Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C313/02—Sulfinic acids; Derivatives thereof
  • C07C313/04—Sulfinic acids; Esters thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/56—Ring systems containing three or more rings
  • C07D209/80—[b, c]- or [b, d]-condensed
  • C07D209/82—Carbazoles; Hydrogenated carbazoles
  • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system

Definitions

• This invention relates to a process for preparing certain 4-hydroxy indole, indazole and 4-hydroxy carbozole compounds useful as intermediates for preparing compounds useful for inhibiting SPLA2 mediated release of fatty acids for conditions such as septic shock.
• Certain lH-indole-3-glyoxamides are known to be potent and selective inhibitors of mammalian sPLJV? useful for treating diseases, such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis and related SPLA2 induced diseases.
• diseases such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis and related SPLA2 induced diseases.
• diseases such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis and related SPLA2 induced diseases.
• diseases such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis and related SPLA2 induced
• 0675110 discloses such compounds.
• U.S. Patent No. 3,449,363 describes trifluoromethylindoles having glyoxylamide groups at the 3 position of the indole nucleus.
• U.S. Patent No. 3,351,630 describes alpha- substituted 3-indolyl acetic acid compounds and their preparation inclusive of glyoxylamide intermediates.
• U.S. Patent No. 2,825,734 describes the preparation of 3- (2-amino-l-hydroxyethyl) indoles using 3- indoieglyoxylamide intermediates such as l-phenethyl-2- ethyi-6-carboxy-N-propyl-3-indoleglyoxylamide (see, Example 30) .
• Conversion to the glyoxamide is achieved by reacting the cc- [ (indol-4-yl) oxy] alkanoic acid ester first with oxalyl chloride, then with ammonia, followed by hydrolysis with sodium hydroxide in ethanol.
• an appropriately substituted propronylacetate is halogenated with sulfuryl chloride.
• the halogenated intermediate is hydrolyzed and decarboxylated by treatment with hydrochloric acid then reacted with an appropriately substituted cyclohexane dione.
• Treatment of the alkylated dione with an appropriate amine affords a 4-keto-indole which is oxidized by refluxing in a high-boiling polar hydrocarbon solvent such as carbitol in the presence of a catalyst, such as palladium on carbon, to prepare the 4-hydroxyindole which may then be alkylated and converted to the desired glyoxamide as described above.
• This process however is limited by the required high temperature oxidation and requires recovery of a precious metal catalyst.
• the present invention provides an improved process for preparing 4-hydroxy-mdole intermediates.
• the process of the present invention can be performed with inexpensive, readily available, reagents under milder conditions.
• the present process allows for transformation with a wider variety of substituents on the indole platform.
• the present invention provides a process for preparing a compound of the formula I
• Y is -CR 4 or -N-;
• R 4 is H, - (C ⁇ -C 6 ) alkyl or when taken together with R 2 forms a cyclohexeny ring
• R 2 is non-interfering substituent
• R 3 is a non-mterfe ⁇ ng substituent
• m is 1-3 both inclusive
• R 1 is selected from groups (a) , (b) and (c) where; (a) is -(C ⁇ -Czo lkyl, - (C 2 -C 20 ) alkenyl, - (C 2 -C 20 ) alkynyl, carbocyclic radicals, or heterocyclic radicals, or
• (b) is a memeber of (a) substituted with one or more independently selected non-mterfe ⁇ ng substituents;
• (c) is the group -(L)-R 80 ; where, (L)- ⁇ s a divalent linking group of 1 to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen, and sulfur; wherein the combination of atoms m -(L)- are selected from the group consisting of (l) carbon and hydrogen only, (n) one sulfur only, (in) one oxygen only, (IV) one or two nitrogen and hydrogen only, (v) carbon, hydrogen, and one sulfur only, and (vi) an carbon, hydrogen, and oxygen only; and where R 80 is a group selected from (a) or (b) ; which process comprises oxidizing a compound of formula III
• the invention provides m addition novel
• RSliX reagents of the formula where R is - (C ⁇ -C 6 ) alkyl, aryl or substituted aryl; and X is -OCOi (d-C 6 ) alkyl provided that when X is -OC0 2 CH 3 , R cannot be tolulyl.
• the present invention provides, in addition novel intermediates of the formula
• R is - (C1-C6) alkyl, aryl or substituted aryl, Y is -CR 4 or -N-;
• R 4 is H, - (C ⁇ -C 6 ) alkyl or when taken together with R 2 forms a cyclohexeny ring
• R 2 is non-interfering substituent;
• R 3 is a non-interfering substituent;
• m is 1-3; and
• R 1 is selected from groups (a) , (b) and (c) where;
• (a) is -(C-Czo) alkyl, - (C 2 -C 20 ) alkenyl, - (C 2 -C 20 ) alkynyl, carbocyclic radicals, or heterocyclic radicals, or
• (b) is a memeber of (a) substituted with one or more independently selected non-interfering substituents;
• (L)- is a divalent linking group of 1 to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen, and sulfur; wherein the combination of atoms in - (L) - are selected from the group consisting of (i) carbon and hydrogen only, (ii) one sulfur only, (iii) one oxygen only, (iv) one or two nitrogen and hydrogen -7-
• R 80 is a group selected from (a) or (b) .
• Such intermediates are useful for preparing compounds useful for inhibiting sPLA 2 mediated release of fatty acids for conditions such as septic shock.
• alkyl by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl tert butyl, n-pentyl, isopentyl, neopentyl, heptyl, hexyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and the like.
• alkyl includes
• alkenyl represents an olefinically unsaturated branched or linear group having at least one double bond.
• groups include radicals such as vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4- hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5- heptenyl, 6-heptenyl as well as dienes and trienes of straight and branched chains.
• alkynyl denotes such radicals as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl as well as di- and tri-ynes.
• (C1-C10) alkoxy denotes a group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n-pentoxy, isopentoxy, neopentoxyl, heptoxy, hexoxy, octoxy, nonoxy, decoxy and like groups, attached to the remainder of the molecule by the oxygen atom.
• (C ⁇ -C ⁇ 0 ) alkoxy includes (C ⁇ C 6 ) alkoxy.
• halo means fluoro, chloro, bromo or iodo .
• aryl means a group having the ring structure characteristic of benzene, pentalene, indene, naphthalene, azulene, heptalene, p enanthrene, anthracene, etc .
• the aryl group may be optionally substituted with 1 to 3 substituents selected from the group consisting of (C ⁇ _-Cg) alkyl (preferably methyl),
• heterocyclic radical refers to radicals derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nuclei having 5 to 14 ring atoms and containing from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur.
• Typical heterocyclic radicals are pyridyl, thienyl, fluorenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, thianaphtheneyl, dibenzothiophenyl, indazolyl, imidazo (1.2-A) pyridinyl, benzotriazolyl, anthranilyl, 1, 2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pryidinyl, dipyridylyl, phenylpyridinyl, benzylpyridinyl, pyrimidin
• carrier radical refers to radicals derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered organic nucleus whose ring forming atoms (other than hydrogen) are solely carbon atoms.
• Typical carbocyclic radicals are cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenylcyclohexeyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (bb) ,
• non-interfering substituent refers to hydrogen, - (C1-C14) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, - (C7-C12) aralkyl, - (C7-C12) alkaryl, - (C3-C8 ) cycloalkyl, - (C3-C8) cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, - (C1-C6) alkoxy, - (C2-C6) alkenyloxy, - (C2-C6) alkynyloxy, - (C1-C12) alkoxyalkyl, - (C1-C12) alkoxyalkyloxy,
• a preferred group of compounds of formula I prepared by the process of the instant invention are those wherein:
• Y is CR 4 where R 4 is H or when taken together with R 2 forms a cyclohexenyl ring;
• R 3 is H, -0(C ⁇ -C 4 ) alkyl, halo, - (C ⁇ -C 6 ) alkyl, phenyl, - (d- C 4 ) alkylphenyl; phenyl substituted with - (d-C 6 ) alkyl, halo, or -CF 3 ; -CH 2 OSi (C ⁇ -C 6 ) alkyl, furyl, thiophenyl, - (C ⁇ -C 6 )hydroxyalkyl, - (C ⁇ -C 6 ) alkoxy (d-C 6 ) alkyl, - (d x - C 6 ) alkoxy (d-C 6 ) alkenyl; or -(CH 2 ) n R 8 where R 8 is H, - CONH 2 , -NR 9 R 10
• the process of the present invention provides an improved method for synthesizing the compounds of formula I using inexpensive, readily available reagents as shown in Scheme I as follows.
• Ketone (III) is dissolved in a suitable solvent preferably an aprotic solvent such as THF.
• suitable solvents include but are not limited to DMF, dioxane, or toluene.
• the substrate/solvent solution may be sonicated or heated slightly, if necessary to facilitate dissolution.
• the amount of solvent used should be sufficient to ensure that all compounds stay in solution until the desired reaction is complete.
• the solution is treated with a base, preferably a strong base such as sodium hydride, then with a sulfinating -12-
• RSX agent of the formula where R is - (C ⁇ -C 6 ) alkyl, aryl or substituted aryl and X is (C ⁇ -C 6 ) alkoxy, halo or -OC0 2 (C ⁇ - C ⁇ ) alkyl.
• the sulfinating reagent may be prepared according to the procedure of J.W. Wilt et al . , J. Org. Chem, 1967, 32, 2097.
• Preferred sulfinating agents include methyl p- tolyl sulfinate, methylbenzene sulfinate or p-toluylsulfinic isobutyric anhydride.
• Suitable bases include but are not limited to LDA, sodium methoxide, or potassium methoxide. Preferably two equivalents of base are used. Preferably, when sodium hydride is employed, the base is added before the sulfinating reagent. The order of addition of reagents is not important when sodium methoxide is used.
• the reaction may be conducted at temperatures from about 25°C to reflux, preferably at reflux and is substantially complete in from one to 24 hours.
• the amount of sulfinating reagent is not critical, however, the reaction is best accomplished using a molar equivalent or excess relative to the starting material (III) •
• the above reactions may be run as a "one pot" process with the reactants added to the reaction vessel in the order given above, preferably with an acid quench of the base prior to reflux.
• Dioxane is a preferred solvent in a "one part” process.
• THF and toluene, respectively, are preferred solvents if a "two pot” process is employed.
• the intermediate (II) can be isolated and purified using standard crystalization or chromatographic procedures. Standard analytical techniques such as TLC or HPLC can be used to monitor the reactions in order to determine when the starting materials and intermediates are converted to product. • 13-
• the sulfinating reagent can be replaced with a disulfide compound of the formula R 20 SSR 20 -where R 20 is alkyl or aryl. Oxidation of the sulfide intermediate can then be readily achieved using an appropriate oxidizing reagent such as hydrogen peroxide or m-chloroperbenzoic acid.
• starting material (1) can be prepared according to the procedure of Peet, N.P., et al, . Heterocycles, Vol. 32, No. 1, 1991, 41.
• starting material V is prepared according to the following procedure.
• R is - (C ⁇ -Cg) alkyl or aryl
• R 30 is H or - (d-C 6 ) alkyl
• propionyl acetate X is first halogenated by treatment with sulfuryl chloride, preferably at equi olar concentrations relative to the starting material, at temperatures of from about 0°C to
• Hydrolysis and decarboxylation of IX is achieved by refluxing with an aqueous acid, such as hydrochloric acid, for from about 1 to 24 hours.
• the solution containing the decarboxylated product VIII is neutralized to adjust the pH to about 7.0-7.5, then reacted with cyclohexanedione VII (preferably at equimolar concentrations) and a base, preferably sodium hydroxide, to yield the triketone monohydrate VI as a precipitate which may be purified and isolated, if desired.
• the reaction is preferably conducted at temperatures of from -20°C to ambient temperatures and is substantially complete in about 1 to 24 hours.
• the above reactions are preferably run as a "one pot" process with the reactants added to the reaction vessel in the order given above.
• the reaction is allowed to proceed without isolating compounds of formula IX or VIII, thus avoiding exposure to these volatile lachrymators .
• V is achieved by refluxing VI in a high boiling non-polar solvent which forms an azeotrope with water, preferably toluene, with an equimolar quantity of an amine of the formula R ⁇ H2, where R ⁇ is as defined above.
• R 1 is hydrogen, hexamethyldisilazane or ammonia may be used.
• Solvents with a boiling point of at least 100°C are preferred, such as toluene, xylene, cymene, benzene, -15-
• Methyl propionylacetate (130.15g, 1.0 mol) is placed into a 2L Morton flask equipped with a mechanical stirrer, nitrogen inlet and thermocouple. External cooling is applied until the internal temperature is 10°C. Sulfuryl chloride (135g, 1.0 mol) is added dropwise at a rate to maintain the temperature ⁇ 15°C. When chromatographic analysis indicaets the total conversion to the desired chloro-compound 1M HC1 (205 mL) is then added, and the reaction mixture is stirred at reflux for 18 hours. After cooling to room temperature, 4N NaOH is added to adjust the pH to 7.0 to 7.5. Cyclohexanedione (112.13g, 1.0 mol) is added and the mixture is cooled in an ice bath. Then, 5N - 1 6-
• Benzylamine (562.6gms, 5.25moles, 1.05eq) was added dropwise over about 30-45 minutes. Following the addition, the mixture turned to an amber colored solution. Heat was applied to the solution and water was azeotroped off until the reaction temperature reached 110°C. The reaction was allowed to stir at 110°C for 2 hours at which time about 4000 mis of solvent was distilled off at atmospheric pressure. The solution was transferred to a Buchi flask and further evaporated to an amber viscous oil.

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• 1999
  • 1999-04-15 WO PCT/US1999/008261 patent/WO1999054295A1/en not_active Application Discontinuation
  • 1999-04-15 JP JP2000544636A patent/JP2002512222A/ja not_active Withdrawn
  • 1999-04-15 AU AU35632/99A patent/AU3563299A/en not_active Abandoned
  • 1999-04-15 EP EP99917535A patent/EP1071661A4/de not_active Withdrawn
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