 hours (preferably 6 hours) to yield the corresponding protected optionally substituted benzoic acid alkyl ester of Formula 511.
Preparation of Formula 1E
The protected optionally substituted benzoic acid ester of Formula
506 or Formula 511 are then deprotected to give the corresponding ester of Formula 1E. The deprotection reaction takes place as described above with reference to Reaction Scheme X, Step 1. The optionally substituted benzoic acid ester of Formula IE may then be hydrolyzed to give the corresponding acid of Formula 1E as described above with reference to Reaction Scheme X, Step 2.
Preparation of Formula 1E where Z6 is Amino
The compounds of Formula 1E where Z6 is nitro are employed as precursors to the corresponding compounds of Formula 1E where Z6 is amino. The nitro compounds are also active as IMPDH inhibitors when tested as described below.
A nitrobenzoic acid of Formula 1E (where Z6 is nitro) is reacted with 1.0 to 3.0 (preferably 2.0) molar proportions of a reducing agent (such as sodium hydrosulfite or preferably tin (II) chloride) in hydrochloric acid solution, optionally in the presence of a water-miscible co-solvent (such as methanol or preferably acetic acid). The reaction takes place at 25 to 100°C (preferably 75°C) for 1 to 24 hours (preferably 4 hours) to afford the corresponding amino-substituted benzoic acid of Formula 1E (where Z6 is amino).
Figure imgf000049_0001
Preparation of Formula 517
As illustrated in Reaction Scheme XVIII, Step 1, a phosphonate of Formula 509 undergoes a base catalyzed condensation (e.g., using 1 molar equivalent of sodium hydride) with tetrahydropyranyloxyacetaldehyde, in a solvent such as dimethylformamide. The reaction takes place at 25°C over a period of 1 to 4 hours, to give E/Z mixture from which the desired product of Formula 517 can be isolated by conventional means, such as
chromatography.
Preparation of Formula 518
As illustrated in Reaction Scheme XVIII, Step 2, the
tetrahydropyranyloxy group of a compound of Formula 517 is hydrolyzed in the presence of a catalytic amount of a dilute acid (e.g., HCl) in aqueous tetrahydrofuran. The reaction takes place at 25°C over a period of 1 to 4 hours, to give the corresponding carbinol of Formula 518.
Preparation of Formula 519
As illustrated in Reaction Scheme XVIII, Step 3, a carbinol of Formula 518 is converted to the halo (e.g., chloro or bromo) derivative of Formula 519 using 1 molar equivalent of triphenylphosphine and either carbon tetrachloride or carbon tetrabromide, in dichloromethane. The reaction takes place at 25°C over a period of 2 hours.
Preparation of Formula 520
As illustrated in Reaction Scheme XVIII, Step 4, a halo derivative of Formula 519 undergoes a base-catalyzed ether formation with the indicated phenol, using 5 molar equivalents of potassium carbonate, in
dimethylformamide. The reaction takes place at 25°C over a period of 4 hours.
Preparation of Formula IE
As illustrated in Reaction Scheme XVIII, Step 5, an ether of Formula 520 is rearranged to give the corresponding ester of Formula IE by a thermal rearrangement catalysed by florisil. The rearrangement takes place in toluene at 110°C over a period of one to four days.
As illustrated in Reaction Scheme XVIII, Step 6, the ether so-produced is hydrolyzed to the corresponding acid of Formula IE as described with reference to Reaction Scheme X, Step 2.
Preparation of Compounds of Formula IF
One method of preparing compounds of Formula 1 where Z is a sidechain of Formula ZF, illustrated as compounds of Formula IF, is shown below in Reaction Scheme XIX.
Figure imgf000050_0001
Figure imgf000051_0001
Preparation of Formula 602
As illustrated in Reaction Scheme XIX, Step 1, an aldehyde of Formula 601, prepared for example as shown in J. Org. Chem.. 1977, p3408, is reduced to a carbinol of Formula 602.
An aldehyde of Formula 601 is reacted with a reducing agent capable of selectively reducing an aldehyde in the presence of ester groups, preferably from 1 to 2 (preferably 1.5) molar equivalents of sodium borohydride in the presence of from 1 to 2 (preferably 1.5) molar
equivalents of cerium chloride trihydrate, in an alcoholic/ethereal solvent mixture (preferably 4:1 tetrahydrofuran:methanol). The reaction takes place at 0 to 40°C (preferably 25°C) for 10 minutes to 2 hours (preferably 30 minutes) to give the corresponding carbinol of Formula 602.
Preparation of Formula 604
As illustrated in Reaction Scheme XIX, Step 2, a phenol of Formula
603 is alkylated with a carbinol of Formula 602 by means of the Mitsonobu reaction to give an ether of Formula 604.
A carbinol of Formula 602 is reacted with an equimolar amount of a phenol of Formula 603 in the presence of from 1 to 3 (preferably 2) molar equivalents of a triarylphosphine, preferably triphenylphosphine, plus from 1 to 3 (preferably 1.5) molar equivalents of diethyl azodicarboxylate in an ethereal solvent (preferably tetrahydrofuran). The reaction takes place at 0 to 40°C (preferably 25°C) for 1 to 10 hours (preferably 3 hours) to give the corresponding ether of Formula 604.
Preparation of Formula 605
As illustrated in Reaction Scheme XIX, Step 3, a phenol of Formula
604 is thermally rearranged to give a diester of Formula 605.
An ether of Formula 604 is heated in an inert solvent (preferably toluene) in the presence of about 10 parts by weight of an activated magnesium silicate, preferably Florisil®. The reaction takes place at reflux temperature for 1 to 10 days (preferably 4 days) to give the corresponding diester of Formula 605.
Preparation of Formula 606
As illustrated in Reaction Scheme XIX, Step 4, a diester of Formula
605 is hydrolyzed to give a dicarboxylic acid of Formula 606.
A diester of Formula 605 is reacted with an excess of an inorganic base, preferably about 50 molar equivalents of lithium hydroxide, in an aqueous solvent (preferably 5:1 methanol:water). The reaction takes place at 0 to 40°C (preferably 25°C) for 1 to 10 days (preferably 2 days) to give the corresponding dicarboxylic acid of Formula 606.
Preparation of Formula IF
As illustrated in Reaction Scheme XIX, Step 5, a dicarboxylic acid of Formula 606 is decarboxylated to give a monocarboxylic acid of Formula 1F.
A dicarboxylic acid of Formula 606 is heated (optionally in the presence of a high boiling inert solvent, for example tetramethylbenzene, but preferably in the absence of any solvent). The reaction takes place at 160 to 240°C (preferably 195°C) for about 5 minutes to give the
corresponding monocarboxylic acid of Formula 1F. Preparation of Compounds of Formula 1G One method of preparing compounds of Formula 1 where Z is sidechain of Formula ZG, illustrated as compounds of Formula 1G, is shown below in Reaction Scheme XX.
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Preparation of Formula 703
As illustrated in Reaction Scheme XX, Step 1, the phenol of Formula 701 is alkylated with 3-hydroxycyclohexene to give the corresponding ether of Formula 703, by means of the Mitsonobu reaction. The Mitsonobu reaction takes place as described with reference to Reaction Scheme XIX, Step 2.
Similarly, by substituting 3-cyclohexene with 3-cycloheptene, and carrying out the procedures of Reaction Scheme XX, the corresponding compounds where Z is a side chain of Formula ZG where D3 is -CH2-CH2- are obtained.
Preparation of Formula 704
As illustrated in Reaction Scheme XX, Step 2, a Claisen rearrangement of the ether of Formula 703 gives the alkylated phenol of Formula 704. The reaction takes place, e.g., at 200°C for 12 to 16 hours in the presence of N,N-diethylaniline.
Preparation of Formula 705
As illustrated in Reaction Scheme XX, Step 3, the alkylated phenol of Formula 704 is protected to give a protected phenol of Formula 705 (where Ra is silyl or tosyl).
An alkylated phenol of Formula 704 is reacted with an equimolar amount of t-butyl dimethylsilyl chloride or p-toluenesulfonyl chloride, in the presence of an equimolar amount, respectively, of imidazole or 4-dimethylaminopyridine. The reaction takes place in dichloromethane at a temperature of 25°C for 1 to 4 hours to give the corresponding protected phenol of Formula 705.
Preparation of Formula 706
As illustrated in Reaction Scheme XX, Step 4, a protected phenol of Formula 705 is converted to the corresponding dialdehyde of Formula 706 by ozonolysis. The ozonolysis reaction takes place as described with reference to Reaction Scheme I, Step 2.
Preparation of Formula 707
As illustrated in Reaction Scheme XX, Step 5, an intramolecular base-catalyzed aldol reaction with a dialdehyde of Formula 706 produces the corresponding formyl cyclopentene of Formula 707. The reaction is conducted with 0.1 moles of dibenzylamine or n-methylaniline
trifluoroacetate in benzene, taking place at 50°C for 30 minutes. Preparation of Formula 708
As illustrated in Reaction Scheme XX, Step 6, a formyl cyclopentene of Formula 707 is reduced to the corresponding carbinol. The reaction employs sodium borohydride/cerium chloride, as described with reference to Reaction Scheme XIX, Step 1.
Preparation of Formula 709
As illustrated in Reaction Scheme XX, Step 7, a carbinol of Formula
708 is converted to the corresponding acetate of Formula 709. The reaction is conducted with equimolar amounts of acetyl chloride and triethylamine, taking place in methylene chloride at 0°C for 1 hour.
Preparation of Formula 710
As illustrated in Reaction Scheme XX, Step 8, an acetate of Formula
709 is converted to the corresponding diester of Formula 710. The reaction is conducted as described in J. Am. Chem. Soc , 102:4730 (1980), with 4 moles of sodium dimethylmalonate, 0.5 moles triphenylphosphine and 0.25 moles of tetrakis triphenylphosphine palladium at 50°C in
tetrahydrofuran. ϋse of sodium dimethylmalonate substituted by Z3 or Z4 leads to a compound of Formula 711 where one of Z3 and Z4 is as defined in the Summary of the Invention and the other is hydrogen.
Preparation of Formula 711
As illustrated in Reaction Scheme XX, Step 9, a diester of Formula
710 is converted to the corresponding ester of Formula 711, by reaction with cesium acetate in hexamethylphosphoric triamide at 120°C for 1 to 3 hours.
Preparation of Formula 1G
As illustrated in Reaction Scheme XX, Step 10, an ester of Formula 111 is hydrolyzed to give the corresponding compound of Formula 1G. The reaction takes place as described with reference to Reaction Scheme X, Step 2.
Preparation of Compounds of Formula 1H
One method of preparing compounds of Formula 1 where Z is sidechain of Formula ZH, illustrated as compounds of Formula 1H, is shown below in Reaction Scheme XXI .
Figure imgf000056_0001
Figure imgf000057_0001
Preparation of Formula 801
As illustrated in Reaction Scheme XXI, Step 1, an aldehyde of Formula 103 is converted to a carbinol by addition of an organometallic compound of Formula 103e (such as a substituted vinyl organolithium, or preferably a Grignard reagent, where M is MgBr; TBS is a tert-butyldimethylsilyl protecting group; and n is 3-5).
A halovinyl (preferably bromovinyl) compound of Formula 103e (where M is halo) is reacted with magnesium metal in an ethereal solvent (such as ether or preferably tetrahydrofuran). The reaction takes place at 30 to
60°C (preferably 40°C) over a period of 1 to 6 hours (preferably 2 hours).
One molar equivalent of the resultant organometallic reagent is added to a solution of an aldehyde of Formula 103 (in the same solvent system used to make the organometallic reagent). The reaction takes place at -80 to 20°C (preferably 0°C) over a period of 5 to 60 minutes (preferably 10 minutes) to give the corresponding silyl-protected carbinol of Formula 801.
Preparation of Formula 802
As illustrated in Reaction Scheme XXI, Step 2, an alkyl ester of
Formula 802 is formed by a Claisen ortho ester rearrangement reaction of a carbinol of Formula 801 and an orthoester compound of Formula 104a (as illustrated in Reaction Scheme I, where Z3 and Z4 are H).
A silyl-protected carbinol of Formula 801 is heated at 50 to 120°C
(preferably about 100°C) with about 10 molar equivalents of an orthoester of Formula 104a, in the presence of from 0.05 to 0.25 molar equivalents (preferably 0.10 molar equivalents) of an organic acid catalyst (such as propionic, butyric, or preferably trimethylacetic acid). The reaction takes place over a period of 1 to 48 hours (preferably 8 hours) to give the corresponding alkyl ester of Formula 802.
Preparation of Formula 803
As illustrated in Reaction Scheme XXI, Step 3, the silyl-protected carbinol of an alkyl ester of Formula 802 is deprotected.
A compound of Formula 803 is reacted with from 5 to 30 (preferably
20) molar equivalents of hydrogen fluoride, in a mixture of water and a water-miscible organic solvent (preferably acetonitrile). The reaction takes place at -20 to 40°C (preferably 25°C) for 5 to 60 minutes
(preferably 30 minutes) to afford the corresponding unprotected
carbinol/alkyl ester of Formula 803.
Preparation of Formula 804
As illustrated in Reaction Scheme XXI, Step 4, a carbinol of Formula 803 is converted to a halide (preferably a bromide) of Formula 804, by means of a one-step or a two-step procedure.
In the one-step procedure, a carbinol of Formula 803 is reacted with from 1.0 to 1.3 (preferably 1.1) molar equivalents of a triaryl (preferably triphenyl) phosphine, and from 1.0 to 1.3 (preferably 1.1) molar
equivalents of a halogen source (such as N-bromosuccinimide or preferably carbon tetrabromide). The reaction is conducted in an inert solvent (such as ether or preferably tetrahydrofuran). The reaction takes place at 0 to
50°C (preferably 25°C) for 1 to 12 hours (preferably 3 hours) to afford the corresponding halide of Formula 804.
Alternatively, in the two-step procedure, which is preferred, a carbinol of Formula 803 is converted first into a sulphonate ester (such as a p-toluenesulphonate or preferably a methanesulphonate) by reaction with from 1.0 to 1.5 (preferably 1.3) molar equivalents a sulphonyl halide (preferably methanesulphonyl chloride) in the presence of an equimolar amount of a tertiary organic base (preferably diisopropylethylamine) in a solvent (such as chloroform or preferably dichloromethane). The reaction takes place at -20 to 30°C (preferably 0°C) for 10 to 60 minutes
(preferably 30 minutes). The so-obtained sulphonate ester is then reacted with from 5 to 20 (preferably 20) molar equivalents of an alkali metal halide (preferably lithium bromide) in a solvent (t-such as 2-butanone or preferably acetone). The reaction takes place at 0 to 56°C (preferably at reflux) for 30 to 180 minutes (preferably 90 minutes) to afford the corresponding halide of Formula 804.
Preparation of Formula 805
As illustrated in Reaction Scheme XXI, Step 5, a halogenated carbinol/alkyl ester of Formula 804 is deprotected at the phenolic group to give the corresponding halogenated carbinol/alkyl ester of Formula 805. The deprotection reaction takes place as described above with reference to Reaction Scheme X, Step 1.
Preparation of Formula 1H
As illustrated in Reaction Scheme XXI, Step 6, a halogenated carbinol/alkyl ester of Formula 805 is subjected to a base-induced cyclization reaction to afford the product of Formula 1H.
A compound of Formula 805 is reacted with from 2.0 to 2.5 (preferably 2.3) molar equivalents of a strong base (such as lithium diisopropylamide, sodium hydride or preferably sodium hexamethyldisilazide) in a solvent (such as dioxane or preferably tetrahydrofuran). The reaction takes place at -20 to 30°C (preferably at 0°C) for 5 to 60 minutes (preferably 15 minutes) to afford the corresponding cycloalkylester of Formula 1H.
The cycloalkyl ester of Formula I-ZH-A1 may then be hydrolyzed to give the corresponding acid of Formula 1H. The hydrolysis takes place as described above with reference to Reaction Scheme X, Step 2.
Compounds of Formula 1 where Z is a sidechain of Formula ZH in which D4 is O or O-CH2, are preferably prepared as described below in Reaction Scheme XXII.
Figure imgf000060_0001
Preparation of Formula 807
As illustrated in Reaction Scheme XXII, Step 1, an aldehyde of
Formula 302 (where Z5 is methyl) undergoes an aldol reaction with the bromo-alkyl oxazolidinone of Formula 806 (where q is 1 or 2), which can be prepared by analogy with the reactions described in J. Amer. Chem. Soc , 103, 2127 , 1981, to give the acyloxazolidinone of Formula 807.
An oxazolidinone of Formula 806 is reacted with an equimolar amount of a base (such as lithium diisopropylamide or preferably di-n-butylboryl trifluoromethane sulphonate/triethylamine), and then with an aldehyde of Formula 302. The reaction takes place at -78°C to 0°C (preferably -40°C) for 1 to 12 hours (preferably 3 hours) to afford the corresponding acyloxazolidinone of Formula 807.
Preparation of Formula 808
As illustrated in Reaction Scheme XXII, Step 2, an acyloxazolidinone of Formula 807 is hydrolyzed to the carboxylic acid of Formula 808.
An acyloxazolidinone of Formula 807 is reacted with 1-5 (preferably 3) molar equivalents of lithium hydroxide in 3 :1 tetrahydrofuran containing 5-20 (preferably 12) molar equivalents of hydrogen peroxide. The reaction takes place at -10 to 25°C (preferably 0°) for 5 to 60 minutes (preferably 30 minutes) to give the corresponding carboxylic acid of Formula 808.
Preparation of Formula 809
As illustrated in Reaction Scheme XXII, Step 3, a carboxylic acid of Formula 808 is deprotected to give the corresponding phenol of Formula 809, using the method described with respect to Reaction Scheme X, Step 1.
Preparation of Formula 810
A phenol of Formula 809 is esterified to give the corresponding ester of Formula 810.
A phenol of Formula 809 is treated with methanol in the presence of 0.05 to 0.2 (preferably 0.1) molar equivalents of an acid catalyst
(preferably p-toluenesulphonic acid). The reaction takes place at 0 to
50°C (preferably 25°C) for 1 to 24 hours (preferably 12 hours) to give the corresponding methyl ester of Formula 810.
Preparation of Formula 1H
A methyl ester of Formula 810 undergoes an intramolecular cyclization reaction to give the corresponding cyclized ester of Formula 1H.
A methyl ester of Formula 810 is treated with 1.9 to 2.5 (preferably 2.0) molar equivalents of a strong base (such as lithium diisopropylamide or preferably sodium hydride) in tetrahydrofuran (or preferably
dimethylformamide). The reaction takes place at -10 to 25°C (preferably 0°) for 1-12 hours (preferably 2 hours) to give the corresponding cyclized ester of Formula IH, which may be hydrolyzed to give the corresponding acid of Formula IH, using the method described with respect to Reaction Scheme X, Step 2.
Preparation of Esters of Formula 1
The esters of Formula 1 (compounds where G is not OH) can be prepared as described in U.S. Patents Nos. 4,727,069 and 4,753,935, incorporated herein by reference, by deprotection of a precursor (e.g., as described with reference to Reaction Scheme X, Steps 1) or as described below by attachment of a leaving group and its replacement by the desired ester.
Preparation of Intermediates of Formula 6
The preparation of a compound of Formula 6 is shown in Reaction Scheme XXIII below.
Figure imgf000062_0001
Figure imgf000063_0001
where Za is a sidechain of Formula Z as defined in the Summary of the
Invention in which G is lower alkoxy, and Zb is a sidechain of Formula Z as defined in the Summary of the Invention in which G is hydroxy.
Preparation of Starting Materials
The compound of Formula 1 (an ester) may be prepared from the corresponding carboxylic acid by reaction with a large excess of an alcohol of the formula GH, where G is lower alkoxy, preferably methanol, with a catalytic amount of an acid catalyst, (such as methanesulfonic acid, sulfuric acid, hydrochloric acid and p-toluenesulfonic acid), preferably p-toluenesulfonic acid). The reaction is carried out in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 1 to 7 days, preferably about 24 hours. The lower alkyl ester of Formula 1 is isolated and purified by conventional means.
Preparation of Compounds of Formula 2
As illustrated in Reaction Scheme XXIII, Step 1, an ester of Formula 1 is converted to the trifluoromethylsulfonyl compound of Formula 2.
A compound of Formula l is reacted in an organic solvent, preferably dichloromethane, with about 1 to 3 molar equivalents, preferably about 2 molar equivalents, of a base, preferably pyridine, and with a slight excess, preferably about 1.1 molar equivalents, of a sulfonic anhydride, (such as a halo lower alkyl sulfonic anhydride, halomethyl sulfonic anhydride, and halosulfonic anhydride, or preferably trifluoromethane- sulfonic anhydride or fluorosulfonic anhydride) or a sulfonyl halide, (such as trifluoromethylsulfonyl bromide, preferably trifluoromethylsulfonyl chloride). The reaction is carried out in an inert solvent, preferably dichloromethane, in the temperature range from about -20°C to 20°C, preferably at about 0°C, for about 15 to 45 minutes, preferably about 30 minutes. The trifluoromethylsulfonyl reaction product, a compound of Formula 2, is isolated and purified by conventional means.
Preparation of Compounds of Formula 3
As illustrated in Reaction Scheme XXIII, Step 2, a
trifluoromethylsulfonyl derivative of Formula 2 is converted to the cyano compound of Formula 3.
A compound of Formula 2 is reacted with about 1 to 3 molar
equivalents, preferably about 1.85 molar equivalents, of potassium cyanide with a catalytic amount of a triarylphosphine palladium complex, preferably tetrakis (triphenylphosphine) palladium, in an organic solvent, preferably 1,4-dioxane. The reaction is carried out in the temperature range from about 70°C to 130°C, preferably at about the reflux temperature of 1,4-dioxane, for about 10 to 30 hours, preferably about 18 hours. The cyano reaction product, a compound of Formula 3, is isolated and purified by conventional means, preferably with extraction by an organic solvent and column chromatography.
Preparation of Compounds of Formula 4
As illustrated in Reaction Scheme XXIII, Step 3, the cyano compound of Formula 3 is hydrolyzed to the carboxy compound of Formula 4.
A compound of Formula 3 is hydrolyzed by reacting it with about 1 to 10 molar equivalents, preferably about 4 molar equivalents, of an inorganic base (e.g., sodium hydroxide, lithium hydroxide, or potassium hydroxide, preferably sodium hydroxide,) in a large excess of organic solvent, preferably in about 3:2 water-.methanol solution. The reaction is carried out in the temperature range from about 40°C to 130°C, preferably at about the reflux temperature of the 3:2 water/methanol solvent, for about 1 to 3 hours, preferably about 2 hours. The reaction solution is distilled, and an additional of about 1 to 1.6 molar equivalents, preferably about 1.3 molar equivalents, of an inorganic base (e.g., sodium hydroxide, lithium hydroxide, or potassium hydroxide, preferably sodium hydroxide,) is added and the reaction is continued in the temperature range from about 40°C to 130°C, preferably at about the reflux temperature of the remaining solution, for about 1 to 3 days, preferably about 2 days. The reaction product, a compound of Formula 4, is isolated and purified by conventional means.
Alternatively, the compound of Formula 4 may be prepared by reacting a corresponding compound of Formula 2 with a catalytic amount of 1,1'-bis (diphenylphosphine)ferrocene palladium dichloride in a large excess of an alkanol (preferably methanol) in an organic solvent (preferably
dimethylformamide) with a slight excess, preferably 1.01 molar equivalents, of an organic base (preferably triethylamine), under a carbon monoxide atmosphere of increased pressure of about 400-1000 PSI, preferably at about 600 PSI. The reaction product, which is a diester of a compound of Formula 4, is then hydrolyzed by reacting it with about 1 to 10 molar equivalents, preferably about 4 molar equivalents, of an inorganic base, preferably aqueous lithium hydroxide, in a large excess of an organic solvent, preferably 4:1 methanol/water solution. The solution is heated to a temperature range from about 30°C to 80°C, preferably from about 50°C to 60°C, for about 1 to 10 hours, preferably for about 2 to 6 hours. The reaction product, a compound of Formula 4, is isolated and purified by conventional means.
Preparation of Compounds of Formula 5
As illustrated in Reaction Scheme XXIII, Step 4, a carboxy derivative of Formula 4 is converted to the ester of Formula 5. The compound of Formula 4 is reacted in a large excess of a compound of the formula GH, where G is lower alkoxy, preferably methanol, with catalytic amounts of an acid catalyst, preferably p-toluenesulfonic acid. The reaction is carried out in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 4 hours to 3 days, preferably about 24 hours. The reaction product, a 4 -carboxy derivative of Formula 5, is isolated and purified by conventional means.
Preparation of Compounds of Formula 6
As illustrated in Reaction Scheme XXIII, Step 5, a 4 -carboxy
derivative of Formula 5 is converted to the 4-isocyanate derivative of Formula 6.
A compound of Formula 5 is reacted with about 1 to 3 molar
equivalents, preferably about 2 molar equivalents, of an organic base, preferably triethylamine, in a large excess of an organic solvent, preferably dimethylformamide, and about 1 to 2 molar equivalents,
preferably about 1.3 molar equivalents, of an alkyl or phenyl haloformate or of a dialkyl or diphenyl halophosphate, preferably diphenyl
chlorophosphate, in the temperature range from about -20°C to 20°C, preferably at about 0°C, allowing it to warm to the temperature range from about 0°C to 40°C, preferably at about 20°C, allowing the reaction to proceed for about 0.5 to 2 hours, preferably about 1 hour. The reaction mixture is recooled to the temperature range from about -20°C to 20°C, preferably at about 0°C, and a large excess of sodium azide is added and the reaction proceeds for about 10 to 30 hours, preferably about 18 hours. The isocyanato reaction product, a compound of Formula 6, is isolated and purified by conventional means.
Alternatively, a compound of Formula 5 is reacted with about 1 to 3 molar equivalents, preferably about 2 molar equivalents, of an organic base, preferably triethylamine, in a large excess of an organic solvent, preferably dimethylformamide, and with a slight excess, preferably 1.2 molar equivalents, of a diphenyl or dialkyl phosphoroazide, preferably diphenyl phosphoroazide, in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 12 to 36 hours, preferably for about 24 hours. The isocyanato reaction product, a compound of Formula 6, is isolated and purified by conventional means.
PREPARATION OF COMPOUNDS OF FORMULA I
In the following Reaction Schemes, it should be noted that Za represents a sidechain of Formula Z as defined in the Summary of the
Invention in which G is lower alkoxy, and Zb represents a sidechain of Formula Z as defined in the Summary of the Invention in which G is hydroxy. 1. Preparation of Compounds of Formula I where R1 and R2 are both
Hydrogen
Compounds of Formula I where R1 and R2 are both hydrogen are depicted as Formula IA:
Figure imgf000066_0002
The preparation of compounds of Formula IA is shown in Reaction Scheme XXIV below.
Figure imgf000066_0001
where Za and Zb are as defined above.
Preparation of Formula IA where Z is Zb
A compound of Formula 6 is hydrolyzed with about 1 to 20 molar equivalents, preferably 10 molar equivalents, of an inorganic base, preferably lithium hydroxide monohydrate, in an inert organic solvent, preferably 3:10 water: 1,4-dioxane. The reaction is carried out in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 1 to 3 hours, preferably about 2 hours. The reaction product, a 4-amino compound of Formula IA where Z is Zb, is isolated and purified by conventional means, preferably column chromatography.
Preparation of Formula IA where Z is Za
A compound of Formula IA is esterified with a lower alkanol of formula GH, where G is lower alkoxy, as described in the preparation of a compound of Formula I as an ester.
Preparation of Compounds of Formula I where R1 is Hydrogen and R2 is -C(O)NR4R5
Compounds of Formula I where R1 is hydrogen and R2 is -C(O)NR4R5 are depicted as Formula IB:
Figure imgf000067_0001
The preparation of compounds of Formula IB is shown in Reaction Scheme XXV below.
m
Figure imgf000067_0002
Preparation of Formula IB where Z is Za
A compound of Formula 6 is reacted with a large excess of an amine compound of the formula HNR4R5, where R4 and R5 are as defined in the Summary of Invention, for example, methylamine, dimethylamine, methylphenylamine, ammonia, and the like, in an inert organic solvent, preferably
tetrahydrofuran. The reaction is carried out in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 30 minutes to 2 hours, preferably about 1 hour. The reaction product, a 4-(optionally substituted ureido) ester of Formula 1B is isolated and purified by conventional means.
Preparation of Formula IB where Z is Zb
An ester of Formula IB is hydrolyzed by reacting with about 1 to 10 molar equivalents, preferably about 4 molar equivalents of an inorganic base, preferably aqueous lithium hydroxide, in a large excess of an organic solvent, preferably 4:1 methanol/water. The solution is heated to a temperature range from about 30°C to 80°C, preferably from about 50°C to 60°C, for about 1 to 10 hours, preferably for about 2 to 6 hours. The reaction product, a 4-(optionally substituted ureido) acid compound of Formula IB, is isolated and purified by conventional means. Preparation of Compounds of Formula I where R1 is Hydrogen and R2 is -C(O)R3
Compounds of Formula I where R1 is hydrogen and R2 is -C(O)R3 are depicted as Formula IC:
Figure imgf000068_0002
The preparation of compounds of Formula IC is shown in Reaction
Scheme XXVI below.
Figure imgf000068_0001
Preparation of Compounds of Formula IC where Z is Za
A compound of Formula IA is reacted in a large excess of an inert organic solvent, preferably dichloromethane, with about 1 to 6 molar equivalents, preferably about 2.5 molar equivalents, of an anhydride compound of the formula (R3C(O))2O or of a acyl chloride of the formula R3C(O)Cl, where R3 is as defined in the Summary of the Invention. The reaction is carried out in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 30 minutes to 2 hours, preferably about 1 hour. The reaction product, a carbamate ester of Formula IC, is isolated and purified by conventional means, preferably by recrystallization.
Preparation of Formula IC where Z is Zb
A compound of Formula IC as an ester is hydrolyzed as described in the preparation of a compound of Formula 1B to give the corresponding compound of Formula IC as a carboxylic acid. Preparation of Compounds of Formula I where R1 is Lower Alkyl and R2 is -C(O)R3
Compounds of Formula I where R1 is lower alkyl and R2 is -C(O)R3 are depicted as Formula ID:
Figure imgf000069_0002
The preparation of compounds of Formula ID is shown in Reaction Scheme XXVII below.
Figure imgf000069_0001
Preparation of Formula ID wherein R1 is Lower Alkyl and Z is Za
A compound of Formula IC is reacted with about 1 to 10 molar equivalents, preferably about 4.5 molar equivalents, of a weak base, preferably potassium carbonate, and with about 1 to 10 molar equivalents, preferably about 4 molar equivalents, of a lower alkyl bromide or iodide, preferably an iodide, in an inert organic solvent, preferably
dimethylformamide . The reaction is carried out in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 12 to 48 hours, preferably about 24 hours. The organic layer is purified to give a carbamate ester of Formula ID where R1 is lower alkyl and G is lower alkoxy.
Preparation of Formula ID wherein R1 is Lower Alkyl and Z is Zb
A carbamate ester of Formula ID where R1 is lower alkyl is hydrolyzed as described in the preparation of a compound of Formula IB to give the corresponding carboxylic acid of Formula ID where R1 is lower alkyl. Preparation of Compounds of Formula I where R1 is Lower Alkyl and R2 is Hydrogen
Compounds of Formula I where R1 is lower alkyl and R2 is hydrogen are depicted as Formula IE:
Figure imgf000070_0002
The preparation of compounds of Formula IE is shown in Reaction Scheme XXVIII below.
Figure imgf000070_0001
Preparation of Formula IE where R1 is Lower Alkyl and Z is Zb
An amido ester of Formula ID is hydrolyzed by reacting with about 1 to 10 molar equivalents, preferably about 4 molar equivalents of an inorganic base (for example sodium hydroxide, preferably lithium
hydroxide), in a large excess of an organic solvent, preferably 4:1 methanol/water. The solution is heated to a temperature range from about 50°C to 100°C, preferably from about 60°C to 80°C, for about 4 to 24 hours, preferably for about 12 hours. The reaction product, a 4-alkylamino acid compound of Formula IE, is isolated and purified by conventional means. Preparation of Compounds of Formula I where G is Lower Alkoxy, Lower
Thioalkoxy, or -O-(CH2)m-N=Y
The compounds of Formula I where Z is a sidechain as defined in the Summary of the Invention in which G is lower alkoxy, lower thioalkoxy, or -O-(CH2)m-N=G3 (i.e., the ester derivatives) may be prepared from the corresponding compounds of Formula I where G is hydroxy (i.e. where Z is Zb), including compounds of Formulae IA, 1B, IC, ID, and IE, by
conventional means, for example as described in the preparation of a compound of Formula 1 as an ester.
Preferred Preparation of Esters of Formula I where G is -O-(CH2)m-N=Y
In a preferred procedure, a compound of Formula I where G is hydroxy is esterified with an heterocyclic aminoalkyl alcohol of the formula GH, where G is -O-(CH2)m-N=Y, in which m and Y are as defined in the Summary of the Invention, by the direct esterification procedure described in the pending application entitled "Direct Esterification of Mycophenolic Acid", Serial No. 07/911635, filed July 10, 1992.
In the direct esterification route, an acid compound of Formula I where G is hydroxy is esterified slowly in a refluxing inert organic solvent capable of azeotropic removal of water (such as toluene, xylene, or a mixture thereof) using only a slight excess (between 1.01 to 1.20 molar equivalents, and preferably, 1.05 to 1.06 molar equivalents) of an heterocyclic aminoalkyl alcohol of the formula HO(CH2)m-N=G3. Water generated by the reaction is removed azeotropically.
For example, with toluene as the solvent: 1) the reaction takes place with (a) a reaction time of 20 to 120 hours, preferably 50 to 100 hours and most preferably 100 hours and (b) an initial pot temperature range of 114 to 120°C increasing to a final pot temperature range of 118 to 130°C, preferably an initial pot temperature range of 115 to 118°C increasing to a final pot temperature range of 118 to 125°C, each depending on solute concentration and atmospheric pressure, and most preferably an initial pot temperature of 116°C increasing to a final pot temperature of 121°C with a ratio of the acid compound of Formula I (where G is hydroxy) to toluene of lgm:2ml at one atmosphere of pressure. The reaction product, a compound of Formula I where Z is a sidechain as defined in the Summary of the Invention in which G is -O-(CH2)m-N=G3, is isolated and purified by conventional means.
Salts of Compounds of Formula I
Some of the compounds of Formula I may be converted to corresponding base addition salts by virtue of the presence of a carboxylic acid group. The conversion is accomplished by treatment with a stoichiometric amount of an appropriate base, such as potassium carbonate, sodium bicarbonate, ammonia, ethylenediamine, monoethanolamine, diethanolamine, triethanolamine and the like. Typically, the free acid is dissolved in a polar organic solvent such as ethanol, methanol or ethyl acetate, and the base added in water, ethanol, methanol or isopropanol. The temperature is maintained at about 0°C to 50°C. The resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent.
The base addition salts of the compounds of Formula I may be decomposed to the corresponding free acids by treating with at least a stoichiometric amount of a suitable acid, such as hydrochloric acid or sulfuric acid, typically in the presence of aqueous solvent, and at a temperature of between about 0°C and 50°C. The free acid form is isolated by conventional means, such as extraction with an organic solvent.
By virtue of the presence of an amine group in the 4 -position or in the group G, some of the compounds of Formula I may be converted to the acid addition salts by the substitution of an organic or inorganic acid for the base in the above procedure. The acid salts can be decomposed to the corresponding free bases by similar treatment with an appropriate base.
Preferred Processes
In summary, compounds of Formula I are prepared according to the following last steps:
A process for preparing compounds of Formula I:
Figure imgf000072_0002
wherein:
R1 is hydrogen or lower alkyl;
R2 is hydrogen, lower alkyl, -C(O)R3, -C(O)NR4R5, -CO2R6, or -SO2R3
where:
R3 is hydrogen, lower alkyl, halo lower alkyl or optionally substituted phenyl;
R4 is hydrogen, lower alkyl or optionally substituted phenyl;
R5 is hydrogen, lower alkyl or optionally substituted phenyl;
R6 is lower alkyl or optionally substituted phenyl; and
Z is a side chain selected from Formulae ZA, ZB, ZC, ZD, ZE, ZF, ZG, and ZH:
Figure imgf000072_0001
wherein:
Z1 is H, lower alkyl, halo or CF3;
Z2 is H, lower alkyl, lower alkoxy, aryl, or -CH2Z13, where
Z13 is aryl or heteroaryl;
Z3 is H, lower alkyl, lower alkenyl, lower alkoxy, phenyl,
P(O) (OCH3)2, -P(O) (OH) (OCH3), or -S(O)mZ12, where
Z12 is lower alkyl, and
m is 0, 1 or 2; Z4 is H, lower alkyl, or phenyl,
or Z3 and Z4 taken together with the carbon to which they are attached form cycloalkyl of three to five carbon atoms; and G is OH, lower alkoxy, lower thioalkyl, -NG1G2, -O(CH2)nNG1G2, or - O(CH2)nN=G3, where
n is an integer from 1 to 6,
G1 is H or lower alkyl,
G2 is H or lower alkyl, and
=G3 is lower alkylene of four to six carbon atoms, or lower alkylene of three to five carbon atoms plus one member that is -O-, -S-, or -N(G4)- where G4 is H or lower alkyl;
provided that when Z1 is methyl, Z2, Z3 and Z4 are not all H; or
Figure imgf000073_0001
wherein:
Z5 is H or lower alkyl;
Z8 is H or lower alkyl;
D1 and D2 together with their adjacent carbon atoms form an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring of 3 to 7 atoms; and
G is as defined above; or
Figure imgf000073_0002
wherein:
Z5, Z8 , and G are as defined above; or
Figure imgf000073_0003
wherein:
D3 is -CH2- or -CHjCHz-; and G is as defined above; or
Figure imgf000074_0001
wherein:
Z6 is H, lower alkyl, lower alkoxy, -COOH, -NH2 or halo;
Z7 is H, lower alkyl, lower alkoxy or halo; and
Z5 and G are as defined above; or
Figure imgf000074_0002
wherein:
Z1 and G are as defined above; or
Figure imgf000074_0003
wherein:
D3, Z2, Z3, Z4 and G are as defined above; or
Figure imgf000074_0004
wherein:
D4 is -CH2-, -CH2CH2-, -CH2CH2CH2- , -O-, or -OCH2-; and
Z1 and G are as defined above;
and the pharmaceutically acceptable salts thereof;
which comprises:
a) reacting a compound of Formula I, wherein G is lower alkoxy, lower thioalkyl, NG1G2, O- (CH2)n-NG1G2, or -O-(CH2)n-N=G3, in which n, G1, G2, and G3 are as defined above; with an inorganic base, to form a compound of Formula I wherein G is hydroxy; or
b) reacting a compound of Formula I wherein G is hydroxy, with a compound of the formula GH, where G is lower alkoxy, lower thioalkyl, NG1G2, O-(CH2)n-NG1G2, or O-(CH2)n-N=G3, in which n, G1, G2, and G3 are as defined above, to form a compound of Formula I wherein G is lower alkoxy,
lower thioalkyl, NG1G2, O- (CH2)n-NG1G2, or O- (CH2)n-N=G3, in which n, G1, G2, and G3 are as defined above; or
c) reacting a compound of Formula I wherein R1 is hydrogen, R2 is - C(O)R3 wherein R3 is hydrogen, and G is lower alkoxy, with a compound of the formula HNG1G2, where G1 and G2 are as defined above, to form a compound of Formula I wherein G1 and G2 are as defined above; or
d) reacting a compound of Formula I wherein R1 and R2 are hydrogen, with a compound of the formula (R3C(O))2O or R3C(O)Cl, to form a compound of
Formula I wherein R2 is -C(O)R3 wherein R3 is lower alkyl, halo lower alkyl or optionally substituted phenyl; or
e) reacting a compound of Formula I wherein R1 is hydrogen,
R2 is -C(O)R3, where R3 is lower alkyl, halo lower alkyl or optionally substituted phenyl, and G is lower alkoxy, with a compound of the formula R1X, where R1 is lower alkyl and X is iodine or bromine, to form a compound of Formula I wherein R1 is lower alkyl; or
f) reacting a compound of Formula I to form a pharmaceutically acceptable salt of that compound; or
g) reacting a salt of Formula I to form the corresponding free compound of Formula I; or
h) converting a pharmaceutically acceptable salt of a compound of Formula I to another pharmaceutically acceptable salt of a compound of Formula I.
Preferred Compounds
Among the family of compounds of the present invention, one preferred category includes the compounds where Z is a sidechain of Formula ZA.
Within this category a preferred group includes the compounds where Z1 is hydrogen, especially where R1 is hydrogen and R2 is hydrogen or -C(O)R3. Within this group a preferred subgroup includes the compounds where R2, Z2 and Z3 are all hydrogen, especially where Z4 is methyl. Another preferred subgroup includes the compounds where R2, Z3 and Z3 are all hydrogen, especially where Z2 is methyl.
Another preferred category includes the compounds where Z is a sidechain of Formula ZB, especially where R1 is hydrogen and R2 is hydrogen or -C(O)R3. Within this category a preferred group includes the compounds where D1 and D2 together with the their adjacent carbon atoms form a saturated carbocyclic ring of 5 or 6 carbon atoms. Within this group a preferred subgroup includes the compounds where D1 and D2 together represent -CH2CH2CH2-, especially where Z5 and Z8 are both hydrogen. A preferred class within this subgroup includes the compounds in which R1 and R2 are both hydrogen.
Another preferred subgroup includes the compounds where D1 and D2 together represent -CH2-CH2CH2CH2-, especially where Z5 and Z8 are both hydrogen. A preferred class within this subgroup includes the compounds in which R1 and R2 are both hydrogen.
Yet another preferred subgroup includes the compounds where D1 and D2 together represent -CH2CH2OCH2-, especially where Z5 and Z8 are both
hydrogen. A preferred class within this subgroup includes the compounds in which R1 and R2 are both hydrogen.
At present, the most preferred compounds are:
(E)-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2(S),4-dimethyl-4-hexenoic acid;
(E)-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3(S),4-dimethyl-4-hexenoic acid;
(E)-2-[2-[2-[4-amino-l,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]cyclopent-1(S)-yl]acetic acid;
and
(E)-2-{4-[2-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)ethylidene]tetrahydropyran-3(S)-yl}acetic acid.
Utility, Testing and Administration
General Utility
The compounds of the present invention, the pharmaceutically
acceptable salts thereof and pharmaceutical compositions therewith
(collectively the "compounds" for purposes of the following description) are useful as immunosuppressive agents, anti-inflammatory agents, anti-tumor agents, anti-proliferative agents, anti-viral agents and anti-psoriatic agents in mammals, whether domestic (cattle, pigs, sheep, goats, horses), pets (cats, dogs), or preferably humans. The compounds are inhibitors of inosine monophosphate dehydrogenase (IMPDH) and thus inhibit de novo purine synthesis; they have anti-proliferative effects (e.g., against smooth muscle cells and both B and T lymphocytes) and inhibit antibody formation and the glycosylation of cell adhesion molecules in lymphocytes and endothelial cells.
As immunosuppressive agents, the compounds are useful in treating auto-immune related disorders, for example: Type I Diabetes Mellitus;
Inflammatory Bowel Disease (e.g., Crohn's Disease and ϋlcerative Colitis); Systemic Lupus Erythematosus; Chronic Active Hepatitis; Multiple Sclerosis; Grave 's Disease; Hashimoto's Thyroiditis; Behcet's Syndrome; Myasthenia Gravis; Sjogren's Syndrome; Pernicious Anemia; Idiopathic Adrenal
Insufficiency; and Polyglandular Autoimmune Syndromes Type I and II.
The compounds are also useful as therapeutic immunosuppressive agents in the treatment of Asthma, Immunohemolytic Anemia, Glomerulonephritis, and Hepatitis. Preventative uses of the compounds as immunosuppressive agents include the treatment of allograft rejection, for example, in cardiac, lung, pancreatic, renal, liver, skin and corneal allografts, and prevention of Graft vs. Host Disease.
The compounds are useful for inhibiting proliferative responses to vascular injury, for example, stenosis following an insult to a blood vessel wall in post-angioplasty restenosis, and post-cardiac by-pass surgery restenosis.
The compounds are useful as anti-inflammatory agents, for example, in treating Rheumatoid Arthritis, Juvenile Rheumatoid Arthritis and Uveitis.
As anti-tumor agents, the compounds are useful in treating solid tumors and malignancies of lymphoreticular origin. For example, the compounds' utility for treatment of solid tumors includes: cancers of the head and neck, including squamous cell carcinoma; lung cancer, including small cell and non-small cell lung carcinoma; mediastinal tumors;
esophageal cancer, including squamous cell carcinoma and adenocarcinoma; pancreatic cancer; cancer of the hepatobiliary system, including
hepatocellular carcinoma, cholangiocarcinoma, gall bladder carcinoma and biliary tract carcinoma; small intestinal carcinoma, including
adenocarcinoma, sarcoma, lymphoma and carcinoids; colorectal cancer, including colon carcinoma and rectal carcinoma; metastatic carcinoma;
cancers of the genitourinary system, including ovarian cancer, uterine sarcoma, and renal cell, ureteral, bladder, prostate, urethral, penile, testicular, vulvar, vaginal, cervical, endometrial, and fallopian tube carcinoma; breast cancer; endocrine system cancer; soft tissue sarcomas; malignant mesotheliomas; skin cancer, including squamous cell carcinoma, basal cell carcinoma and melanoma; cancer of the central nervous system; malignant bone tumors; and plasma cell neoplasms.
As anti-tumor agents for the treatment of malignancies of
lymphoreticular origin, the compounds are useful in treating, for example: Lymphomas and Leukemias, including B, T and promonocyte cell line
malignancies, Mycoses Fungoides, Non-Hodgkins Lymphoma, Malignancies of Burkitt Lymphoma Cells and other EBV-transformed B-lymphocytes, Lymphomas resulting from Epstein-Barr viral infections in allograft recipients,
Chronic Lymphocytic Leukemia, Acute Lymphocytic Leukemia and Hairy Cell Leukemia.
As anti-viral agents, the compounds are useful in treating, for example: retroviruses, including Human T-leukemia Viruses, Types I and II (HTLV-1 and HTLV-2) , Human Immuno Deficiency Viruses, Types I and II
(HIV-1, HIV-2) and, Human Nasopharyngeal Carcinoma Virus (NPCV) and in treating Herpes Viruses, including EBV infected B-lymphocytes, CMV infection, Herpes Virus Type 6, Herpes Simplex, Types 1 and 2, (HSV-1, HSV-2) and Herpes Zoster.
As anti-psoriatic agents, the compounds are useful in treating, for example, psoriasis and psoriatic arthritis.
Testing
Activity testing is conducted as described in the following
references, and by modifications thereof.
General anti-inflammatory, anti-viral, anti-tumor, anti-psoriatic and/or immunosuppressive activity is associated with the inhibition of Inosine 5'-Monophosphate Dehydrogenase ("IMPDH"). In vitro assays measuring the inhibition of IMPDH, for example, by determining the level of NADH formation according to the method of Anderson, J.H. and Sartorelli, A.C., J. Biol . Chem. , 243:4762-4768 (1968) are predictive of such activity.
Initial animal screening tests to determine anti-inflammatory activity potential include the adjuvant arthritis assay, e.g., according to the method of Pearson, Proc Soc Exp. Biol . Med. , 91:95-101 (1956). Also, in vitro tests, for example those using synovial explants from patients with rheumatoid arthritis, Dayer, et al., J. Exp. Med. , 145:1399-1404 (1977), are useful in determining whether compounds exhibit anti- inflammatory activity.
Autoimmune activity is determined, for example, utilizing
experimental allergic encephalomyelitis, by a modification of a procedure initially described by Grieg, et. al., J. Pharmacol . Exp. Ther. , 173:85 (1970).
Human clinical trials for efficacy in the treatment of asthma are conducted, e.g., as described by Erzurum, Leff, Cochran, et al. "Lack of benefit of methotrexate in severe, steroid-dependent asthma. A double- blind, placebo controlled study." Ann. Int . Med. , 114:353-360 (1991).
Activity to prevent the rejection of organ or tissue allografts in experimental animals is determined, for example, as described by Hao, et al., J. Immunol . , 139:4022-4026 (1987). In addition, U.S. Patent
No. 4,707,443 and EP 226062, incorporated herein by reference, also describe assays for activity in prevention of allograft rejection by detection of IL-2R levels. Human clinical trials to establish efficacy in preventing rejection of solid organ transplants (such as renal) are conducted, e.g., as described by Lindholm, Albrechtsen, Tufveson, et al., "A randomized trial of cyclosporin and prednisolone versus cyclosporin, azathioprine and prednisolone in primary cadaveric renal transplantation," Transplantation, 54:624-631 (1992). Human clinical trials for graft vs. host disease are conducted, e.g., as described by Storb, Deeg, Whitehead, et al., "Methotrexate and cyclosporin compared with cyclosporin alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia." New England J. Med. , 314:729-735 (1986).
Immunosuppressive activity is determined by both in vivo and in vitro procedures. In vivo activity is determined, e.g., utilizing a modification of the Jerne hemolytic plaque assay, [Jerne, et al., "The agar plaque technique for recognizing antibody producing cells," Cell -bound Antibodies, Amos, B. and Kaprowski, H. editors (Wistar Institute Press, Philadelphia) 1963, p. 109]. In vitro activity is determined, e.g., by an adaptation of the procedure described by Greaves, et al., "Activation of human T and B lymphocytes by polyclonal mitogens," Nature, 248:698-701 (1974).
Anti-viral activity is determined, for example, by the procedure described by Smee, et al. ["Anti-Herpesvirus Activity of the Acyclic
Nucleoside 9-(1,3-Dihydroxy-2-Propoxymethyl)Guanine, " Antimicrobial Agentε and Chemotherapy, 23 (5) :676-682 (1983)], or as described by Planterose
["Antiviral and cytotoxic effects of mycophenolic acid," Journal of
General Virology, 4:629 (1969)].
Anti-viral activity can likewise be determined by measurement of reverse transcriptase activity, for example, according to the method described by Chen et al., Biochem. Pharm. , 36:4361 (1987).
Human clinical trials for anti-HIV efficacy (together with clinical treatment scenarios) are described and cited, for example, by Sande, et al., "Antiretroviral Therapy for Adult HIV-Infected Patients," JAMA,
270(21):2583-2589 (1993). A large scale clinical trial can be conducted, e.g., as described by Volberding, P.A., et al. "Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD4 positive cells per cubic millimeter, " New England J. Med., 322(14):941-949 (1990). A smaller scale (Phase I) clinical trial can be conducted, e.g., as described by Browne, et al., "2 ',3'-Didehydro-3'-deoxythymidine (d4T) in Patients with AIDS or AIDS-Related Complex:
A Phase I Trial," J. Infectious Diseases, 167:21-29 (1993).
Tests for systemic activity in psoriasis can be carried out, for example, as described by Spatz, et al., "Mycophenolic acid in psoriasis," Bri tish Journal of Dermatology, 98:429 (1978).
Tests for anti-tumor activity can be performed, for example, as described by Carter, et al. ["Mycophenolic acid: an anticancer compound with unusual properties," Nature, 223:848 (1969)].
In vitro activity for treating stenosis is demonstrated, for example, by inhibiting the proliferation of smooth muscle cells, as established by the following human arterial smooth muscle cell proliferation assay. Human smooth muscle cells are grown in culture. A test group is treated with the test compound added at selected concentrations in fresh media. Both groups receive 2μCi tritiated thymidine (3HTdR), a radioisotope label. After 24 hours, the cells are harvested and the amount of label incorporated into DNA is counted by scintillation; this is compared for the test and control groups, the amount being proportional to cell proliferation. Inhibition of smooth muscle proliferation is established when the test group has a lower radioisotope count than the control group. The concentrations of test compound required to inhibit proliferation by 50% (the IC50), and to inhibit proliferation by more than 95% are determined.
In vivo activity for treating stenosis is demonstrated, for example, in rat and pig models for arterial stenosis. In the rat model, a test group is treated with the test compound, starting 6 days before and continuing for 14 days after injury to the left carotid artery; the test group is compared to a control group receiving vehicle without the test compound. Injury is achieved by a gentle perfusion of air through a 10 mm long section of the left artery. The right artery is left intact.
Arterial cross-sections (10 μm) are taken from both the left and right arteries of each subject, and the area of the vessel wall (endothelium, intima, media) is measured, The amount of vascular proliferation is calculated by subtracting the mean area of the intact, right carotid artery from the mean area of the injured, left carotid artery. Reduction in vascular proliferation is established when the test group shows less proliferation than the control group.
Human clinical trials for restenosis after coronary angioplasty are conducted, e.g., as described by Serruys, Rutsch, Heyndrickx, et al., "Prevention of restenosis after percutaneous transluminal coronary antioplasty with thromboxane A2-receptor blockade: a randomozed, double-blind, placebo-controlled trial." Circulation, 84:1568-80 (1991).
Administration
The compounds of Formula I are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease states previously described. Administration of the compounds of the invention or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities. The compounds can be used both prophylactically (e.g., to prevent allograft rejection) and therapeutically.
While human dosage levels have yet to be optimized for the compounds of the invention, generally, a daily dose is from about 0.01 to 100.0 mg/kg of body weight, preferably about 0.1 to 64.3 mg/kg of body weight, and most preferably about 0.3 to 43.0 mg/kg of body weight. Thus, for
administration to a 70 kg person, the dosage range would be about 0.7 mg to 7 g per day, preferably about 7.0 mg to 4.5 g per day, and most preferably about 21 mg to 3.0 g per day. The amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration (e.g., oral administration one day prior to cancer
chemotherapy and intravenous administration during cancer chemotherapy) and the judgment of the prescribing physician.
In employing the compounds of this invention for treatment of the above conditions, any pharmaceutically acceptable mode of administration can be used. The compounds of Formula I can be administered either alone or in combination with other pharmaceutically acceptable excipients, including solid, semi-solid, liquid or aerosol dosage forms, such as, for example, tablets, capsules, powders, liquids, injectables, suspensions, suppositories, aerosols or the like. The compounds of Formula I can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for the prolonged administration of the compound at a predetermined rate, preferably in unit dosage forms suitable for single administration of precise dosages. The compositions will typically include a conventional pharmaceutical carrier or excipient and a compound of Formula I or a pharmaceutically acceptable salt thereof. In addition, these compositions may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc., such as multidrug resistance modifying agents, steroids, immunosuppressants such as
cyclosporine A, azathioprene, rapamycin, FK-506, brequinar, leflunomide and vincrystine.
Generally, depending on the intended mode of administration, the pharmaceutically acceptable composition will contain about 0.1% to 90%, preferably about 0.5% to 50%, by weight of a compound or salt of Formula I, the remainder being suitable pharmaceutical excipients, carriers, etc.
One preferred manner of administration for the conditions detailed above is oral, using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. For such oral
administration, a pharmaceutically acceptable composition is formed by the incorporation of any of the normally employed excipients, such as, for example, mannitol, lactose, starch, povidone, magnesium stearate, sodium saccharine, talcum, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate, and the like. Such compositions take the form of solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations and the like.
Preferably the compositions will take the form of a pill or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; a disintegrant such as croscarmellose sodium or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose and derivatives thereof, and the like.
Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, suspending agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, sodium acetate, sodium citrate, cyclodextrine derivatives, polyoxyethylene, sorbitan monolaurate or stearate, etc.
Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington 's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 15th Edition, 1975. The composition or formulation to be administered will, in any event, contain a quantity of the active compound in an amount effective to alleviate the symptoms of the subject being treated.
Dosage forms or compositions containing active ingredient in the range of 0.005% to 95% with the balance made up from pharmaceutically acceptable carrier may be prepared.
For oral administration, a pharmaceutically acceptable composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, povidone, cellulose derivatives, croscarmellose sodium, glucose, sucrose, magnesium carbonate, sodium saccharin, talcum and the like. Such compositions take the form of solutions, suspensions, tablets, capsules, powders, sustained release formulations and the like. Such compositions may contain 0.01%-95% active ingredient, preferably 0.1-50%.
For a solid dosage form containing liquid, the solution or
suspension, in for example propylene carbonate, vegetable oils or
triglycerides, is preferably encapsulated in a gelatin capsule. Such ester solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Patents Nos. 4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g. in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g. water, to be easily measured for administration.
Alternatively, liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g. propylene carbonate) and the like, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
Other useful formulations include those set forth in U.S. Patents Nos. Re. 28,819 and 4,358,603.
Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously. Injectables can be prepared in conventional forms, either as liquid solutions or
suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, solubility enhancers, and the like, such as for example, sodium acetate, polyoxyethylene, sorbitan monolaurate, triethanolamine oleate, cyclodextrins, etc.
A more recently devised approach for parenteral administration employs the implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained. See, e.g., U.S. Patent No. 3,710,795.
The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.01% to 10% in solution are
employable, and will be higher if the composition is a solid which will be subsequently diluted to the above percentages. Preferably the composition will comprise 0.2-2% of the active agent in solution.
Formulations of the active compound or a salt may also be
administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in
combination with an inert carrier such as lactose. In such a case, the particles of the formulation have diameters of less than 50 microns, preferably less than 10 microns.
EXAMPLES
The following examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.
PREPARATION 1
Preparation of Compounds of Formula 1
IA. Preparation of 1 where Z is ZA, in which Z1 is Methyl, Z2, Z3, and Z4 are Hydrogen. and G is Methoxy
A solution of 15.1 g (47.1 mmol) of (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid
(mycophenolic acid) and 0.7 g (3.7 mmol) of p-toluenesulfonic acid in 400 ml of methanol was allowed to stand at room temperature for 3 days.
The mixture was concentrated under reduced pressure to approximately 75 ml and then partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic phase was further washed with brine and then dried over sodium sulfate. Concentration of the organic phase under reduced pressure gave 15.4 g (46.0 mmol, 98%) of methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate as a white solid, mp 104-105°C.
1B. Preparation of 1, varying Z
Similarly, following the procedures of Preparation 1A above, but replacing (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoιsobenzofuran-5-yl)-4-methyl-4-hexenoic acid with:
(E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oyoisobenzofuran-5-yl)-2(RS),4-dimethyl-4-hexenoic acid;
(E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2(R),4-dimethyl-4-hexenoic acid;
(E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2(S),4-dimethyl-4-hexenoic acid;
(E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3(RS),4-dimethyl-4-hexenoic acid;
(E)-2-[2-[2-[1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl]ethylidene]cyclopent-1(S)-yl]acetic acid;
(E)-2-[2-[2-[1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]cyclohex-1(RS)-yl]acetic acid;
(E)-2-[2-[2-[1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]cyclohex-1(S)-yl]acetic acid; and
(E)-2-{4-[2-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)ethylidene]tetrahydropyran-3(RS)-yl}acetic acid;
and optionally replacing methanol by ethanol, the following intermediates of Formula 1 were prepared:
ethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2(RS),4-dimethyl-4-hexenoate, mp 59-63°C;
methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2(R),4-dimethyl-4-hexenoate;
methyl (E)-6-(l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2(S),4-dimethyl-4-hexenoate;
methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3(RS),4-dimethyl-4-hexenoate;
methyl (E)-2-[2-[2-[1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]cyclopent-1(S)-yl]acetate;
methyl (E)-2-[2-[2-[l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]cyclohex-1(RS)-yl]acetate, mp 92-99°C; ethyl (E)-2-[2-[2-[l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]cyclohex-1(S)-yl]acetate, mp 72-74°C; and methyl (E)-2-{4-[2-(l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)ethylidene]tetrahydropyran-3(RS)-yl}acetate.
1C. Preparation of 1. varying Z
Similarly, following the procedures of Preparation 1A above, but optionally replacing (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid with other compounds of Formula (1) where Z is a sidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G is hydroxy, and optionally replacing methanol with other alkanols of formula GH, where G is lower alkoxy, other intermediates of Formula 1 in which Z is a sidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G is lower alkoxy, are prepared.
PREPARATION 2
Preparation of Compounds of Formula 2
2A. Preparation of 2 where Z is ZA. in which Z' is Methyl. Z2, Z3, and Z4 are Hydrogen, and G is Methoxy
To a 0°C solution of 4.59 g (13.7 mmol) of methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate and 2.22 ml (27.4 mmol) of pyridine in 100 ml of methylene chloride was added 2.55 ml (15.1 mmol) of trifluoromethanesulfonic anhydride dropwise. After 30 minutes, the reaction mixture was poured into 1N aqueous sodium hydrogen sulfate. This mixture was extracted with dichloromethane, and the organic phase was further washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Trituration of the residue with hexane gave 5.7 g of methyl (E)-6-(1,3- dihydro-6-methoxy-7-methyl-4-trifluoromethylsulfonyloxy-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate as a white solid, mp 53-55°C.
2B. Preparation of 2, varying Z
Similarly, following the procedures of Preparation 2A above, but replacing methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate with other compounds of Formula 1, the following intermediates of Formula 2 were prepared:
ethyl (E)-6-(1,3-dihydro-6-methoxy-7-methyl-4-trifluoromethylsulfonyloxy-3-oxoisobenzofuran-5-yl)-2(RS),4-dimethyl-4-hexenoate, oil;
methyl (E)-6-(1,3-dihydro-6-methoxy-7-methyl-4-trifluoromethylsulfonyloxy-3-oxoisobenzofuran-5-yl)-2(R),4-dimethyl-4-hexenoate;
methyl (E)-6-(1,3-dihydro-6-methoxy-7-methyl-4-trifluoromethylsulfonyloxy-3-oxoisobenzofuran-5-yl)-2(S),4-dimethyl-4-hexenoate;
methyl (E)-6-(1,3-dihydro-6-methoxy-7-methyl-4-trifluoromethylsulfonyloxy-3-oxoisobenzofuran-5-yl)-3(RS),4-dimethyl-4-hexenoate;
ethyl (E)-2-[2-[2-[1,3-dihydro-6-methoxy-7-methyl-4-trifluoromethylsulfonyloxy-3-oxoisobenzofuran-5-yl]ethylidene]cyclopent-1(S)-yl]acetate, oil;
methyl (E)-2-[2-[2-[1,3-dihydro-6-methoxy-7-methyl-4-trifluoromethylsulfonyloxy-3-oxoisobenzofuran-5-yl]ethylidene]cyclohex-1(RS)-yl]acetate, oil;
ethyl (E)-2-[2-[2-[1,3-dihydro-6-methoxy-7-methyl-4-trifluoromethylsulfonyloxy-3-oxoisobenzofuran-5-yl]ethylidene]cyclohex-1(S)-yl]acetate, oil; and
methyl (E)-2-{4-[2-(1,3-dihydro-6-methoxy-7-methyl-4-trifluoromethylsulfonyloxy-3-oxoisobenzofuran-5-yl)ethylidene]tetrahydropyran-3(RS)-yl}acetate.
2C. Preparation of 2. varying Z
Similarly, following the procedures of Preparation 2A above, but replacing methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate with other compounds of Formula 1 where Z is a sidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G is lower alkoxy, other intermediates of Formula 2 are prepared.
PREPARATION 3
Preparation of Compounds of Formula 3
3A. Preparation of 3 where Z is ZA, in which Z' is Methyl. Z2. Z3. and Z4 are Hydrogen, and G is Methoxy
A nitrogen-flushed mixture of 5.8 g (12.4 mmol) of methyl (E)-6-(1,3-dihydro-6-methoxy-7-methyl-4-trifluoromethyl-sulfonyloxy-3- oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate, 1.5 g (23.0 mmol) of potassium cyanide, and 1.11 g (0.96 mmol) of tetrakis (triphenylphosphine) palladium in 100 ml of 1,4-dioxane was heated at reflux for 18 hours. Upon cooling, the mixture was partitioned between water and ethyl acetate. The organic phase was washed with water six times, with brine once, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting solid was stirred with hexane for 18 hours and then filtered off. This solid was further purified by silica gel chromatography using 5:4 hexane:ethyl acetate to give 4.0 g (11.7 mmol) of methyl (E)-6-(4-cyano-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate, mp 87-88°C.
3B. Preparation of 3. varying Z
Similarly, following the procedures of Preparation 3A above, but replacing methyl (E)-6-(l,3-dihydro-6-methoxy-7-methyl-4-trifluoromethylsulfonyloxy-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate with other compounds of Formula 2, the following intermediates of Formula 3 were prepared:
ethyl (E)-6-(4-cyano-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2(RS),4-dimethyl-4-hexenoate, mp 63-66°C;
methyl (E)-6-(4-cycmo-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2(R),4-dimethyl-4-hexenoate;
methyl (E)-6-(4-cyano-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2(S),4-dimethyl-4-hexenoate;
methyl (E)-6-(4-cyano-l,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3(RS),4-dimethyl-4-hexenoate;
ethyl (E)-2-[2-[2-[4-cyano-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]cyclopent-1(S)-yl]acetate, oil;
methyl (E)-2-[2-[2-[4-cyano-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]cyclohex-1(RS)-yl]acetate, mp 150-151°C; ethyl (E)-2-[2-[2-[4-cyano-l,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]cyclohex-1(S)-yl]acetate, mp 126-128°C; and
methyl (E)-2-{4-[2-(4-cyano-l,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)ethylidene]tetrahydropyran-3(RS)-yl}acetate.
3C. Preparation of 3. varying Z
Similarly, following the procedures of Preparation 3A above, but replacing methyl (E)-6-(1,3-dihydro-6-methoxy-7-methyl-4-trifluoromethylsulfonyloxy-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate with other compounds of Formula 2, where Z is a sidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G is lower alkoxy, other
intermediates of Formula 3 are prepared:
PREPARATION 4
Preparation of Compounds of Formula 4
4A. Preparation of 4 where Z is ZA. in which Z1 is Methyl, Z2, Z3, and Z4 are Hydrogen, and G is Hvdroxy A mixture of 4.0 g (11.7 mmol) of methyl (E)-6-(4-cyano-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate and 1.86 g (46.5 mmol) of sodium hydroxide in 100 ml of 3:2 water:methanol was heated at reflux for 2 hours. The resulting homogenous solution was distilled until 30 ml of distillate was recovered. An additional 0.6 g (15 mmol) of sodium hydroxide was added to the reaction solution and it was refluxed for
2 days . Upon cooling the solution was partitioned between 1N aqueous HCl and ethyl acetate. The organic phase was washed twice with water, once with brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a solid. This solid was stirred with hexane and then filtered off to give 3.88 g (11.1 mmol) of (E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid as a white solid, mp 172-174°C.
4B. Preparation of 4. varying Z
Similarly, following the procedures of Preparation 4A above, but replacing methyl (E)-6-(l,3-dihydro-4-cyano-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate with other compounds of Formula 3, the following intermediates of Formula 4 were prepared:
(E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2(RS),4-dimethyl-4-hexenoic acid, mp 149-150ºC;
(E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2(R),4-dimethyl-4-hexenoic acid;
(E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-y1)-2(S),4-dimethyl-4-hexenoic acid;
(E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3(RS),4-dimethyl-4-hexenoic acid;
(E)-2-[2-[2-[4-carboxy-l,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]cyclopent-1(S)-yl]acetic acid, mp 142-148°C;
(E)-2-[2-[2-[4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]cyclohex-1(RS)-yl]acetic acid, mp 194-195°C;
(E)-2-[2-[2-[4-carboxy-l,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]cyclohex-1(S)-yl]acetic acid, mp 193-197°C; and
(E)-2-{4-[2-(4-carboxy-l,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)ethylidene]tetrahydropyran-3(RS)-yl}acetic acid.
4C. Preparation of 4 , varying Z
Similarly, following the procedures of Preparation 4A above, but replacing methyl (E)-6-(4-cyano-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate with other compounds of Formula
3 where Z is a sidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G is lower alkoxy, other intermediates of Formula 4 where G is hydroxy are prepared. PREPARATION 5
Preparation of Compounds of Formula 5
5A. Preparation of 5 where Z is ZA. in which Z1 is Methyl, Z2, Z3. and Z4 are Hydrogen, and G is Methoxy
A solution of 3.88 g (11.1 mmol) of (E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid and 0.2 g (1.0 mmol) of p-toluenesulfonic acid in methanol (60 ml) was stirred at room temperature for 8 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and this solution was washed twice with water, once with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a solid which was recrystallized from ethyl acetate to give 3.37 g (9.3 mmol) of methyl (E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate as a white solid, mp 169-170°C.
5B. Preparation of 5. varying Z
Similarly, following the procedures of Preparation 5A above, but replacing (E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid with other compounds of Formula 4, the following intermediates of Formula 5 were prepared:
methyl (E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2(RS),4-dimethyl-4-hexenoate, mp 157-159°C;
methyl (E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2(R),4-dimethyl-4-hexenoate;
methyl (E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2(S),4-dimethyl-4-hexenoate;
methyl (E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3(RS),4-dimethyl-4-hexenoate;
methyl (E)-2-[2-[2-[4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]cyclopent-1(S)-yl]acetate, mp 145-146°C; methyl (E)-2-[2-[2-[4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]cyclohex-1(RS)-yl]acetate, mp 155-157°C; methyl (E)-2-[2-[2-[4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]cyclohex-1(S)-yl]acetate, mp 156-157°C; and
methyl (E)-2-{4-[2-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)ethylidene]tetrahydropyran-3(RS)-yl}acetate.
5C. Preparation of 5. varying Z
Similarly, following the procedures of Preparation 5A above, but replacing (E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid with other compounds of
Formula 4 where Z is a sidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G is hydroxy, and optionally replacing methanol with other alkanols of formula GH, where G is lower alkoxy, other intermediates of Formula 5 where G is lower alkoxy are prepared. PREPARATION 6
Preparation of Compounds of Formula 6
6A. Preparation of 6 where Z is ZA. in which Z1 is Methyl. Z2, Z3, and Z4 are Hydrogen, and G is Methoxy
To a stirred, 0°C solution of 6.0 g (16.6 mmol) of methyl (E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate in 150 ml of dimethylformamide was added 4.62 ml (33.1 mmol) of triethylamine followed by dropwise addition of 4.5 ml (21.8 mmol) of diphenylchlorophosphate. The mixture was allowed to stir at room
temperature for 1 hour and then recooled to 0°C, and treated with 10.8 g (166 mmol) of sodium azide. This mixture was stirred for 24 hours at 0°C and then partitioned between aqueous sodium hydrogen sulfate and ethyl acetate. The organic phase was washed four times with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with hexane to give 5.8 g of methyl (E)-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate. A small sample was further purified by rapid silica gel chromatography with an eluant of 1:1 hexane:ethyl acetate followed by recrystallization from hexane-ethyl acetate to give purified methyl (E)-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate, mp 95-101°C.
6B. Preparation of 6. varying Z
Similarly, following the procedures of Preparation 6A above, but replacing methyl (E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate with other compounds of Formula 5, the following intermediates of Formula 6 were prepared:
methyl (E)-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2(RS),4-dimethyl-4-hexenoate;
methyl (E)-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2(R),4-dimethyl-4-hexenoate;
methyl (E)-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2(S),4-dimethyl-4-hexenoate;
methyl (E)-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3(RS),4-dimethyl-4-hexenoate;
methyl (E)-2-[2-[2-[1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]cyclopent-1(S)-yl]acetate;
methyl (E)-2-[2-[2-[1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]cyclohex-1(RS)-yl]acetate;
methyl (E)-2-[2-[2-[1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]cyclohex-1(S)-yl]acetate; and
methyl (E)-2-{4-[2-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)ethylidene]tetrahydropyran-3(RS)-yl}acetate.
6C. Preparation of 6, varying Z
Similarly, following the procedures of Preparation 6A above, but replacing methyl (E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate with other compounds of Formula 5 where Z is a sidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G is lower alkoxy, other intermediates of Formula 6 where G is lower alkoxy are prepared.
EXAMPLE 1
Preparation of Compounds of Formula I
IA. Formula IA where Z is ZA, in which Z1 is Methyl. Z2, Z3, and Z4 are Hydrogen, and G is Hydroxy
2.0 g (5.5 mmol) of methyl (E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate, a compound of
Formula 5, was converted to crude methyl E-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate, a compound of Formula 6, as described in Preparation 6 above without purification. The resulting 4-isocyanate was redissolved in 50 ml of 1,4-dioxane and treated with 16 ml of water and 2.0 g (47.7 mmol) of lithium hydroxide monohydrate. The mixture was stirred at room temperature for 2 hours and then partitioned between aqueous IN sodium hydrogen sulfate and ethyl acetate. The organic phase was washed twice with water, once with brine, and was dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel, using 50:40:1 hexane:ethyl acetate:acetic acid as eluant to give 1.28 g (4.0 mmol) of (E)-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid as a white solid,
mp 130-131°C.
1B. Preparation of IA, varying Zb
Similarly, following the procedures of Example IA above, but replacing methyl E-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate with other compounds of Formula 6, in which Za is as defined above, the following compounds of Formula IA in which Zb is as defined above were prepared:
(E)-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2(RS),4-dimethyl-4-hexenoic acid, mp 173-174°C (tert butylmethyl ether);
(E)-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2(R),4-dimethyl-4-hexenoic acid, mp 133-136°C (tert butylmethyl ether/hexane);
(E)-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2(S),4-dimethy1-4-hexenoic acid, mp 133-136°C (tert butylmethyl ether);
(E)-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3(RS),4-dimethyl-4-hexenoic acid;
(E)-2-[2-[2-[4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]cyclopent-1(S)-yl]acetic acid,
mp 152-153°C (ethyl acetate/hexane);
(E)-2-[2-[2-[4-amino-l,3-dihydro-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl]ethylidene]cyclohex-1(RS)-yl]acetic acid, mp 163-177°C (tert butylmethyl ether/hexane);
(E)-2-[2-[2-[4-amino-1,3-dihydro-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl]ethylidene]cyclohex-1(S)-yl]acetic acid, mp 175-177°C (tert butylmethyl ether); and
(E)-2-{4-[2-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)ethylidene]tetrahydropyran-3(RS)-yljacetic acid. 1C. Preparation of IA, varying Z in which G is Hydroxy
Similarly, following the procedures of Example IA above, but replacing methyl E-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate with other compounds of Formula 6, in which Za is a sidechain of Formula Z as defined in the Summary of the Invention in which G is lower alkoxy, the corresponding compounds of Formula IA in which G is hydroxy are prepared:
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000092_0002
Figure imgf000092_0003
Figure imgf000093_0001
Figure imgf000094_0001
EXAMPLE 2
Preparation of Compounds of Formula I
2A. Formula IA where Z is ZA, in which Z1 is Methyl, Z2, Z3, and Z4 are Hydrogen, and G is Methoxy
To a solution of 2.5 g (7.8 mmol) of (E)-6-(4-amino-l,3-dihydro-6- methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid in 50 ml (1.234 mol) of metheinol was added 0.125 g (0.66 mmol) of p-toluenesulfonic acid monohydrate. The solution was stirred at room temperature for 2 days and then concentrated to a small volume. The residue was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to a solid. Recrystallization of this solid from hexane-ethyl acetate gave 2.48 g of methyl (E)-6-(4-amino-1,3- dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate, mp 91-93°C.
2B. Preparation of IA, varying Z in which G is Lower Alkoxy
Similarly, following the procedures of Example 2A above, but optionally replacing (E)-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid with other compounds of Formula IA where Z is a sidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G is hydroxy, and optionally replacing methanol with other alkanols of formula GH, where G is lower alkoxy, the corresponding compounds of Formula IA where G is lower alkoxy are prepared.
EXAMPLE 3
Preparation of Compounds of Formula I
3A. Formula IA where Z is ZA. in which Z1 is Methyl. Z2, Z3, and Z4 are Hydrogen, and G is Morpholinoethoxy
7g (0.02 moles) of (E)-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid and toluene (25ml) are warmed gently to form a solution. A slight excess (1.05 molar equivalents) of 2-morpholinoethanol (3g, 0.021 moles) and toluene (25ml) are added. The reaction mixture is stirred for half an hour and then heated to reflux at an initial pot temperature of 117°C (which increases a few degrees during reflux) under a Dean-Stark trap for 80 hours. The reaction mixture is cooled, washed with water (2 × 15ml), 10% aqueous sodium bicarbonate
(2 × 15ml) and finally with water (15ml). The toluene layer is stripped to a volume of about 20ml in vacuo. n-hexane (30ml) is added and the resulting slurry is aged at room temperature for 2 hours. The product is filtered, washed with n-hexane (ca. 10 ml) and dried in vacuo at 60°C to yield
2-(morpholin-4-yl)ethyl (E)-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate.
3B. Preparation of IA, varying Z in which G is Morpholinoethoxy
Similarly, following the procedures of Example 3A above, but replacing (E)-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid with other compounds of Formula IA where Z is a sidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G is hydroxy, the corresponding compounds of Formula IA where G is
morpholinoethoxy are prepared.
EXAMPLE 4
Preparation of Compounds of Formula I
4A. Formula IB where R4 and R5 are Methyl, and Z is ZA. in which Z1 is Methyl. Z2, Z3, and Z4 are Hydrogen, and G is Methoxy
A solution of 0.65 g (1.8 mmol) of methyl (E)-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate in 10 ml of tetrahydrofuran was treated with 5 ml of a solution of 40% dimethylamine in water. After 1 hour the reaction was partitioned between water and ethyl acetate. The organic phase was washed with water three times, dried over magnesium sulfate, and concentrated under reduced pressure to give 0.4 g of methyl (E)-6-[1,3-dihydro-4-(3,3-dimethylureido)-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate,
mp 116-118°C.
4B. Preparation of IB, varying Z
Similarly, following the procedures of Example 4A above, but replacing methyl (E)-6-(l,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate with other compounds of Formula 6 where Z is a sidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF, ZG, or ZH, in which G is lower alkoxy, the corresponding compounds of Formula 1B where G is lower alkoxy are prepared.
EXAMPLE 5
Preparation of Compounds of Formula I
5A. Formula IB where R4 and R5 are Methyl, and Z is ZA. in which Z1 is Methyl, Z2, Z3, and Z4 are Hydrogen, and G is Hydroxy
To a solution of 0.3 g (0.74 mmol) of methyl (E)-6-[1,3-dihydro-4- (3,3-dimethylureido)-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl- 4-hexenoate in 7.4 ml of 4:1 methanol :water was added 0.13 g (2.96 mmol) of lithium hydroxide monohydrate. The solution was heated at 50-60°C for 4 hours. Upon cooling, the reaction was partitioned between aqueous sodium hydrogen sulfate and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to (E)-6-[1,3- dihydro-4-(3,3-dimethylureido)-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]- 4-methyl-4-hexenoic acid. Recrystallization from hexane-ethyl acetate gave 0.27 g (0.7 mmol) of (E)-6-[1,3-dihydro-4-(3,3-dimethylureido)-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoic acid, mp 170-190°C. 5B. Preparation of IB, varying R4, R5, and Z in which G is Hydroxy
Similarly, following the procedures of Example 5A above, but replacing methyl (E)-6-[1,3-dihydro-4-(3,3-dimethylureido)-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate with other compounds of Formula 1B where Z is a sidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G is lower alkoxy, the following compounds of Formula 1B where G is hydroxy are prepared:
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000097_0002
Figure imgf000098_0001
Figure imgf000098_0002
Figure imgf000099_0001
Figure imgf000099_0002
EXAMPLE 6
Preparation of Compounds of Formula I
6A. Formula IC where R3 is -CH- or -CF3, and Z is ZA, in which Z1 is Methyl. Z2, Z3. and Z4 are Hydrogen, and G is Methoxy To a solution of 0.5 g (1.5 mmol) of methyl (E)-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate in 5 ml of dichloromethane was added 0.5 ml (3.5 mmol) of trifluoroacetic anhydride. After 1 hour the reaction was partitioned between water and dichloromethane. The organic layer was washed twice with water, dried over magnesium sulfate, and concentrated to a solid. Recrystallization of this solid from hexane-ethyl acetate gave 0.520 g of methyl (E)-6-[1,3-dihydro-6-methoxy-7-methyl-4-trifluoroacetylamino-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate as a white solid, mp 107-109°C.
6B. Formula IC where R3 is -CF3, and Z is ZA, in which Z1 is Methyl, Z2, Z3, and Z4 are Hydrogen, and G is Morpholinoethoxy
By following the procedure of Example 3A above, but replacing E-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid by (E)-6-[1,3-dihydro-6-methoxy-7-methyl-4-trifluoroacetylamino-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoic acid, the following compound is obtained:
2-(morpholin-4-yl)ethyl (E)-6-[1,3-dihydro-6-methoxy-7-methyl-4-trifluoroacetylamino-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate.
6C. Formula IC where R3 is -CF3, and Z is ZA, in which Z1 is Methyl. Z2. Z3, and Z4 are Hydrogen, and G is Hydroxy
By following the procedure of Example 6A above, but replacing methyl (E)-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate by methyl (E)-6-[1,3-dihydro-amino-6-methoxy-7-methyl-4-trifluoroacetylamino-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate and methyl (E)-6-[4-acetamido-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate, the following compounds were obtained:
(E)-6-[1,3-dihydro-6-methoxy-7-methyl-4-trifluoroacetylamino-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoic acid, mp 140-141°C; and
(E)-6-[4-acetamido-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran- 5-yl]-4-methyl-4-hexenoic acid, mp 206-210°C.
6D. Preparation of IC, varying R3 and Z
Similarly, following the procedures of Example 6A, 6B, and/or 6C above, but optionally replacing methyl (E)-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate with other compounds of Formula IA where Z is a sidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G is lower alkoxy, and replacing
trifluoroacetic anhydride with other compounds of the formula (R3C(O))2O or of the formula R3C(O)Cl, where R3 is as defined in the Summary of the
Invention, the following compounds of Formula IC where G is hydroxy are prepared:
Figure imgf000101_0001
Figure imgf000101_0002
Figure imgf000102_0001
Figure imgf000102_0002
Figure imgf000103_0001
Figure imgf000103_0002
Figure imgf000104_0001
EXAMPLE 7
Preparation of Compounds of Formula I
7A. Formula ID where R1 is Methyl. R3 is -CF3, and Z is ZA, in which Z1 is Methyl. Z2, Z3, and Z4 are Hydrogen, and G is Methoxy
To a solution of 0.35 g (0.82 mmol) of methyl (E)-6-[1,3-dihydro-6- methoxy-7-methyl-4-(trifluoroacetylamino)-3-oxoisobenzofuran-5-yl]-4- methyl-4-hexenoate in 4 ml of dimethylformamide was added 0.47 g
(3.40 mmol) of potassium carbonate and 0.23 ml (3.69 mmol) of iodomethane. The mixture was stirred for 24 hours and then partitioned between ethyl acetate and water. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give methyl (E)-6-[1,3-dihydro-6-methoxy-7-methyl-4-(N-trifluoroacetyl-N-methylamino)- 3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate, an oil.
NMR: δ 5.22-5.17 (multiplet ("m"), 2H) ; 5.10-5.04 (broad triplet, 1H); 3.81 (singlet ("s"), 3H); 3.62 (s, 3H); 3.42-3.27 (m, 5H); 2.45-2.25 (m, 5H); 1.75 (s, 3H).
7B. Preparation of ID. varying R1, R3, and Z
Similarly, following the procedures of Example 7A above, but optionally replacing methyl (E)-6-[1,3-dihydro-6-methoxy-7-methyl-4- (trifluoroacetylamino)-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate with other compounds of Formula IC where Z is a sidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G is lower alkoxy, and optionally replacing iodomethane by other lower alkyl halides of the formula R1Br or R1I, the following compounds of Formula ID are prepared:
Figure imgf000105_0001
Figure imgf000105_0002
Figure imgf000106_0001
Figure imgf000106_0002
Figure imgf000107_0001
Figure imgf000107_0002
Figure imgf000108_0001
7C. Preparation of ID, varying R1. R3, and Z
Hydrolysis of the compounds of Formula ID where G is lower alkoxy to compounds of Formula ID where G is hydroxy is accomplished as shown in Example 5A above.
Conversion of the compounds of Formula ID where G is hydroxy to compounds of Formula ID where G is lower alkoxy or morpholinoethoxy is accomplished as shown in Example 2A or 6B above.
EXAMPLE 8
Preparation of Compounds of Formula I
8A. Formula IE where R1 is Methyl and Z is ZA, in which Z1 is Methyl, Z2, Z3, and Z4 are Hydrogen, and G is Hydroxy
Hydrolysis of (E)-6-[1,3-dihydro-6-methoxy-7-methyl-4- (N-trifluoroacetyl-N-methylamino)-3-oxoisobenzofuran-5-yl]-4-methyl-4- hexenoic acid was carried on the same manner as shown in Example 5A, to give (E)-6-(1,3-dihydro-6-methoxy-7-methyl-4-methylamino-3- oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid, mp 121-124°C.
8B. Preparation of IE, varying R1 and Z
Similarly, following the procedures of Example 8A above, but replacing (E)-6-[1,3-dihydro-6-methoxy-7-methyl-4-(N-trifluoroacetyl-N- methylamino)-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoic acid with other compounds of Formula ID where Z is a sidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G is lower alkoxy or hydroxy, the following compounds of Formula IE are prepared:
Figure imgf000109_0001
Figure imgf000109_0002
Figure imgf000110_0001
Figure imgf000110_0002
Figure imgf000111_0001
Figure imgf000111_0002
Figure imgf000112_0001
Conversion of the compounds of Formula IE where G is hydroxy to compounds of Formula IE where G is lower alkoxy or morpholinoethoxy is accomplished as shown in Examples 2A or 6B above.
EXAMPLE 9
This example illustrates the preparation of a representative pharmaceutical formulation for oral administration containing an active compound of Formula I, e.g., (E)-6-(1,3-dihydro-4-amino-6-methoxy-7-methyl- 3-oxoisobenzofuran-5-yl)-2,4-dimethyl-4-hexenoic acid.
Ingredients Quantity per
tablet, mgs.
Active Compound 200
Lactose, spray-dried 148
Magnesium stearate 2
The above ingredients are mixed and introduced into a hard-shell gelatin capsule.
Other compounds of Formula I, such as those prepared in accordance with Examples 1-8, can be used as the active compound in the preparation of the orally administrable formulations of this example.
EXAMPLE 10
This example illustrates the preparation of another representative pharmaceutical formulation for oral administration containing an active compound of Formula I, e.g., (E)-6-(1,3-dihydro-4-amino-6-methoxy-7-methyl- 3-oxoisobenzofuran-5-yl)-2,4-dimethyl-4-hexenoic acid.
Ingredients Quantity per
tablet, mgs.
Active Compound 400
Cornstarch 50
Croscarmellose sodium 25
Lactose 120
Magnesium stearate 5
The above ingredients are mixed intimately and pressed into single scored tablets.
Other compounds of Formula I, such as those prepared in accordance with Examples 1-8, can be used as the active compound in the preparation of the orally administrable formulations of this example.
EXAMPLE 11
This example illustrates the preparation of a representative pharmaceutical formulation containing an active compound of Formula I, e.g., (E)-6-(1,3-dihydro-4-amino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2,4-dimethyl-4-hexenoic acid.
An oral suspension is prepared having the following composition.
Ingredients
Active Compound 1.0 g
Fumaric acid 0.5 g
Sodium chloride 2.0 g
Methyl paraben 0.15 g
Propyl paraben 0.05 g
Granulated sugar 25.5 g
Sorbitol (70% solution) 12.85 g
Veegum K (Vanderbilt Co.) 1.0 g
Flavoring 0.035 ml
Colorings 0.5 mg
Distilled water q.s. to 100 ml
Other compounds of Formula I, such as those prepared in accordance with Examples 1-8, can be used as the active compound in the preparation of the orally administrable formulations of this example.
EXAMPLE 12
This example illustrates the preparation of a representative pharmaceutical formulation for oral administration containing an active compound of Formula I, e.g., (E)-6-(1,3-dihydro-4-amino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2,4-dimethyl-4-hexenoic acid.
An injectable preparation buffered to a suitable pH is prepared having the following composition:
Ingredients
Active Compound 0.2 g
Sodium Acetate Buffer Solution (0.4 M) 2.0 ml
HCL (1N) or NaOH (1N) q.s. to pH 4
Water (distilled, sterile) q.s. to 20 ml
Other compounds of Formula I, such as those prepared in accordance with Examples 1-8, can be used as the active compound in the preparation of the injectable formulations of this example.
EXAMPLE 13
This example illustrates the preparation of a representative pharmaceutical formulation for topical application containing an active compound of Formula I, e.g., (E)-6-(1,3-dihydro-4-amino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2,4-dimethyl-4-hexenoic acid.
Ingredients grams
Active compound 0.2-10
Span 60 2
Tween 60 2
Mineral oil 5
Petrolatum 10
Methyl paraben 0.15
Propyl paraben 0.05
BHA (butylated hydroxy anisole) 0.01 Water q.s. to 100
All of the above ingredients, except water, are combined and heated to 60°C with stirring. A sufficient quantity of water at 60°C is then added with vigorous stirring to emulsify the ingredients, and water then added q.s. 100 g.
Other compounds of Formula I, such as those prepared in accordance with Examples 1-8, can be used as the active compound in the preparation of the topical formulations of this example.
EXAMPLE 14
This example illustrates the preparation of a representative pharmaceutical formulation containing an active compound of Formula I, e.g., (E) -6-(1,3-dihydro-4-amino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2,4-dimethyl-4-hexenoic acid.
A suppository totalling 2.5 grams is prepared having the following composition:
Ingredients
Active Compound 500 mg
Witepsol H-15* balance
Ctriglycerides of saturated vegetable fatty acid; a product of Riches-Nelson, Inc., New York, N.Y.)
Other compounds of Formula I, such as those prepared in accordance with Examples 8-22, can be used as the active compound in the preparation of the suppository formulations of this example.
EXAMPLE 15
In Vitro Determination of Therapeutic Activity
(As an Anti-Inflammatory, Anti-Viral, Anti-Tumor,
Anti-Psoriatic and/or Immunosuppressive Agent) Utilizing the Inhibition of IMP Dehydrogenase Assay
This assay is a modification of the method of Anderson, J.H. and Sartorelli, A.C., Jour. Biol . Chem, 243:4762-4768 (1968). It measures the formation of NADH (λmax = 340 nm, ∊340 = 6,220 M-1cm-1) as Inosine
5'-monophosphate ("IMP") is converted to Xanthosine 5'-monophosphate ("XMP") by the human Type II IMP dehydrogenase ("IMPDH").
Compounds are dissolved and diluted in DMSO, and reaction solutions containing compounds at 0, 0.01, 0.10, 1.0, 10, and 100μM are prepared in disposable methacrylic plastic microcuvets ('UV-transparent' plastic, 1 cm pathlength, 1.5 ml capacity). The solutions (0.5-1 ml) contain the following: 0.1 M TrisHCL, pH 8.0; 0.1 M KCL; 3.0 mM EDTA; 100 μg/ml BSA; 0.05 mM IMP; 0.10 mM NAD; 10% DMSO; 5-15 nM IMPDH (0.003-0.010 units/ml; one unit of enzyme catalyzes the formation of one μmol NADH per minute at 40°C at saturating substrate concentrations - 200 μM IMP and 400 μM NAD). Reactions are performed at 40°C and initiated by the addition of enzyme. Mycophenolic acid (IC50 ≈ 0.02μM) serves as the positive control. The reactions are monitored at 340 nm for 10 minutes in a UV/VIS spectrophotometer, and rate data are collected.
The 50% inhibitory value ("IC50") is determined by fitting the fractional activities relative to control to the following equation on a Macintosh computer by the program Systat:
Fractional activity = MAX/((X/IC50)n+1).
X is the concentration of the compound, and the term n accounts for deviations of the data from a simple competitive inhibition model.
The compounds of the present invention inhibit IMPDH when tested by this method, indicating their activity as anti-inflammatory, anti-viral, anti-tumor, anti-psoriatic and/or immunosuppressive agents, as shown in the below table.
Compd # R1 R2 Z1 Z2 Z3 Z4 G IC50 (μM)
1 H - C (O) N (CH3) 2 CH3 H H H H 27 . 6
2 H -C (O) OCF3 CH3 H H H H >100
3 H -C (O) CH3 CH3 H H H H >100
4 H - C (O) NH2 CH3 H H H H 22 .3
5 H - C (O) CH3 CH3 H H H H >100
6 H - C (O) H CH3 H H H H >100 EXAMPLE 16
In Vitro Determination of Immunosuppressive Activity Utilizing Responses of Human Peripheral Blood Lymphocytes to T- and B-cell Mitogens
This procedure is a modification of a procedure initially described by Greaves, et al. ["Activation of human T and B lymphocytes by polyclonal mitogens," Mature, 248:698-701 (1974)].
Human mononuclear cells ("PBL") are separated from heparinized whole blood by density gradient centrifugation in Ficoll-Plaque (Pharmacia).
After washing, 2 × 103 cells/well are cultured in microtiter plates with RPMI 1640 supplemented with 5% fetal calf serum, penicillin and
streptomycin. PHA (Sigma) at 10 μg/ml is then added. Test materials are tested at concentrations between 104 and 108M, by addition to the culture at time 0. Cultures are set up in quadruplicate and incubated at 37°C in a humidified atmosphere with 7% CO, for 72 hours. A pulse of 0.5 μCi/well of3H-thymidine is added for the last 6 hours. Cells are collected on glass fiber filters with an automatic harvester and radioactivity is measured by standard scintillation procedures. The 50% inhibitory concentration ("IC50") for mitogenic stimulation is determined graphically.
To evaluate differential effects on T- and B-lymphocytes, different mitogens are used: PWM (Sigma) at 20 μg/ml and Staphylococcus Protein A bound to Sepharose (SPA) (Sigma) 2 mg/ml or 14 μg/ml of Protein A.
The compounds of the present invention show immunosuppressive activity when tested by this meteod. EXAMPLE 17
Determination of Immunosuppressive Activity Utilizing the
Hemolytic Plague Forming Cell Assay
This procedure is a modification of "The agar plaque technique for recognizing antibody producing cells," a procedure initially described by Jerne et al., [Cell-bound Antibodies, Amos and Kaprowski editors (Wistar Institute Press, Philadelphia, 1963), p. 109].
Groups of 5-6 adult C578B1/6 male mice were sensitized with 1X108 sheep red blood cells ("SRBC") and simultaneously treated with an oral dosage form of the test material in an aqueous vehicle. Animals in a control group receive the same volume of vehicle. Four days after SRBC inoculation, spleens are dispersed in loose Ten Broeck homogenizers. The number of nucleated cells ("WBC") is determined and the spleen cell suspension is mixed with SRBC, guinea pig complement and agar solution at 0.5% concentration. Aliquots of the above mixture (0.1 ml) are dropped on four separate quadrants of a Petri dish and are covered with cover slips. After two hours incubation at 37°C, areas of hemolysis around
plaque-forming cells ("PFC") are counted with a dissecting microscope. Total WBC/spleen, PFC/spleen and PFC/106 WBC ("PPM") are calculated for each mouse spleen. Geometric means of each treatment group are then compared with the vehicle-treated control group.
The compounds of the present invention show immunosuppressive activity when tested by this method, as shown in the below table.
Dose PFC/Spl % % WBC/Spl %chg
Compta N mg/kg/day Rte ×103 inhib PPM inhib ×106 WBC
- - - - - - - - - - - - -- - - - - - - - - - - - -- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
1 5 100.0 P.O. 47 50 518 39 82 -21
2 5 100.0 P.O. 129 16 1091 0 122 -16
3 5 100.0 P.O. 28 82 207 80 123 -16
4 4 100.0 P.O. 85 45 782 24 103 -30
5 5 100.0 P.O. 104 32 1021 1 101 -31
While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such
modifications are intended to be within the scope of the claims appended hereto.

Claims

WHAT IS CLAIMED IS:
1. A compound represented by the formula:
Figure imgf000117_0002
wherein:
R1 is hydrogen or lower alkyl;
R2 is hydrogen, lower alkyl, -C(O)R3, -C(O)NR4R5, -CO2R6, or -SO2R3
where:
R3 is hydrogen, lower alkyl, halo lower alkyl or optionally substituted phenyl;
R4 is hydrogen, lower alkyl or optionally substituted phenyl;
R3 is hydrogen, lower alkyl or optionally substituted phenyl; R6 is lower alkyl or optionally substituted phenyl; and
Z is a side chain selected from Formulae ZA, ZB, ZC, ZD, ZE, ZF, ZG, and ZH:
Figure imgf000117_0001
wherein:
Z1 is H, lower alkyl, halo or CF3;
Z2 is H, lower alkyl, lower alkoxy, aryl, or -CH2Z13, where
Z13 is aryl or heteroaryl;
Z3 is H, lower alkyl, lower alkenyl, lower alkoxy, phenyl,
P(O) (OCH3)2, -P(O) (OH) (OCH3), or -S(O)mZ12, where
Z12 is lower alkyl, and
m is 0, 1 or 2;
Z4 is H, lower alkyl, or phenyl,
or Z3 and Z4 taken together with the carbon to which they are attached form cycloalkyl of three to five carbon atoms; and G is OH, lower alkoxy, lower thioalkyl, -NG1G2, -O(CH2)nNG1G2, or - O(CH2)nN=G3, where
n is an integer from 1 to 6,
G1 is H or lower alkyl,
G2 is H or lower alkyl, and =G3 is lower alkylene of four to six carbon atoms, or lower alkylene of three to five carbon atoms plus one member that is -O- , -S-, or -N(G4) - where G4 is H or lower alkyl;
provided that when Z1 is methyl, Z2, Z3 and Z4 are not all H; or
Figure imgf000118_0001
Formula ZB
wherein:
Z3 is H or lower alkyl;
Z8 is H or lower alkyl;
D1 and D2 together with their adjacent carbon atoms form an optionally substituted, saturated or unsaturated carbocyclic or
heterocyclic ring of 3 to 7 atoms; and
G is as defined above; or
Figure imgf000118_0002
wherein:
Z5, Z8, and G are as defined above; or
Figure imgf000118_0003
wherein:
D3 is -CH-- or -CH2CH2-; and
G is as defined above; or
Figure imgf000119_0001
wherein:
Z6 is H, lower alkyl, lower alkoxy, -COOH, -NH, or halo;
Z7 is H, lower alkyl, lower alkoxy or halo; and
Z5 and G are as defined above; or
Figure imgf000119_0002
wherein:
Z1 and G are as defined above; or
Figure imgf000119_0003
wherein:
Z4 and G are as defined above; or
Figure imgf000119_0004
wherein:
D4 is -CH2-, -CH2CH2-, -CH2CH2CH2-, -O- , or -OCH2-; and
Z1 and G are as defined above;
or a pharmaceutically acceptable salt thereof.
2. The compound or salt of Claim 1, wherein Z is sidechain ZA.
3. The compound or salt of Claim 2, wherein Z1 is methyl.
4. The compound or salt of Claim 3, wherein R1 is hydrogen and R2 is hydrogen or -C(O)R3.
5. The compound or salt of Claim 4, wherein R2, Z2 and Z3 are all hydrogen, and Z4 is methyl.
6. The compound or salt of Claim 4, wherein R2, Z2 and Z4 are all hydrogen, and Z3 is methyl.
7. The compound or salt of Claim 1, wherein Z is sidechain ZB.
8. The compound or salt of Claim 7, wherein R1 is hydrogen and R2 is hydrogen or -C(O)R3.
9. The compound or salt of Claim 8, wherein D1 and D2 together with their adjacent carbon atoms form a saturated carbocyclic ring of 5 or 6 carbon atoms.
10. The compound or salt of Claim 9, wherein D1 and D2 together represent -CH,CH,CH,-, and Z3 and Z8 are both hydrogen.
11. The compound or salt of Claim 10, wherein R1 and R2 are both hydrogen.
12. The compound or salt of Claim 9, wherein D1 and D2 together represent -CH2CH2CH2CH2- , and Z5 and Z8 are both hydrogen.
13. The compound or salt of Claim 12, wherein R1 and R2 are both hydrogen.
14. The compound or salt of Claim 8, wherein D1 and D2 together with their adjacent carbon atoms form a saturated heterocyclic ring of 5 or 6 atoms.
15. The compound or salt of Claim 14, wherein D1 and D2 together represent CH2CH2OCH2-, and Z3 and Z8 are both hydrogen.
16. The compound or salt of Claim 15, wherein R1 and R2 are both hydrogen.
17. A pharmaceutical composition comprising a pharmaceutically acceptable non-toxic excipient and a therapeutically effective amount of a compound of Claim 1, or a pharmaceutically acceptable salt thereof.
18 A method of treatment for immune, inflammatory, tumor, proliferative, viral or psoriatic disorders in a mammal, comprising administering a therapeutically effective amount of a compound or salt of Claim 1 to a mammal in need thereof.
19. A process for preparing compounds of Formula I:
Figure imgf000120_0001
wherein: R1 is hydrogen or lower alkyl;
R2 is hydrogen, lower alkyl, -C(O)R3, -C(O)NR4R3, -CO,R6, or -SO,R3
where:
R3 is hydrogen, lower alkyl, halo lower alkyl or optionally substituted phenyl;
R4 is hydrogen, lower alkyl or optionally substituted phenyl;
R3 is hydrogen, lower alkyl or optionally substituted phenyl;
R6 is lower alkyl or optionally substituted phenyl; and
Z is a side chain selected from Formulae ZA, ZB, ZC, ZD, ZE, ZF, ZG, and ZH:
Figure imgf000121_0001
wherein:
Z1 is H, lower alkyl, halo or CF3;
Z2 is H, lower alkyl, lower alkoxy, aryl or -CH2Z13, where
Z13 is aryl or heteroaryl;
Z3 is H, lower alkyl, lower alkenyl, lower alkoxy, phenyl, - P(O) (OCH3)2, -P(O) (OH) (OCH3), or -S(O)mZ12, where
Z12 is lower alkyl, and
m is 0, 1 or 2;
Z4 is H, lower alkyl, or phenyl,
or Z3 and Z4 taken together with the carbon to which they are attached form cycloalkyl of three to five carbon atoms; and G is OH, lower alkoxy, lower thioalkyl, -NG1G2, -O(CH2)nNG1G2, or - O(CH2)nN=G3, where
n is an integer from 1 to 6,
G1 is H or lower alkyl,
G2 is H or lower alkyl, and
=G3 is lower alkylene of four to six carbon atoms, or lower alkylene of three to five carbon atoms plus one member that is -O-, -S-, or -N(G4)- where G4 is
H or lower alkyl;
provided that when Z1 is methyl, Z2, Z3 and Z4 are not all H; or wherein:
Figure imgf000122_0001
Z3 is H or lower alkyl;
Z8 is H or lower alkyl;
D1 and D2 together with their adjacent carbon atoms form an optionally substituted, saturated or unsaturated carbocyclic or
heterocyclic ring of 3 to 7 atoms; and
G is as defined above; or
Figure imgf000122_0002
wherein:
Z3, Z8, and G are as defined above; or
Figure imgf000122_0003
wherein:
D3 is -CH2- or -CH2CH2- ; and
G is as defined above; or
Figure imgf000122_0004
wherein:
Z6 is H, lower alkyl, lower alkoxy, -COOH, -NH2 or halo;
Z7 is H, lower alkyl, lower alkoxy or halo; and
Z3 and G are as defined above; or
Figure imgf000123_0001
wherein:
Z1 and G are as defined above; or
Figure imgf000123_0002
wherein:
D3, Z2, Z3, Z4 and G are as defined above; or
Figure imgf000123_0003
wherein:
D4 is -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-, or -OCH2- ; and
Z1 and G are as defined above;
and the pharmaceutically acceptable salts thereof;
which comprises:
a) reacting a compound of Formula I, wherein G is lower alkoxy, lower thioalkyl, NG1G2, O- (CH2)n-NG1G2, or -O- (CH2)n-N=G3, in which n, G1, G2, and G3 are as defined above; with an inorganic base, to form a compound of Formula I wherein G is hydroxy; or
b) reacting a compound of Formula I wherein G is hydroxy, with a compound of the formula GH, where G is lower alkoxy, lower thioalkyl, NG1G2, O-(CH2)n-NG1G2, or O-(CH2)n-N=G3, in which n, G1, G2, and G3 are as defined above, to form a compound of Formula I wherein G is lower alkoxy,
lower thioalkyl, NG1G2, O-(CH2)n-NG1G2, or O-(CH2)n-N=G3, in which n, G1, G2, and G3 are as defined above; or
c) reacting a compound of Formula I wherein R1 is hydrogen, R2 is -C(O)R3 wherein R3 is hydrogen, and G is lower alkoxy, with a compound of the formula HNG1G2, where G1 and G2 are as defined above, to form a compound of Formula I wherein G1 and G2 are as defined above; or d) reacting a compound of Formula I wherein R1 and R2 are hydrogen, with a compound of the formula (R3C(O))2O or R3C(O)Cl, to form a compound of Formula I wherein R2 is -C(O)R3 wherein R3 is lower alkyl, halo lower alkyl or optionally substituted phenyl; or
e) reacting a compound of Formula I wherein R1 is hydrogen,
R2 is -C(O)R3, where R3 is lower alkyl, halo lower alkyl or optionally substituted phenyl, and G is lower alkoxy, with a compound of the formula R1X, where R1 is lower alkyl and X is iodine or bromine, to form a compound of Formula I wherein R1 is lower alkyl; or
f) reacting a compound of Formula I to form a pharmaceutically acceptable salt of that compound; or
g) reacting a salt of Formula I to form the corresponding free compound of Formula I; or
h) converting a pharmaceutically acceptable salt of a compound of Formula I to another pharmaceutically acceptable salt of a compound of Formula I.
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AU1875395A (en) 1995-09-04
ATE165826T1 (en) 1998-05-15
LV12149A (en) 1998-10-20
DE69502380T2 (en) 1998-10-08
ZA951293B (en) 1996-08-16
CN1141039A (en) 1997-01-22
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US5538969A (en) 1996-07-23
FI963220A (en) 1996-10-16
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ES2116078T3 (en) 1998-07-01
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HK1010784A1 (en) 1999-06-25
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WO1995022537A3 (en) 1995-10-26

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