MXPA98001045A - Derivatives of aza-antraciclin - Google Patents
Derivatives of aza-antraciclinInfo
- Publication number
- MXPA98001045A MXPA98001045A MXPA/A/1998/001045A MX9801045A MXPA98001045A MX PA98001045 A MXPA98001045 A MX PA98001045A MX 9801045 A MX9801045 A MX 9801045A MX PA98001045 A MXPA98001045 A MX PA98001045A
- Authority
- MX
- Mexico
- Prior art keywords
- amino
- formula
- hydrogen
- compound
- alkyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- 239000001257 hydrogen Substances 0.000 claims abstract description 56
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 56
- 238000000034 method Methods 0.000 claims abstract description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 14
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- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
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- 125000000217 alkyl group Chemical group 0.000 claims description 37
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 32
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- 125000003118 aryl group Chemical group 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
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- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 7
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- 238000002360 preparation method Methods 0.000 abstract description 22
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- 239000003638 reducing agent Substances 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 230000002739 subcortical Effects 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
Compounds of formula (1) are described wherein X1 and X2 are C = 0, C = NH0CH2, X3 is CH2, CO, CHOH, formula (III), formula (IV), wherein n = 2 or 3, and C = N (R9) wherein R9 is hydroxy or amino-aryl and each of R1, R2, R3, R4, R5, R6, R7 and R8 are hydrogen or an organic residue, which are useful in the treatment of amyloidosis. A process for their preparation and the pharmaceutical compositions containing them are also described.
Description
DERIVATIVES OF AZA-ANTRACICLINONA
Field of the Invention The present invention relates to new aza-anthracyclinone derivatives, their use for the treatment of amyloidosis, methods for their preparation and pharmaceutical compositions containing them.
Background of the Invention The relationship between amyloidosis, cell death and loss of tissue function seems to be important for different types of neurodegenerative disorders. Therefore, the prevention of amyloid substance formation can be an important therapeutic tool for all pathological disorders associated with amyloidosis including AL amyloidosis and neurodegenerative disorders of the Alzheimer type.
The present invention provides novel aza-anthracyclines and their use in the treatment of amyloidosis. The new compounds are characterized by the presence of a heterocyclic ring bridged with an anthraquinone system.
The new class of molecules is called antrazalinone and the related compound, indicated as antrazalone, can be considered related to 8-aza-anthracyclines
REP: 26779
Antrazalona
More particularly, the present invention provides an anthrazalinone derivative of formula 1:
Where: Xi and X2 are independently selected from C = 0, C = NH, and CH2, X3 is selected from: CH2, C = 0, CHOH,
enVdonde n = 2 or 3, and C = N (Rg) where Rg is hydroxy or amino-aryl, Rl? R2, R3 and
R4 are independently selected from: hydrogen, hydroxyl, C? -6 alkyl, C-i6 alkoxy, C3-8 cycloalkoxy, halogen, amino which can be unsubstituted or mono-or-di-substituted by acyl, trifluoroacyl, aralkyl or aryl, and OS02 (Rio) wherein Rio is alkyl or aryl; R5 and R8 are independently selected from: hydroxyl hydrogen, C6-6 alkoxy, halogen, amino which may be unsubstituted or mono- or di-substituted by acyl, trifluoroacyl, aralkyl or aryl groups, and OS02 (Rio) wherein Rio it is as defined above; Re is selected from: hydrogen, RB-CH2- wherein RB represents an aryl or heterocyclyl group or a
group of formula RC-CH = CH-, wherein Rc is hydrogen or C 1-5 alkyl, C 1 - 6 alkyl, C 2 8 alkylene, C 3-3 cycloalkyl, acyl of formula C (R n) = 0 wherein R n is selected from: hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl / hydroxyalkyl, heterocyclyl, aryl araloxyalkyl, acyloxyalkyl and a naturally occurring amino acid residue, for example glycine, cysteine, phenylalanine or leucine or a synthetic amino acid or a residue of a di- or tri-peptide, for example Gli-Gli, Gli-Fe, Gli-Leu, or Gli-Fe-Leu, Gli- Leu-Fe; and R is selected from: hydrogen, methyl, CH2OH, CH2O-R12 wherein R12 is the tetrahydropyranyl group (THP), or a saccharide of the formula:
Where R13 is amino or aminoacyl, R1 and R15 are both hydrogen or one of R? or Ri5 is hydrogen and the other of R? or R15 is hydroxy or alkoxy or halogen or a group 0S02 (Rio) as previously defined, CH2-0-Ph (amino) wherein the amino can be unsubstituted or mono- or disubstituted by an alkyl, acyl, trifluoroacyl group, aralkyl or aryl; and CH2-amino wherein the amino is mono- or di-substituted by an alkyl, acyl, trifluoroacyl, aralkyl or aryl group or the amino is within a heterocyclic ring, for example a piperidino or morpholino ring optionally substituted with C1-6alkyl 16 or Ci-iß alkyloxy or aryloxy, or a pharmaceutically acceptable salt thereof.
Preferred compounds of formula 1 are those wherein:
Xi and X2 are independently selected from: C = 0 and C = NH; X3 is selected from: CH2, C = 0, CHOH and C = N (Rg) wherein Rg is hydroxy or amino-aryl, Ri, R2, R3 and
R - are independently selected from: hydrogen, hydroxyl, C1-4 alkoxy, C3-3 cycloalkoxy,
O-mesyl (0-S02CH3), amino and amino-benzyl; R5 and R8 are independently selected from: hydrogen, hydroxyl, C1-4 alkoxy, halogen, amino, amino-benzyl and amino-trifluoroacetyl; R6 is selected from: Hydrogen, RB-CH2, wherein RB is as defined above, C? -? Alkyl or C2-6 alkenyl acyl of formula -C (R? 2) = 0 wherein Ri2 is selected from : Ci-io alkyl, hydroxyalkyl, heterocyclyl, aryl araloxyalkyl, acyloxyalkyl and a naturally occurring amino acid residue, for example glycine, cysteine, phenylalanine, leucine, or a synthetic amino acid or a di-or tri-peptide residue, for example Gli-Gli, Gli-Fe, Gli-Leu, Gli-Fe-Leu, Gli- Leu-Fe; and R7 is selected from: hydrogen,
methyl, CH2OH, CH2O-R12 wherein Ri2 is the tetrahydropyranyl group (THP), or a saccharide of the formula:
wherein R13 is amino or aminotrifluoroacetyl or aminoacetyl, R15 is hydrogen and R4 is hydroxy or iodo or O-mesyl, CH2-0-Ph-NH-COR wherein R is alkyl, aralkyl or aryl, CH amino, wherein the amino is within a heterocyclic ring, for example a piperidino, pyrrolidino, morpholino or dihydropyridino ring optionally substituted with C1-10 alkyl or Ci-5 alkyloxy or aryloxy.
The most preferred compounds of formula 1 are those wherein: Xi and X2 are independently selected from: C = 0 and C = NH; X3 is selected from: CH2, C = 0 and CHOH,
if R 2 and R 4 are independently selected from: hydrogen, hydroxyl, methyl, methoxy, O-mesylate, amino, amino-benzyl, fluorine and chlorine; R5 and R8 are independently selected from:
hydrogen, hydroxyl, methoxy, ethoxy, amino and amino-trifluoroacetyl R6 is selected from: hydrogen, benzyl, allyl, 3,4-dimethoxybenzyl, pyridinmethyl, (N-methyl-dihydropyridine) -methyl, nicotyl, glycyl and
isoleucyl; and R7 is selected from: Hydrogen, Methyl, CH0H, CH2O-R12, wherein Ri2 is the tetrahydropyranyl group (THP), or a saccharide of the formula:
'15 R .. '14
wherein R13 is amino or aminotrifluoroacetyl or aminoacetyl, R15 is hydrogen and R1 is iodo and CH2-amino, wherein the amino is within a morpholino ring.
Additional preferred compounds of formula 1 are those wherein: - Xi and X2 are both C = 0; - X3 is C = 0; - Ri, R2 and R3 are each hydrogen and R4 is hydrogen, hydroxy or methoxy; - Rs and R8 are independently selected from hydrogen, hydroxyl, methoxy and amino; - Rd is selected from hydrogen, pyridinmethyl, (N-methyl-dihydropyridin) -methyl, nicotyl, glycyl and isoleucyl; and - R7 is methyl.
An "alkyl" group is typically a C? -C? 6 alkyl group. A C? -C? 6 alkyl group includes straight or branched chain alkyl groups. Perfectly a C? -C? 6 alkyl group is a C? -C? 2 alkyl group such as a hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl group or a branched chain isomer thereof.
Preferably, a C? -C? 2 alkyl group is a C? -C6 alkyl group or a C1-C5 alkyl group such as a methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl or pentyl group, or a branched chain isomer thereof. The alkyl groups mentioned above can be substituted with one or more substituents, for example a halo substituent such as fluorine, chlorine, bromine or iodine, CF3, an alkoxy substituent, an aryl substituent, an alkyl-aryl substituent, a haloaryl substituent, an cycloalkyl substituent or an alkylcycloalkyl substituent.
The term "alkenyl" as used herein includes straight and branched chain radicals of up to 8 carbons, for example, allyl, butenyl, hexenyl, octenyl.
The term "cycloalkyl" as used herein means a cycloalkyl group having 3 to 8 carbons, preferably 3 to 5 carbons.
Examples include cyclopropyl, cyclopentyl, cyclopentylmethyl, cycloheptyl and cyclooctyl.
The heterocyclyl group is a saturated or unsaturated heterocyclyl ring of 3 to 6 members, for example of 3, 4, 5 or β members, which contains at least one heteroatom selected from 0, S and N, which is optionally fused to a second saturated or unsaturated heterocyclyl group, of 5 to 6 members, or a cycloalkyl group or an aryl group as defined hereinbelow.
Examples of heterocyclyl groups are pyrrolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, thiazolyl, thienyl, pyridinyl, dihydro-pyridinyl, piperidinyl, piperazinyl, pyrazinyl, pyrimidinyl, pyranyl, pyridazinyl, furanyl, pyrazolyl, isothiazolyl, isoxazolyl, morpholinyl groups. , thiopyranyl, benzothienyl, benzothiazolyl or benzoxazolyl.
Such groups can be substituted with hydroxy groups, primary or secondary amino, or tertiary amino, the radicals being at the secondary and tertiary amino, for example straight or branched chain alkyl groups C? Cl ?, phenyl, benzyl, alkoxy, phenoxy groups or benzyloxy or halogen atoms.
The term "aryl" as used herein includes both aromatic, monocyclic or bicyclic groups, containing from 6 to 10 carbons in the ring portion, such as phenyl, naphthyl, substituted phenyl or substituted naphthyl, wherein the substituent in the phenyl or in the naphthyl it can be, for example, C? -6 alkyl, halogen or C? -6 alkoxy?
The term "halogen" as used herein means fluorine, chlorine, bromine or iodine.
The term "aralkyl" as used herein refers to alkyl groups as previously mentioned having a substituted aryl, as defined above, for example, benzyl; 3, 4-dimethoxybenzyl, phenethyl, diphenylmethyl and triphenylmethyl.
The term "aroyl" as used herein refers to a group of the formula -COAr wherein Ar denotes an "aryl" group as defined above.
The term "alkoxy" or "aryloxy" as used herein includes any of the alkyl or aralkyl groups indicated above linked to an oxygen atom.
The term "alkoxyalkyl" as used herein means any alkyl as indicated above attached to
any alkoxy as indicated above, for example, ethoxypropyl.
The term "aryloxyalkyl" as used herein means any alkyl as indicated above linked to an aryl as indicated above by an oxygen atom, for example, phenoxyethyl.
The term "araloxyalkyl" as used herein means an aralkyl as indicated above linked to an alkyl as indicated above by an oxygen atom, for example, benzyloxyethyl.
The term "acyloxyalkyl" as used herein means a C 1 -io acyl group linked to an alkyl group as defined above by an oxygen atom, for example, acetoxymethyl.
The term "hydroxyalkyl" as used herein means an alkyl group as indicated above linked to a hydroxyl group, for example, hydroxyethyl. An acyl group is typically a Ci-Cio acyl group, for example, a C1-C6 acyl group such as a methanoyl, ethanoyl, n-propanoyl, i-propanoyl, n-butanoyl, t-butanoyl, sec-butanoyl, pentanoyl group or hexanoyl.
This invention also includes all possible isomers of the compounds of the formula (I) and mixtures of
the same, for example, diastereomeric mixtures and racemic mixtures. Thus, the stereocenters in position 7 and position 9 may be in the R or S configuration (or both, ie, a mixture of stereoisomers is present). Similarly, the glycosidic binding of the saccharides can be in the α or β configuration (or both, ie, a mixture of stereoisomers is present). The present invention also provides the salts of those compounds of formula 1 having salt-forming groups, especially the salts of the compounds having a carboxylic group or a basic group (eg, an amino group).
The present invention includes salts of the anthrazalinone derivative of the formula 1. The salts are typically physiologically tolerable or pharmaceutically acceptable salts, for example, alkali metal or alkaline earth metal salts (eg, sodium, potassium, lithium, calcium salts). and magnesium), ammonium salts and salts with an organic amine or an appropriate amino acid (eg, arginine, procaine salts), and addition salts formed with suitable organic or inorganic acids, eg, hydrochloric acid, sulfuric acid , carboxylic acid and organic sulfonic acids (e.g., acetic acid, trifluoroacetic, p-toluenesulfonic).
The compounds of formula 1 wherein R6 represents a group RB-CH2 can be prepared: (a) by reacting a compound of formula 2:
Where Xi, X2 and Ri to R7 are as defined above, and W represents a leaving group, with an amine of the formula: H2N-CH2-RB Where RB is as defined above, to give a compound of formula I wherein R6 is RB-CH2-; (b) if desired, converting the compound thus obtaining of the formula (I) into another compound of the formula (I); I
(c) if desired, converting the compound of formula (I) to a pharmaceutically acceptable salt thereof.
Suitable groups W include O-saccharides such as O-daunosaminyl, O-acyl derivatives such as for example O-trifluoroacetyl or O- (p-nitrobenzoyl) or 0-ethoxycarbonyl, 0-acetal such as 0-THP. Preferred amines of formula H2-CH2-RB include
alkylarylamines, for example, benzylamine, 3,4-dimethoxybenzylamine or pyridinmethylamine.
A compound of formula 2 is typically reacted with an amine of formula HN-CH2RB as defined above. The amine is typically present in excess of 1 to 10 times. The reaction can take place in a compatible organic solvent such as methylene chloride or pyridine. An organic base, such as pyridine, may be present. The reaction can take place over a period of from 6 to 48 hours, typically from -10 ° C to room temperature (i.e., about 20 ° C).
Preferably a four-fold excess of amine of formula H2-CH2RB is used. The solvent is more typically pyridine. The preferred reaction conditions are room temperature for a period of from 12 to 24 hours.
It should be noted that this reaction is new in the field of chemistry of anthracyclines and anthracyclines.
Anthrazalinone derivatives wherein Re represents hydrogen can be prepared, for example, by deblocking the corresponding N-CH 2 'B derivative, wherein R' B is a 3,4-dimethoxyphenyl or vinyl group. Unlocking is typically achieved by oxidation, for example, by treatment with 5, β-dicyano-1,4-benzoquinone
(DQQ) The reaction can be conducted in the presence of a suitable solvent. Preferably an equivalent amount of DDQ is used. Preferably, the solvent is a mixture of methylene chloride and water (typically in a ratio of 20: 1 by volume). The reaction is typically conducted at room temperature for 1 to 10 hours.
The anthrazalinone derivatives of formula 1 can be further functionalized to different 8-N-substituted derivatives by means of standard chemical methods.
For example, the 8-N-alkyl, -alkenyl, -cycloalkyl anthrazalinones of formula 1 are preferably prepared by reacting a compound of formula 1 wherein Re is a hydrogen with a group of formula R6-X wherein R6 is C1-6 alkyl. C, C2-C8 alkenyl or C3-C8 cycloalkyl and X is a leaving group such as a halogen, 0-S02-CH3, 0-S02CF3 or 0-S02-C6H4CH3. Preferably x is halogen. More preferably, X is iodine. A suitable solvent may be present. An excess of Rβ-X is preferably used 2 to 20 times. Preferably, the reaction is carried out in an organic solvent such as methylene chloride or dimethylformamide. The reaction typically occurs at 40 to 80 ° C for 4 to 24 hours.
The 8-N-acyl-anthrazalinones of formula 1 are preferably prepared by reacting a compound of formula 1 wherein Re is hydrogen with an acyl derivative of the formula Rn-CO-Hal or (RnCO) wherein Rn is as defined above above and Hai is halogen preferably chlorine. An excess of acyl derivative of 2 to 20 times is preferably used. A solvent is typically present, for example, an organic solvent such as methylene chloride or dimethylformamide. Preferably the reaction is carried out at -10 to 40 ° C for 1 to 24 hours.
In a further example, the N-acyl-anthrazalinones of formula 1 can be prepared by reacting an anthrazalinone of formula 1 wherein R is hydrogen with an acid derivative of formula Rn -COOH in the presence of a condensing agent such as dicyclohexylcarbodiimide or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinone (EEDQ) in an anhydrous organic solvent. An excess of acid of 1 to 4 times is preferred. Preferably the dry organic solvent is dimethylformamide. An equivalent amount of EEDQ is typically used. The reaction is generally carried out at room temperature for 15 hours.
The compounds of the formula I, wherein R is a residue of an amino acid or a di-tripeptide can be prepared analogously according to the condensation conditions known in peptide chemistry.
In addition, the C-13-carbonyl group can be reduced to C-13-dihydro or functionalized to hydrazone and then reduced to C-13-deoxo derivatives by means of methods known from anthracycline chemistry.
For example to prepare C-13-dihydro derivatives of formula 1, an anthrazalinone of formula 1 (X3 = CO) is reacted with a reducing agent in an organic solvent at -10 ° C at room temperature for 5 to 30 minutes .
Preferred conditions comprise dissolving an aglycone of formula 1 as previously defined in dry methylene chloride and treating it with 5 to 10 times excess of tetrabutylammonium borohydride at room temperature for 5 minutes.
The compounds of formula 2 can be obtained from natural sources or can be prepared following known synthesis methods starting from known anthracyclines or anthracyclines.
For example, the 7-O-saccharide wherein the sugar is daunosaminyl can be derived from a natural source such as daunorubicin, or it can be prepared by means of the synthetic modification thereof.
Other aglycones functionalized at the C-7 position can be separated by means of well known procedures.
For example, the 7-O-THP derivatives of formula 2 (compounds wherein it is O-THP) are readily prepared by reacting an aglycone of formula 3:
With dihydropyran in an organic solvent and in the presence of an acid catalyst at room temperature for 1 to 4 hours.
Preferably the compound of formula 3 is dissolved in methylene chloride and reacted with 4 equivalents of dihydropyran in the presence of a catalytic amount of p-toluenesulfonic acid at room temperature for 2 hours. The 7-0-THP derivative is recovered by washing the reaction mixture with aqueous sodium hydrogen carbonate and water, then removing the solvent under reduced pressure.
The 7-O-acyl derivatives of formula 2 are prepared by reacting the compound of formula with an acid
suitable carboxyl, an acid anhydride or acyl chloride in organic solvent and in the presence of a base at -10 at room temperature for 1 to ß hours.
For example, a 7-O-acetyl derivative of formula 2 (= -0-COCH3) is prepared by reacting the compound of formula 3 with acetic anhydride in an organic solvent such as methylene chloride and in the presence of an organic base such as pyridine.
The compound is recovered by precipitating the crude material in an apolar solvent such as hexane.
Some of the starting materials for the preparation of compounds of formula 1 are known, the others can be prepared analogously starting from anthracyclines or anthracyclines by known methods.
For example, the following anthracyclines are known and can be represented by the same formula 2:
Daunorubicin (2a: R? = R2 = R3 = H, R4 = OCH3, R5 = R8 = OH, X? = X2 = CO, R7 = CH3, L = 0-daunosaminil), doxorubicin (2b: R? = R2 = R3 = H, R4 = 0CH3, R5 = R8 = OH, X? = X2 = CO, R7 = CH2OH, L = 0-daunosaminil), 4-demethoxydaunorubicin (2c: R? = R2 = R3 = R4H, H, R5 = R8 = OH, X? = X2 = CO R = CH3, l = 0-daunosaminil), 11-deoxidaunorubicin (2d: R? = R2 = R3 = H, R4 = OCH3, R5 = OH, R8 = H, X ? = X2 = CO, R7 = CH3 / L = 0-
daunosaminil), 11-aminodaunorubicin (2e: R? = R2 = R3 = H, R4 = OCH3, R5 = OH, R8 = NH2, Xi = X2 = CO, R7 = CH3, L = 0-dauno-saminyl), 6 -deoxidaunorubicin (2f: R? = R2 = R3 = H, R4 = OCH3, R5 = OH, R8 = OH, X? = X2 = CO, R7 = CH3, 1 = 0 daunosaminil), 6-aminodaunorubicin (2g_: R ? = R2 = R3 = H, R4 = OCH3, R5 = 0H, R8 = NH2, X?, X2 = C0, R7 = CH3, L = 0-daunosaminil), 4-aminodaunorubicin (2h: R? = R2 = R3 = H, R4 = NH2, R5 = R8 = 0H, XlfX2 = C0, R7 = CH3, L = 0 daunosaminyl), 9-deacetyl-9-formyl-N-trifluoroacetyl-daunorubicin (2i: R? = R2 = R3 = H, R 4 = OCH 3, R 5 = R 8 = OH, X? = X 2 = C 0, R 7 = H, L = 0 (N-trifluoroacetyl-daunosaminyl).
Some 7-0 derivatives of formula 2 are also known, for example, ethoxycarbonyldaunomycinone (2j_: R? = R2 = R3 = H,
R4 = CH03, R5 = R8 = OH, X? = X2 = C0, R7 = CH3, L = 0-COOC2H5), 7-0- (tetrahydropyranyl) daunomycinone (2k: R = R2 = R = H, R4 = OCH3 ,
R5 = R8 = OH, X? = X2 = C0, R7 = CH3, L = 0-THP), 7-0-acetyldaunomycinone (21: R? = R2 = R3 = H, R4 = OCH3, R5 = R8 = OH , Xi = X2 = C0, R7 = CH3, L = 0-C0CH3).
The compounds of the present invention are characterized by the high inhibitory activity of amyloidosis. The present invention therefore further provides the use of a compound of formula I, as defined above, or a pharmaceutically acceptable salt thereof, in the treatment of amyloidosis.
A human or animal, for example. , a mammal, can therefore be treated by means of a method comprising
the administration thereto of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The term amyloidosis indicates several diseases whose common feature is the tendency of particular proteins to aggregate and precipitate, as insoluble fibrils in the extracellular space causing structural and functional damage to organs and tissues. The classification of amyloid substance and amyloidosis has recently been reviewed in the Bulletin of the World Health Organization 71 (1): 105 (1993).
The different types of amyloid substance share the same ultrastructural organization in antiparallel β-folded layers despite the fact that they contain a variety of protein subunits that differ widely [see: Glenner GG, New England J. Med. 302 (23): 1283 81980)]. AL amyloidosis is caused by light chains of peculiar monoclonal immunologlobulin that form amyloid fibrils. These monoclonal light chains are produced by monoclonal plasma cells with a low mitotic index that provides their well-known insensitivity to chemotherapy.
The malignancy of these cells consists of their protidosynthetic activity.
The clinical course of the disease depends on the selectivity of the organ's commitment; the prognosis
it can be extremely unfavorable in case of cardiac infiltration (median survival <12 months) or more benign in case of kidney involvement (average survival approximately 5 years).
Considering the relative insensibility of amyloidogenic deposits to proteolytic digestion, a molecule that can block or decrease amyloid formation and increase the solubility of existing amyloid deposits seems to be the only reasonable hope for patients who have AL amyloidosis. Furthermore, as the supramolecular organization of amyloid fibers is the same for all types of amyloid substance, the availability of a drug that interferes with the formation of amyloid substance and increases the solubility of existing deposits, allowing debugging by mechanisms, could be very beneficial for all types of amyloidosis, and in particular for the treatment of Alzheimer's disease.
Actually, the main pathological feature of Alzheimer's disease (AD), Down's syndrome, pugilistic dementia and cerebral amyloid angiopathy is the disposition of the amyloid substance in the cerebral parenchyma and the walls of the vessels. These markers are associated with the loss of neutral cells in the cerebral cortex, limb regions and subcortical nuclei.
Several studies have shown that selective damage to several neural systems and loss of synapses in the frontal cortex have been correlated with cognitive decline. The pathogenesis and molecular basis of the neurogenerative processes in AD are not known, but the role of the β-amyloid substance, deposited in the cerebral parenchyma and the vessel walls has been in recent reports on its neurotoxic activity in vi tro and in vivo (Yan er et al., Science, 245: 417, 1990. Kowall et al PNAS, 88: 7247, 1991).
In addition, the segregation of familial AD with mutation of the amyloid substance precursor protein (APP) gene has aroused interest in the potential pathogenic function of the β-amyloid substance in AD [Mullan, M. col., TINS, 16 (10): 392 (1993)], the neurotoxicity of the β-amyloid substance has been associated with the fibrilogenic properties of the protein. Studies with homologous synthetic peptides indicate that the hippocampal cells were insensitive to exposure to a recent β-42 solution for 24 h. While its viability decreased when the neurons were exposed to Aßl-42 previously stored in saline for 2-4 days at 37 ° C to favor the aggregation of peptides. The relationship between fibrils and neurotoxicity is further supported by recent evidence showing that the soluble form of the β-amyloid substance is
produced in vivo and in vi tro during normal cell metabolism (Hass et al., Nature, 359, 322, 1993) and only when added in congophilic formation was it associated with dystrophic neuritis.
On the other hand, the non-congofilic "preaminoid" formation of the β-amyloid substance was not associated with neuronal alteration (Tagliavini et al Neurosci, Lett 93: 191, 1988).
The neurotoxicity of the peptide homozygous β-amyloid substance 25-35 (ß25-35) retains the self-aggregating properties of the β-42 fragment of the complete β-amyloid substance.
Chronic but non-acute exposure of hippocampal neurons to micromolar concentration of the β25-35 fragment induced neural death by the activation of a programmed cell death mechanism known as apoptosis (Forloni et al Neuro Report, 4: 523, 1993). Here again, neurotoxicity was associated with the self-aggregating property of ß25-35.
Other neurodegenerative disorders such as spongiform encephalopathy (SE) are characterized by neutral death and extracellular deposition of amyloid substance, in this case originating in the prion protein (PrP). In analogy with observation
that the β-amyloid substance is neurotoxic, the effects of the synthetic peptides homologous to different segments of PrP on the viability of the primary rat hippocampal neurons have been investigated. Chronic peptide application corresponding to PrP 106-126 induced neuronal death by apoptosis while under the same conditions all other peptides tested and the mixed sequence of PrP 106-126 did not reduce cell viability (Forloni et al., Nature 362 : 543). PrP 106-126 was highly fibrillogenic in vi tro and when the Congo red was detected, the peptide aggregate showed green birefringence indicative of the comparison of β-layers characteristic of the amyloid substance.
The compounds of the present invention can be used to prepare medicaments useful for preventing or arresting the progress of diseases caused by amyloid proteins, such as AL amyloidosis, Alzheimer's disease or Down syndrome. The compounds of the present invention were tested for their intrinsic cytotoxicity on PC12 cell cultures, according to standard procedures.
All compounds were found to be non-cytotoxic at a concentration of 10 μm.
The present invention also includes within its scope pharmaceutical compositions comprising one or more compounds of the formula (I) as active ingredients, in association with pharmaceutically acceptable carriers, excipients or other additives, if necessary.
Pharmaceutical compositions containing a compound of formula 1 or salts thereof can be prepared in a conventional manner employing conventional non-toxic pharmaceutical carriers or diluents in various dosage forms and modes of administration.
In particular, the compounds of formula 1 can be administered:
A) orally, for example, as tablets, lozenges, lozenges, aqueous or oily suspensions, powders or dispersible granules, emulsions, hard or soft capsules, or syrups or elixirs. The pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives to provide elegant and palatable pharmaceutical preparations.
The tablets contain the active ingredient mixed with pharmaceutically acceptable non-toxic excipients which are suitable for the preparation of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; binding agents, for example, corn starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate or steric acid or talc. The tablets can be uncoated by means of known techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide a sustained action over a prolonged period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
The formulation for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules wherein the ingredient active is mixed with water or an oily medium, for example, peanut oil, liquid paraffin or olive oil. The aqueous suspensions contain active materials mixed with excipients suitable for the preparation of aqueous suspensions.
Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxy, propylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; Dispersing or wetting agents can be naturally occurring phosphates, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with aliphatic chain alcohols long, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides of hexitol, for example, polyoxyethylene sorbitan monooleate. The aforesaid aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more sweetening agents, such as sucrose or saccharin. The oily suspension can be formulated by suspending the active ingredient in a vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, solid paraffin or ethyl alcohol. Agents
Sweeteners, such as those indicated above, and flavoring agents, can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. The dispersible powders and granules for the preparation of an aqueous suspension by the addition of water provide the active ingredient mixed with a dispersing or wetting agent, a suspending agent and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients may also be present, for example, sweetening and flavoring agents.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example, liquid paraffin or mixtures thereof. Suitable emulsifying agents can be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soybeans, lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, monooleate sorbitan, and products
of condensation of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs can be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
B) Parenterally, either subcutaneously or intravenously or intramuscularly, or intrasternally, or by infusion techniques, in the form of a sterile or oily injectable aqueous suspension. The pharmaceutical compositions may be in the form of a sterile or oily injectable aqueous suspension.
This suspension can be formulated according to the known art using the suitable dispersing or wetting and suspending agents mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents that can be used are r, Ringer's solution and isotonic sodium chloride solution.
In addition, sterile, non-volatile oils are conventionally employed as a solvent or suspending medium. For this purpose, any light non-volatile oil can be conventionally employed including synthetic mono- or diglycerides.
In addition, fatty acids such as oleic acid can be used in the preparation of injectables.
The present invention also provides a method for controlling amyloidosis diseases, and / or preventing or arresting the progress of diseases caused by amyloid proteins, which method comprises administering a therapeutically effective amount of one or more compounds of formula 1 to a human being or an animal, eg. , a mammal, which requires such treatment.
The daily doses are in the range of approx. 0.1 approx. 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease, and the frequency and route of administration; preferably, the daily dosage levels are in the range of 5 mg to 2 g. The amount of active ingredient that can be combined with the carrier materials to produce a unit dosage form will vary depending on the
treated host and the particular mode of administration. For example, a formulation intended for oral administration may contain from 5 mg to 2 g of active agent compound with an appropriate and convenient amount of carrier material which may vary from ca. 5 to approx. 95 percent of the total composition. The unit dosage forms will generally contain between approx. 5mg and approx. 500 mg of the active ingredient.
The following Examples illustrate the invention without limiting it.
Example 1: Preparation of 8-N- (3,4-dimethoxybenzyl) -anthrazalone (la)
Daunorubicin (2a, 1, 58g, 3 mmoles) was dissolved in dry pyridine (20 ml), 3,4-dimethoxybenzylamine (2 g, 12 mmol) was added and maintained at room temperature for 16 hours. After this, aqueous IN HCl (400 mL) was added to the reaction mixture and extracted with methylene chloride (200 mL). The phase
organic was washed with r (2x200 ml), dried over anhydrous sodium sulfate, concentrated to a small volume under reduced pressure and chromatographed instantaneously on silica gel using a toluene acetone mixture (9: 1 by volume) as a eluent to give the title compound _la (lg). TLC on Kieselgel F254 plate (Merck), eluent system methylene chloride acetone (95: 5 by volume) Rf = 0.56. FAB-MS (+): m / z 530 [MH] +; 380 [M - CH2 (C6H3) 2 + 2H] +;
: HNMR (400 MHz, CDC13) s
1.43 (s, 3H, CH 3); 2.34 (d, J = 17.5Hz, 1H, CH (H) -12);
2.66, 2.77 (two doublets, J = 19.4 Hz, 2H, CH2-10); 2.81
(dd, J = 7.3, 17.5Hz, 1H, CH (H) -12); 3.24, 3.79 (two doublets, J = 12, 8Hz, 2H, N-CH2-Ph); 3.85, 3.86 (2xs, 6H,
2xOCH3); 4.08 (S, 3H, 4-OCH3); 4.77 (d, J = 7.3 Hz, 1H, H-7);
6.6-6.8 (m, 3H, aromatic hydrogens); 7.38 (d,
J = 7, ßHz, 1H, H-3); 7.77 (dd, J = 7.6, 7.8 Hz, 1H, H-2);
8.03 (d, J = 7.8 Hz, 1H, H-1); 13.22 (s, 1H, OH-11); 13.50 (s, 1H, OH-6).
Example 2: Preparation of antrazalone (Ib)
8-N- (3,4-dimethoxybenzyl) -anthrazalone (0.5 g, 1 mmol) was dissolved in a mixture of methylene chloride (20 ml) and water (1 ml) and treated with 2, 3 -dichloro-5-ß-dicyan-l, 4-benzoquinone (DDQ, 0.25 g, 1 mmol) at room temperature. After 4 hours, the reaction mixture was washed with aqueous 5% sodium hydrogen carbonate (3x100 ml), then with water. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give the title compound lb (0.35 g) which was converted to the corresponding hydrochloride salt derivative by treatment with anhydrous methanolic hydrogen chloride.
TLC on Kieselgel plate F254 (Merck), eluent system methylene chloride acetone (90:10 by volume) Rf = 0.2β.
FD-MS: 380 [MH] +; 362 [M-NH3] \ XHNMR (400 MHz, CDC13) s:
1.45 (s, 3H, CH 3); 2.43 (d, J = 17.5Hz, 1H, CH (H) -12); 2.76, 2.84 (two doublets, J = 19.2Hz, CH2-10); 2.86 (dd, J = 7.3, 17.5 Hz, 1H CH (H) -12); 4.08 (s, 3H, OCH3); 5.14 (d, j = 7.3 Hz, 1H, H-7); 7.37 (d, J = 8.5 Hz, 1H, H-3); 7.76 (dd, J = 7.7, 8.5 Hz, 1H, H-2); 8.01 (d, J = 7.7 Hz, 1H, H-1); 13.14 (s, 1H, OH-11); 13.60 (s, 1H, OH-6).
Example 3: Preparation of 8-N- (pyridinmethyl) -antrazalone (le)
The title compound was prepared from daunorubicin (2a, 1.58 g, 3 mmol) and 4-aminomethylpyridine (1.2 g, 12 mmol) following the same procedure as described in Example 1.
Yield 0.95 g. TLC on Kieselgel F2s4 plate (Merck), eluent system methylene chloride acetone (80:20 by volume) Rf = 0.4.
FAB-MS (+): m / z 471 [MH] +; 380 [M-CH2 (C5H4N) + 2H] +;
XHNMR (400 MHz, CDCl 3) s: 1.39 (s, 3H, CH 3); 2.50 (d, J = 17.9Hz, 1H, CH (H) -12); 2.78 (s, 2H, CH.2-10); 2.96 (dd, J = 7.3 Hz, 17.9 Hz, 1H CH (H) -12); 3.70, 4.07 (two doublets, J = 16.7 Hz, 2H, N + -CH2-pyrid.); 4.07 (S, 3H, OCH3); 4.76 (d, J = 7.3 Hz, 1H, H-7);
7. 40 (d, J = 7.3 Hz, 1H, H-3); 7.79 (dd, J = 7.3 Hz, 1H, H-2); 7.89 (d, J = 6, OHz, 2H, pyridine hydrogens); 8.02 (d, J = 7.7Hz, 1H, H-1); 8.70 (d, J = 6, OHz, 2H, pyridine hydrogens); 13.14 (s, 1H, OH-11); 13.45 (s, 1H, OH-6).
Example 4:
Preparation of 4-demethoxy-8-N- (pyridinmethyl) -anthrazalone (Id):
The title compound Id. Was prepared from 4-demethoxydaunorubicin (2_3, 1, 38g, 3 mmoles) and 4-aminomethylpyridine (1.2 g, 12 mmoles) following the same procedure as described in Example 1.
Yield, 0.87 g, TLC on Kieselgel F254 plate (Merck), eluent system methylene chloride acetone (80:20 by volume) Rf = 0.46.
FAB-MS (+): m / z 441 [MH] +: 350 [M-CH 2 (C 5 H 4 N) + 2 H] +; HNMR (200 MHz, CDCl 3) s: 1.41 (s, 3H, CH 3); 2.46 (d, J = 17, ßHz, 1H, CH (H) -12); 2.73 (m, 2H, CH2-10); 2.89 (dd, J = 7.0, 17.6Hz 1H CH (H) -12); 3.37, 3.85 (two doublets, J = 14.6Hz, 2H, N + -CH-pyrid.); 2.73 (d, J = 7, OHz, 1H, H-7); 7.24 (m, 2H, pyridine hydrogens); 7.80 (m, 2H, H-2 + H-3); 8.28 m, 2H, H-1 + H-4); 8.54 (2H, pyridine hydrogens); 13, 05, 13.16 (2xs, 2H, OH-6 + OH-11).
Example 5: Preparation of 8-N-benzyl-anthrazalone (le):
The title compound l_e was prepared from daunorubicin (2a, 1.58 g, 3 mmol) and benzylamine (1.2 g, 12 mmol) following the same procedure as described in Example 1:
Yield, 1 g. TLC on Kieselgel F2s4 plate (Merck), eluent system methylene chloride acetone (90:10 by volume) Rf = 0.7.
FAB-MS (+): m / z 470 [MH] +: 320 [M-CH2 (C5H5) + 2H] +; XHNMR (200 MHz, CDCl 3) s: 1.42 (s, 3H, CH 3); 2.37 (d, J = 17.4 Hz, 1H, CH (H) -12); 2.68, 2.76 (two doublets, J = 19.6Hz, 3H, CH2-10); 2.81 (dd, J = 7.0, 17.4 Hz 1H CH (H) -12); 3.30, 3.84 (two doublets, J = 13.2Hz, 2H, N-CH2-Ph); 4.07 (s, 3H, 4-OCH3); (d, J = 7, OHz, 1H, H-7); 7.2-7.3 (m, 5H, phenyl hydrogens); 7.38 (dd, J = 1.0, 8.4Hz, 1H, H-3); 7.7 (dd, J, 1.0.7, 7Hz, 1H, H-1); 13.22, 13.42 (2xs, 2H, OH-6 + OH-11).
Example 6: Preparation of 4-demethoxy-8-N-benzyl-anthrazalone (lf;
The title compound l_f was prepared from 4-ethoxy-daunorubicin (2_c, 1.38 g, 3 mmole) and benzylamine (1.2 g, 12 mmole) following the same procedure as described in Example:
Yield, 0.9 g. TLC on Kieselgel F25 plate (Merck), eluent system methylene chloride acetone (80:20 by volume) Rf = 0.84.
FAB-MS (+): m / z 440 [MH] +: 290 [M-CH 2 (C 6 H 5) + 2 H] +; XHNMR (200 MHz, CDCl 3) s: 1.44 (s, 3H, CH 3); 2.38 (d, J = 17, 4Hz, 1H, CH (H) -12); 2.70, 2.78 (two doublets, J = 19, 7Hz, 2H, CH2-10); 2.85 (dd, J = 7.2 Hz, 17.4 Hz 1H CH (H) -12); 3.31, 3.87 (two doublets, OHz, 2H, N-CH2-Ph); 4.74 (d, J = 7.2 Hz, 1H, H-7); 7.2-7.3 (m, 5H, phenyl hydrogens); 7.83 (m, 2H, H-2 + H-3); 8.33 (m, 2H, H-1H-4); 13.1, 13.2 (2xs, 2H, OH-6 + OH-11).
Example 7
Preparation of 4-demethoxy-8-N- (3,4-dimethoxybenzyl-anthrazalone (lg)
The title compound l_g_ was prepared by reacting 4-demethoxy-daunorubicin (2, 1.38 g, 3
mmoles) and 3-dimethoxybenzylamine (2 g, 12 mmol) as described in Example 1. Yield lg.
TLC on Kieselgel F254 plate (Merck), eluent system methylene chloride acetone (95: 5 by volume) Rf = 0.65.
FAB-MS (+): m / z 500 [MH] +: 350 [M-CH 2 (C 6 H 3) (OCH 3) 2 + 2 H] +;
Example 8: Preparation of 4-demethoxy-anthrazalone (lh):
4-demethoxy-8-N- (3,4-dimethoxybenzyl) -anthrazalone (Lg_, 0.5 g, lmmol) was transformed into the title compound lh. in the presence of DDQ as described in Example 2. Yield 0.4 g.
TLC on Kieselgel F254 plate (Merck), methylene chloride acetone eluent system (95: 5 by volume) Rf = 0.34.
FD-MS: 350 [MH] +; XHNMR (200 MHz, CDCl3) s:
1.46 (s, 3H, CH3); 2.45 (d, J = 17.7Hz, 1H, CH (H) -12); 2.81, 2.86 (two doublets, J = 19.4Hz, 2H, CH2-10); 2.87 (dd, J = 7.0 Hz, 17.7 Hz 1H CH (H) -12); 5.14 (d, J = 7.0 Hz, 1H, H-7); 7.83 (m, 2H, H-2 + H-3); 8.33 (m, 2H, H-1H-4); 13.18, 13.25 (2xs, 2H, OH-6 + OH-11).
Example 9: Preparation of 8-N-allyl-anthrazalone (li):
The title compound Li was prepared by reacting daunorubicin (2a, 1.58 g, mmol) with allylamine (0.9 g, 12 mmol) as described in Example 1. The raw material was flash chromatographed on silica gel using a mixture of methylene chloride and acetone (98: 2 by volume) as the eluent to give pure li (0.85 g).
TLC on Kieselgel plate F254 (Merck), methylene chloride eluent system Rf = 0, XHNMR (200 MHz, CDCl3) s: 1.37 (s, 3H, CH3); 2.41 (d, J = 17.6Hz, 1H, CH (H) -12);
2.64, (m, 2H, CH2-10); 2.88 (dd, J = 7.2Hz, 17.6Hz, 1H,
CH (H) -12); 2.8-3.4 (m, 2H, CH2CH = CH2); 4.04 (s, 3H, 4-
OCH3); 5.0-5.2 (m, 2H, CH2CH = CH2); 5.90 (m, 1H, CH2CH = CH2);
7.37 (d, J = 8.4Hz, 1H, H-3); 7.75 (dd, J = 7, β, 8.4Hz, 1H,
H-2); 8.00 (d, J = 7.6Hz, 1H, H-1); 13.0, 13.5 (2x, 2H, OH-6 + OH-11).
Example 10: Preparation of 8-N-benzyl-13-dihydro-anthrazalone (lj
8-N-benzylanthrazon (le, 0.75 g, 1.5 mmol), prepared as described in Example 5, was dissolved in anhydrous methylene chloride (290 ml) and treated with tetrabutylammonium borohydride (1.6 g). ) at room temperature for 5 minutes. After this, the reaction mixture was poured into IN aqueous hydrochloric acid and extracted with methylene chloride. The organic phase was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude material was flash chromatographed on silica gel using a mixture of toluene and acetone (9: 1 by volume) as the eluent to give the title compound 1j (0.65 g).
TLC on Kieselgel F254 plate (Merck), eluent system methylene chloride acetone (90:10 by volume) Rf = 0.4. : HNMR (200 MHz, CDCl 3) s: 1.42 (s, 3H, CH 3); I, 51 (m, 1H, CH (H) -12); 2, β (m, 2H, CH (H) -12) + CH (H) -10); 3.06 (d, J = 19.6Hz, 1H, CH (H) -10); 3.21 3.79 (two doublets, J = 12.9Hz, 2H, N- CH2Ph); 4.08 (s, 3H, 4-OCH3); 4.20 (m, 1H, H-9); 4.34 (d, J = 7.2 Hz, 1H, H-7); 7.1-7.3 (m-5H, phenyl hydrogens); 7.37 (dd, J = 1.0, 8.8Hz, 1H, H-3); 7.76 (dd, J = 7.7, 8.8 Hz, 1H, H-2), 8.02 (dd, J = 1.0, 7.7 Hz, H-1); 13.24, 13.51 (2xs, 2H, OH-6 + OH-11).
Example 11: Preparation of 8-N- (3,4-dimethoxybenzyl) -13-dihydro-anthrazalone (lk)
8-N- (3, -dimethoxybenzyl) anthrazalone (500 mg, 1.1 mmol) was dissolved under argon in THF 820 ml) and added, 13 g, 4.4MgBr2.OEt2 (1.13 g, 4.4 mmoles) under agitation. The mixture was cooled to -50 ° C and NaBH 4 (84 mg, 2.2 g.
mmoles) in small portions for 10 minutes. Methanol (2 ml) was added and the reaction mixture was stirred for an additional hour. Acetone (2 ml) was added and poured into a solution of oxalic acid in cooled water (100 mg in 100 ml of water) and extracted with methylene chloride. The organic phase was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the raw material chromatographed instantaneously on silica gel using a mixture of methylene chloride, methanol, acetic acid (30: 2: 1 by volume) as the eluent system to give 320 mg of a product of a only isomer. TLC on Kieslgel plate F2s4 (Merck), eluent system methylene chloride, methanol, acetic acid (30: 2: 1 by volume) Rf = 0.5.
FAB-MS (+): m / z 532 [MH] +: 382 [M-CH2C6H3 (OCH3) 2 + 2H] +; XHNMR (ßOO MHz, DMSO-d6) s: 1.57 (m, 1H, H-8); l, 70 (s, 3H, CH 3); 2.74 (m, 1H, H-8); 2.98 (d, 1H, J = 19, OHz, H-10); 3.40 (d, 1H, J = 19, OHz, H-10);
3.64 (s, 3H, OCH3); 3.74 (s, 3H, OCH3); 3.84 (m, CH (H) -Ph);
3.99 (s, 3H, OCH3); 4.33 (m, 1H, H-9); 4.42, (m, 1H, CH (H) -Ph); 4.53 (m, 1H, H-7); 5.95 (s, 1H, OH-9);
6.77 (m 1H, aromatic hydrogen); 6.92 (m, 1H, aromatic hydrogen); 6.94 (m, 1H, aromatic hydrogen); 7.69 (m,
1H, aromatic hydrogen); 7.94 (m, 2H, aromatic hydrogen); 11.09 (broad signal, 1H, NH +); 13.03 (s, 1H,
OH), 13.56 (s, 1H, OH).
Example 12: Preparation of 8-N- (pyridinmethyl) -13-anthrazalone oxime
(eleven)
8-N- (pyridinmethyl) -13-anthrazalone (le, 210 mg, 0.5 mmol) was dissolved in EtOH (10 ml) and treated with hydroxylamine hydrochloride (59.5 mg, 08.85 mmol) and hydroxylamine trihydrate. Sodium acetate (66 mg, 0.5 mmol) dissolved in 0.25 ml of water. The reaction mixture was refluxed for two hours under stirring, poured into water and extracted with methylene chloride. The organic phase was separated, washed with water and dried over anhydrous sodium sulfate.
The solvent was removed under reduced pressure and the crude material was flash chromatographed on silica gel using a mixture of methylene chloride and acetone (8: 2 by volume) as the eluent to give 120 mg of the oximes mixture.
TLC: Kieselgel F254 plate (Merck), eluent system methylene chloride and acetone (8: 2 by volume), Rf = 0.44 and 0.36.
FAB-MS (+): m / z 486 [MH] +; 3 m / z 470 [M + H-0] +; m / z 468 [M + H-H20] +
XHNMR (400 MHz, DMSO-d6) s: 1.40 (s, 3H, OCH3), 2.52 (d, 1H, J = 17.2Hz, H-8a), 2.57 (d, lH, 1H , J = 18.8Hz, H-10); 2.89 (dd, 1H, J = 17.2 and 6.8Hz, H-8β); 2.97 (d, 1H, J = 18.8 Hz, H-10); 3.63 (D, 1H, J = 18, OHz, CH (H) -Ph), 3.96 (s, 3H, CH3); 4.22 (d, 1H, J = 18, OHz, CH (H) -Ph); 4.52 (d, 1H, J = 6.8Hz, H-7); 7.65 (dd, -1H, J = 6.8 and 2.9 Hz, H-3), 7.91 (m, 2H, H-1 + H-2); 7.95 (m, 2H, H-3 '+ H-5'); 8.78 (m, 2H, H-2 '+ H-6'); 10.77 (s, 1H, = N-OH), 13.09 (s, lH, OH), 13.53 (s, 1H, OH)
Biological test
The anthrazalinone derivatives of formula 1 interfere with the self-aggregating activity of fragment 25-35 of the β-amyloid substance and fragment 106-126 of PrP using light scattering analysis.
The ß25-35 fragment (GSNKGAIIGLH) and PrP 106-126 (KTNMKHMAGAAAAGAVVGGLG) were synthesized using solid phase chemistry by an Applied Biosystems Instruments 430a apparatus and purified by reverse phase HPLC.
(Beckman Inst., Mod 243) according to Forloni et al., Nature 362: 543, 1993.
The light scattering of the peptide solutions was elevated by spectrofluorometry (Perkin Elmer LS 50B), excitation and emission were monitored at 600 nm.
The fragment 25-35 of β-amyloid substance and PrP 106-126 were dissolved at a concentration of 0.5 to 1 mg / ml (0.4-0.8 mM and 0.2-0.4 mm respectively) in a buffer solution of phosphate pH 5, 10 mM were added spontaneously in the interval of one hour.
8-N-pyridinmethylene-anthrazalone (le), dissolved in various concentrations (0.2-2 mM) in 5 mM Tris buffer pH 7.4, was added to the peptide solutions at the time of its preparation to evaluate the fibrilogenesis process.
The compound, added at an equimolar concentration with fragment 25-35 of the β-amyloid substance and Prp 106-126, showed that it completely avoided aggregation.
Thioflavin T assay
Aβ25-35 peptide A stock solutions were prepared by dissolving the lyophilized peptide in
dimethylsulfoxide (DMSO) at a concentration of 7.07 mg / ml.
Aliquots of this solution were dissolved in 50 mM phosphate buffer solution 5 so as to obtain a final peptide concentration of 100 mM and incubated for 24 hours at 25 ° C with or without 30 mM test compound in final volume of 113 ml . The compounds were previously dissolved in DMSO at a concentration of 3.39 mM; the final percentage of DMSO (v / v) in the incubation mixtures was less than 3%.
Fluorescence measurements were performed as described by Naiki et al., In Anal. Biochem. 177, 244., 1989, and H. LeVine III, in Protein Sci, 2,404, 1993. Briefly, the incubated samples were diluted to a peptide concentration of 8 mg / ml in 50 mM sodium citrate buffer solution pH 5 containing 47mM Thioflavin T (ThT) in a final volume of 1.5 ml. Fluorescence was measured with excitation at 420 nm and emission at 490 nm in a Kontron fluorescence spectrophotometer and the values were averaged after subtracting the background fluorescence of 47 mM ThT.
The results are expressed as relative fluorescence i.e., the percentage of the fluorescence of Aβ25-35 peptide incubated alone (control). Table 1 reports the results of some of the compounds.
COMPOSITE RELATIVE FLUORESCENCE __ 40.26 le 6.82 lk 15.70 11 1.99
It is noted that in relation to this date, the best known method for carrying out the invention by the Applicant, is that which is clear from the present description of the invention.
Having described the invention as above, the content of the following is claimed as property
Claims (14)
- A compound of formula I characterized in that: Xi and X2 are independently selected from: C = 0, C = NH, and CH2, X3 is selected from: CH2, c = or CHOH, O8"'- where n = 2 or 3, and C = N (R5) wherein R9 is hydroxy or amino-aryl R, R3 and R4 are independently selected from: hydrogen, hydroxyl, C? _6 alkyl, C16 alkoxy, C3.8 cycloalkoxy, halogen, amino it may be unsubstituted or mono- or disubstituted by acyl, trifluoroacyl, aralkyl or aryl groups, and 0S02 (Rio) wherein Rio is alkyl or aryl; R5 and R8 are independently selected from: hydrogen, hydroxyl, C? -? S alkoxy, halogen, amino which may be unsubstituted or mono-or-di-substituted by acyl, trifluoroacyl, aralkyl or aryl groups, and OS02 (Rio) where Rio is as defined above; R6 is selected from: hydrogen, R3-CH2 ~ wherein RB represents an aryl or heterocyclyl group or a group of formula RC-CH = -CH-, wherein Rc is hydrogen or C1-5 alkyl, C C-α6-alkenino C2-s cycloalkyl C3-8 acyl alkyl of formula -C (Ru) = 0 wherein Rn is selected from: C alquilo-β6 alkyl, C3-8 cycloalkyl hydroxyalkyl, heterocyclyl, aryloxyalkyl, acyloxyalkyl and a residue of a naturally occurring amino acid or a synthetic amino acid or a residue of a di- or tri-peptide: and R7 is selected from the group: hydrogen, methyl, CH2OH, CH20-R? 2 wherein R? 2 is the tetrahydropyranyl group (THP), or a saccharide of the formula: wherein Ri3 is amino or aminoacyl, R4 and R15 are both hydrogen or one of R14 or R15 is hydrogen and the other of Ri4 or R15 is hydroxy or alkoxy or halogen or group OS02 (Rio) as defined above, CH2 -0-Ph- (amino) where the amino can be unsubstituted or mono- or di-substituted by an alkyl, acyl, trifluoroacyl, aralkyl or aryl group; and CH2-amino wherein the amino is mono-or-di-substituted by an alkyl, acyl, trifluoroacyl, aralkyl or aryl group or the amino is within a heterocyclic ring optionally substituted with C1-16 alkyl or C16 alkyloxy? 6 or aryloxy, or an acceptable pharmaceutical salt thereof.
- 2. A compound according to claim 1, characterized in that: Xi and X2 are independently selected from: C = 0, and C = NH; X3 is selected from: CH2, C = 0, CHOH, and C = N (Rg) wherein Rg is hydroxy or amino-aryl, Ri, R2, R3 and R4 are independently selected from: hydrogen, hydroxyl, C1-4 alkoxy , C3_8 cycloalkoxy, O-mesyl (0-S02CH3), amino and amino-benzyl; R5 and R8 are independently selected from: hydrogen, hydroxyl, C 1 -4 alkoxy, halogen, amino, and amino-benzyl R 5 and R 8 are independently selected from: hydrogen, hydroxyl, C? -4 alkoxy, halogen, amino amino-benzyl and amino-trifluoroacetyl; R6 is selected from hydrogen RB-CH2, wherein RB is as defined in claim 1, Ci-io alkyl, C-6 alkenyl, acyl of formula -C (Rn) = 0 wherein Ru is selected from the group consisting of: C? -? o alkyl, hydroxyalkyl, heterocyclyl, aryl araloxyalkyl, acyloxyalkyl and a residue of a naturally occurring or synthetic amino acid or a residue of a di-o-tri-peptide and R7 is selected from: hydrogen, methyl CH2OH, CH2? -R? 2 where R? 2 is the tetrahydropyranyl group (THP) ), or saccharide of the formula: wherein Ri3 is amino or aminotrifluoroacetyl or aminoacetyl, Ris is hydrogen and Ri is hydroxy or iodo or 0-mesyl, CH2-0-Ph-NH-COR wherein R is alkyl, arachyl or aryl, CH2 amino, wherein the amino is within a heterocyclic ring optionally substituted with Ci-io alkyl or C?-5 alkyloxy or aryloxy; or a pharmaceutically acceptable salt thereof.
- 3. A compound according to claim 1, characterized in that: Xi and X2 are independently selected from: C = 0, and C = NH; X3 is selected from: CH2, C = 0, and isoleucyl and R7 is selected from: hydrogen, methyl, CH2OH, CH2O-R12, wherein RX2 is the tetrahydropyranyl group (THP), or a saccharide of formula: wherein Ri3 is amino or aminotrifluoroacetyl or aminoacetyl, R15 is hydrogen and R14 is iodo and CH2-amino, wherein the amino is within a morpholino ring; or a pharmaceutically acceptable salt thereof.
- 4. A compound according to claim 1, characterized in that: Xi and X2 are both C = 0 X3 is C = 0; Ri, R2 and R3 are each hydrogen and R is hydrogen, hydroxy or methoxy; Re and R8 are independently selected from hydrogen, hydroxyl, methoxy and amino; Rβ is selected from hydrogen, pyridinmethyl, (n-methyl-dihydropyridine) -methyl, nicotyl, glycyl and isoleucyl; Y CHOH, Ri / R2, R3 and R4 are independently selected from: hydrogen, hydroxyl, methyl, methoxy, O-mesylate, amino, amino-benzyl, fluorine and chlorine Rs and R8 are independently selected from: hydrogen, hydroxyl, methoxy, ethoxy , amino and amino-trifluoroacetyl R6 is selected from: hydrogen benzyl, allyl, 3,4-dimethoxybenzyl, pyridinmethyl, (N-methyl-dihydropyridine) -methyl, nicotyl, glycyl; and R7 is methyl, or a pharmaceutically acceptable salt thereof.
- 5. A process for producing a compound of formula I, according to claim 1, characterized in that it comprises: (a) reacting a compound of formula 2: wherein Xi, X2 and R to R7 are as defined in claim 1, and represent a leaving group, with an amine of the formula: HN-CH2-RB wherein RB is as defined in claim 1, to give a compound of formula I wherein Re is RB-CH2-; (b) if desired, converting the thus obtained compound of the formula (I) into another compound of the formula (I); I (c) if desired, converting the compound of formula (I) to a pharmaceutically acceptable salt thereof.
- 6. A process according to claim 5, characterized in that step (a) is carried out with a 1 to 10 times excess of amine, in an organic solvent for this, in the presence of an organic base for from 6 to 48 hours, from -10 ° C to room temperature.
- 7. A process according to claim 5 or 6, characterized in that, in step (b) the compound of formula (I) wherein Re is RB-CH2- is converted to a compound of formula I wherein Re is hydrogen.
- 8. A process according to claim 7, characterized in that RB is a 3, 4-dimethoxyphenyl or vinyl group and the conversion is carried out by oxidation.
- 9. A process according to claim 8, characterized in that RB is a 3,4-dimethoxyphenyl group and the oxidation is carried out using 2,3-dichloro-5-6-dicyano 1,4-benzoquinone
- 10. A process according to claim 7, characterized in that it further comprises converting the compound of formula (I) wherein R is hydrogen into a compound of formula I wherein R6 is C6-C6 alkyl, C2.8 alkenyl, C3-cycloalkyl 8, an acyl group of formula -C (Ru) = 0, wherein Ru is as defined in claim 1, or a residue of an amino acid or a di- or tripeptide.
- 11. A process according to any of claims 5, 6, 7 or 10, characterized in that step (b) comprises the reduction of a compound of formula (I) wherein X3 is C = 0 to give a compound of formula I, wherein X3 is CHOH or CH2.
- 12. A pharmaceutical composition comprising, as an active ingredient, a compound of formula 1 according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier or diluent.
- 13. A compound of formula 1, according to any of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for use in the treatment of amyloidosis.
- 14. A compound of formula 1, according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for use in the treatment of AL amyloidosis, Alzheimer's disease or Down syndrome.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9516349.9A GB9516349D0 (en) | 1995-08-09 | 1995-08-09 | Aza-anthracyclinone derivatives |
GB9516349.9 | 1995-08-09 |
Publications (2)
Publication Number | Publication Date |
---|---|
MX9801045A MX9801045A (en) | 1998-10-31 |
MXPA98001045A true MXPA98001045A (en) | 1999-01-11 |
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