WO2007122199A1 - Synthesis and uses of pyroglutamic acid derivatives - Google Patents
Synthesis and uses of pyroglutamic acid derivatives Download PDFInfo
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- WO2007122199A1 WO2007122199A1 PCT/EP2007/053900 EP2007053900W WO2007122199A1 WO 2007122199 A1 WO2007122199 A1 WO 2007122199A1 EP 2007053900 W EP2007053900 W EP 2007053900W WO 2007122199 A1 WO2007122199 A1 WO 2007122199A1
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Definitions
- the present invention refers to a new synthesis of pyroglutamic acid derivatives, their isolated optically active stereoisomers and mixtures thereof and their uses, and to new intermediates towards the synthesis of the same.
- the present invention also refers to the therapeutic use of said pyroglutamic acid derivatives, their optically active stereoisomers and mixtures thereof.
- European patent EP 0768308 Bl discloses mixtures of stereoisomers of pyroglutamic acid derivatives having the following general formula
- the process disclosed therein for the synthesis of said compounds comprises reacting L-serine with a molar excess of acetic anhydride and pyridine under heat. Therefore, as disclosed in said document, the different stereoisomers have never been isolated and the in vivo and in vitro assays disclosed therein are performed with the mixtures of the four possible optically active stereoisomers all together. No indication regarding pure or enriched mixtures of the individual stereoisomers is disclosed. Further, no indication regarding the isolation of the different optically active stereoisomers from the mixture disclosed is given.
- a compound may have therapeutic effects while its enantiomer may be toxic. Examples of such situations are well known to the skilled person.
- Dextromethorphan is a decongestant
- levomethorphan is a potent narcotic.
- thalidomide which was administered as a racemic mixture to pregnant women in order to treat mourning sickness.
- the present invention provides a process for obtaining pyroglutamic acid derivatives, their optically active stereoisomers and mixtures thereof.
- the process involves the use of an optically active stereoisomer of a precursor of a pyroglutamic acid derivative which can be easily separated and subsequently transformed in order to yield the desired optically active stereoisomer.
- the inventors have envisaged a synthesis in which the different intermediates are isolated, if desired, with the desired stereochemistry. These intermediate products may be further transformed in order to provide the desired pyroglutamic acid derivative either in the form of the desired substantially pure stereoisomer or in the form of a mixture of stereoisomers.
- the inventors start from an enantiomerically pure compound of formula IV, generating then diastereomeric intermediates and final products which can be easily separated and purified.
- Said compound of formula IV may be synthesized using enantiomerically pure glutamic acid.
- the present invention is directed to a process to obtain a substantially pure stereoisomer of a compound of formula I, or mixtures thereof, which comprises reacting a compound of formula IV with a compound of formula V in order to obtain a substantially pure stereoisomer of a compound of formula III or mixtures thereof; transforming said substantially pure stereoisomer of a compound of formula III or mixtures thereof into a substantially pure stereoisomer of a compound of formula II or mixtures thereof; and, finally, reacting said substantially pure stereoisomer of a compound of formula II or mixtures thereof with a compound of formula HX to render the desired pyroglutamic acid derivative of formula I as a substantially pure stereoisomer or mixtures thereof.
- a further aspect of the present invention relates to a substantially pure stereoisomer of a compound of formula I (i.e., Ia, Ib, Ic or Id).
- Some compositions comprising mixtures of the substantially pure stereoisomers of a compound of formula Ia, Ib, Ic and/or Id constitute a further aspect of the present invention, such as a composition comprising the stereoisomers of formula Ia, Ib, Ic and/or Id with the proviso that said composition does not simultaneously contain mixtures of all four stereoisomers of the following compounds:
- a further aspect of the present invention relates to a substantially pure stereoisomer of a compound of formula III or mixtures thereof.
- the process to obtain the said compound constitutes an additional aspect of the present invention.
- a further aspect of the present invention relates to a process to obtain a substantially pure stereoisomer of a compound of formula II, or a substantially pure stereoisomer of said compound of formula I.
- a substantially pure stereoisomer of a compound of formula II i.e., Ha, Hb, Hc or Hd
- Some compositions comprising mixtures of the substantially pure stereoisomers of a formula Ha, lib, Hc and/or Hd also constitute a further aspect of the present invention.
- a further aspect of the present invention relates to some pharmaceutical compositions comprising a compound selected from the group of compounds of formula Ia, Ib, Ic, Id and mixtures thereof, and a pharmaceutically acceptable excipient.
- a further aspect of the present invention relates to the use of a compound selected from the group of compounds of formula Ia, Ib, Ic, Id and some mixtures thereof, in the manufacture of a composition for preventing or treating tumors.
- FIGURES Figure 1 is a graph showing the inhibitory effect of the isomers (1-4) assayed on
- FIG. 1 is a graph showing the inhibitory effect of the isomers (1-4) assayed on Renca tumour cell growth compared to placebo (P. S.) [Example 6], expressed as the median of tumour volumes.
- Figure 3 is a graph showing the inhibitory effect of the isomers (1-4) assayed on Renca tumour cell growth compared to placebo (P. S.) [Example 6], expressed as the mean of tumour surfaces.
- Figure 4 is a graph showing the inhibitory effect of the isomers (1-4) assayed on Renca tumour cell growth compared to placebo (P. S.) [Example 6], expressed as the mean of tumour volumes.
- Alkyl refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, having 1-12, preferably one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e. g., methyl, ethyl, n-propyl, i-propyl, n- butyl, t-butyl, n-pentyl, etc.
- Alkyl radicals may be optionally substituted by one or more substituents such as halo, hydroxy, alkoxy, O- propyl, O-benzyl, 0-benzoate, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, imino, nitro, mercapto and alkylthio.
- substituents such as halo, hydroxy, alkoxy, O- propyl, O-benzyl, 0-benzoate, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, imino, nitro, mercapto and alkylthio.
- Alkenyl refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing at least one unsaturation, having 1-12, preferably one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e. g., methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, etc.
- Alkyl radicals may be optionally substituted by one or more substituents such as halo, hydroxy, alkoxy, O-propyl, O-benzyl, O-benzoate, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, imino, nitro, mercapto and alkylthio.
- substituents such as halo, hydroxy, alkoxy, O-propyl, O-benzyl, O-benzoate, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, imino, nitro, mercapto and alkylthio.
- Alkoxy refers to a radical of the formula -O-alkyl, where alkyl has been previously defined, e. g., methoxy, ethoxy, propoxy, etc.
- Aryl refers to an aromatic hydrocarbon radical such as phenyl, naphthyl or anthracyl.
- the aryl radical may be optionally substituted by one or more substituents such as hydroxy, mercapto, halo, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl and alkoxycarbonyl, as defined herein.
- Aryloxy refers to a radical of formula -O-aryl, where aryl has been previously defined. Some examples of araloxy compopounds are -O-phenyl, -O-p-tolyl, -O-m- tolyi, -O-o-tolyl or -O-naphtyl.
- Amino refers to a radical of the formula -NH 2 , -NHRa, -NRaRb, wherein Ra and Rb are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl or substituted or unsubstituted heterocyclyl; or Ra and Rb together form a substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl or substituted or unsubstituted cycloalkenyl.
- Alkyl refers to an aryl group linked to an alkyl group such as benzyl and phenethyl.
- Carboxyester refers to a -CO 2 Ra, wherein Ra is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl or substituted or unsubstituted heterocyclyl.
- Cycloalkyl refers to a saturated carbocyclic ring having from 3 to 8 carbon atoms.
- Cycloalkenyl refers to a carbocyclic ring having from 3 to 8 carbon atoms and at least one unsaturation.
- Heterocyclyl refers to a stable 3- to 15- membered ring which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulphur, preferably a 4-to 8-membered ring with one or more heteroatoms, more preferably a 5-or 6-membered ring with one or more heteroatoms.
- the heterocycle may be a monocyclic, bicyclic or tricyclic ring system, which may include fused ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidised; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated or aromatic.
- heterocycles include, but are not limited to, azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran.
- Heteroaryl refers to a heterocyclic group wherein at least one of the rings is an aromatic ring.
- Protecting group refers to a group that blocks an organic functional group and can be removed under controlled conditions. Protecting groups, their relative reactivities and conditions under which they remain inert are known to the skilled person.
- references herein to substituted groups in the compounds of the present invention refer to the specified moiety that may be substituted at one or more available positions by one or more suitable groups, e. g., halogen such as fluoro, chloro, bromo and iodo; cyano; hydroxyl; nitro; azido; alkanoyl such as a Ci-C 6 alkanoyl group such as acyl and the like; carboxamido; alkyl groups including those groups having 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1-3 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen linkages and from 1 to about 12 carbon atoms or 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether link
- pharmaceutically acceptable anion makes reference to any anion which is capable of forming a pharmaceutically acceptable salt when in the presence of an appropriate counter cation.
- pharmaceutically acceptable anions are Cl “ , Br “ , I “ , F “ , SO 4 2* , acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulphonate, p-toluenesulphonate, etc.
- pharmaceutically acceptable anions may be apparent to the skilled person.
- pharmaceutically acceptable salts refers to any pharmaceutically acceptable salt, which, upon administration to the recipient is capable of providing (directly or indirectly) a compound as described herein.
- non-pharmaceutically acceptable salts also fall within the scope of the invention since those may be useful in the preparation of pharmaceutically acceptable salts.
- the preparation of salts can be carried out by methods known in the art.
- salts of compounds provided herein may be acid addition salts, base addition salts or metallic salts, and they can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
- such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two.
- non-aqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
- Examples of the acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulphonate and p-toluenesulphonate.
- Examples of the alkali addition salts include inorganic salts such as, for example, ammonium, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine, glucamine and basic aminoacids salts.
- Examples of the metallic salts include, for example, sodium, potassium, calcium, magnesium, aluminium and lithium salts.
- Enantiomerically enriched applied to a mixture of enantiomers refers to a mixture of enantiomers of a compound in which one of them is present in greater amounts than the other enantiomer. Therefore, enantiomerically enriched mixtures have an enantiomeric excess above 0% with regard to one of its enantiomers, preferably above 20%, preferably above 40%, preferably above 70%, more preferably above 80%, more preferably above 90% and more preferably above 95%.
- An “enantiomerically pure” compound can be considered as a mixture of two enantiomers having enantiomeric excess above 95%, preferably above 98%, more preferably above 99%, more preferably above 99.5%.
- a "substantially pure" compound in the present patent application makes references to a compound having purity above 95%, preferably above 98%, more preferably above 99%, more preferably above 99.5%.
- stereoisomer in the present patent application makes reference to compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable.
- Nonrogen containing nucleophile refers to a molecule having at least one nitrogen with at least one free pair of electrons, said pair of electrons being capable of forming a bond with an electrophilic (electron deficient) moiety of another molecule or within the same molecule.
- nitrogen containing nucleophiles are primary, secondary or terciary amines, unsubstituted nitrogen atoms forming part of an heterocycle, even the nitrogen atom of an amide moiety may under certain circumstances act as a nucleophile.
- EP 0768308 Bl yields mixtures of stereoisomers of piro glutamic acid derivatives
- BLAS-320(Ac) (l-(l-acetyI-3-acetylamino-5- carboxy-2-oxopyrrolidin-3-ylmethyl)pyridiniurn acetate) was synthesized using different procedures.
- the compound of formula BLAS-320(Ac) was obtained as a mixture of stereoisomers impossible to purify, mainly due to solubility problems (compound BLAS-320(Ac) was only soluble in water and methanol).
- the invention relates to a process, hereinafter referred to as the process of the invention, for the synthesis of a substantially pure stereoisomer of a compound of formula I
- Ri is selected from -OH, -ORa, wherein Ra is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl or substituted or unsubstituted heterocyclyl;
- R 2 , R 3 and R 4 are independently selected from hydrogen, a nitrogen protecting group which hydrolyzes under acidic conditions or phtalamide; X is a pharmaceutically acceptable anion; and Y is an organic residue selected from (i) a N-containing group of formula Via
- X is that previously defined
- Ra and Rb are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl or substituted or unsubstituted heterocyclyl; or Ra and Rb together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycle; or mixtures thereof; which comprises a) reacting an enantiomerically pure compound of formula IV
- R 4 is that previously defined; to render a substantially pure stereoisomer of a compound of formula III,
- Ri, R 2 and R 4 are those previously defined;
- R 5 is selected from a negative charge or R 3 , wherein R3 is that previously defined;
- Y is a N-containing organic residue selected from
- any nitrogen protecting group which can protect the nitrogen atom until step c) is suitable for the present invention.
- Preferred nitrogen protecting groups which hydrolyze under acidic conditions are those which may be hydrolyzed during step c) at the same time the salt or disalt is formed to yield a compound of formula 1. In this way, during step c) the nitrogen atoms of the molecule are deprotected and the salt or disalt is formed in a single synthetic step.
- R 2 , R 3 and R4 are phtalamide
- the starting compound of formula IV of the process of the invention may be in the form of an enantiomerically pure compound (i.e., R or S) or in the form of a mixture of enantiomers (R and S), optionally enriched in one of them.
- R or S an enantiomerically pure compound
- R and S a mixture of enantiomers
- the term "mixture of enantiomers” includes any mixture of two enantiomers, either in equimolar ratios or not, and, as such, includes not only racemic mixtures of said two enantiomers but also mixtures enriched in any of said enantiomers.
- the above mentioned reaction may yield two products (steroisomers), one corresponding to the attack from the ⁇ -face and another one corresponding to the attack from the ⁇ -face.
- the reaction shows low stereoselectivity and a mixture of the two possible compounds (steroisomers) is obtained from each of the enantiomers of the compound of formula IV.
- the compound of formula IV is in the form of an enantiomerically pure compound. If the S isomer of the compound of formula IV is used as starting material, the reaction yields, in general, a mixture of a compound of formula Ilia
- the resulting compound of formula III obtained will be, generally, in the form of a mixture of its steroisomers of formula Ilia and IUb.
- said compound of formula III, in the form of said mixture of steroisomers may be isolated by conventional methods (e.g., silica, recrystallization, etc.) in order to obtain a mixture of
- said mixture of steroisomers of formula Ilia and HIb may be treated by conventional methods (e.g., recrystallization, chromatography, etc.) in order to separate each steroisomer and to obtain the stereoisomers of formula Ilia and HIb as enantiomerically pure compounds.
- reaction yields, in general, a mixture of a compound of formula HIc,
- the resulting compound of formula III obtained will be, generally, in the form of a mixture of its steroisomers of formula IIIc and HId.
- said compound of formula III, in the form of said mixture of steroisomers may be isolated by conventional methods in order to obtain a mixture of UIc and IHd, either in an equimolar proportion or not, or alternatively, said mixture of steroisomers may be treated by conventional methods in order to separate each steroisomer and to obtain the stereoisomers of formula IHc and HId as enantiomerically pure compounds.
- the inventors have found that the compounds of the mixture eventually obtained from the reaction of the compound of formula IV with the compound of formula V can be easily separated into the corresponding substantially pure stereoisomers of a compound of formula III, i.e., Ilia, Mb, IHc or IHd. This allows the synthesis of the substantially pure stereoisomers of a compound of formula I, which is an aspect of the present invention.
- the compound of formula IV is in the form of a mixture of the two possible enantiomers (R or S), optionally, enantiomerically enriched with regard to one of said enantiomers.
- the resulting compound of formula III is selected from a mixture of IHa, IHb, IHc and Hid (in equimolar ratios or not); a mixture of Ilia and HIc in an equimolar ratio or not; or a mixture of HIb and Hid in an equimolar ratio or not.
- the compound of formula IV can be obtained by processes known in the art. For example, one of the synthetic approaches used by the inventors is described in Scheme 1.
- the glutamic acid 1 (in this case, D-glutamic acid) may be transformed into a compound of formula 2 as described in Silverman, R.B.; Levy, M.A., J. Org. Chem. 1980, 45, 815.
- the second step is the protection of the amido nitrogen, using a known method (Flyn, D.L., et al., J. Org. Chem., 1983, 48, 2424) to obtain a compound of formula 3.
- a first variant of the above mentioned method for the synthesis of compound 5 comprises the transformation of glutamic acid 1 (in this case, D-glutamic acid) into the pyroglutamic acid of formula 1' as described in Lennox, J. R.; Turner, S. C; Rapoport, H. J. Org. Chem. 2001, 66, 7078-7083. Said pyroglutamic acid of formula 1' is then transformed into the compound of formula 2 described above by esterif ⁇ cation in the presence of ethanol and SOCI2 (see scheme 2).
- a second variant of the above mentioned method for the synthesis of compound 5 comprises the transformation of the compound of formula 2 into the compound of formula 3 using DMAP as a base and acetonitrile (MeCN) as solvent.
- a third variant of the above mentioned method for the synthesis of compound 5 comprises the transformation of the compound of formula 3 into a compound of formula 4' by reaction with tBuOCH(NMe2)2 (Bredereck's reagent). Said compound of formula 4' is transformed into the compound of formula 5 in a two step sequence. First, by reacting the compound of formula 4' with diluted HCl. Then, by reacting the resulting compound with aqueous HCHO (37%) in the presence of an inorganic base as described in WO 2004039314 (see scheme 3).
- the compound of formula V is N-tosyliminobenzyliodinane (Baron E.; O'Brien P.; Towers T. D. Tetrahedron Lett., 2002, 43, 723), which may be synthesized following the method described in Gillepia, K., Synthetic Medn.
- the reaction of the enantiomerically pure compound of formula IV, or mixtures thereof, with the compound of formula V to render a substantially pure stereoisomer of a compound of formula III, or mixtures thereof, can be carried out, if desired, in the presence of a catalyst, preferably a copper based catalyst, more preferably selected from Cu(ft) 2 or Cu(acac) 2 , wherein "ft” is phtalocianine and "acac” is acetoacetate.
- a catalyst preferably a copper based catalyst, more preferably selected from Cu(ft) 2 or Cu(acac) 2 , wherein "ft" is phtalocianine and "acac” is acetoacetate.
- substantially pure stereoisomers of the compound of formula III, or mixtures thereof can be used for obtaining substantially pure stereoisomers of the pyroglutamic acid derivatives of formula I, or mixtures thereof, via the substantially pure stereoisomers of a compound of formula II or mixtures thereof.
- a substantially pure stereoisomer of a compound of formula III or mixtures thereof is further transformed into a substantially pure stereoisomer of a compound of formula II or mixtures thereof, by means of a strategy which depends on the nature of R 5 and Y, thus:
- the synthesis of a substantially pure stereoisomer of a compound of formula II, or mixtures thereof comprises reacting a substantially pure stereoisomer of a compound of formula III, or a mixture thereof, with - a compound of formula Villa, or alternatively with, a compound of formula VIIIb, and, if desired, with a compound of formula X, or alternatively with, a compound of formula Villa and with a compound of formula X.
- the starting compound of formula III may be in the form of a substantially pure stereoisomer [i.e., (3R,5R); (3S,5S); (3R,5S); or (3S,5R)] or in the form of a mixture of said substantially pure stereoisomers, e.g., as a mixture of diastereomers, etc., in the same or in different proportions.
- the term "mixture of stereoisomers” includes any mixture of two or more stereoisomers of a compound, either in an equimolar ratio or not. In general, the stereochemistry of the starting material (compound of formula III) is maintained in the resultant product (compound of formula II).
- the compound of formula III is in the form of an essentially pure stereoisomer thereof [i.e., (3R,5R); (3S,5S); (3R,5S); or (3S,5R)], in which case, an essentially pure compound of formula Il which maintains the stereochemistry of the starting compound of formula III is obtained.
- the compound of formula III is in the form of a mixture of said stereoisomers (i.e., a mixture of two or more stereoisomers selected from the compounds of formula Ilia, IHb, IUc and Old), in an equimolar ratio or not.
- a mixture of stereoisomers of the compound of formula Il is obtained maintaining the stereochemistry of the starting stereoisomers of formula III.
- the mixture of stereoisomers of formula II may be separated into its corresponding substantially pure stereoisomers following conventional methods such as silica gel chromatography or recrystallization.
- a substantially pure stereoisomer of a compound of formula III, or a mixture thereof is reacted with a compound of formula Villa to yield a substantially pure stereoisomer of a compound of formula II, or mixtures thereof, wherein R 5 is a negative charge and Y is a N-containing organic residue of formula
- the nitrogen containing nucleophile Villa is a pyridine of formula IX
- n is O, 1, 2, 3, 4 or 5; and R ⁇ is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, halogen, substituted or unsubstituted carboxyester, substituted or unsubstituted amino and/or the pyridine forms one or more substituted or unsubstituted fused rings.
- said pyridine of formula IX is selected from pyridine and one of the following compounds
- the nitrogen containing nucleophile Villa is a compound of formula
- the reaction of the substantially pure stereoisomer of a compound of formula III, or a mixture thereof, with the compound of formula Villa is carried out under heating.
- reactions such as the transformation of the compound of formula III into a compound of formula II, namely the ring opening of the aziridine ring in the presence of a nucleophile, usually require heat.
- Microwaves can be used, if desired.
- heating is achieved by irradiating the reaction mixture under microwaves which easily allows to reach the desired temperature and maintaining the same for the desired period of time.
- the reaction is performed in the presence of a catalyst, such as montmorillonite, a porous acid catalyst (e.g.
- a substantially pure stereoisomer of a compound of formula III, or a mixture thereof is reacted with a compound of formula VIIIb, and, optionally with a compound of formula X, to render a substantially pure stereoisomer of a compound of formula II, or mixtures thereof, wherein Rs is R3 and Y is a N- containing organic residue of formula VIIb [Option (B)J.
- the nitrogen containing nucleopliile VIIIb is a compound selected from the following compounds:
- the compound of formula II has two chiral centres; therefore, it can be in the form of any of the essentially pure stereoisomers or mixtures thereof.
- the compound of formula II is selected from the group consisting of: a) a substantially pure compound of formula Ua,
- Ri, R2, R4, R5 and Y are those previously defined,- and e) any mixture of the above mentioned compounds of formula Ha, Hb, Hc and/or Hd (in an equimolar ratio or not).
- a substantially pure stereoisomer of a compound of formula II, or mixtures thereof, immediate precursor of the substantially pure stereoisomer of the piroglutamic acid derivative of formula I, or mixtures thereof, with the desired stereochemistry may be obtained by either purifying the resulting mixture of stereoisomers of the compound of formula III and then reactiong the isolated stereoisomers with the corresponding reagents, or, alternatively, by purifying the resulting mixture of the reaction between said compound of formula III and the nucleophile of formula Villa or VIlIb and X (if needed).
- a substantially pure stereoisomer of a compound of formula II, or mixtures thereof is converted into the substantially pure stereoisomer of the pyroglutamic acid derivative of formula I, or mixtures thereof, by contacting said substantially pure stereoisomer of a compound of formula II, or mixtures thereof, with an acid media comprising an acid of formula HX, wherein X is defined as above.
- an acid media comprising an acid of formula HX, wherein X is defined as above.
- HX suitable to perform the reaction with the substantially pure stereoisomer of a compound of formula Il or mixtures thereof.
- said acid HX is an inorganic acid, such as HCI, HBr, etc.
- HX is HBr.
- the reaction requires 1 or 2 equivalents of HX.
- the substantially pure stereoisomer of a compound of formula II, or mixtures thereof is placed into contact with an excess of an acid of formula HX, wherein X is defined as above.
- the substantially pure stereoisomer of a compound of formula II or mixtures thereof is dissolved in aqueous HBr and heated.
- a one-pot process for the synthesis of a substantially pure stereoisomer of a compound of formula I or mixtures thereof which comprises reacting a substantially pure stereoisomer of a compound of formula III or mixtures thereof, with a nitrogen containing nucleophile of formula Villa or VIIIb; and, subsequently, reacting the compound resulting from the previous step with an acid of formula HX.
- the compound of formula I has two chiral centers; therefore, it can be in the form of any of the substantially pure stereoisomers thereof or in the form of a mixture thereof.
- Preferred compounds of formula I, including their essentially pure stereoisomers are mentioned below under the corresponding heading.
- the compounds of formula I have two chiral centers; therefore, they can be in the form of any of the essentially pure stereoisomers or of a mixture thereof.
- the compound of formula I is selected from the group consisting of: a) a substantially pure stereoisomer compound of formula Ia
- Ri, R2, R3, R 4 , X and Y are those previously defined; d) a substantially pure stereoisomer compound of formula Id wherein Ri, R 2 , R 3 , R 4 , X and Y are those previously defined; and e) any mixture of the above mentioned substantially pure compounds of formula Ia, Ib, Ic and/or Id, in an equimolar ratio or not, wherein said mixture does not contain simultaneously all four stereoisomers of the following compounds: (i) 1 -(3-amino-5-carboxy-2-oxopyrrolidin-3-ylmethyl)pyridinium chloride hydrochloride, or (ii) l-(l-acetyl-3-amino-5-carboxy-2-oxopyrrolidin-3-ylmethyl) pyridinium chloride hydrochloride.
- Ri is -OH or -ORa, wherein Ra is that previously defined, preferably -OH.
- K 2 is hydrogen, a nitrogen protecting group which hydrolyzes under acidic conditions or phtalamide, preferably hydrogen.
- R 3 or R 4 independently, is hydrogen, a nitrogen protecting group which hydrolyzes under acidic conditions or phtalamide, preferably both of them are, simultaneously, hydrogen.
- X is a pharmaceutically acceptable anion, preferably bromide or chloride.
- Rj is OH or ORa, preferably OH;
- R 2 is hydrogen, a nitrogen protecting group which hydrolyzes under acidic conditions or phtalamide, preferably hydrogen;
- R 3 or R 4 independently, are hydrogen, a nitrogen protecting group which hydrolyzes under acidic conditions or phtalamide, preferably R3 or R 4 are, simultaneously, hydrogen;
- X is a pharmaceutically acceptable anion, preferably bromide or chloride.
- Y is an organic residue selected from
- Y is an organic residue selected from
- the compound of formula I is a substantially pure compound of formula I'a
- Ri , R 2 , R O and n are those previously defined.
- said compound of formula I is a substantially pure compound of formula Fb wherein R 1 , R 2 , Re and n are those previously defined.
- said compound of formula I is a substantially pure compound of formula I'c
- Ri, R 2 , R O and n are those previously defined.
- said compound of formula I is a substantially pure compound of formula I'd
- Rj, R 2 , R ⁇ and n are those previously defined.
- a mixture comprising two or more compounds of formula Va, Vb, I'c and/or I'd is provided, in equimolar ratios or not; e.g., a mixture comprising compounds of formula I'a and I'b, or comprising compounds of formula I'a and I'c, or comprising compounds of formula Fa and I'd, or comprising compounds of formula Fb and I'c, or comprising compounds of formula I'b and I'd, or comprising compounds of formula I'c and I'd, or comprising compounds of formula Fa, Vb and I'c, or comprising compounds of formula I'a, I'b and I'd, or comprising compounds of formula Fb, Fc and Fd, or comprising compounds of formula Fa, Fb, Fc and Fd.
- the compound of formula I is selected from the group consisting of:
- the invention further provides a composition comprising a mixture of said compounds of formula Ia, Ib, Ic and/or Id, in equimolar ratios or not, wherein said mixture does not contain simultaneously all four stereoisomers of the following compounds
- the invention relates to a substantially pure compound of formula Ha, lib, Hc and Hd.
- the invention relates to a mixture of the above mentioned compounds of formula Ila, lib, Hc and/or Hd, in any molar ratio, wherein said mixture does not contain simultaneously all four stereoisomers of the following compounds: l-(3-amino-5-carboxy-2-oxopyrrolidin-3-ylmethyl)pyridinium acetate; 1 -( 1 -acetyl-3-amino-5-carboxy-2-oxopyrrolidin-3-ylmethyl)pyridinium acetate; l-(l-acetyl-3-acetylamino-5-carboxy-2-oxo-pyrrolidin-3-ylmethyl)pyridinium acetate; or
- the substantially pure stereoisomer of a compound of formula II, or mixtures thereof is a compound wherein Ri is -ORa, preferably wherein Ra is an alkyl group.
- the substantially pure stereoisomer of a compound of formula II, or mixtures thereof is a compound wherein R 2 , R) and R 5 , are, independently, hydrogen.
- the substantially pure stereoisomer of a compound of formula II, or mixtures thereof is a compound wherein R 1 is -OH.
- the substantially pure stereoisomer of a compound of formula II, or mixtures thereof is a compound wherein R-5 is a negative charge.
- the invention also relates to a composition
- a composition comprising a compound selected from the group consisting of the above mentioned compounds of formula Ha, Hb, Hc, Ud and mixtures thereof, in any molar ratio, wherein said mixture does not contain simultaneously all four stereoisomers of the following compounds: l-CS-amino-S-carboxy-l-oxopyrrolidin-S-ylmethy ⁇ pyridinmm acetate; 1 -(I -acetyl-S-amino-S-carboxy ⁇ -oxopyrrolidin-S-ylmethy ⁇ pyridinium acetate; 1 -( 1 -acetyl-3-acetylamino-5-carboxy-2-oxo-pyrrolidin-3-ylmethyl)pyridinium acetate; or l-(l-acetyl-3-acetylamino-5-carboxy-2-oxo-pyrrolidin-3-ylmethyl)pyridin
- the substantially pure stereoisomer of a compound of formula II or mixtures thereof can be obtained, as mentioned above, by means of a process which comprises reacting a substantially pure stereoisomer of a compound of formula III or mixtures thereof, with a compound of formula VIUa, or alternatively with, a compound of formula VIIIb, and, if desired, with a compound of formula X, or alternatively with, a compound of formula Villa and with a compound of formula X.
- Said process constitutes a further aspect of the present invention and makes possible the synthesis of substantially pure stereoisomers of the compound of formula II or mixtures thereof.
- the invention relates to a substantially pure stereoisomer of a compound of formula III or mixtures thereof.
- Said compound of formula III has two chiral centers; therefore, it can be in the form of any of the substantially pure stereoisomer or a mixture thereof.
- the compound of formula III is selected from the group consisting of the compounds of formula Ilia, IHb, IHc, IIId and any mixture thereof.
- the invention relates to a mixture comprising two or more compounds of formula HIa, IHb, IHc and Hid.
- said mixtures include mixtures of two of those compounds (e.g., mixtures of HIa and IHb, HIa and IHc, HIa and IHd, HIb and IHc, IHb and IHd or HIc and Hid), or mixtures of three of said compounds (e.g., mixtures of HIa, IHb and UIc, IHa, HIb and
- Hid or HIb, IIIc and IHd
- mixtures of said four compounds e.g., a mixture of Ilia,
- Each particular compound (IHa to Hid) may be present in said mixture in any proportion or ratio, e.g., in equimolar proportions or ratios or in different proportions or ratios wherein one or more of said compounds are in excess with respect to the other(s).
- the substantially pure stereoisomer of a compound of formula III, or mixtures thereof is a compound wherein Ri is -ORa, preferably wherein Ra is an alkyl group.
- the substantially pure stereoisomer of a compound of formula III, or mixtures thereof is a compound wherein R 2 is - (O)C-O-Ra, preferably the BOC group.
- the substantially pure stereoisomer of a compound of formula IU, or mixtures thereof is a compound wherein R 2 , R 4 and R5, are, independently, hydrogen.
- the substantially pure stereoisomer of a compound of formula III or mixtures thereof can be obtained, as mentioned above, by means of a process which comprises reacting a compound of formula IV, either in an enatiomerically pure form or in the form of a mixtures of enantiomers, with a compound of formula V. Said process constitutes a further aspect of the present invention. By means of said process, it is also possible to obtain substantially pure stereoisomers of a compound of formula III or mixtures thereof.
- substantially pure stereoisomers of a compound of formula I, or mixtures thereof may be used as active ingredients of medicaments for the treatment and/or prophylaxis of some conditions in a subject, e.g., tumours, immunodeficiencies, infections, etc.
- Illustrative, non- limitative, examples of conditions susceptible of being treated with the substantially pure stereoisomer of a compound of formula I or mixtures thereof include: A) Cancer- or tumour-related conditions: comprising practically all cancer and tumour types, including Acute Lymphoblastic Leukemia, Adult Acute Lymphoblastic Leukemia, Childhood Acute Myeloid Leukemia, Adult Acute Myeloid Leukemia, Adrenocortical Carcinoma, Acquired Immunodeficiency Syndrome (AIDS)-Related Cancers, Anal Cancer, Astrocytoma, Childhood Cerebellar Astrocytoma, Basal CaIi Carcinoma, Bile Duct Cancer, Extrahepatic Bladder Cancer, Bladder Cancer, Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma, Brain Stem Glioma, Brain Tumor, Malignant Glioma, Ependymoma, Medulloblastoma, Supratentorial Primitiva
- Infections comprising practically all type of infections, such as infections of bacterial, fungal, and viral origin; or
- Autoimmune diseases comprising practically all autoimmune diseases mentioned in the web site of the "American Autoimmune Related Diseases Association" [http://www.aarda.org], including multiple sclerosis (MS), Crohn's disease, rheumatoid arthritis, type 1 diabetes mellitus, psoriasis, lupus, ulcerous colitis, vitiligo, coeliac disease, vasculitis, dermatomyositis, polymyositis, thyroiditis (Hashimoto, Graves), myasthenia gravis, Guillain-Barre syndrome, uveitis, flat lichen, temporal arteritis, sarcoidosis, dry syndrome (Sj ⁇ egren), bronchial asthma, pemphigus, ankylosing spondilitis, sclerodermia, fibromyalgia, rheumatic fever, etc.
- MS multiple sclerosis
- Crohn's disease Crohn's disease
- the invention relates to a pharmaceutical composition, hereinafter referred to as the pharmaceutical composition of the invention, comprising a compound of formula I, its substantially pure stereoisomers Ia, Ib, Ic or Id, or mixtures thereof in equimolar ratios or not, wherein said mixture does not contain simultaneously all four stereoisomers of the following compounds: (i) l-(3-amino-5- carboxy-2-oxopyrrolidin-3-ylmethyl)pyridinium chloride hydrochloride, or (ii) 1-(1- acetyl-3-amino-5-carboxy-2-oxopyrrolidin-3-ylmethyl)pyridinium chloride hydrochloride, and a pharmaceutically acceptable carrier.
- a pharmaceutical composition hereinafter referred to as the pharmaceutical composition of the invention, comprising a compound of formula I, its substantially pure stereoisomers Ia, Ib, Ic or Id, or mixtures thereof in equimolar ratios or not, wherein said mixture does
- the pharmaceutical composition of the invention comprises, as active ingredient, at least one substantially pure stereoisomer of a compound of formula I, i.e. Ia, Ib, Ic or Id, or mixtures thereof in equimolar ratios or not, wherein said mixture does not contain simultaneously all four stereoisomers of the above mentioned compounds (i) or (ii), in a therapeutically effective amount.
- therapeutically effective amount refers to the quantity of active ingredient calculated to produce the desired effect and will generally be determined, among other reasons, by the own features of the active ingredient used and the therapeutic effect to be obtained.
- the dose of active ingredient administered to a subject in need of treatment for the treatment and/or prophylaxis of the above mentioned conditions is within the range of 10 '10 to 10 10 mg/kg of body weight, typically between 10 3 and 10 3 mg/kg of body weight.
- carrier refers to a diluent, adjuvant, excipient, or vehicle with which the active ingredient is administered.
- Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
- Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin.
- the term “pharmaceutically acceptable” refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human.
- pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
- the pharmaceutical composition of the invention may be administered by any appropriate route (via), such as, oral (e.g., oral, sublingual, etc.), parenteral (e.g., subcutaneous, intramuscular, intravenous, intramuscular, etc.), vaginal, rectal, nasal, topical, ophtalmic, etc.
- oral e.g., oral, sublingual, etc.
- parenteral e.g., subcutaneous, intramuscular, intravenous, intramuscular, etc.
- vaginal e.g., vaginal, rectal, nasal, topical, ophtalmic, etc.
- the pharmaceutical composition of the invention obtained by mixing the active ingredient(s) with the suitable pharmaceutically aceptable carrier(s) may be administered in a plurality of pharmaceutical forms of administration, e.g., solid, liquid, etc.
- suitable pharmaceutically aceptable carrier(s) may be administered in a plurality of pharmaceutical forms of administration, e.g., solid, liquid, etc.
- said pharmaceutical forms of administration of the pharmaceutical composition of the invention include oral drops (solution, suspension, emulsion, etc.); oral formulations (liquid, solution, suspension, emulsion, gel, paste, powder, etc.); oral lyophilisate; oral gum; powder for oral solution or suspension; granules; gastro-resistant granules; prolonged-release granules; modified- release granules; granules for oral suspension; powder and solvent for oral solution or suspension; syrup; powder for syrup; granules for syrup; tablets (e.g., soluble tablet, dispersible tablet, coated tablet, film-coated tablet,
- the carriers and auxilliary substances necessary to manufacture the desired pharmaceutical form of administration of the pharmaceutical composition of the invention will depend, among other factors, on the elected administration pharmaceutical form.
- Said pharmaceutical forms of administration of the pharmaceutical composition will be manufactured according to conventional methods known by the skilled person in the art. A review of different active ingredient administration methods, excipients to be used and processes for producing them can be found in "Tratado de Farmacia Galenica", C. Fauli i Trillo, Luzan 5, S.A. de Ediations, 1993.
- the invention relates to the use of a substantially pure stereoisomer of a compound of formula I, i.e. Ia, Ib, Ic or Id, or mixtures thereof in equimolar ratios or not wherein said mixture does not contain simultaneously all four stereoisomers of the following compounds: (i) l-(3-amino-5-carboxy-2-oxopyrrolidin- 3-ylmethyl)pyridinium chloride hydrochloride, or (ii) l-(l-acetyl-3-amino-5-carboxy-2- oxopyrrolidin-3-ylmethyl)pyridinium chloride hydrochloride, for the manufacture of a pharmaceutical composition for enhancing an immuneresponse in a subject, or for the manufacture of an antitumoral pharmaceutical composition, or for the manufacture of a pharmaceutical composition for treating an infection of bacterial, fungal or viral origin, or for the manufacture of a pharmaceutical composition for treating an autoimmune disease.
- a pharmaceutical composition for enhancing an
- the present invention is directed to said use for the manufacture of a pharmaceutical composition for the treatment and/or prophylaxis of a disease or condition selected form the group consisting of colorectal cancer, breast cancer, prostate cancer, melanoma, mastocytoma, lung cancer and renal cancer.
- the present invention is directed to said use for the manufacture of a pharmaceutical composition for the treatment and/or prophylaxis of AIDS and related diseases.
- Illustrative, non- limitative, examples of conditions susceptible of being treated with the pharmaceutical composition provided by the instant invention include those previously mentioned.
- a chromatographic column Luna C18 (150 x 4.6 mm) 5 ⁇ m Phenomenex was used, with a mobile phase formed by a triple gradient of 4% aq. formic acid (A), water (B) and acetonitrile (C). The gradient started as A (2.5%), B (93%) and C (4.5%) and, in 30 minutes reached A (2.5%), B (4.5%) and (93%).
- the fragmenter operated at 7OeV. Elemental analysis was performed on a LECO CHNS-932 instrument. All yields correspond to isolated pure compounds.
- Example 1 relates to the synthesis of (2R-4-methylene-5-oxopyrrolidine-l,2- dicarboxylic acid 1-tertbutyl ester 2-ethyl ester), a starting material of the process of the invention (compound of formula IV).
- Example 2 relates to the synthesis of the compound of formula V, a starting material of the process of the invention.
- Examples 3 and 4 relate to the synthesis of (3R,5R), (3S,5S), (3R,5S) and (3S,5R)- l-(3-amino-5-carboxy-2-oxopyrrolidin-3-ylmethyl)pyridinium bromide hydro- bromide, which are compounds of formula I, using a one-pot sequence.
- Example 5 relates to the one-pot synthesis of 3S,5S-l-(3-amino-5-carboxy-2- oxopyrrolidin-3-ylmethyl)pyridinium bromide hydrobromide following a step-wise synthesis.
- Example 6 analyzes the effect of the different isomers of a compound of formula I on tumour growth (tumour assayed: RENCA).
- a lO L reactor was charged with D-glutamic acid 1 (1 kg, 6.80 mol) in absolute ethanol (5.0 L), cooled to -10 0 C and through a dropping-funnel, thionyl chloride (2.0 kg, 14.9 mol) was added slowly over 2 h. After the addition was complete, the mixture was stirred at room temperature for 1 h and then heated to 8O 0 C for one more hour. The resulting solution was concentrated to dryness (CARE: HCI and SO2 vapours evolved).
- the formed solid was removed by filtration and the solution concentrated to give the diethyl ester of 1 as a waxy solid.
- a mixture of the aziridine 7c (200 mg, 0.46 mmol), montmorillonite MKlO (20% weight, 40 mg) and pyridine (37 ⁇ L, 0.46 mmol) was irradiated under microwaves (300 W) at 100 0 C, and for 10 minutes.
- the crude mixture was diluted with ethyl acetate [EtOAc] (10 mL), filtered and evaporated under vacuum until HPLC analysis showed no remaining pyridine.
- the betaine 8c was used in the next step without further purification (93% purity by HPLC).
- the crude brown oil was dissolved in aqueous 48% HBr (20 mL) and heated under reflux for 18 hours.
- a mixture of the aziridine 7d (200 mg, 0.46 mmol), montmorillonite MKlO (20% weight, 40 mg) and pyridine (37 ⁇ L, 0.46 mmol) was irradiated under microwaves (300 W) at 100 0 C, and for 10 minutes.
- the crude mixture was diluted with EtOAc (10 mL), filtered and evaporated under vacuum until HPLC analysis showed no remaining pyridine.
- the betaine 8d was used in the next step without further purification (93% purity by HPLC).
- the crude brown oil was dissolved in aqueous 48% HBr (20 mL) and heated under reflux for 18 hours.
- This compound was dissolved in aqueous 48% HBr (10 niL) and heated under reflux for 18-72 hours. The reaction was monitored by HPLC-Ms analysis. The crude oil was triturated with acetone to yield a brown solid. This solid was dissolved in the minimum amount of MeOH (ImL) and EtiO or acetone were added until precipitation was observed. The solid was then filtered and dried under vacuum (CARE: the product is highly hygroscopic). The process was repeated twice and the purity of the product was determined by HPLC analysis (80 % yield).
- IR (KBr, cm “1 ): 2982, 2936, 1799, 1749, 1371, 1330, 1252, 1203, 1154, 1093, 989, 687.
- a mixture of aziridine 7a (311 mg, 0.71 mmol), montmorillonite MKlO (20% weight, 60 mg) and pyridine (58 ⁇ L, 0.71 mmol) was irradiated under microwaves (300 W) at 100 0 C, and for 10 minutes.
- the crude mixture was diluted with EtOAc (1OmL), filtered and evaporated under vacuum until HPLC analysis showed no remaining pyridine.
- the betaine 8a was used in the next step without further purification (93% purity by HPLC).
- the crude brown oil was dissolved in aqueous 48% HBr (30 mL) and heated under reflux for 18 hours.
- the mixture was diluted with water and washed with EtOAc (3x10 mL), the aqueous phase was evaporated to dryness.
- the crude oil was purified by chromatography employing Cellulose powder: SiO2: Cellulose powder: activated charcoal, (lcm:0.5cm:0.5cm:2cm) as stationary phase, yielding 9a as a solid (110 mg, 40%).
- the betaine 8a was obtained by heating the same reaction mixture (aziridine 7a (311 mg, 0.71 mmol), montmorillonite MKlO (20% weight, 60 mg) and pyridine (58 ⁇ L, 0.71 mmol)) at 90 0 C for 7 hours.
- the crude mixture was diluted with
- This assay was made in order to check the effect of each stereoisomer on in vivo rumour growth in mice challenged with Renca cells. Their effect was compared with placebo.
- the stereoisomers assayed were:
- Renca is a renal cell carcinoma originated in Balb/c mouse strain, and therefore syngeneic in mice with Balb/c genetic background [Melder RJ et al., Cancer Immunol. Immunother., 2005, 54:535-547; Felluga B et al., 1969, J. Natl. Cancer Inst. 43:319- 333]. Renca is considered a moderate immunogenic tumour and used as suitable model for testing immuno intervention approaches [Salup RR, et al., 1992, The Journal of Urology, 147: 1 120-1123].
- Renca cells (CLS, Eppelheim, Germany) were maintained in vitro by serial passages every 3-4 days. Cultures were performed with RPMI medium medium (RPMI, 10% foetal calf serum, 2 mM L-glutamine, non essential amino acids, 1 mM sodium pyruvate, 20 mM HEPES, 80 ⁇ g/mL gentamycin; all of them were purchased from Sigma, St. Louis, MO, USA) by seeding 5 x 10 6 cells onto 75 cm 2 culture flasks. Tumour cells collected from 48 hour cultures upon trypsinization (Sigma, St. Louis, MO, USA) were used as source of Renca cells for the studies described below. Drugs in study
- the vehicle in which the isomers were diluted was physiological saline.
- mice (Balb/c) were inoculated with 0.2 niL containing 10 5 viable Renca cells. The day of subcutaneous inoculation will be considered Day 0 of the test.
- Tumour surface L x W (mm 2 )
- Tumour volume L x W 2 x 1/2 (mm 3 )
- Results were expressed as single values and/or as the mean ⁇ SD or median from each experimental group.
- Tables 1 and 2 show the results of each experimental group expressed as the median values. These tables summarize the median of surface (Table 1) or volume (Table 2) in isomers or P. S. mice group on each day scored. Table 1
- Tables 3 and 4 show the results of each experimental group expressed as the mean values. These tables summarize the mean of surface (Table 3) or volume (Table 4) in isomers or P.S. mice group on each day scored.
- Figure 2 represents the graph of the median of tumour volumes (Groups Al, Cl, C2, C3, C4). As can be seen in these figures there were differences in the Renca tumour growth rate among mice receiving isomer 3 and isomer 4 vs. placebo.
- Figure 3 represents the graph of mean tumour surfaces (Groups Al, Cl, C2, C3, C4) whereas Figure 4 represents the graph of mean tumour volumes (Groups Al, Cl, C2, C3, C4). As can be seen in these figures there were differences in the Renca tumour growth rate among mice receiving isomer 3 and isomer 4 vs. placebo.
- ASB XIV is a pulmonary squamous cell carcinoma originated in Balb/c mouse strain, and therefore syngeneic in mice with Balb/c genetic background.
- ASB XIV cells (CLS, Eppelheim, Germany) were maintained in vitro by serial passages every 3-4 days. Cultures were performed with RPMI medium medium (RPMI, 10% foetal calf serum, 2 mM L-glutamine, non essential aminoacids, 1 niM sodium pyruvate, 20 mM HEPES, 80 ⁇ g/mL gentamycin; all of them were purchased from Sigma, St. Louis, MO, USA) by seeding 5 x 10 6 cells onto 75 cm 2 culture flasks. Tumour cells collected from 48 hour cultures upon trypsinization (Sigma, St. Louis, MO, USA) were used as source of ASB XIV cells in the present example.
- RPMI medium medium RPMI, 10% foetal calf serum, 2 mM L-glutamine, non essential aminoacids, 1 niM sodium pyruvate, 20 mM HEPES, 80 ⁇ g/mL gentamycin; all of them were purchased
- BLAS mixture of isomers 1, 2, 3 and 4
- Isomer 1 (9b) at a concentration of 65 ⁇ g/mL in sterile physiological saline.
- Isomer 2 (9c) at a concentration of 65 ⁇ g/mL in sterile physiological saline.
- Isomer 3 (9a) at a concentration of 65 ⁇ g/mL in sterile physiological saline.
- Isomer 4 (9d) at a concentration of 65 ⁇ g/mL in sterile physiological saline.
- Placebo Physiologic saline (Grifols, Barcelona, Spain)
- sample size necessary to reach significance was 26 animals per group. This sample size was calculated using Epi-info v6.0 software and was estimated for a 0.8 statistical power, with a confidence level of 0.95 for a two-fold decrease in tumour surface and a 1-1 control-case ratio.
- Tumours were established by subcutaneous inoculation in the right hind flank. Mice (Balb/c) were inoculated with 0.2 mL containing 2 x 10 5 viable ASB XIV cells. The day of subcutaneous inoculation will be considered Day 0 of the test.
- mice inoculated with ASB XIV cells were distributed into 6 experimental groups:
- tumour surface dl x d2 (mm 2 )
- Tumour volume dl x d2 ⁇ x 1/2 (mm 3 )
- Results were expressed as single values and/or as the mean ⁇ SD or median from each experimental group.
- mice per group Thirty one mice per group (thirty two from placebo group) were studied. Two mice from isomer 4 (9d) group died for unknown causes the first week after tumour inoculation and were excluded.
- Tables 5 and 6 show the results of each experimental group expressed as the median values. These tables summarize the median of surface or volume in BLAS, isomers or P. S. mice group on each day scored.
- Tables 7 and 8 show the results of each experimental group expressed as the mean values. These tables summarize the mean of surface or volume in BLAS, isomers or P.S. mice group on each day scored.
- This assay was made in order to compare the effect of each stereoisomer on in vivo tumour growth in mice with the effect of the mixture of all of them challenged with Ehlrich tumours.
- the same products, equipment, reagents, doses, vehicle and route of administration as in example 8 were used.
- mice were inoculated with Ehrlich tumour cells. It was described as a murine mammary adenocarcinoma.
- Ehrlich tumour is a murine mammary carcinoma originally raised in an outbred mouse, and therefore it belongs to the so-called non-specific tumours (Subiza JL, Vinuela JE, Rodriguez R, Gil J, Figueredo MA, de Ia Concha. EG. Development of splenic natural suppressor (NS) cells in Ehrlich tumor bearing mice.. Int J Cancer, 44:307 315; 1989). It may grow across histocompatibility barriers and therefore is not mouse strain specific (Carry PJ, Prescott DM, Ogilvie GK. Resistance to Ehrlich ascites tumor in a strain of dystrophic mice.
- Ehrlich cells were maintained in vitro by serial passages every 3-4 days. Cultures were performed with RPMl medium medium (RPMI, 10% foetal calf serum, 2 mM L-glutamine, non essential aminoacids, 1 mM sodium pyruvate, 20 mM HEPES, 80 ⁇ g/mL gentamycin; all of them were purchased from Sigma, St. Louis, MO, USA) by seeding 5 x 10 6 cells onto 75 cm 2 culture flasks. Tumour cells collected from 48 hour cultures were used as source of cells for the studies described below.
- RPMl medium medium RPMI, 10% foetal calf serum, 2 mM L-glutamine, non essential aminoacids, 1 mM sodium pyruvate, 20 mM HEPES, 80 ⁇ g/mL gentamycin; all of them were purchased from Sigma, St. Louis, MO, USA
- mice were inoculated with 0.2 mL containing 2 x 10 5 viable Ehrlich cells. The day of subcutaneous inoculation will be considered Day 0 of the test. Balb/c mice inoculated with Ehrlich cells were distributed into 6 experimental groups:
- tumour surface L x W (mm 2 )
- Tumour volume L x W 2 x 1/2 (mm 3 )
- Results were expressed as single values and/or as the mean ⁇ SD or median from each experimental group.
- mice per group were planned to be studied.
- Tables 9 and 10 show the results of each experimental group expressed as the median values (n (first day) is in all cases 16 and the dosage is 260 ng/mouse). These tables summarize the median of surface or volume in BLAS, isomers or P. S. mice group on each day scored.
- VOL LUUMMEE ((mmm 3 )
- Tables 11 and 12 show the results of each experimental group expressed as the mean values (n (first day) is in all cases 16 and the dosage is 260 ng/ mouse). These tables summarize the mean of surface or volume in BLAS, isomers or P. S. mice group on each day scored.
- This assay was made in order to compare the effect of isomer 4 (9d) on in vivo tumour growth in mice with the effect of the mixture of isomer 4 (9d) + Cisplatin challenged with KLN 205 tumours and Lewis lung cells.
- the same equipment, reagents, vehicle, and route and volume of administration was used as those used in example 7.
- Tumour surface dl x d2 (mm)
- Tumour volume dl x d2 x 1/2 (mm 3 )
- Results were expressed as single values and/or as the mean ⁇ SD or median from each experimental group.
- This assay was made in order to check the effect on in vivo tumour growth in mice challenged with KLN 205 cells. Their effect was compared with the combination of Cisplatin plus 9d and/or placebo.
- Tumor KLN 205 is a lung cell carcinoma originated in DBA/2 mouse strain, and therefore syngeneic in mice with DBA/2 genetic background (Kaneko T and LePage GA. Growth characteristics and drug responses of a murine lung carcinoma in vitro and in vivo. Cancer Res. 38: 2084-2090; 1978).
- KLN 205 cells (CLS, Eppelheim, Germany) were maintained in vitro by serial passages every 3-4 days. Cultures were performed with RPMI medium (RPMI, 10% foetal calf serum, 2 mM L-glutamine, non essential aminoacids, 1 niM sodium pyruvate, 20 mM HEPES, 80 ⁇ g/mL gentamycin; all of them were purchased from Sigma, St. Louis, MO, USA) by seeding 5 x 10 6 cells onto 75 cm 2 culture flasks. Subcultures were carried out by collecting detached cells after treatment with trypsin- EDTA (Sigma, St. Louis, MO, USA). Tumour cells, collected from 48 hour cultures, were used as source of KLN 205 cells for the studies described below.
- RPMI medium RPMI, 10% foetal calf serum, 2 mM L-glutamine, non essential aminoacids, 1 niM sodium pyruvate, 20 mM HEPES, 80
- Cisplatin was tested at the dose levels of 65 ⁇ g administrated twice a week for three weeks after tumour inoculation.
- Isomer 4 (9d) was tested at the dose levels of 250 ng administrated twice a week for three weeks after tumour inoculation.
- Tumours were established by subcutaneous inoculation in the right hind flank. Mice (DBA/2) were inoculated with 0.2 mL containing 2 x 10 5 viable KLN 205 cells. The day of subcutaneous inoculation will be considered Day 0 of the test.
- mice inoculated with KLN 205 cells were distributed into 6 experimental groups:
- mice Sixteen or fifteen mice per group were planned to be studied. Tables 14 and 15 show the results of each experimental group expressed as the median values. These tables summarize the median of surface or volume in 9d, Cisplatin, 9d+Cisplatin or P.S. mice group on each day scored. Table 14
- Tables 16 and 17 show the results of each experimental group expressed as the mean values. These tables summarize the mean of surface or volume in 9d, Cisplatin, 9d+Cisp latin or P.S. mice group on each day scored.
- Cisplatin vs. placebo were statistically significant (p ⁇ 0.05) all days scored after day 20th of tumour development as calculated by t-test.
- cisplatin and 9d or Cisplatin inhibit the in vivo growth of KLN 205 cell.
- 9d and Cisplatin have a sinergic effect.
- This assay was made in order to check the effect on in vivo tumour growth in mice challenged with KLN 205 cells. Tumours where established by subcutaneous, intradermal or intramuscular inoculation. The effect of the combination of cisplatin and/Or Isomer (9d) was compared with placebo in mice challenged intradermally. Moreover, the effect of 9d on in vivo tumour growth in mice challenged by intramuscular or subcutaneous route was compared with placebo.
- KLN 205 is a lung cell carcinoma originated in DBA/2 mouse strain, and therefore syngeneic in mice with DBA/2 genetic background (Kaneko T and LePage GA. Growth characteristics and drug responses of a murine lung carcinoma in vitro and in vivo. Cancer Research. 38: 2084-2090; 1978).
- KLN 205 cells (CLS, Eppelheim, Germany) were maintained in vitro by serial passages every 3-4 days. Cultures were performed with RPMI medium (RPMI, 10% foetal calf serum, 2 mM L-glutamine, non essential aminoacids, 1 mM sodium pyruvate, 20 mM HEPES, 80 ⁇ g/mL gentamycin; all of them were purchased from Sigma, St. Louis, MO, USA) by seeding 5 x 10 6 cells onto 75 cm 2 culture flasks. Subcultures were carried out by collecting detached cells after treatment with trypsin- EDTA (Sigma, St. Louis, MO, USA). Tumour cells, collected from 48 hour cultures, were used as source of KLN 205 cells for the studies described below.
- RPMI medium RPMI, 10% foetal calf serum, 2 mM L-glutamine, non essential aminoacids, 1 mM sodium pyruvate, 20 mM HEPES, 80 ⁇
- Cisplatin was tested at the dose levels of 65 ⁇ g administrated on days 7, 11, 14, 18, 21, 25 and 28 after tumour inoculation.
- Isomer (9d) was tested at the dose levels of 250 ng administrated on days 7, 1 1, 14, 18, 21, 25 and 28 after tumour inoculation.
- Tumours were established by subcutaneous and intradermal inoculation in the right hind flank, and intramuscular in the right hind leg. Mice (DBA/2) were inoculated with 0.05 mL containing 2 x 10 5 viable KLN 205 cells. The day of subcutaneous, intradermal and intramuscular inoculation will be considered Day 0 of the test.
- mice inoculated with KLN 205 cells were distributed into 8 experimental groups:
- mice were treated on days 32 and 35.
- mice per group were planned to be studied.
- Tables 18 and 19 show the results of each experimental group expressed as the median values. These tables summarize the median of surface or volume on each day scored.
- Tables 20 and 21 show the results of each experimental group expressed as the mean values. These tables summarize the mean of surface or volume on each day scored.
- This assay was made in order to check the effect on in vivo tumour growth in mice challenged with Lewis lung cells. Their effect will be compared with the combination of chemotherapeutic agents plus 9d and/or placebo.
- Lewis Lung is a lung cell carcinoma originated in C57BL/6J mice strain, and therefore syngeneic in mice with C57BL/6J genetic background (Rodrigo Garz ⁇ n M, Tirapu Fernandez de Ia Cuesta I, Arina Iraeta A, Noel Centelles Llorente M and Zulueta Frances J. Use of Gene Therapy in a Subcutaneous Murine Model of Lung Cancer. Arch Bronconeumology. Al: 526 - 532; 2006).
- Lewis lung cells (CLS, Eppelheim, Germany) were maintained in vitro by serial passages every 3-4 days. Cultures were performed with RPMI medium (RPMI, 10% foetal calf serum, 2 mM L-glutamine, non essential aminoacids, 1 mM sodium pyruvate, 20 mM HEPES, 80 ⁇ g/mL gentamycin; all of them were purchased from RPMI medium (RPMI, 10% foetal calf serum, 2 mM L-glutamine, non essential aminoacids, 1 mM sodium pyruvate, 20 mM HEPES, 80 ⁇ g/mL gentamycin; all of them were purchased from RPMI medium (RPMI, 10% foetal calf serum, 2 mM L-glutamine, non essential aminoacids, 1 mM sodium pyruvate, 20 mM HEPES, 80 ⁇ g/mL gentamycin; all of them were purchased from RPMI medium (RPMI, 10%
- Subcultures were carried out by collecting detached cells after treatment with trypsin- EDTA (Sigma, St. Louis, MO, USA ). Tumour cells, collected from 48 hour cultures, were used as source of Lewis Lung cells for the studies described below.
- Cisplatin was tested at the dose levels of 65 ⁇ g administrated on days 7, 1 1, 14,
- Isomer 4 (9d) was tested at the dose levels of 250 ng administrated on days 7, 11, 14, 18, 21, 24 and 27 after tumour inoculation.
- Tumours were established by subcutaneous inoculation in the right hind flank. Mice were inoculated with 0.2 niL containing 2 x 10 5 viable cells. The day of subcutaneous inoculation will be considered Day 0 of the test.
- Tumour surface dl x d2 (mm 2 )
- Tumour volume dl x d2 2 x 1/2 (mm 3 )
- Results were expressed as single values and/or as the mean ⁇ SD or median from each experimental group.
- Cisplatin or 9d+Cisplatin had a deletereous effect on tumoral growth.
- mice per group were planned to be studied.
- One mice from placebo group died for unknown causes the second week after rumour inoculation and was excluded.
- Tables 22 and 23 show the results of each experimental group expressed as the median values. These tables summarize the median of surface or volume in P. S, 9d, Cisplatin or 9d+Cisplatin mice group on each day scored.
- Tables 24 and 25 show the results of each experimental group expressed as the mean values. These tables summarize the mean of surface or volume in P.S, 9d, Cisplatin or 9d+Cisplatin mice group on each day scored. Table 24
- VOL LUUMMEE ((mmm 3 )
- This assay was made in order to check the tolerance (iethality/toxicity) of BLAS and IL-2 treatments in mice.
- BLAS equimolar mixture of isomers 1, 2, 3 and 4
- Human recombinant IL-2 at 18x10 6 IU/mL (Proleukin; Chiron Iberia, Madrid,
- the vehicle in which BLAS and 1L-2 were diluted was sterile physiological saline for injection (Grifols, Barcelona, Spain) and sterile distilled water for injection (Grifols, Barcelona, Spain)
- Table 26 shows the lethality observed with either treatment. Results are expressed as percentage of survival. As can be seen in this table, two mice from Group B2, receiving the highest dose of IL-2, died on day 6 and 7 after the first dose. No more death were observed in any other group of mice, whether treated with IL-2 (lower dose) or BLAS at any dose used.
- Table 27 shows the toxicity observed in mice with either treatment as scored with the criteria described above. Results are expressed as the toxic score accumulated per group of treatment.
- This assay was made in order to perform a preliminary study to address the toxic effect of Isomer 4 (9d) used at a high dose on healthy mice. Its eventual toxicity will be compared with placebo.
- the vehicle in which Isomer 4 was diluted was sterile physiological saline for injection (Grifols, Barcelona, Spain) and sterile distilled water for injection (Grifols, Barcelona, Spain)
- Tables 28 and 29 show the weight of each C57BL/6 mice every day scored as well as mean, standard deviation and median. No differences on weight between groups were observed as detected by Mann- Whitney U test (p>0.05)
- isomer 4 is well tolerated by mice even a doses that greatly exceed its therapeutic range. Local toxicity at the inoculation site is not observed in any mouse challenged.
- Isomer 4 (compound 9d) at 65 ⁇ g/mL in sterile physiological saline. Placebo Physiologic saline (Grifols, Barcelona, Spain).
- Laminar flood hood Laminar flood hood, Flow cytometer, Adjustable pipettes, Sterile syringes, Sterile needles, EDTA stelile tubes, Plastic tubes.
- Rat anti-mouse Ly6G-FITC (Beckman Coulter, Fullerton, CA, USA)
- the vehicle in which Isomer 4 was diluted is physiological saline.
- the treatments were given by intraperitoneal route.
- the volume inoculated was 200 ⁇ l/animal.
- mice (Balb/C) treated with two doses (once per week) of compound 9d show an increment of CDl Ib, Ly6G and CDl Ib + Ly6G positive cells in peripheral blood, compared with control mice (physiological saline). These cells were checked by flow cytometry three days after the last dose of the treatment.
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CA2649762A CA2649762C (en) | 2006-04-20 | 2007-04-20 | Synthesis and uses of pyroglutamic acid derivatives |
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BRPI0710538-0A BRPI0710538A2 (en) | 2006-04-20 | 2007-04-20 | process for the synthesis of a substantially pure stereoisomer, compounds, pharmaceutical composition comprising a compound, process for the synthesis of a compound and use thereof. |
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JP3445986B1 (en) * | 2002-09-27 | 2003-09-16 | 松下電器産業株式会社 | Servers, devices and communication systems connected to the Internet |
EP1847536A1 (en) * | 2006-04-20 | 2007-10-24 | Prodimed, S.A. | Synthesis and uses of pyroglutamic acid derivatives |
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2006
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2007
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN111323529A (en) * | 2020-04-23 | 2020-06-23 | 广东华南药业集团有限公司 | Method for separating and measuring dextromethorphan and levomethorphan by liquid chromatography |
CN111323529B (en) * | 2020-04-23 | 2023-08-25 | 广东华南药业集团有限公司 | Method for separating and measuring dextromethorphan and levomethaphen by liquid chromatography |
Also Published As
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JP2009534361A (en) | 2009-09-24 |
MX2008013435A (en) | 2009-01-09 |
EP1847536A1 (en) | 2007-10-24 |
EP2021334A1 (en) | 2009-02-11 |
US8835466B2 (en) | 2014-09-16 |
CA2649762C (en) | 2015-09-29 |
US20090163555A1 (en) | 2009-06-25 |
CN101454309B (en) | 2014-03-19 |
RU2008145775A (en) | 2010-05-27 |
US20070249678A1 (en) | 2007-10-25 |
JP2007291050A (en) | 2007-11-08 |
CN101454309A (en) | 2009-06-10 |
JP5616628B2 (en) | 2014-10-29 |
AU2007242793A1 (en) | 2007-11-01 |
EP2021334B1 (en) | 2015-04-22 |
US7671206B2 (en) | 2010-03-02 |
BRPI0710538A2 (en) | 2012-06-05 |
RU2456271C2 (en) | 2012-07-20 |
ES2543199T3 (en) | 2015-08-17 |
CA2649762A1 (en) | 2007-11-01 |
AU2007242793B2 (en) | 2012-12-13 |
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