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WO1996016980A1 - Derives morpholino-ethylamides - Google Patents

Derives morpholino-ethylamides Download PDF

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Publication number
WO1996016980A1
WO1996016980A1 PCT/EP1995/004508 EP9504508W WO9616980A1 WO 1996016980 A1 WO1996016980 A1 WO 1996016980A1 EP 9504508 W EP9504508 W EP 9504508W WO 9616980 A1 WO9616980 A1 WO 9616980A1
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WIPO (PCT)
Prior art keywords
phenyl
acid
formula
amino
lower alkoxy
Prior art date
Application number
PCT/EP1995/004508
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English (en)
Inventor
Guido Bold
Shripad Subray Bhagwat
Hans-Georg Capraro
Alexander Fässler
Marc Lang
Satish Chandra Khanna
Original Assignee
Novartis Ag
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Publication date
Application filed by Novartis Ag filed Critical Novartis Ag
Priority to AU41173/96A priority Critical patent/AU4117396A/en
Publication of WO1996016980A1 publication Critical patent/WO1996016980A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • the invention relates to morpholinoethylamide derivatives of aspartate protease substrate isosteres and salts thereof, to processes for the preparation of those compounds and salts thereof, to pharmaceutical compositions that comprise those compounds or salts thereof, and to the use of those compounds or salts thereof in the therapeutic or diagnostic treatment of the human or animal body or in the preparation of pharmaceutical composi ⁇ tions.
  • an enzyme that is active in the conversion of retroviral RNA into DNA such as 3'-azido-3'-deoxythymidine (AZT) or dideoxyinosine (DDI), have mainly been used, and, in addition, trisodium phosphonoformate, ammonium-21-tungsto-9-antimonate, l- ⁇ -D-ribofuranoxyl-l ⁇ . -triazole-S-carboxamides and dideoxycytidine and also adriamycin.
  • T4-cell receptor which is present on certain cells of the defence system in the human body and is responsible for the anchoring and insertion of infectious virus particles into those cells and hence for their infection, into the body, for example in the form of a recombinant molecule or molecule fragment. This would titrate away binding sites for the virus, with the result that the virions could no longer bind to the cells.
  • compounds that prevent the virus from penetrating the cell membrane in other ways such as polymannoacetate.
  • the object of the present invention is to provide a new class of compounds that are furthermore equipped, in particular, with advantageous pharmacological properties, such as good pharmacokinetics, such as high bio-availability and/or high achievable blood levels, and/or with good tolerability.
  • R 5 , R 5 ', R , R 7 , R g , R 8 ', R 9 and R 10 are each independently of the others hydrogen or lower alkyl
  • any asymmetric carbon atoms present may be in the (R)-, the (S)- or the (Reconfigura ⁇ tion, preferably in the (R)- or the (S)-configuration. Accordingly, the compounds in question may be in the form of mixtures of isomers or in the form of pure isomers, espec ⁇ ially in the form of diastereoisomeric mixtures, pairs of enantiomers or, preferably, in the form of pure enantiomers.
  • the lower alkoxy radical is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, while lower alkanoyl is preferably fo ⁇ nyl (the corresponding radical is then a lower alkoxy ⁇ carbonyl radical, which is preferred, especially methoxycarbonyl, ethoxycarbonyl or tert- butoxycarbonyl), or also acetyl or propionyl.
  • Halogen is fluorine, chlorine, bromine or iodine, especially fluorine or chlorine.
  • Tetrahydropyranyl is especially tetrahydropyran-2-yl or -4-yl that is preferably unsubsti ⁇ tuted and preferably bonded in the (R)-, the (S)- or, especially, the (R,S)-form if it is bonded via the 2-carbon atom.
  • 4H-l-benzopyranyl is especially 4H-l-benzopyran-2-yl that is unsubstituted or preferably substituted by oxo, such as 4-oxo-4H-l-benzopyran-2-yl.
  • the lower alkoxy radical in lower alkoxy-lower alkanoyl Rj is unsubstituted or substituted by one or more, especially by 1 up to and including 3, of the mentioned radicals, espec ⁇ ially by phenyl, such as in benzyloxycarbonyl, or also (preferably mono- to especially tri- substituted) by halogen, especially fluorine, or (preferably mono-substituted) by one of the other radicals mentioned, especially (preferably mono-substituted) by lower alkoxy, especially methoxy, or (mono-substituted) by pyrrolidinyl, especially pyrrolidin-2-yl or idin-2-yl or -5-yl, that is unsubstituted or, especially, substituted by oxo.
  • lower alkanoyl R that is unsubstituted or substituted by piperidinyl, pyrrolidinyl, tetra ⁇ hydropyranyl, tetrahydrofuranyl, thiazolidinyl, thiazolyl, indolyl, 4H-l-benzopyranyl, piperidinyloxy, pyrrolidinyloxy, tetrahydropyranyloxy, tetrahydrofuranyloxy, thiazol- idinyloxy, thiazolyloxy, indolyloxy or 4H-l-benzopyranyloxy, each of which is unsubsti ⁇ tuted or substituted by one or more substituents (preferably one substituent) selected independently of one another from oxo, hydroxy, amino, lower alkyl, lower alkoxy ⁇ carbonyl and phenyl-lower alkoxycarbonyl, lower alkanoyl is especially formyl (producing with one of the mentioned radicals the thi
  • N-lower alkoxycarbonyl-piperi- dinyl-lower alkanoyl for example -carbonyl, such as N-ethoxycarbonyl-piperidin-4-yl- carbonyl, pyrrolidinyl-lower alkanoyl, such as -carbonyl, that is substituted by hydroxy at a carbon atom and/or by phenyl-lower alkoxycarbonyl at the nitrogen atom and that is preferably in the (R)-, the (R,S)- or, especially, the (S)-form at the bonding carbon atom, such as (L)-trans-4-hydroxyprolyl or (L)-N-benzyloxycarbonyl-trans-4-hydroxyprolyl, aminothiazolidinyl-lower alkanoyl, e.g.
  • Heterocyclyl is preferably an unsubstituted or substituted heterocyclic ring having from 5 to 7, preferably 5 or 6, ring atoms, wherein 1 or 2 ring carbon atoms have been replaced by a hetero atom selected from O, N and S, is unsaturated or completely or partially saturated and may be in the form of a single ring or may be benzo-fused, cyclopenta-fused or cyclohexa-fused, the radical preferably being substituted by one or more (preferably one or two) substituents selected independently of one another from oxo, hydroxy, amino, lower alkyl, lower alkoxycarbonyl and phenyl-lower alkoxycarbonyl; and is selected especially from morpholinyl, piperazinyl, e.g.
  • Aryl is preferably C 6 -C 14 aryl, for example phenyl, naphthyl, such as 1- or 2-naphthyl, or also fluorenyl, such as fluoren-9-yl, and is unsubstituted or substituted by one or more (preferably from one to three) radicals selected independently of one another from lower alkyl, phenyl-lower alkyl, halogen, cyano, hydroxy, lower alkoxy, phenyl-lower alkoxy, lower alkoxy-lower alkoxy, lower alkylenedioxy (bonded to two adjacent carbon atoms of the respective aryl ring), pyridyl-lower alkoxy, and phenyl-lower alkanesulfonyl which is unsubstituted or substituted in the phenyl radical by one or more radicals selected indepen ⁇ dently of one another from halogen, such as chlorine; and is especially phenyl.
  • arylcarbonyl substituted by heterocyclyl or by heterocyclyl-lower alkyl such as espec ⁇ ially heterocyclylmethyl, or in heterocyclylcarbonyl substituted likewise by one or more of those radicals
  • aryl and heterocyclyl are as defined immediately above, preferably as stated there as being preferred; preferably, only one substituent heterocyclyl or hetero ⁇ cyclyl-lower alkyl is present.
  • R 2 and R 3 are each independently unsubstituted or substituted, as indicated, lower alkylenedioxy being attached to 2, preferably adjacent, carbon atoms of the respec ⁇ tive ring.
  • the compounds of formula I having a basic group, for example an amino group can form acid addition salts, for example with inorganic acids, for example hydrohalic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic, sulfonic, sulfo or phospho acids or N-substituted sulfamic acids, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicot- inic acid, or with amino acids, for example the ⁇ -amino acids mentioned hereinbefore
  • R 4 is lower alkyl, preferably isopropyl or sec-butyl
  • R and R 0 are each independently of the other hydrogen or methyl, preferably each hydrogen;
  • radicals are as defined for compounds of formula I, free functional groups in the starting materials of formulae II and III (or III'), with the exception of those participating in the reaction, being, if necessary, in protected form, and removing any protecting groups, or b) for the preparation of compounds of formula
  • radicals are as defined for compounds of formula I, with nucleophilic substi ⁇ tution taking place, free functional groups in the starting materials of formulae DC (or DC) and X, with the exception of those participating in the reaction, being, if necessary, in protected form, and removing any protecting groups, or
  • n and the radicals are as defined for compounds of formula I.
  • the compounds of the formulae shown with an apostrophe that is, F, la', m ⁇ ⁇ ia', V, VF, VH' and DC, having the indicated stereospecificity are especially preferred to the corresponding compounds of formulae I, la, HI, Ilia, V, VI, VII and IX in which the stereospecificity is not indicated; less preferred than the compounds marked with an apostrophe but more preferred than the corresponding compounds in which the stereospecificity is not indicated are in each case the correspond ⁇ ing compound mixtures in which the carbon atoms carrying the radical R 2 -CH -, the radical R 3 -CH 2 - and the OH group lying between those radicals [in the indicated order C(5), C(2) and C(4)] are in the (2R,4S,5S)- and the (2S,4R,5R)-configuration.
  • the corresponding compound mixtures having the (2R,4S,5S)- and (2S,4R,5R)-configuration or, especially, the compounds of the respectively corresponding formulae shown with an apostrophe may be used in each case in place of the compounds of formulae I, la, HI, Ilia, V, VI, VII and DC insofar as that is chemically meaningful; this applies also to the section on Additional Process Steps and Starting Materials.
  • a protected carboxy group esterified by a lower alkyl group is, for example, methoxy- carbonyl or ethoxycarbonyl.
  • a protected carboxy group is preferably tert-lower alkoxycarbonyl, for example tert-but ⁇ oxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl or diphenylmethoxycarbonyl, or a carboxy group protected in the form of a lactone, espe ⁇ cially a ⁇ -lactone.
  • acyl is, for example, the acyl radical of an organic carboxylic acid having, for example, up to 18 carbon atoms, especially an unsubstituted or substituted, for example halo- or aryl-substituted, lower alkanecarboxylic acid or an unsubstituted or substituted, for example halo-, lower alkoxy- or nitro-substituted, benzoic acid, or, prefer ⁇ ably, of a carbonic acid semiester.
  • an organic carboxylic acid having, for example, up to 18 carbon atoms, especially an unsubstituted or substituted, for example halo- or aryl-substituted, lower alkanecarboxylic acid or an unsubstituted or substituted, for example halo-, lower alkoxy- or nitro-substituted, benzoic acid, or, prefer ⁇ ably, of a carbonic acid semiester.
  • Such acyl groups are preferably lower alkanoyl, such as formyl, acetyl, propionyl or pivaloyl, halo-lower alkanoyl, for example 2-haloacetyl, such as 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloro-acetyl, unsubsti ⁇ tuted or substituted, for example halo-, lower alkoxy- or nitro-substituted, benzoyl, such as benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, lower alkoxycarbonyl, preferably lower alkoxycarbonyl that is branched in the 1 -position of the lower alkyl radical or suitably substituted in the 1 - or 2-position, for example tert-lower alkoxy ⁇ carbonyl, such as tert-butoxycarbonyl, 1-aryl-
  • aryl radicals are especially unsubstituted or substituted phenyl radicals.
  • Such groups are, for example, benzyl-, diphenylmethyl- or especially trityl-amino.
  • the mercapto group is especially in the form of substituted arylthio or aryl-lower alkylthio, wherein aryl is, for example, phenyl that is unsubstituted or substituted, for example, by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by nitro, for example 4-nitrophenylthio.
  • aryl is, for example, phenyl that is unsubstituted or substituted, for example, by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by nitro, for example 4-nitrophenylthio.
  • acyl is, for example, the corresponding radical of a lower alkanecarboxylic acid, of a benzoic acid that is unsubstituted or substituted, for example, by lower alkyl, such as methyl or tert- butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by nitro, or espe ⁇ cially of a carbonic acid semiester, such as a carbonic acid lower alkyl semiester.
  • lower alkyl such as methyl or tert- butyl
  • lower alkoxy such as methoxy
  • halogen such as chlorine
  • espe ⁇ cially of a carbonic acid semiester such as a carbonic acid lower alkyl semiester.
  • Preferred amino-protecting groups are lower alkoxycarbonyl, phenyl-lower alkoxycar ⁇ bonyl, fluorenyl-lower alkoxycarbonyl, 2-lower alkanoyl-lower alk- 1 -en-2-yl and lower alkoxycarbonyl-lower alk-l-en-2-yl, especially tert-butoxycarbonyl and benzyloxy ⁇ carbonyl.
  • a hydroxy group can also be protected by tri-lower alkylsilyl, for example trimethylsilyl, triisopropylsilyl or tert-butyl-dimethylsilyl, a readily removable etherifying group, for example an alkyl group, such as tert-lower alkyl, for example tert-butyl, an oxa- or a thia-aliphatic or -cycloaliphatic, especially 2-oxa- or 2-thia-aliphatic or -cycloaliphatic, hydrocarbon radical, for example 1 -lower alkoxy-lower alkyl or 1 -lower alkylthio-lower alkyl, such as methoxymethyl, 1-methoxyethyl, 1-ethoxy- ethyl, methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa- or 2-thia-cyclo- alkyl having from 5 to 7
  • Anhydrides of acids may be symmetric or preferably mixed anhydrides of those acids, for example anhydrides with inorganic acids, such as acid halides, especially acid chlorides (obtainable, for example, by treatment of the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride; acid chloride method), azides (obtainable, for example, from a corresponding acid ester via the corresponding hydrazide and treatment thereof with nitrous acid; azide method), anhydrides with carbonic acid semiesters, for example carbonic acid lower alkyl semiesters (obtainable, for example, by treatment of the corresponding acid with chloroformic acid lower alkyl esters or with a 1 -lower alkoxy- carbonyl-2-lower alkoxy- 1 ,2-dihydroquinoline; mixed O-alkylcarbonic acid anhydrides method), or anhydrides with dihalogenated, especially dichlorinated, phosphoric acid (obtainable, for example, by treatment of the corresponding
  • Suitable cyclic amides are especially amides having five-membered diazacycles of aromatic character, such as amides with imidazoles, for example imidazole (obtainable, for example, by treatment of the corresponding acid with N,N'-carbonyldiimidazole; imidazole method), or pyrazole, for example 3,5-dimethylpyrazole (obtainable, for example, via the acid hydrazide by treatment with acetylacetone; pyrazolide method).
  • imidazole obtainable, for example, by treatment of the corresponding acid with N,N'-carbonyldiimidazole; imidazole method
  • pyrazole for example 3,5-dimethylpyrazole (obtainable, for example, via the acid hydrazide by treatment with acetylacetone; pyrazolide method).
  • Phosphoric acid anhydrides of the carboxylic acids of formula II can also be prepared in situ by reacting an alkylphosphoric acid amide, such as hexa- methylphosphoric acid triamide, in the presence of a sulfonic acid anhydride, such as 4-toluenesulfonic acid anhydride, with a salt, such as a tetrafluoroborate, for example sodium tetrafluoroborate, or with another derivative of hexamethylphosphoric acid tri ⁇ amide, such as benzotriazol-l-yl-oxy-tris(dimethylamino)phosphonium hexafluoride, preferably in the presence of a racemisation-reducing additive, such as N-hydroxybenzo ⁇ triazole, and, where appropriate, in the presence of a tertiary nitrogen base, such as N-methylmo ⁇ holine.
  • a sulfonic acid anhydride such as 4-toluenesulfonic acid anhydride
  • the amino group of compounds of formula ⁇ i that participates in the reaction preferably carries at least one reactive hydrogen atom, especially when the carboxy group reacting therewith is in reactive form; it may, however, itself have been derivatised, for example by reaction with a phosphite, such as diethylchlorophosphite, 1,2-phenylenechlorophosphite, ethyldichlorophosphite, ethylenechlorophosphite or tetraethylpyrophosphite.
  • a derivative of such a compound having an amino group is, for example, also a carbamic acid halide, the amino group that participates in the reaction being substituted by halocarbonyl, for example chlorocarbonyl.
  • the condensation of activated esters, reactive anhydrides or reactive cyclic amides with the corresponding amines is customarily carried out in the presence of an organic base, for example simple tri-lower alkylamines, for example trieti-ylamine or tributylamine, poly-H ⁇ nig base or one of the above-mentioned organic bases.
  • an organic base for example simple tri-lower alkylamines, for example trieti-ylamine or tributylamine, poly-H ⁇ nig base or one of the above-mentioned organic bases.
  • a condensation agent is additionally used, for example as described for free carboxylic acids.
  • the condensation of acid anhydrides with amines can also be effected, for example, in die presence of inorganic carbonates, for example ammonium or alkali metal carbonates or hydrogen carbonates, such as sodium or potassium carbonate or hydrogen carbonate (usually together with a sulfate).
  • inorganic carbonates for example ammonium or alkali metal carbonates or hydrogen carbonates, such as sodium or potassium carbonate or hydrogen carbonate (usually together with a sulfate).
  • Carboxylic acid chlorides or carboxylic acid 4-nitrophenyl esters, and also the chloro- carbonic acid derivatives derived from the acid of formula H, are condensed with the corresponding amines preferably in the presence of an organic amine, for example the above-mentioned tri-lower alkylamines or heterocyclic bases, where appropriate in the presence of a hydrogen sulfate.
  • an inert gas protective gas
  • an inert gas atmosphere for example
  • Aqueous for example alcoholic, solvents, for example ethanol, or aromatic solvents, for example benzene or toluene, may also be used.
  • solvents for example ethanol
  • aromatic solvents for example benzene or toluene
  • alkali metal hydroxides are present as bases, a lower alkanone, such as acetone, can also be added where appropriate.
  • the substitution takes place especially in the absence of bases or in the presence of rela ⁇ tively weak bases, such as suitable sterically hindered nitrogen bases, that is to say steri- cally hindered nitrogen bases that are not tiiemselves capable of nucleophilic substitution under the reaction conditions, for example a corresponding tertiary nitrogen base, such as 4-dimethylaminopyridine, pyridine, triethylamine or ethyldiisopropylamine, or in the presence of hydroxide-containing bases, especially a metal hydroxide, for example an alkali metal hydroxide, such as sodium or potassium hydroxide; or also in the presence of a strong base, for example an alkali metal alcoholate, which can also be prepared in situ from the corresponding alcohol and an alkali metal, or an alkali metal hydride, such as sodium or potassium hydride; in the absence or, preferably, in the presence of suitable solvents or solvent mixtures, such as an aqueous or non
  • die substitution may take the form of a first-order or second-order nucleophilic substitution.
  • protecting groups that are not constituents of the desired end product of formula I, for example the carboxy-, amino-, hydroxy- and/or mercapto-protecting groups, is effected in a manner known per se, for example by means of solvolysis, especially hydrolysis, alcoholysis or acidolysis, or by means of reduction, especially hydrogenolysis or by means of other reducing agents, as well as photolysis, as appropriate stepwise or simultaneously, it being possible also to use enzymatic methods.
  • the removal of the protecting groups is described, for example, in the standard works mentioned hereinabove in me section relating to protecting groups.
  • protected carboxy for example lower alkoxycarbonyl (preferably branched in the 1 -position), such as tert-lower alkoxycarbonyl, lower alkoxycarbonyl substituted in the 2-position by a trisubstituted silyl group or in the 1 -position by lower alkoxy or by lower alkylthio, or unsubstituted or substituted diphenylmethoxycarbonyl can be con ⁇ verted into free carboxy by treatment with a suitable acid, such as formic acid, acetic acid, hydrogen chloride or trifluoroacetic acid, where appropriate with the addition of a nucleo ⁇ philic compound, such as phenol or anisole.
  • a suitable acid such as formic acid, acetic acid, hydrogen chloride or trifluoroacetic acid
  • Unsubstituted or substituted benzyloxy ⁇ carbonyl can be freed, for example, by means of hydrogenolysis, i.e. by treatment with hydrogen in die presence of a metal hydrogenation catalyst, such as a palladium catalyst.
  • a metal hydrogenation catalyst such as a palladium catalyst.
  • substituted benzyloxycarbonyl such as 4-nitrobenzyloxycarbonyl
  • 2-halo-lower alkoxycarbonyl (where appropriate after conversion of a 2-bromo-lower alkoxycarbonyl group into a corres ⁇ ponding 2-iodo-lower alkoxycarbonyl group) or aroylmethoxycarbonyl can also be con ⁇ verted into free carboxy.
  • Aroylmethoxycarbonyl can be cleaved also by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate or sodium iodide.
  • the carboxy group can be freed from 1-aryl-lower alkoxycarbonyl, for example arylmethoxy carbonyl, such as benzyloxycarbonyl, also by hydrolysis in the presence of a base, such as an alkali metal hydroxide, for example sodium or potassium hydroxide.
  • arylmethoxy carbonyl such as benzyloxycarbonyl
  • a base such as an alkali metal hydroxide, for example sodium or potassium hydroxide.
  • 2-(Tri-substituted silyl)-lower alkoxycarbonyl such as 2-tri-lower alkylsilyl-lower alkoxy ⁇ carbonyl
  • a salt of hydrofluoric acid tiiat yields die fluoride anion, such as an alkali metal fluoride, for example sodium or potassium fluoride, where appropriate in the presence of a macrocyclic polyetiier ("crown ether”), or with a fluoride of an organic quaternary base, such as a tetra-lower alkyl- ammonium fluoride or tri-lower alkylaryl-lower alkylammonium fluoride, for example tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic, polar solvent, such as dimethyl sulfoxide, N,N-dimethylformamide or N,N-di
  • die fluoride anion such as
  • Carboxy protected in the form of an internal ester such as in the form of ⁇ -lactone
  • a hydroxide-containing base such as an alkaline earth metal hydroxide or, especially, an alkali metal hydroxide, for example NaOH, KOH or LiOH, especially LiOH, the correspondingly protected hydroxy group being freed at die same time.
  • Aroylmethoxycarbonylamino can be cleaved also by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium tiiiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal dithionite, for example sodium ditiiionite.
  • a nucleophilic, preferably salt-forming, reagent such as sodium tiiiophenolate
  • 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal dithionite, for example sodium ditiiionite.
  • Unsubstituted or substituted diphenylmemoxycarbonylamino, tert-lower alkoxycarbonylamino or 2-(tri-substituted silyl)-lower alkoxycarbonylamino, such as 2-tri-lower alkylsilyl-lower alkoxycarbonylamino, can be cleaved by treatment with a suitable acid, for example formic acid or trifluoroacetic acid, for example in a halo ⁇ genated hydrocarbon, such as methylene chloride or chloroform (especially when hydroxy protected by benzyl is not to be freed at the same time); 1-aryl-lower alkoxycarbonyl ⁇ amino, such as unsubstituted or substituted benzyloxycarbonylamino, can be cleaved, for example, by means of hydrogenolysis, i.e.
  • 2-haloacetyl for example 2-chloroacetyl
  • 2-chloroacetyl can be freed by treatment with thiourea in the presence of a base, or with a thiolate salt, such as an alkali metal thiolate of thiourea, and subsequent solvolysis, such as alcoholysis or hydrolysis, of the resulting substitution product.
  • a thiolate salt such as an alkali metal thiolate of thiourea
  • Amino protected in the form of an azido group is converted into free amino, for example, by reduction, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst, such as platinum oxide, palladium or Raney nickel, by reduction using mercapto compounds, such as dithiothreitol or mercaptoetiianol, or by treatment with zinc in the presence of an acid, such as acetic acid.
  • the catalytic hydrogenation is preferably carried out in an inert solvent, such as a halogenated hydrocarbon, for example methylene chloride, or in water or in a mixture of water and an organic solvent, such as an alcohol or dioxane, at approximately from 20°C to 25°C, or with cooling or heating.
  • a hydroxy or mercapto group protected by a suitable acyl group, by a tri-lower alkylsilyl group or by unsubstituted or substituted l-aryl(such as l-phenyl)-lower alkyl is freed analogously to a correspondingly protected amino group.
  • a hydroxy or mercapto group protected by 2,2-dichloroacetyl is freed, for example, by basic hydrolysis, and a hydroxy or mercapto group protected by tert-lower alkyl or by a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical is freed by acidolysis, for example by treatment with a mineral acid or a strong carboxylic acid, for example trifluoroacetic acid.
  • a hydroxy group protected by benzyloxy is freed, for example, by hydrogenolysis, mat is to say by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, for example bonded to a carrier, such as carbon, preferably in polar solvents, such as di-lower alkyl-lower alkanoylamides, for example dimetiiylformamide, ethers, such as cyclic ethers, for example dioxane, esters, such as lower alkylalkanoates, for example ethyl acetate, or alcohols, such as methanol, ethanol or propanol, with methanol being especially preferred, preferably at about room temperature.
  • a suitable hydrogenation catalyst such as a palladium catalyst
  • a carrier such as carbon
  • polar solvents such as di-lower alkyl-lower alkanoylamides, for example dimetiiylformamide
  • ethers such as cyclic ether
  • Mercapto protected by pyridyldiphenylmetiiyl can be freed, for example, using mercury(H) salts at pH 2-6 or by zinc/acetic acid or by electrolytic reduction; acetamidomethyl and iso- butyrylamidomediyl can be freed, for example, by reaction with mercury(H) salts at pH 2-6; 2-chloroacetamidomed ⁇ yl can be freed, for example, using 1-piperidinothio- carboxamide; and S-ethylthio, S-tert-butylthio and S-sulfo can be freed, for example, by thiolysis with thiophenol, tiiioglycolic acid, sodium tiiiophenolate or 1,4-diti ⁇ ioti.reitol.
  • Two hydroxy groups or an adjacent amino and hydroxy group that are protected togetiier by means of a bivalent protecting group preferably, for example, by a methylene group mono- or di-substituted by lower alkyl, such as lower alkylidene, for example isopropyl- idene, cycloalkylidene, for example cyclohexylidene, or benzylidene, can be freed by acid solvolysis, especially in die presence of a mineral acid or a strong organic acid.
  • a tri- lower alkylsilyl group is likewise removed by acidolysis, for example by a mineral acid, preferably hydrofluoric acid, or a strong carboxylic acid.
  • 2-Halo- lower alkoxycarbonyl is removed using the above-mentioned reducing agents, for example a reducing metal, such as zinc, reducing metal salts, such as chromium( ⁇ ) salts, or using sulfur compounds, for example sodium ditiiionite or preferably sodium sulfide and carbon disulfide.
  • reducing agents for example a reducing metal, such as zinc, reducing metal salts, such as chromium( ⁇ ) salts, or using sulfur compounds, for example sodium ditiiionite or preferably sodium sulfide and carbon disulfide.
  • Esterified hydroxy groups for example lower alkanoyloxy, such as acetyloxy, can also be freed by esterases, and acylated amino can be freed, for example, by suitable peptidases.
  • the temperatures for die freeing of the protected functional groups are preferably from -80°C to the boiling temperature of the reaction mixture, especially from -80° to 110°C, most preferably from -20° to 50°C, for example from 10° to 35°C, such as at about room temperature, or at from 80°C to the boiling temperature of the reaction mixture in question, for example at about 100°C.
  • Acid addition salts of compounds of formula I are obtained in customary manner, for example by treatment with an acid or a suitable anion-exchange reagent.
  • Internal salts of compounds of formula I containing acid and basic salt-forming groups, for example a free carboxy group and a free amino group, can be formed, for example, by neutralisation of salts, such as acid addition salts, to the isoelectric point, for example with weak bases, or by treatment with ion-exchangers.
  • Salts can be converted in customary manner into the free compounds; metal and ammonium salts can be converted, for example, by treatment with suitable acids or acidic ion-exchangers, and acid addition salts, for example, by treatment with a suitable basic agent or basic ion-exchangers.
  • Stereoisomeric mixtures of compounds of formula I that is to say mixtures of diastereo- isomers and/or enantiomers, such as, for example, racemic mixtures, can be separated into the corresponding isomers in a manner known per se by suitable separating processes.
  • mixtures of diastereoisomers can be separated into the individual diastereo- isomers by fractional crystallisation, chromatography, solvent partition or other customary processes.
  • the free acid can be used or the free acid can be converted into one of the reactive derivatives mentioned above under Process a) and reacted with a corresponding alcohol, or the free acid or a reactive salt, for example the caesium salt, can be reacted with a reactive deriv ⁇ ative of an alcohol for the esterification.
  • the caesium salt of a carboxylic acid can be reacted witii a halide or organic sulfonic acid ester corresponding to the alcohol (with halogen or the radical of an organic sulfonic acid, such as toluenesulfonic acid, in place of the hydroxy group).
  • esterification of the carboxy group can also be carried out with other customary alkylating agents, for example with diazomethane, lower alkyl halides, sulfonic acid esters, Meerwein salts or 1 -substituted 3-aryltriazenes.
  • customary alkylating agents for example with diazomethane, lower alkyl halides, sulfonic acid esters, Meerwein salts or 1 -substituted 3-aryltriazenes.
  • a lower alkoxycarbonyl-lower alkoxy group that is present as a substituent for example of phenyl or naphti yl R 2 and/or R 3 , can be converted by reduction into a hydroxy-lower alkoxy group (wherein the lower alkyl radical has at least 2 carbon atoms), for example by reduction witii complex hydrides that selectively reduce the carbonyl ester group, under suitable reaction conditions, for example with LiBH 4 in 1 ,2-dimeti ⁇ oxyeti ⁇ ane at tempera ⁇ tures of from 0°C to the reflux temperature, preferably at approximately from 15° to 30°C.
  • a free amino or imino group can be acylated, for example by introducing a lower alkoxycarbonyl radical at die nitrogen of piperidinylcarbonyl R,.
  • the acylation is carried out analogously to die methods described above under Process a) or to one of the methods mentioned for protecting groups.
  • groups that correspond to protecting groups, or also suitable radicals R j apart from hydrogen can be removed by one of the methods mentioned under Process f). especially by hydrolysis, for example in the presence of bases, such as alkali metal or alkaline earth metal hydroxides, for example lithium or sodium hydroxide, or acids, such as organic acids or mineral acids, for example a hydrohalic acid, such as hydrochloric acid.
  • bases such as alkali metal or alkaline earth metal hydroxides, for example lithium or sodium hydroxide
  • acids such as organic acids or mineral acids, for example a hydrohalic acid, such as hydrochloric acid.
  • the hydrolysis is carried out under the customary conditions, for example in aqueous solution or in anhydrous solvents, especially in ethers, such as dioxane, at temperatures of from -50°C to the reflux temperature of the corresponding reaction mixture, for example at from 0°C to 50°C, preferably in the presence of a protective gas, such as argon or nitrogen, or by hydrogenolysis (for example in the case of benzyloxycarbonyl radicals), preferably in polar solvents, such as alcohols, for example methanol or ethanol, or esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, at the temperatures last mentioned and in the presence of suitable hydrogenation catalysts, such as a palladium catalyst, which is preferably bonded to a carrier, such as carbon.
  • a protective gas such as argon or nitrogen
  • hydrogenolysis for example in the case of benzyloxycarbonyl radicals
  • polar solvents such as alcohols, for example
  • the phenyl radical(s) in question can be selec ⁇ tively hydrogenated to form corresponding cyclohexyl radicals.
  • the hydrogenation is preferably carried out in die presence of a catalyst that allows the selective hydrogenation of double bonds in d e presence of amide bonds, especially a catalyst consisting of heavy metal oxides, such as a Rh(IH)/Pt(VI) oxide catalyst according to Nishimura (S. Nishi- mura, Bull. Chem. Soc.
  • the cyclohexenyl radical in question can be selectively hydrogenated to form the corres ⁇ ponding cyclohexyl radical, in suitable solvents or solvent mixtures, preferably dissolved in an alcohol, such as methanol or ethanol, an ester, for example a lower alkanoic acid lower alkyl ester, such as etiiyl acetate, or in a mixture of those solvents, in the presence of a catalyst, for example palladium, which is preferably bonded to a carrier, such as carbon, preferably activated carbon, at preferred temperatures of from 10° to 50°C, preferably at room temperature, at slightly elevated or reduced pressure or, preferably, at normal pressure.
  • a carrier such as carbon, preferably activated carbon
  • the invention relates also to pharmaceutical compositions comprising compounds of formula I, especially of formula F.
  • the pharmacologically acceptable compounds of die present invention may be used, for example, in the preparation of pharmaceutical compositions that comprise an effective amount of the active ingredient together or in admixture witii a significant amount of inorganic or organic, solid or liquid, pharmaceutically acceptable carriers.
  • compositions according to the invention are compositions for enteral, such as nasal, buccal, rectal or oral, or parenteral, such as intramuscular or intravenous, administration to warm-blooded animals (human beings and animals) that comprise an effective dose of the pharmacological active ingredient alone or together with a significant amount of a pharmaceutically acceptable carrier.
  • the dose of the active ingredient depends on the species of warm-blooded animal, body weight, age and individual condi ⁇ tion, individual pharmacokinetic data, the disease to be treated and the mode of admin ⁇ istration.
  • the invention relates also to pharmaceutical compositions and to a process or a method for treating diseases caused by retroviruses, for example AIDS or the preceding stages thereof, especially when HIV-2 or more especially HTV-1 is the cause of the disease, or analogous diseases in non-human warm-blooded animals caused, for example, by SIV in monkeys or by FTV in cats, or the preceding stages thereof, preferably wherein a compound of formula I or especially F according to the invention is present in an amount that is dierapeutically effective against retroviral diseases, such as AIDS or the preceding stages thereof or analogous diseases in non-human warm-blooded animals, in a pharma ⁇ ceutical composition that is suitable for administration to a warm-blooded animal, espec ⁇ ially a human being, for the treatment of a retroviral disease, such as, especially, AIDS, or analogous diseases in non-human warm-blooded animals, or wherein a compound of formula I or especially F is administered in die treatment method to a warm-blooded animal
  • the dose to be administered to warm-blooded animals is from approximately 3 mg to approximately 10 g, preferably from approximately 20 mg to approximately 4 g, for example approximately from 100 mg to 1.5 g per person per day, divided preferably into 1 to 3 single doses which may, for example, be of equal size.
  • "Therapeutically effective" means especially that the onset of the particular disease can be slowed down in comparison with untreated patients, at least one symptom can be delayed or alleviated, at least one cell type (for example human CD4 cells) can be completely or partially protected from the disease or the disease can even be cured competely.
  • the invention relates to a pharmaceutical composition that is suitable for the treatment of diseases caused by retroviruses and that comprises a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, in an amount that is effective against retroviral diseases, and at least one pharmaceutically acceptable carrier.
  • compositions comprise from approximately 1 % to approximately 95 %, preferably from approximately 20 % to approximately 90 %, active ingredient.
  • Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, dragees, tablets or capsules.
  • Solutions of the active ingredient, and also suspensions or dispersions, and especially isotonic aqueous solutions, dispersions or suspensions are preferably used, it being possible, for example in the case of lyophilised compositions at comprise the active ingredient alone or together with a carrier, for example mannitol, for such solutions, dispersions or suspensions to be made up prior to use.
  • the pharmaceutical compositions may be sterilised and/or may comprise excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers, and are prepared in a manner known per se, for example by means of conventional dissolving or lyophilising processes.
  • the said solutions or suspensions may comprise viscosity-increasing substances, such as sodium carboxymediylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.
  • Suspensions in oil comprise as the oil component the vegetable, synthetic or semi- synthetic oils customary for injection pu ⁇ oses.
  • oil component the vegetable, synthetic or semi- synthetic oils customary for injection pu ⁇ oses.
  • espe ⁇ cially liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid or linoleic acid, if desired with the addition of anti- oxidants, for example vitamin E, ⁇ -carotene or 3,5-di-tert-butyl-4-hydroxytoluene.
  • anti- oxidants for example vitamin E, ⁇ -caro
  • the alcohol component of those fatty acid esters has a maximum of 6 carbon atoms and is a mono- or poly-hydric, for example a mono-, di- or tri-hydric, alcohol, for example methanol, ethanol, propanol, butanol or pentanol or the isomers thereof, but especially glycol and glycerol.
  • fatty acid esters are therefore to be mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375” (polyoxyethylene glycerol trioleate, Gattefosse, Paris), "Miglyol 812” (triglyceride of saturated fatty acids with a chain length of C 8 to C 12 , H ⁇ ls AG, Germany), but especially vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and more especially groundnut oil.
  • vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and more especially groundnut oil.
  • the injection compositions are prepared in customary manner under sterile conditions; die same applies also to introducing the compositions into ampoules or vials and sealing the containers.
  • compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture, and processing the mixture, if desired or necessary, after the addition of appropriate excipients, into tablets, dragee cores or capsules, or by preparing dispersions, preferably with phospholipids, which are introduced into vials. It is also possible for the active ingredients to be inco ⁇ orated into plastics carriers that allow the active ingredients to diffuse or be released in measured amounts.
  • Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and or calcium phosphates, for example tri- calcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrol- idone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt tiiereof, such as sodium alginate.
  • fillers such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and or calcium phosphates, for example tri- calcium phosphate or calcium
  • Excipients are especially flow conditioners and lubri ⁇ cants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
  • Drag ⁇ e cores are provided with suitable, optionally enteric, coatings, there being used, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as ethylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
  • Capsules are dry-filled capsules made of gelatin and also soft, sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol.
  • the dry-filled capsules may comprise the active ingredient in the form of granules, for example with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and if desired with stabilisers.
  • the active ingredient is preferably suspended or dissolved in suitable oily excipients, such as conventional vegetable, synthetic or semi- synthetic oils.
  • liquid fatty acid esters that contain as the acid component a long-chained fatty acid, for example of from 8 to 22, especially from 12 to 22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid or linoleic acid, where appropriate with the addition of antioxidants, for example vitamin E, ⁇ -carotene or 3,5-di-tert-butyl-4-hydroxytoluene.
  • antioxidants for example vitamin E, ⁇ -carotene or 3,5-di-tert-butyl-4-hydroxytoluene.
  • the alcohol component of those fatty acid esters has a maximum of 6 carbon atoms and is a mono- or poly-hydric, for example mono-, di- or tri-hydric, alcohol, for example methanol, ethanol, propanol, butanol or pentanol or the isomers d ereof, but especially ethylene glycol or propylene glycol and glycerol.
  • Suitable emulsifiers are especially oleic acid, non-ionic surfactants of the fatty acid polyhydroxy alcohol ester type, such as sorbitan monolaurate, monooleate, monostearate or monopalmitate, sorbitan tristearate or trioleate, polyoxyethylene adducts of fatty acid polyhydroxyalcohol esters, such as polyoxyethylene sorbitan monolaurate, monooleate, monostearate, monopalmitate, tristearate or trioleate, polyethylene glycol fatty acid esters, such as polyoxyethyl stearate, polyoxyethylene glycol (300 or 400) stearate, polyethylene glycol 2000 stearate, espec ⁇ ially ethylene oxide/propylene oxide block polymers of the ®Pluronic type (Wyandotte Chem.
  • the active ingredient is not soluble in the mentioned oils, it is preferably in the form of a suspension, for example with a particle size of the active ingredient of approximately from 1 to lOO ⁇ m.
  • Dyes or pigments may be added to the tablets or dragee coatings or to the capsule casings, for example for identification pu ⁇ oses or to indicate different doses of active ingredient.
  • the present invention relates also to novel starting materials and/or intermediates and to processes for their preparation.
  • the starting materials used and the reaction conditions selected are preferably those which result in the compounds described as being preferred.
  • free functional groups that are not intended to participate in the reaction in question may be in unprotected form or, if necessary, in protected form; for example they may be protected by the protecting groups mentioned above under Process a), which can be introduced at suitable stages analogously to the methods mentioned therein.
  • Protecting groups, or rather the protected groups can be freed at suitable times analogously to the methods described under Process f).
  • Starting materials and intermediates having salt-forming groups can be used in each case as free compounds or in die form of salts, and at any stage salts can be formed or converted into the free compounds again.
  • the etherification is preferably effected with diazomethane or witii lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, pyridyl-lower alkyl, cyano-lower alkyl, mo ⁇ holinyl-lower alkyl or lower alkoxy-lower alkyl halides or sulfonic acid esters.
  • the hydrogenation is preferably carried out in the presence of a catalyst that allows the selective hydrogenation of double bonds in the presence of peptide bonds, especially a catalyst consisting of heavy metal oxides, such as a Rh(IH)/Pt(VI) oxide catalyst according to Nishimura (see Bull. Chem. Soc. Japan 33, 566 (I960)), in suitable solvents, especially water, alcohols, such as methanol or ethanol, esters, such as ethyl acetate, or ethers, such as dioxane, for example in methanol, at temperatures of from 0° to 150°C, preferably from 10° to 50°C, for example at room temperature, and at hydrogen pressures of from 0.01 to 50 bar, for example at normal or reduced pressure.
  • a catalyst that allows the selective hydrogenation of double bonds in the presence of peptide bonds
  • a catalyst consisting of heavy metal oxides such as a Rh(IH)/Pt(VI) oxide catalyst according to Nishimura (see Bull. Chem
  • the cyclohexenyl radical in question can at suitable stages of die reaction be selectively hydrogenated to form the corresponding cyclohexyl radical, for example in suitable solvents or solvent mixtures, preferably dissolved in an alcohol, such as metiianol or ethanol, an ester, for example a lower alkanoic acid lower alkyl ester, such as ethyl acetate, or in a mixture of those solvents, in the presence of a catalyst, for example palladium, which is preferably bonded to a carrier, such as carbon, preferably activated carbon, at preferred temperatures of from 10° to 50°C, preferably at room temperature, at slightly elevated or reduced pressure or, especially, at normal pressure.
  • a carrier such as carbon, preferably activated carbon
  • the carboxylic acids of formulae II and IV, or reactive derivatives thereof, are known, are commercially available or can be prepared in accordance with processes known per se.
  • R 2 is as defined for compounds of formula I and Pa is an amino-protecting group, especially lower alkoxycarbonyl, such as tert-butoxycarbonyl, or 1 -phenyl-lower alkoxy ⁇ carbonyl, such as benzyloxycarbonyl, (or analogues thereof containing hydrogen in place of Pa, which can then be protected subsequently) by reduction to a compound of formula
  • the reduction of amino acid derivatives of formula XI to the corresponding aldehydes XH is effected, for example, by reduction to the corresponding alcohols and subsequent oxida ⁇ tion to the aldehydes of formula XH.
  • the reduction to the alcohols is effected especially by hydrogenation of the corresponding acid halides or other activated carboxylic acid derivatives mentioned under Process a), or by reaction of activated carboxylic acid derivatives of compounds of formula XI, espe ⁇ cially anhydrides with organic carboxylic acids, preferably those of haloformic acid esters, such as chloroformic acid isobutyl ester, (which are preferably obtained by reaction of compounds of formula XI in the presence of basic amines, for example tri-lower alkyl ⁇ amines, such as triethylamine, in organic solvents, such as cyclic ethers, for example dioxane, at temperatures of from -50° to 80°C, preferably from 0° to 50°C) with complex hydrides, such as alkali metal borohydrides, for example sodium borohydride, in aqueous solution in the presence or absence of the organic solvents last used, at temperatures of from -50° to 80°C, preferably from
  • the subsequent oxidation of the resulting alcohols is preferably effected with those oxidising agents which selectively convert the hydroxy group into an aldehyde group, for example chromic acid or derivatives thereof, such as pyridinium chromate or tert-butyl chromate, dichromate/sulfuric acid, sulfur trioxide in the presence of heterocyclic bases, such as pyridine/SO 3 (preferably dissolved in di-lower alkyl sulfoxides, such as dimethyl sulfoxide, aromatic solvents, such as toluene, or mixtures of those solvents), also nitric acid, pyrolusite or selenium dioxide, in water, aqueous or organic solvents, such as halogenated solvents, for example methylene chloride, carboxylic acid amides, such as dimethylformamide, and/or cyclic ethers, such as tetrahydrofuran, in die presence or absence of basic amines, for example tri-lower al
  • Direct reduction of die compounds of formula XI to the aldehydes is also possible, for example by hydrogenation in the presence of a partially poisoned palladium catalyst or by reduction of the corresponding amino acid esters, for example the lower alkyl esters, such as etiiyl esters, with complex hydrides, for example boron hydrides, such as sodium boro ⁇ hydride, or preferably aluminium hydrides, for example lithium aluminium hydride, lithium tri(tert-butoxy)aluminium hydride or especially diisobutylaluminium hydride, in non-polar solvents, for example in hydrocarbons or aromatic solvents, such as toluene, at from -100° to 0°C, preferably from -70° to -30°C, and subsequent reaction to form die corresponding semicarbazones, for example with the corresponding acid salts of semi- carbazones, such as semicarbazide hydrochloride, in aqueous solvent systems, such as alcohol/
  • the corresponding esters are obtained by reaction of the amino acids witii the corresponding alcohols, for example ethanol, analogously to the conditions used in die condensation under Process b), for example by reaction with inorganic acid halides, such as tiiionyl chloride, in organic solvent mixtures, such as mixtures of aromatic and alcoholic solvents, for example toluene and ethanol, at temperatures of from -50° to 50°C, preferably from -10° to 20°C.
  • inorganic acid halides such as tiiionyl chloride
  • organic solvent mixtures such as mixtures of aromatic and alcoholic solvents, for example toluene and ethanol
  • R 2 is as defined for compounds of formula I; an amino-protecting group Pa, for example tert-butoxycarbonyl, is re-introduced into die corresponding olefin, as described under Process a) for the introduction of amino-protecting groups, especially with the aid of an acid anhydride in a chlorinated hydrocarbon, such as mediylene chloride or chloroform, at temperatures of from -50° to 80°C, especially from 0° to 35°C, there being obtained a protected amino-olefin of formula
  • die double bond is converted into an oxirane, preferably stereoselectively using peroxides, especially peroxycarboxylic acids, for example haloperbenzoic acid, such as m-chloroperbenzoic acid, in an inert organic solvent, preferably a halogenated hydrocarbon, such as methylene chloride or chloroform, at temperatures of from -50° to 60°C, especially from -10° to 25°C, and, if necessary, diastereoisomers are separated, there being obtained an epoxide of formula
  • a suitable malonic acid diester for example malonic acid dimetiiyl ester or malonic acid dietiiyl ester
  • a suitable malonic acid diester for example malonic acid dimetiiyl ester or malonic acid dietiiyl ester
  • an alkali metal for example sodium
  • a polar anhydrous solvent such as an alcohol, for example methanol or ethanol
  • an acid for example a carboxylic acid, such as citric acid
  • Rj 4 is lower alkoxy, for example methoxy or etiioxy, and die remaining radicals are as last defined; if desired, in tiiose compounds in which R 2 is phenyl that is unsubsti ⁇ tuted or substituted as described for compounds of formula I, that radical is reduced to cyclohexyl, especially by hydrogenation, preferably in die presence of catalysts, such as noble metal oxides, for example mixtures of Rh(IH)/Pt(VI) oxides (in accordance witii Nishimura), preferably in polar solvents, such as alcohols, for example methanol, at normal pressure or at up to 5 bar, preferably at normal pressure, at temperatures of from -20° to 50°C, preferably from 10° to 35°C; a compound of formula XVH obtained directly or after hydrogenation is reacted with a reagent that introduces the radical R 3 -CH 2 -, for example of formula
  • R 3 is as defined for compounds of formula I and W is a nucleofugal leaving group preferably selected from hydroxy esterified by a strong inorganic or organic acid, such as hydroxy esterified by a mineral acid, for example a hydrohalic acid, such as hydrochloric, hydrobromic or hydriodic acid, or by a strong organic sulfonic acid, such as an unsubsti ⁇ tuted or substituted, for example halo-substituted, such as fluoro-substituted, lower alkane- sulfonic acid or an aromatic sulfonic acid, for example benzenesulfonic acid tiiat is unsub ⁇ stituted or substituted by lower alkyl, such as metiiyl, halogen, such as bromine, and/or by nitro, for example a methanesulfonic, trimethanesulfonic or p-toluenesulfonic acid, and hydroxy esterified
  • the compound of formula XDC is hydrolysed and decarboxylated, for example by hydrolysis by means of a base, such as an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide, at temperatures of from -50° to 80°C, preferably approximately from 0° to 35°C, in an organic solvent, for example an ether, such as 1 ,2-dimethoxyethane, or an alcohol, such as ethanol, and subsequent decarboxylation by heating in an inert solvent, preferably a hydrocarbon, for example an aromatic hydrocarbon, such as toluene, at temperatures of from 40° to 120°C, preferably from 70° to 120°C, there being obtained a compound of formula
  • die radicals are as last defined; the resulting (R,S,S)- and (S,S,S)-isomers are separated by column chromatography, and the (R,S,S)-isomer is used further and, for die pu ⁇ ose of opening d e lactone ring, is reacted witii a base, such as an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide, in an inert solvent, such as an etiier, for example dimethoxyethane, or an alcohol, such as ethanol, yielding a compound of formula
  • a base such as an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide
  • an inert solvent such as an etiier, for example dimethoxyethane
  • alcohol such as ethanol
  • a hydroxy-protecting group Py for example one of the hydroxy-protecting groups mentioned under Process a) under the conditions mentioned tiierein, especially a tri-lower alkylsilyl group with the aid of the corresponding halo-tri-lower alkylsilane, for example tert-butyldimediylchlorosilane, in a polar solvent, such as a di-lower alkyl-lower alkanoyl- amide, such as dimethylformamide, in die presence of a sterically hindered amino compound, such as a cyclic amine, for example imidazole, at temperatures of from -50° to 80°C, preferably from 0° to 35°C, and die carboxy group, which was silylated at the same time, is freed by reaction with a basic metal salt, especially an alkali metal hydroxide or an alkali metal hydrogen carbonate or, preferably
  • a compound of formula IH or HI' having the radicals indicated under Process a) is prepared from a compound of formula XXH, for example by condensation with a compound of formula VI wherein the radicals are as defined under Process c), under conditions analogous to mose indicated for Process a), especially by in situ reaction in the presence of a condensation agent, such as N,N-di- cyclohexylcarbodiimide, cyanophosphonic acid ethyl ester, benzotriazol-l-yl-oxy-tris(di- methylamino)phosphonium hexafluorophosphate or O-benzotriazol-l-yl-N,N,N',N'-tetra- methyluronium hexafluorophosphate, a sterically hindered amine, such as triethylamine or N-methylmo ⁇ holine, and, where appropriate, a compound hindering racemisation
  • a condensation agent such as N,
  • the afore-mentioned compounds of formula XTV can also be in the (R,S)-configuration at die carbon atom carrying the radical -NH 2 instead of in die (S)-configuration shown, and the compounds of formulae XI, XH, XIH, and especially those of formulae XV, XVI, XVH, XDC, XX, XXI and/or XXH, can also be in the (R,S)-configuration at the carbon atom carrying the radical Pa-NH- instead of in die (S)-conf ⁇ guration.
  • the afore-mentioned compounds of formulae XV, XVI and XVH can also be in the form of racemates.
  • a compound of formula XX wherein the radicals are as defined is also prepared from a compound of formula X ⁇ wherein the radicals are as defined, by reacting an aldehyde of formula X ⁇ with a 2-halopropionic acid ester, especially a 2-iodopropionic acid lower alkyl ester, such as 2-iodopropionic acid ethyl ester, there being obtained a compound of formula
  • radicals are as defined and wherein the carbon atom carrying the radical Pa-NH- may alternatively also be, for example, in the (R,S)-configuration.
  • the reaction is carried out first with the formation of the homoenolate of the 2-halo- propionic acid lower alkyl (such as ethyl) ester in the presence of a mixture of Zn/Cu in a di-lower alkyl-lower alkanoylamide, such as dimethylacetamide, or an aromatic hydro ⁇ carbon, such as toluene, or mixtures thereof, at temperatures of from 0° to 100°C, espe ⁇ cially from 20° to 80°C, where appropriate under protective gas, such as argon or nitrogen.
  • a titanium tetrahalide such as titanium tetrachloride
  • a suitable tetra-lower alkyl orthotitanate such as tetraisopropyl ortho- titanate
  • an aromatic solvent such as toluene or xylene
  • a halogenated hydrocarbon such as methylene chloride
  • the zinc homoenolate solution is added dropwise thereto at temperatures of from -50° to 0°C, especially from -40° to -25°C, and tiien die aldehyde of formula XH in a halogenated hydrocarbon, for example methylene chloride, is added dropwise, the reaction taking place at from -50° to 30°C, preferably approximately from -40° to 5°C, with the formation of a lower alkyl (especially ethyl) ester precursor, especially the etiiyl ester, of die compound of formula XXH!.
  • a halogenated hydrocarbon for example methylene chloride
  • the corresponding compound of formula XX is then obtained by deprotonation with a strong base, to produce the carbanion formed at the ⁇ -carbon atom adjacent to the oxo group of the lactone, and by subsequent nucleophilic substitution of the radical W of a compound of formula XVIII wherein R 3 and W are as defined above for the preparation of compounds of formula XDC (W is especially bromo), the reaction preferably resulting stereoselectively in the (R)-configuration at the carbon atom carrying the radical R 3 -CH 2 - in the compound of formula XX.
  • the reaction with the strong base, especially with an alkali metal organosilicon amide compound is preferably carried out in an inert organic solvent, especially an ether, for example a cyclic ether, such as tetrahydrofuran, or l,3-dimed ⁇ yl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), or mixtures of those solvents, at temperatures of from -100° to 0°C, preferably from -78° to -50°C, and the nucleophilic substitution is effected in situ by adding die compound of d e formula R 3 -CH 2 -W, in the same solvent, at temperatures of from -100° to 0°C, preferably from -60° to
  • a solution of 9.74 g of m-chloroperbenzoic acid in 50 ml of methylene chloride is added at 0 to 5°C, within a period of 15 min, to a solution of 1.45 g of N-Boc-1 -phenyl- 3-butene-2(S)-amine in 20 ml of methylene chloride.
  • the reaction mixture is stirred for a further 8 h to complete die reaction, while warming to RT, and is poured onto ice-cold 10 % sodium carbonate solution.
  • the aqueous phase is extracted three times with ether.
  • the combined organic phases are washed, in succession, three times with 10 % sodium sulfite solution, three times with saturated sodium hydrogen carbonate solution, with sodium thiosulfate solution and brine, and dried over sodium sulfate.
  • Example 2 5(S)-[Z-(L)-Asn-aminol-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-fluoro- phenylmethyl)-hexanoyl-(L)-Val-N-(2-(morpholin-4-yl)-ethyl)amide
  • the starting material is prepared as follows:
  • the Zn homoenolate solution is decanted from die metallic solid by means of tubules and is added dropwise to the trichlorotitanium isoprop- anolate, the temperature being maintained at from -40°C to -30°C (— » deep-red solution), the solution is heated for 5 min at -25°C and is cooled again to -40°C.
  • a solution of 9.0 g of N-(S)-Boc-phenylalaninal see DJ. Kempf, J. Org. Chem. 51 .
  • That intermediate is heated in 295 ml of toluene and 9 ml of acetic acid at 80°C for 2.5 h.
  • 0.5 1 of water is added to the reaction mixture, the aqueous phase is separated off and extracted with 2 portions of ether, and the organic phases are washed with saturated sodium hydrogen carbonate solution, water and brine and dried with sodium sulfate.
  • the starting material is prepared as follows:
  • the reaction mixture is acidified with 10 % citric acid, the THF is partially evaporated using a RE, and die residue is partitioned between 3 portions of ethyl acetate, 2 portions of 2N sodium hydroxide solution, water, saturated sodium hydrogen carbonate solution and brine.
  • the organic phases dried with sodium sulfate and concentrated by evaporation, are dissolved in a small amount of methylene chloride and crystallised by the addition of hexane to yield the title compound.
  • the Zn homoenolate is formed from 16.7 g of 2-iodoprop- ionic acid ethyl ester (Example 3b) in 124 ml of toluene, 8.1 g of Zn Cu and 12.4 ml of dimethylacetamide.
  • the Zn homoenolate is transferred by means of tubules to trichloro ⁇ titanium isopropanolate (prepared from 5.11 ml of tetraisopropyl orthotitanate and 5.71 ml of titanium tetrachloride in 16 ml of toluene and 88.5 ml of methylene chloride) that has been cooled to from -40°C to -25°C.
  • Crystalline 5(S)-(Boc- amino)-4(S)-hydroxy-6-(p-fluorophenyl)-hexanoic acid ethyl ester is obtained as an inter ⁇ mediate. That intermediate is heated in 244 ml of toluene and 7.3 ml of acetic acid at 100°C for 2 h.
  • the starting material is prepared as follows:
  • reaction mixture After being partially concentrated by evaporation, the reaction mixture is poured onto a mixture of ice, 1 12 ml of sat. NH C1 solution, 9.4 ml of 10 % citric acid solution and 46 ml of methylene chloride, and methanol is added until the solid which has precipitated dissolves clearly in the 2 phases.
  • reaction mixture After being partially concentrated by evaporation, the reaction mixture is poured onto a mixture of ice, 132 ml of sat. NH 4 C1 solution, 11 ml of 10 % citric acid solution and 54 ml of methylene chloride, and methanol is added until the solid which has precipitated dissolves.
  • the starting material is prepared as follows:
  • the starting material is prepared as follows:
  • Example 3c Analogously to Example 3d), 5.0 g (16.37 mmol) of 5(S)-[l(S)-(Boc-amino)-2-phenyl- ethyl]-dihydrofuran-2-(3H)-one [Example 3c)], dissolved in 75 ml of THF, are deproton ⁇ ated at -75°C with 32.7 ml of lithium bis(trimethylsilyl)amide, IM in THF, and alkylated at -75°C initially (warming over a period of 60 min to a maximum of -50°C) with 3.4 g (18.0 mmol) of 3-fluorobenzyl bromide (Fluka; Buchs, Switzerland).
  • Column chromato ⁇ graphy SiO 2 , hexane/ethyl acetate 3:1
  • Example 13 5(S)-(Boc-amino)-4(S)-hvdroxy-6-phenyl-2(R)-r(2.4-difluoro-phenyl)- methyll-hexanoyI-(L)-VaI-N-(2-(morpholin-4-yl)-ethyl)amide
  • the starting material is prepared as follows:
  • Example 3d Analogously to Example 3d), 5.0 g (16.37 mmol) of 5(S)-[l(S)-(Boc-amino)-2-phenyl- ethyl]-dihydrofuran-2-(3H)-one [Example 3c)], dissolved in 100 ml of THF, are deproton ⁇ ated at -75°C with 32.7 ml of lithium bis(trimethylsilyl)amide, IM in THF.
  • Example 14 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)- ⁇ fp-(2-phenyl-ethyP- phenyllmethyl)-hexanoyl-(L)-Val-N-(2-(morpholin-4-yl)-ethyPamide
  • the starting material is prepared as follows: 14a) p-(2-Phenyl-ethyI)-benzyl alcohol
  • Example 15 5(SHBoc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-benzyloxy-phenyD- methyll-hexanoyl-(L)-Val-N-(2-(morpholin-4-yl)-ethyl)amide
  • Example 16 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-hydroxy-phenyl)- methyll-hexanoyl-(L)-Val-N-(2-(morpholin-4-yl)-ethyPamide
  • Example 17 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(phenyl-methyP- hexanoyl-(L)-Val-N-(2-methyl-2-morpholino)propylamide
  • Example 20 5(S)-(N-(Z-(L)-VaPamino)-4(S)-hydroxy-6-phenyl-2(R)-(phenyl- methyl)-hexanoyl-(L)-Val-N-(2-morpholino)ethylamide
  • the starting compound is prepared as follows:
  • Example 22 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-f(p-(ethoxycarbonyl- methoxy)-phenyl)-methyIl-hexanoyl-(L)-Val-N-(2-morpholin-4-yl-ethyl)amide:
  • Example 25 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-(cyanomethoxy)- phenyP-methyn-hexanoyl-(L)-Val-N-(2-morpholin-4-yl-ethypamide:
  • Example 28 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(4- ⁇ 2-hydroxy-ethoxy ⁇ - phenyP-methyl]-hexanoyl-(L)-Val-N-(2-morpholin-4-yl-ethyl)amide:
  • Example 29 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-(2-(methoxy)- ethoxy ⁇ -phenyP-methyl1-hexanoyl-(L)-Val-N-(2-morpholin-4-yl-ethyPamide:
  • active ingredient 3 mg gelatin 150.0 mg phenol 4.7 mg dist. water comprising 20 % cyclodextrins as solubilisers 1.0 ml
  • active ingredient 1000 g corn starch 680 g - 121 -
  • a mixture of one of the compounds of formula I mentioned in the preceding Examples, as active ingredient, 50 g of corn starch and the colloidal silica is processed with a starch paste prepared from 250 g of corn starch and 2.2 kg of demineralised water to form a moist mass.
  • the mass is forced through a sieve of 3 mm mesh size and dried in a fluidised bed drier at 45° for 30 min.
  • the dried granules are pressed through a sieve of 1 mm mesh size, mixed with a previously sieved mixture (1 mm sieve) of 330 g of corn starch, the magnesium stearate, the stearic acid and the sodium carboxymethyl starch and the resulting mixture is compressed to form slightly convex tablets.
  • the ED 90 (effective dose at which only 10 % of the viruses are still found in comparison with a control in the absence of an inhibitor) is determined by measuring the activity of reverse transcriptase. Only the results of measurements resulting in accurate ED 90 values are given:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne des composés de la formule (I), ou des sels de ceux-ci, dans laquelle R1 représente un radical acyle choisi parmi alcoxy inférieur-alcanoyle inférieur (notamment alcoxy inférieur-carbonyle), le radical alcoxy inférieur n'étant pas substitué ou l'étant par halogène, phényle ou alcoxy inférieur; ou par un radical hétérocyclique choisi parmi pipéridinyle, pyrrolidinyle, tétrahydropyranyle, tétrahydrofuranyle, thiazolidinyle, thiazolyle, indolyle et 4H-1-benzopyranyle, chacun de ceux-ci n'étant pas substitué ou l'étant par oxo, hydroxy, amino, alkyle inférieur, alcoxycarbonyle inférieur et/ou phényl-alcoxycarbonyle inférieur; parmi alcanoyle inférieur qui n'est pas substitué ou l'est par un des radicaux hétérocycliques non substitués ou substitués, dernièrement mentionnés; et parmi arylcarbonyle ou hétérocyclylcarbonyle substitués chacun par hétérocyclyle ou par hétérocyclyl-alkyle inférieur; ou bien R1 représente le reste d'un acide aminé défini dans la description (qui n'est pas acylé ou est N-acylé par un radical acyle mentionné ci-dessus); R2 et R3 représentent chacun indépendamment cyclohexyle, cyclohexényle, phényle, naphtyle ou tétrahydronaphtyle, qui sont chacun non substitués ou substitués par alkyle inférieur, phényl-alkyle inférieur, halogène, halo-alkyle inférieur, cyano, hydroxy, alcoxy inférieur, phényl-alcoxy inférieur, pyridyl-alcoxy inférieur, alcoxy inférieur-alcoxy inférieur, alcoxy inférieur-carbonyl-alcoxy inférieur, carboxy-alcoxy inférieur, hydroxy-alcoxy inférieur possédant au moins deux atomes de carbone, hydroxy n'étant pas lié dans la position 1, carbamoyl-alcoxy inférieur, cyano-alcoxy inférieur, morpholinyl-alcoxy inférieur, alkylènedioxy inférieur, ou phényl-alcanesulfonyle inférieur qui n'est pas substitué ou l'est dans le radical phényle par halogène; ou alkyle inférieur; R4 représente alkyle inférieur, cyclohexyle ou phényle et R5, R5', R6, R7, R8, R8', R9 et R10 représentent chacun indépendamment hydrogène ou alkyle inférieur. Les composés décrit possèdent une activité anti-rétrovirale.
PCT/EP1995/004508 1994-11-29 1995-11-16 Derives morpholino-ethylamides WO1996016980A1 (fr)

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WO2006113097A3 (fr) * 2005-04-15 2007-03-15 Univ North Carolina Procede pour faciliter la survie cellulaire a l'aide de mimetiques de neurotrophine
WO2007129745A1 (fr) 2006-05-09 2007-11-15 Daiichi Sankyo Company, Limited Derive acide carboxylique inferieur d'heteroarylamide
EA017528B1 (ru) * 2006-07-20 2013-01-30 Смитклайн Бичам Корпорейшн Аналоги морфолинила и пирролидинила
EP2498782A4 (fr) * 2009-11-12 2014-03-12 Pharmatrophix Inc Formes cristallines de composés mimétiques de neurotrophines et leurs sels
US8686045B2 (en) 2005-06-08 2014-04-01 The University Of North Carolina At Chapel Hill Methods of facilitating neural cell survival using non-peptide and peptide BDNF neurotrophin mimetics
US9828332B2 (en) 2013-03-15 2017-11-28 PharmatorophiX, Inc. Non-peptide BDNF neurotrophin mimetics
US9828330B2 (en) 2013-03-15 2017-11-28 Pharmatrophix, Inc. Non-peptide BDNF neurotrophin mimetics
US9884833B2 (en) 2012-09-27 2018-02-06 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US10273219B2 (en) 2009-11-12 2019-04-30 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts

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WO1991010422A1 (fr) * 1990-01-12 1991-07-25 The Liposome Company, Inc. Lyposomes et gels a fusion d'interdigitation
EP0532466A2 (fr) * 1991-09-12 1993-03-17 Ciba-Geigy Ag Dérivés d'acide 5-amino-4-hydroxy-hexanoique et leur application comme agents thérapeutiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991010422A1 (fr) * 1990-01-12 1991-07-25 The Liposome Company, Inc. Lyposomes et gels a fusion d'interdigitation
EP0532466A2 (fr) * 1991-09-12 1993-03-17 Ciba-Geigy Ag Dérivés d'acide 5-amino-4-hydroxy-hexanoique et leur application comme agents thérapeutiques

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8916556B2 (en) 2005-04-15 2014-12-23 The University Of North Carolina At Chapel Hill Pharmaceutical formulations comprising neurotrophin mimetics
JP2008536844A (ja) * 2005-04-15 2008-09-11 ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒル ニューロトロフィン類似体を用いた細胞生存促進法
US7723328B2 (en) 2005-04-15 2010-05-25 The University Of North Carolina At Chapel Hill Methods of facilitating cell survival using neurotrophin mimetics
WO2006113097A3 (fr) * 2005-04-15 2007-03-15 Univ North Carolina Procede pour faciliter la survie cellulaire a l'aide de mimetiques de neurotrophine
JP2013047236A (ja) * 2005-04-15 2013-03-07 Univ Of North Carolina At Chapel Hill ニューロトロフィン類似体を用いた細胞生存促進法
US9604907B2 (en) 2005-06-08 2017-03-28 The University Of North Carolina At Chapel Hill Methods of facilitating neural cell survival using non-peptide and peptide BDNF neurotrophin mimetics
US8686045B2 (en) 2005-06-08 2014-04-01 The University Of North Carolina At Chapel Hill Methods of facilitating neural cell survival using non-peptide and peptide BDNF neurotrophin mimetics
WO2007129745A1 (fr) 2006-05-09 2007-11-15 Daiichi Sankyo Company, Limited Derive acide carboxylique inferieur d'heteroarylamide
EA017528B1 (ru) * 2006-07-20 2013-01-30 Смитклайн Бичам Корпорейшн Аналоги морфолинила и пирролидинила
US9271986B2 (en) 2009-11-12 2016-03-01 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
EP2498782A4 (fr) * 2009-11-12 2014-03-12 Pharmatrophix Inc Formes cristallines de composés mimétiques de neurotrophines et leurs sels
EP3470402A1 (fr) * 2009-11-12 2019-04-17 Pharmatrophix Inc. Formes cristallines de composés mimétiques de la neurotrophine et leurs sels
US10273219B2 (en) 2009-11-12 2019-04-30 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US10532988B2 (en) 2009-11-12 2020-01-14 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US11225467B2 (en) 2009-11-12 2022-01-18 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US9884833B2 (en) 2012-09-27 2018-02-06 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US9828332B2 (en) 2013-03-15 2017-11-28 PharmatorophiX, Inc. Non-peptide BDNF neurotrophin mimetics
US9828330B2 (en) 2013-03-15 2017-11-28 Pharmatrophix, Inc. Non-peptide BDNF neurotrophin mimetics

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