WO1990008128A1 - Novel prodrug derivatives of biologically active agents containing hydroxyl groups or nh-acidic groups - Google Patents

Novel prodrug derivatives of biologically active agents containing hydroxyl groups or nh-acidic groups Download PDF

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WO1990008128A1
WO1990008128A1 PCT/DK1990/000020 DK9000020W WO9008128A1 WO 1990008128 A1 WO1990008128 A1 WO 1990008128A1 DK 9000020 W DK9000020 W DK 9000020W WO 9008128 A1 WO9008128 A1 WO 9008128A1
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compound
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Hans Bundgaard
Erik Falch
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Hans Bundgaard
Erik Falch
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D263/00Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/38Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
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    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00Carboxylic acid amides
    • C07C233/01Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07C233/16Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/25Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07C235/00Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/06Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06Esters of carbamic acids
    • C07C271/08Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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    • C07D233/66Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72Two oxygen atoms, e.g. hydantoin
    • C07D233/74Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
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    • C07D233/66Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91Nitro radicals
    • C07D233/92Nitro radicals attached in position 4 or 5
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    • C07D285/00Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01Five-membered rings
    • C07D285/02Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/121,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/1251,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135Nitrogen atoms
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    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D473/00Heterocyclic compounds containing purine ring systems
    • C07D473/02Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
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    • C07D473/04Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
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    • C07D473/00Heterocyclic compounds containing purine ring systems
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    • C07D473/18Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
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    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems
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    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08Hetero rings containing eight or more ring members, e.g. erythromycins
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    • C07H19/02Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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    • C07H19/16Purine radicals
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    • C07J1/00Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051Estrane derivatives
    • C07J1/0066Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
    • C07J1/007Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
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    • C07J41/00Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/005Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
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    • C07J43/00Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
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    • C07J5/0046Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0053Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16

Definitions

  • the present invention relates to novel biolabile, in-vitro solution stable and water soluble prodrug forms of drugs containing one or more hydroxyl groups or NH-acidic groups, to methods for preparing the prodrug forms, to pharmaceutical compositions containing such prodrug forms, and to methods for using the prodrug forms.
  • prodrug denotes a derivative of a known and proven prior art compound which derivative, when administered to warm-blooded animals, e.g. humans, is converted into the proven drug.
  • the enzymatic and/or chemical hydrolytic cleavage of the compounds of the present invention occurs in such a manner that the proven drug form (parent hydroxyl-containing or NH-acidic drug) is released, and the moiety or moieties split off remain non-toxic or are metabolized so that non-toxic metabolic products are produced.
  • esters of certain amino acids are characterized by possessing a high water solubility and by combining a high susceptibility to undergo enzymatic hydrolysis in-vivo with a high stability in aqueous solution.
  • esters have been described and used to increase the aqueous solubility of hydroxyl-containing agents, e.g. dicarboxylic acid hemiesters, sulfates, phosphates and aminoalkanoyloxy derivatives.
  • dicarboxylic acid hemiesters e.g. dicarboxylic acid hemiesters, sulfates, phosphates and aminoalkanoyloxy derivatives.
  • their use is not without problems, considering the ideal properties of such prodrugs: They should possess adequate aqueous solubility, sufficient aqueous solution stability to allow long-term storage of ready-to-use solutions and yet they should be converted quantitatively and rapidly in-vivo to the active parent drug.
  • succinate esters are not good substrates for hydrolytic enzymes and often show a slow and incomplete regeneration of the parent drug in-vivo as is the case for such esters of several corticosteroids, chloramphenicol and metronidazole (Nahata & Powell, 1981; Bundgaard, 1985, Larsen et al., 1988). Furthermore, such esters have limited solution stability (Bundgaard, 1985). Other ester derivatives which are readily converted to the active drug in-vivo exhibit, on the other hand, poor solution stability.
  • Such derivatives include, for example, various aliphatic amino acid esters of metronidazole (Bundgaard et al., 1984), corticosteroids (Kawamura et al., 1971; Anderson et al., 1985) and paracetamol (Cognacq, 1977; Higasava et al., 1979).
  • Other derivatives may possess the requisite solubility, stability and biolability, but exhibit other disadvantages.
  • an amine-containing ester prodrug of methylprednisolone apparently fulfilling these requirements was found to cause local toxicity and irritation upon intramuscular or intravenous administration (Anderson et al., 1987).
  • N- ⁇ -acyloxyalkyl prodrug derivatives of NH-acidic drugs increased water solubility has in the past been achieved by incorporating an ionizable acyl group in the ester part such as an amino acid residue.
  • an ionizable acyl group in the ester part such as an amino acid residue.
  • amino- containing N-acyloxymethyl allopurinol prodrugs derived from ⁇ -amino acids have been disclosed in the US Patent 4,694,006.
  • water soluble esters of the formula I below are surprisingly stable in aqueous solution, yet being readily cleaved enzymatically in-vivo, e.g. by plasma enzymes, with release of the parent drug.
  • Yet another object of the present invention is to provide prodrugs of bio-affecting agents containing a hydroxyl group or an NH- acidic function which are capable of making the parent drugs more bioavailable from the site of administration such as the gastrointestinal tract, the rectum, the skin or the eye of the human body.
  • D represents the dehydrogenated residue of a hydroxyl group- containing drug or the dehydrogenated residue of an NH-acidic group- containing drug; the substituents in the phenyl ring and
  • the phenyl ring additionally may be substituted with one, two, three or four substituents selected from the group consisting of an alkyl group, a halogen, a hydroxyl group or an alkoxy group; m is an integer 0 or 1;
  • p is an integer of 0 or 1 ;
  • n is an integer from 1 to 4.
  • R 1 is selected from the group consisting of hydrogen, an alkyl group , an aryl group , an aralkyl group, a group having the formula -COOR 5 , wherein R 5 is an alkyl or aralkyl group, or a carbamoyl group of the formula -CONR 6 R 7 , wherein R 6 and R 7 are the same or different and are hydrogen, an alkyl group, or together with the adjacent nitrogen atom form a 4-, 5-, 6- or 7-membered heterocyclic ring, which in addition to the nitrogen may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;
  • R 2 is hydrogen or an alkyl group
  • R 3 and R 4 are the same or different and are selected from the group consisting of hydrogen, an alkyl group, an aralkyl, an alkenyl group, a cycloalkyl group, in which the alkyl, aralkyl, alkenyl or cycloalkyl group is unsubstituted or substituted with one or more substituents selected from: a hydroxyl group
  • hetero-cyclic ring which in addition to the nitrogen atom may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and which hetero-cyclic ring may be substituted with a hydroxyl group, a carbonyl group, an alkyl group, an alkyl group substituted with a hydroxyl group or an acyloxy group having the formula R 5 COO-, wherein R 5 is as defined above, an alkoxycarbonyl group having the formula -COOR 5 as defined above, or a carbamoyl group of the formula -CONR 6 R 7 as defined above;
  • the dehydrogenated residue of a hydroxyl group-containing drug means the residue attached to the hydroxyl group from which the hydrogen has been removed.
  • the dehydrogenated residue of an NH-acidic group containing drug means the residue attached to the NH-acidic moiety from which the hydrogen has been removed.
  • alkyl designates C 1-8 alkyl which may be straight or branched, such as methyl, ethyl, propyl, isopropyl, butyl, tert. butyl, pentyl, hexyl, heptyl, or octyl.
  • alkenyl designates a C 2-6 -mono-unsaturated aliphatic hydrocarbon group which may be straight or branched, such as propenyl, butenyl or penteny.
  • aryl encompasses aryl radicals such as pehnyl and naphtyl and also the corresponding aryl radicals containing one or more substituents, which may be the same or different, such as alkylthio, alkyl, halogen, alkoxy, aryloxy, nitro, alkanoyl, dialkylamino, alkanoyloxy or hydroxy groups.
  • substituents such as alkylthio, alkyl, halogen, alkoxy, aryloxy, nitro, alkanoyl, dialkylamino, alkanoyloxy or hydroxy groups.
  • cycloalkyl designates a radical containing 4 to 7 carbon atoms, e.g. cyclohexy.
  • aralkyl designates a radical of the type -alkylene-aryl, wherein aryl is as defined above and the alkylene moiety contains 1 to 6 carbon atoms and can be straight or branched-chain, e.g. methylene, and the like.
  • non-toxic pharmaceutically acceptable acid addition salts generally includes the non-toxic acid addition salts of compounds of formula I, formed with non-toxic inorganic or organic acids.
  • the salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulphuric, sulphamic, nitrie, phosphoric acid and the like; and the salts with organic acids such as acetic, propionic, succinic, fumaric, maleic, tartaric, citric, glycolic, lactic, stearic, malic, pamoic, ascorbic, phenylacetic, benzoic, glutamic, salicylic, sulphuric, sulphanilic acid, and the like.
  • the quaternary ammonium derivatives of the compounds of the present invention may be represented by formula I wherein the terminal amino group is substituted by an additional group as depicted below
  • R 3 and R 4 alone or taken together with the nitrogen atom to which each is attached have the meanings defined above;
  • R 8 is a lower alkyl group of from 1 to 4 carbon atoms, preferably methyl or ethyl;
  • X' represents an anion, e.g. X is I, Br, Cl, CH 3 SO 3 or CH 3 COO.
  • an NH-acidic function, group or moiety is defined as a structure with the formula -NH-CO- or -NH-SO 2 - or as a heterocyclic nitrogen structure. Examples of NH-acidic structures encompassed within the present invention include the following: Secondary carboxamides
  • Such structures may contain more than one NH-acidic function.
  • the uracil ring contains two NH-acidic funtions.
  • prodrug derivatives formed at both NH-acidic functions are also part of the present invention.
  • ADTN 2-Amino-6,7-dihydroxytetrahydronaphthalene
  • D in formula I is derived from one
  • a most important characteristic of the novel prodrug derivatives of the formula I is their combination of high water solubility, high stablity in aqueous solution at pH values affording the high water solubility (i.e., weakly acidic pH values) and facile enzymatic cleavage in the body with quantitative release of the parent drug.
  • novel compounds of the present invention make them particularly suitable for administration as sterile aqueous solutions by intravenous injection, intravenous infusion, or intramuscular or subcutaneous injection, or for topical administration to the eye.
  • the prodrugs of this invention are also highly useful for peroral administration, e.g. to improve the bioavailability of slightly water soluble parent drugs containing a hydroxyl group or an NH-acidic group.
  • the solubility and stability charateristics of the novel prodrugs make them highly suitable for rectal or dermal administration.
  • the lipophilicity of the prodrug derivatives of the formula I can be readily modified or controlled by the appropriate selection of the amino group (-NR 3 R 4 in formula I) in the compounds both in terms of amine basicity, and hence degree of ionization at physiological pH values, and in terms of hydrophobicity of the substituents (R 3 and R 4 ) on the nitrogen atom.
  • prodrug derivatives of the formula I which through a combination of improved water solubility and lipophilicity are capable of providing increased biomembrane transport so that the parent drugs are more bioavailable from the site of administra-tion such as the gastro-intestinal tract, the rectum, the skin or the eye of the human body.
  • the prodrug derivatization of the present invention makes it feasible to protect the phenolic group in the parent drug against metabolic inactivation processes during or following e.g. peroral or rectal absorption.
  • the prodrug compounds of formula I of the present invention can be used to treat any condition for which the parent hydroxyl or NH-acidic group containing drug, medicament or pharmaceutical is useful.
  • the ester prodrug can be used for any condition or treatment for which metronidazole would be administered.
  • the prodrug compounds of formula I may be administered orally, topically, parenterally, rectally or by inhalation spray in dosage forms or formulations containing conventional, non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • the formulation and preparation of any of this broad spectrum of dosage forms into which the subject prodrugs can be disposed is well-known to those skilled in the art of pharmaceutical for-mulation. Specific information can, however, be found in the text entitled "Remington' s Pharmaceutical Sciences” , Sixteenth Edition, 1980.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous suspensions, or solutions, dispersible powders og granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide a pharmaceutically elegant and palatable preparation.
  • Formulations for oral use include tablets which contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium chloride, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, potato starch, or algi-nic acid, binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations 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 as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin, or olive oil.
  • typical dosage forms include suppositories, rectal gelatin capsules (solutions and suspensions), and enemas or micro-enemas (solutions and suspensions).
  • any one of the compounds of this invention is combined with any pharmaceutically acceptable suppository base such as cocoa butter, esterified fatty acids (C 10 -C 18 ), glycerinated gelatin, and various water-soluble or dispersible bases like polyethylene glycols and polyoxyethylene sorbitan fatty acid esters.
  • Various additives like salycilates or surfactant materials may be incorporated.
  • Enemas or micro-enemas of the solution type may simply be prepared by dissolving the water-soluble prodrugs of this invention in water or in water containing e.g. 0.5% methylcellulose or another viscosity-in-creasing agent.
  • creams, ointments, gels, solutions or the like containing the prodrugs are employed according to methods recognized in the art.
  • Sterile aqueous solutions of the compounds of Formula I for parenteral administration or ophthalmic use typically will contain other components such as preservatives, anti-oxidants, chelating agents, buffer substances, or other stabilizers.
  • therapeutic dosage range for the compounds of the present invention will vary with the size and needs of the patient and the particular pain or disease symptom being treated. However, generally speaking, the following dosage guide-lines will suffice.
  • the therapeutic dose required for a compound of the present invention will generally, on a molecular basis, mimic that for the parent hydroxyl- or NH-acidic drug.
  • application of an 0.01% to 5% concentration of a compound of the present invention (in a suitable topical carrier material) to the affected site should suffice.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration to humans may contain from 5 mg to 5 g of the active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total composition.
  • Other dosage forms such as ophthalmic dosage forms contain less active ingredient such as for example from 0.1 mg to 5 mg.
  • Dosage unit forms will generally contain between from about 0.1 mg to about 500 mg of active ingredient. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors
  • the compounds of the present invention may be prepared by various means, and it will be apparent from the following that the aminecontaining ester moiety attached to the OH-group of the parent OH- containing drug or to the -CHOH
  • I group of the parent NH-acidic drug may be introduced by reaction with an appropriate starting material amino acid which provides the entire moiety, or said ester moiety may be introduced by a sequence of two or more reactions.
  • One method for preparing compounds of the formula I comprises reacting the OH-containing drug of the formula A
  • R 3 and R 4 are as defined above.
  • leaving groups Y may be mentioned chlorine, bromide and iodine.
  • Group Y may also be an acyloxy group, i.e. the reacting compound of formula C may be an anhydride or a mixed anhydride.
  • a dehydrating agent e.g. a carbodiimide
  • a sulfonic acid or '4- (N,N-dimethylamino)pyridine is added as a catalyst.
  • reaction utilizing compound C in which Y is hydroxy is conveniently carried out in an inert solvent such as dichloromethane, dioxane, pyridine, N,N-dimethylformamide or the like, at a temperature of from -10oC to 60oC, for from 1 to 72 h.
  • an acid halogenide starting material e.g.
  • Y in formula C is chlorine
  • the process leading to compounds of formula D can be conveniently carried out in an inert solvent such as benzene, dichloromethane, acetone, N,N- dimethylformamide, dioxane, acetonitrile or the like, at from -10C° to reflux temperature, for from 1 to 24 h, in the presence of an acid scavenger such as an alkali metal carbonate, or an organic base such as triethylamine or pyridine.
  • an inert solvent such as benzene, dichloromethane, acetone, N,N- dimethylformamide, dioxane, acetonitrile or the like
  • Br and Y is OH, Cl or Br and methods for preparing them are known from the literature, see e.g. Singhe & Lilienfeld (1943); Smith & Menger (1969); Day & Gohil (1976).
  • the process of reacting a compound of formula D with an amine of formula E can be conveniently carried out in the absence of a solvent or in an inert solvent such as acetone, acetonitrile, tetrahydro furan, ethanol, dichloromethane, N,N-dimethylformamIde, or the like, at from -10C° to reflux temperature, for from 1 to 72 h.
  • Z in a reacting compound of formula D is chlorine
  • sodium iodide may be added as a catalyst to the reaction mixture.
  • Another method (method B) for preparing compounds of formula I comprises reacting a compound of formula A or B with a compound having the formula F
  • R 3 or R 4 is hydrogen
  • the reaction may preferably be carried out by using a compound of formula F in which the amino group is suitably protected with a protecting group such as a carbobenzoxycarbonyl or a tert-butyloxycarbonyl group.
  • a protecting group such as a carbobenzoxycarbonyl or a tert-butyloxycarbonyl group.
  • Deprotection is subsequently performed by known methods, e.g. by hydrogenation or hydrolysis.
  • the reaction is performed under the same conditions as those used to prepare compounds of formula D.
  • Z is as defined above, with a compound of formula J wherein n, R 2 , R 3 and R4 are as defined above and N + is a counter ion such as Na + , K + , Ag + or trialkylammonium.
  • the reaction can be conveniently carried out in an inert solvent such as ethyl acetate, acetone, dimethylformamide or the like, at from room temperature to reflux, for from 0.5 to 48 h. If Z in formula G and H is chlorine, sodium iodide may be added as a catalyst to the reaction mixture.
  • the starting materials of formula B may be prepared by reacting the NH-acidic drug with an aldehyde, preferably formaldehyde, of formula K
  • N- ⁇ -hydroxyalkyl or N-hydroxymethyl derivatives of formula B and methods for their preparation are known in the literature, e.g. for allopurinol (Bansal et al., 1981 b; Bundgaard & Falch, 1987); phenytoin and other hydantoins (Zejc, 1968; Bundgaard & Johansen, 1980); 5-fluorouracil (Buur et al., 1986; Ahmad et al., 1987); benzimidazoles (Hideg & Hanskovsky, 1967; Varma et al., 1980); chlorzoxazone (Varma & Nobles, 1968), theophylline (Bodor & Sloan, 1977); various imides (Vail & Pierce, 1972; Buc, 1947); mitindomide (Deutsch et al., 1986; Haugwitz et al., 1987); barbituric acids (Bansal et al., 1981 b); urac
  • An alternative method (method D) for preparing compounds of the formula I, wherein m - 1, comprises reacting a parent NH-acidic drug with a compound of the formula L.
  • R 1 , R 2 , p, n and Z are as defined above, and then reacting the resultant compound of formula D with an amine of the formula E as described above.
  • Compounds of formula L are prepared by known means e.g. by the procedures described by Bigler et al. (1978), Waranis & Sloan (1987), Binderup & Hansen (1984), Barcelo et al. (1986) and Senet et al. (1988).
  • n, R 2 , R 3 and R 4 are as defined above. If either R 3 or R 4 is hydrogen, the reaction is preferably carried out by using a compound of formula 0 in which the amino group is suitably protected such as described above.
  • Compounds of formula M and N may conveniently be prepared by treating compounds of formula A and B, respectively, with phosgene or a phosgene-releasing agent.
  • the basic methods described above can be used to prepare any of the compounds of the invention, certain con-ditions and/or modifications therein are made in specific instances.
  • the basic methods may be modified in the cases where the parent drug contains a free primary or secondary amino group. In such cases, it is preferable to block this amino group before reacting the parent compound as described above.
  • the protected ester prodrug thus obtained is then deprotected by known methods, e.g. by
  • the quaternary ammonium salts of the compounds of formula I are formed by reacting said compounds with a suitable alkylating agent such as dimethyl sulphate, diethyl sulphate, methyl bromide, methyl iodide or ethyl iodide.
  • a suitable alkylating agent such as dimethyl sulphate, diethyl sulphate, methyl bromide, methyl iodide or ethyl iodide.
  • the compound was prepared from hydrocortisone 21-(3-chloromethyl)-benzoate and imidazole by essentially the same procedure as described in Example 3. After recrystallization from ethanol-water, the yield was 80%. Mp 203-205°C (dec).
  • hydrocortisone 21- (3-chloromethyl)benzoate (2.67 g, 5 mmol), sodium iodide (0.75 g, 5 mmol) and 1-methylpiperazine (5.0 ml, 45 mmol) in 50 ml of acetone was stirred at 60°C for 5 h. Upon cooling to room temperature, the mixture was filtered and evaporated in vacuo. The residue obtained was slurried with 90% ethanol (10 ml) and the precipitate filtered off. Recrystallization from ethanol afforded 2.0 g of the title compound as the monohydrate. Mp 173-175°C.
  • a dihydrochloride salt was prepared by dissolving 1 g of the free base in a mixture of hot ethanol (40 ml) and acetone (10 ml) and adding an excess of 2.5 M methanolic HCl following by the addition of ether. Upon standing at 4°C overnight the precipitate formed was filtered off and re-crystallized from methanol to give 0.85 g of the title compound as the dihydrochloride. Mp 235-236°C (dec).
  • the compound was prepared from prednisolone 21-(3-chloromethyl)benzoate and 1-methylpiperazine by essentially the same procedure as described in Example 5. After recrystallization from methanol-ether, the yield was 77%.
  • the dihydrochloride salt was obtained as described in Example 10 , mp 212-215°C(dec).
  • Methylprednisolone 21- [3- (N-methyl-N- [2-dimethylaminoethyl]-aminomethyl)] benzoate, dihydrochloride
  • the compound was prepared from methylprednisolone 21-(3-chloromethyl)benzoate and N,N,N' -trimethylethylenediamine by essentially the same procedure as described in Example 6. After recrystallization from acetonitrile-ether, the yield was 81%.
  • the compound was prepared from 7-(3-chloromethyl-benzoyloxymethyl)- theophylline and imidazole by essentially the same procedure as described in Example 23. After recrystallization from ethanol-water, the yield was 71%.
  • the hydrochloride salt was formed with HCl in methanol-ether. Mp 211-212°C (dec).
  • Phenyl 3-[4-methylpiperazin-1-yl)methyl]benzoate, dihydrochloride The compound was prepared from phenyl 3-chloromethyl-benzoate and 1-methylpiperazine by essentially the same procedure as described in Example 28. After recrystallization from methanol, the yield was 75%. Mp 259-261°C.
  • the compund was prepared from ⁇ -estradiol 3-(3-chloro-methylbenzoate and 1-methylpiperazine by essentially the same procedure as described in Example 31. After recrystallization from ethanol-ether, the yield was 55%. Mp 254-255°C.
  • Pregnanolone 3- (3-N,N-diethylaminomethyl)benzoate, hydrochloride
  • a mixture of pregnanolone 3-(3-chloromethyl)benzoate (471 mg, 1 mmol), sodium iodide (150 mg, 1 mmol), diethylamine (0.83 ml, 8 mmol) and 10 ml of acetone was stirred at 60°C for 6 h. It was cooled to 25°C, filtered and evaporated in vacuo. The residue obtained was taken up in ethyl acetate (50 ml) and the solution washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo.
  • pregnanolone 3-(3-chloromethyl) -benzoate was prepared from pregnalonone (pregnan-3 ⁇ -ol-20-one) and 3-chloromethylbenzoyl chloride by essentially the same procedure as described in
  • the compound was prepared from pregnanolone 3-(3-chloromethyl)benzoate and 1-methylpiperazine by essentially the same procedure as described in Example 35. After recrystallization from ethanol-ether, the yield was 67%.
  • the compound was prepared from 3-(3-chloromethyl-benzoyloxymethyl)phenytoin and 1-methylpiperazine by essentially the same procedure as described in Example 34.
  • the compound was prepared from N-(3-chloromethyl-benzoyloxymethyl)chlorzoxazone and 1-methylpiperazine by essentially the same procedure as described In Example 19. After recrystallization from methanol, the yield was 70%.
  • the compound was prepared by a method analogous to that described in Example 41, starting from 2.57 g (15 mmol) of metronidazole and 4-chloromethylbenzoyl chloride (15 mmol).
  • the crude product was purified by flash chromatography on silica gel (eluent: toluene containing ethyl acetate). Yield (from cyclohexane) : 3.01 g (62%). Mp 112-115°C.
  • Metronidazole 3-dimethylaminomethylbenzoate The compound was prepared by a method analogous to that described in Example 43, from metronidazole 3-chloromethyl-benzoate (456 mg, 1.5 mmol), dimethylamlne (0.82 ml of a 33% solution in ethanol, 6 mmol), sodium iodide (20 mg) and ace-tone (20 ml). Treatment of the title compound with fumaric acid yielded the salt with 1.5 equivalent fumaric acid which crystallized from 2-propanol-ether with 0.25 mole of water: Mp 141-143°C.
  • the compound was prepared by a method analogous to that described in Example 43.
  • the title compound was recrystallized from etherpetroleum. Mp 73-74°C.
  • the compound was prepared by a method analogous to that described in Example 47.
  • the yield of the difumarate of the title compound was 52%.
  • the compound was prepared from metronidazole 4-dimethylaminomethylbenzoate (60 mg, 0.18 mmol) by the method described above in Example 53. Yield: 76 mg. Mp 203-206°C (dec.)
  • the title compound was also prepared by the following method: A mixture of 1-(hydroxymethyl)allopurinol (448 mg, 3 mmol), 4-morpholinomethylbenzoic acid hydrochloride (771 mg, 3 mmol), N,N'-dicyclohexylcarbodiimide (618 mg, 3 mmol) , p-toluene-sulfonic acid (40 mg) and pyridine (10 ml) was stirred at room temperature for 20 h. Methylene chloride (20 ml) was added to the reaction mixture. After stirring for 2 h the mixture was filtered, and the filtrate evaporated in vacuo.
  • the hydrochloride was prepared by adding a solution of hydrochloric acid in ethyl acetate to a solution of the base in ethanol.
  • the precipitate was shown to be identical (IR-spectrum, mp and TLC) to the compounds prepared by the two other methods above.
  • the compound was prepared from 1-(3-chloromethylbenzoyl-oxymethyl)allopurinol (1.5 mmol) and 1-methylpiperazine (6 mmol) by essentially the same procedure as described in Example 57.
  • the compound crystallized from ethyl acetate with 2/3 mol of ethyl acetate. The yield was 46%. Mp 129-131°C.
  • the compound was prepared from 1-(4-chloromethylbenzoyl-oxymethyl)allopurinol (3 mmol) and 1-methylpiperazine (12 mmol) by essentially the same procedure as described in Example 57.
  • the compound was crystallized from 2-propanol-ethyl acetate. The yield was 29%.
  • the compound was prepared from aciclovir and 4-dimethylaminomethylbenzoyl chloride hydrochloride by the method described above in Example 63. Yield: 75%. Mp 185-186oC (from ethanol-water).
  • the compound was prepared from aciclovir and 3-di ⁇ ropylaminomethyl benzoyl chloride hydrochloride by the method described in Example 63. Yield: 79%. Mp 195-197°C (from ethanol-water).
  • the compound was prepared from ganciclovir and 4-diethylaminomethylbenzoyl chloride hydrochloride by the method described in Example 66. Yield: 65%. Mp 150-152°C.
  • the hydrochloride salt of the title compound was prepared as follows : To a solution of the title compound (490 mg, 1 mmol) in acetone (30 ml) was added 0.5 ml of a 2.5 M methanolic HCl solution. The solution was evaporated in vacuo and the residue obtained recrystallized from ethanol (about 30 ml) with the addition of two drops of water. Mp 247-249°C.
  • the compound was prepared from 1 , 3-dipropyl-8-(p-hydroxyphenyl)xanthine and 3(N,N-dipropylaminomethyl)benzoyl chloride hydrochloride by the method described above in Example 69. Yield: 73%. Mp 194-195°C (from N,N-dimethylformamide-ethanol).
  • BIOCONVERSION OF THE PRODRUGS To demonstrate the bioconversion of the compounds of formula I to the parent drug in plasma, samples of human plasma were diluted to 80% with 0.05 M phosphate buffer (pH 7.4) and warmed to 37°C in a water bath. Aliquots of 100 ⁇ l of aqueous or ethanolie solutions of the prodrug derivatives were added to 5.00 ml of the plasma samples , the initial concentration of the derivatives being about 10 -4 M. At various times aliquots of 250 ⁇ l of the solutions were withdrawn and deproteinized by mixing with methanol, acetonitrile or a 1% ZnSO 4 solution (methanol-water 1:1). After centrifugation, the clear supernatant was analyzed by HPLC for remaining derivative as well as for parent drug .
  • phosphate buffer pH 7.4
  • the various prodrug derivatives were found to be cleaved quantitatively to the parent drugs in human plasma solutions.
  • An example is shown in Fig. 1.
  • the cleavage of the derivatives displayed strict first-order kinetics.
  • An example is shown in Fig. 2.
  • the half-lives of hydrolysis of various derivatives in 80% human plasma solutions at 37°C are given in Table 1 and 2. As can be seen from the data thederivatives are readily converted to the parent drugs at conditions similar to those prevailing in-vivo.
  • novel compounds of the present invention were found to exhibit at very high stability in aqueous solutions of pH 3-5, thus affording long term storage af solutions of said novel compounds.
  • the stability of the compounds was assessed by keeping aqueous buffer solutions of the compounds at constant temperatures and analyze the solutions for intact prodrug derivative as well as parent drug formed by the HPLC methods mentioned above.
  • the pH of the solution was found to have a marked impact on the stability as seen from the pH-rate profile for a hydrocortisone prodrug in Fig. 3.
  • Maximal stability for the compounds of the present invention generally occurs in the pH-range 3-5 at which pH values high solubilities of the compounds also are achieved due to protonation of their amino function(s) .
  • shelf-lives in excess of two years at 25°C were predicted.
  • the hydrocortisone prodrug the pH-rate for degradation of which is shown in Fig. 3 was to possess a shelf-life in aqueous solutions of pH 4.0 of 6.0 and 10.2 years at 25 and 20°C, respectively.
  • the stability or shelf-life of solutions of compounds of the present invention can be prolonged by decreasing the storage temperature, e.g. to temperatures from 4 to 20oC.
  • a remarkable feature of the compounds of the present invention with regard to providing highly stable aqueous solutions is the solubilizing capacity of the compounds for their parent drugs.
  • the solubility of hydro-cortisone in water is 0.40 mg/ml at 21°C
  • the solubility was found to be increased to 3.5 mg/ml in a 10% w/v solution of the prodrug hydrocortisone 21-[3-(4-methylpiperazin-1-ylmethyl)]benzoate dihydrochloride.
  • This unexpected behaviour greatly prolongs the shelf-life of aqueous prodrug solutions in cases where the shelf-life is limited by precipitation of parent drug formed upon hydrolysis rather than loss in prodrug.
  • the compounds of Formula I exhibit the highest stability in water when pH of their solution is maintained in the range 3-5.
  • buffers can be employed to maintain the pH at or near the desired level throughout the shelf-life of the formulation.
  • Suitable buffers are those which are physiologically acceptable and exhibit sufficient buffer capacity in the pH range 3-5, e.g. acetate, citrate, succinate or phthalate buffers.
  • the quantity of buffer used is determined by means known in the art and will depend on the pH desired, the concentration of the solution, and the buffering capacity of the buffer.
  • the amine-containing prodrugs of this invention were found to be highly soluble in water when present in salt forms. Solubilities of hydrochloride or fumarate salts were generally found to exceed 15% w/v. The solubilities were assessed by rotating mixtures of excess amounts of the compounds in water for 24-28 h and analyzing an aliquot of the filtered saturated solutions for prodrug derivative by HPLC. The lipophilicity of the derivatives of the present invention was assessed by measuring the apparent partition coefficients (P) of the compounds between octanol and 0.02M phosphate buffer of pH 7.4. The log P values for some compounds of the present invention are shown in Table 3.

Abstract

Compounds of formula (I), wherein D represents the dehydrogenated residue of a hydroxyl group-containing drug or the dehydrogenated residue of an NH-acidic group-containing drug; the substituents in the phenyl ring α and β are in either meta- or para-position to each other; and the phenyl ring additionally may be substituted; m is an integer of 0 or 1; p is an integer of 0 or 1; n is an integer from 1 to 4; R1 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, a group having the formula -COOR5, wherein R5 is an alkyl or aralkyl group, or a carbamoyl group of the formula -CONR6R7, wherein R6 and R7 are the same or different and are hydrogen, an alkyl group, or together with the adjacent nitrogen atom form a 4-, 5-, 6-, or 7-membered heterocyclic ring; R2 is hydrogen or an alkyl group; R3 and R4 are the same or different and are hydrogen, or optionally substituted alkyl, aralkyl, alkenyl or cycloalkyl; or R3 and R4 are combined so that -NR3R4 forms an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring, which in addition to the nitrogen atom may contain one or two further heteroatoms selected from nitrogen, oxygen, and sulfur; with the proviso that m is 0 when D represents the dehydrogenated residue of a hydroxyl group-containing drug and m is 1 when D represents the dehydrogenated residue of an NH-acidic group-containing drug; and the pharmaceutically acceptable acid addition salts or quaternary ammonium salts thereof.

Description

NOVEL PRODRUG DERIVATIVES OF BIOLOGICALLY ACTIVE AGENTS CONTAINING HYDROXYL GROUPS OR NH-ACIDIC GROUPS
BACKGROUND OF THE INVENTION
Field of the invention The present invention relates to novel biolabile, in-vitro solution stable and water soluble prodrug forms of drugs containing one or more hydroxyl groups or NH-acidic groups, to methods for preparing the prodrug forms, to pharmaceutical compositions containing such prodrug forms, and to methods for using the prodrug forms. For purposes of this specification, the term "prodrug" denotes a derivative of a known and proven prior art compound which derivative, when administered to warm-blooded animals, e.g. humans, is converted into the proven drug. The enzymatic and/or chemical hydrolytic cleavage of the compounds of the present invention occurs in such a manner that the proven drug form (parent hydroxyl-containing or NH-acidic drug) is released, and the moiety or moieties split off remain non-toxic or are metabolized so that non-toxic metabolic products are produced.
These novel prodrug forms are esters of certain amino acids. These esters are characterized by possessing a high water solubility and by combining a high susceptibility to undergo enzymatic hydrolysis in-vivo with a high stability in aqueous solution.
Description of the prior art
It is well-known that a wide variety of compounds containing a hydroxyl group (-OH) or an NH-acidic group (e.g. an imide, uracil or imidazole function) are useful active agents for the treatment or management of various disease states or conditions. It is also well-known that such prior art compounds are characterized by certain inherent disadvantages, notably bioavailability problems upon administration as well as stability or pharmaceutical formulation problems. Such reduced bioavailability can be attributed in part to poor aqueous solubility and also to metabolic losses during and following conventional administration. Also, the poor water solubility of many such prior art compounds, such as corticosteroids, chloramphenicol, aciclovir, phenytoin, allopurinol and paracetamol, makes it difficult or impossible to prepare formulations suitable for intravenous or intramuscular injection or ophthalmic delivery.
A promising approach to solve such problems may be esterification of the hydroxyl function or N-α-acyloxy-alkylation of the NH-acidic function in the drugs to produce more water soluble prodrug forms. Several types of esters have been described and used to increase the aqueous solubility of hydroxyl-containing agents, e.g. dicarboxylic acid hemiesters, sulfates, phosphates and aminoalkanoyloxy derivatives. However, their use is not without problems, considering the ideal properties of such prodrugs: They should possess adequate aqueous solubility, sufficient aqueous solution stability to allow long-term storage of ready-to-use solutions and yet they should be converted quantitatively and rapidly in-vivo to the active parent drug. For example, succinate esters are not good substrates for hydrolytic enzymes and often show a slow and incomplete regeneration of the parent drug in-vivo as is the case for such esters of several corticosteroids, chloramphenicol and metronidazole (Nahata & Powell, 1981; Bundgaard, 1985, Larsen et al., 1988). Furthermore, such esters have limited solution stability (Bundgaard, 1985). Other ester derivatives which are readily converted to the active drug in-vivo exhibit, on the other hand, poor solution stability. Such derivatives include, for example, various aliphatic amino acid esters of metronidazole (Bundgaard et al., 1984), corticosteroids (Kawamura et al., 1971; Anderson et al., 1985) and paracetamol (Cognacq, 1977; Higasava et al., 1979). Other derivatives may possess the requisite solubility, stability and biolability, but exhibit other disadvantages. Thus, an amine-containing ester prodrug of methylprednisolone apparently fulfilling these requirements was found to cause local toxicity and irritation upon intramuscular or intravenous administration (Anderson et al., 1987). For N-α-acyloxyalkyl prodrug derivatives of NH-acidic drugs, increased water solubility has in the past been achieved by incorporating an ionizable acyl group in the ester part such as an amino acid residue. For example, amino- containing N-acyloxymethyl allopurinol prodrugs derived from α-amino acids have been disclosed in the US Patent 4,694,006.
Such derivatives exhibit the same disadvantage as similar esters of hydroxyl-containing drugs in possessing a very limited solution stability, making it impossible to formulate ready-to-use solutions (Bundgaard & Falch, 1985). The same applies to similar N-acyloxymethyl derivatives of chlorzoxazone (Johansen & Bundgaard, 1981) and phenytoin (Varia et al., 1984). Thus, there exists a clear need for new prodrug derivatives of biologically active substances containing a hydroxyl group or an NH-acidic group which derivatives would be devoid of those disadvantages and drawbacks that to date have characterized the prior art compounds. In accordance with the present invention it has now been discovered that water soluble esters of the formula I below are surprisingly stable in aqueous solution, yet being readily cleaved enzymatically in-vivo, e.g. by plasma enzymes, with release of the parent drug.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a novel water soluble amine-containing prodrug type characterized by possessing a high stability in aqueous solutions in-vitro and at the same time being readily cleaved enzymatically in-vivo to regenerate the parent active drug.
It is another object of this invention to provide novel bioreversible derivatives of drugs or biologically active agents having a hydroxyl group or an NH-acidic function which derivatives, when administered to warm-blooded animals, e.g. humans, elicit the bioaffecting/pharmacological response characterized of the agents from which they are derived, yet which are characterized by enhanced water solubility and in-vitro stability.
Yet another object of the present invention is to provide prodrugs of bio-affecting agents containing a hydroxyl group or an NH- acidic function which are capable of making the parent drugs more bioavailable from the site of administration such as the gastrointestinal tract, the rectum, the skin or the eye of the human body.
It is a further object of the present invention to provide such derivatives of conventional bio-affecting agents containing a hydroxyl group or an NH-acidic function which are prodrugs designed to cleave in such a manner as to enable the original parent drug form to be released at its therapeutic site or sites of activity, while the remaining cleaved moiety is non-toxic and/or is metabolized in a nontoxic fashion. Other objects, features and advantages of the invention will be apparent to those skilled in the art from the detailed description of the invention which follows.
The foregoing objects, features and advantages are provided by the novel compounds of the formula I:
Figure imgf000006_0001
wherein D represents the dehydrogenated residue of a hydroxyl group- containing drug or the dehydrogenated residue of an NH-acidic group- containing drug; the substituents in the phenyl ring
Figure imgf000006_0002
and
:
Figure imgf000007_0001
are in either meta- or para-position to each other;
the phenyl ring additionally may be substituted with one, two, three or four substituents selected from the group consisting of an alkyl group, a halogen, a hydroxyl group or an alkoxy group; m is an integer 0 or 1;
p is an integer of 0 or 1 ;
n is an integer from 1 to 4;
R1 is selected from the group consisting of hydrogen, an alkyl group , an aryl group , an aralkyl group, a group having the formula -COOR5, wherein R5 is an alkyl or aralkyl group, or a carbamoyl group of the formula -CONR6R7, wherein R6 and R7 are the same or different and are hydrogen, an alkyl group, or together with the adjacent nitrogen atom form a 4-, 5-, 6- or 7-membered heterocyclic ring, which in addition to the nitrogen may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;
R2 is hydrogen or an alkyl group;
R3 and R4 are the same or different and are selected from the group consisting of hydrogen, an alkyl group, an aralkyl, an alkenyl group, a cycloalkyl group, in which the alkyl, aralkyl, alkenyl or cycloalkyl group is unsubstituted or substituted with one or more substituents selected from: a hydroxyl group
a straight or branched-chain alkoxy group
a carbamoyl group having the formula -CONR5R7 as defined above
an amino group having the formula -NR6R7 , wherein R6 and R7 are as defined above; or R3 and R4 are combined so that -NR3R4 forms a 4- , 5-, 6- or
7-membered heterocyclic ring, which in addition to the nitrogen atom may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and which hetero-cyclic ring may be substituted with a hydroxyl group, a carbonyl group, an alkyl group, an alkyl group substituted with a hydroxyl group or an acyloxy group having the formula R5COO-, wherein R5 is as defined above, an alkoxycarbonyl group having the formula -COOR5 as defined above, or a carbamoyl group of the formula -CONR6R7 as defined above;
with the proviso that m is 0 when D represents the dehydrogenated residue of a hydroxyl group-containing drug and m is 1 when D represents the dehydrogenated residue of an NH-acidic group-containing drug;
and the pharmaceutically acceptable acid addition salts or quaternary ammonium salts thereof.
In the present context, the dehydrogenated residue of a hydroxyl group-containing drug means the residue attached to the hydroxyl group from which the hydrogen has been removed. Similarly, the dehydrogenated residue of an NH-acidic group containing drug means the residue attached to the NH-acidic moiety from which the hydrogen has been removed.
In the present context, the term "alkyl" designates C1-8 alkyl which may be straight or branched, such as methyl, ethyl, propyl, isopropyl, butyl, tert. butyl, pentyl, hexyl, heptyl, or octyl. The term "alkenyl" designates a C2-6-mono-unsaturated aliphatic hydrocarbon group which may be straight or branched, such as propenyl, butenyl or penteny. The term "aryl" encompasses aryl radicals such as pehnyl and naphtyl and also the corresponding aryl radicals containing one or more substituents, which may be the same or different, such as alkylthio, alkyl, halogen, alkoxy, aryloxy, nitro, alkanoyl, dialkylamino, alkanoyloxy or hydroxy groups. The term "cycloalkyl" designates a radical containing 4 to 7 carbon atoms, e.g. cyclohexy. The term "aralkyl" designates a radical of the type -alkylene-aryl, wherein aryl is as defined above and the alkylene moiety contains 1 to 6 carbon atoms and can be straight or branched-chain, e.g. methylene, and the like. When R3 and R4 in the formula I and R6 and R7 in the formula -NR6R7 together with the adjacent nitrogen atom form a 4-, 5-, 6- or 7-membered heterocyclic ring which in addition to the nitrogen atom may contain 1 or 2 further hetero atoms selected from the group consisting of nitrogen, oxygen, and sulfur, it may, for instance, be 1-piperidyl, 1-pyrrolidinyl, 1-piperazinyl, 4-methylpiperazin-1-yl, hexamethyleneimino, morpholino, thiomorpholino, 1-pyrazolyl, 1-imidazolyl and 2-methylimidazol-1-yl. The term "non-toxic pharmaceutically acceptable acid addition salts" as used herein generally includes the non-toxic acid addition salts of compounds of formula I, formed with non-toxic inorganic or organic acids. For example, the salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulphuric, sulphamic, nitrie, phosphoric acid and the like; and the salts with organic acids such as acetic, propionic, succinic, fumaric, maleic, tartaric, citric, glycolic, lactic, stearic, malic, pamoic, ascorbic, phenylacetic, benzoic, glutamic, salicylic, sulphuric, sulphanilic acid, and the like. The quaternary ammonium derivatives of the compounds of the present invention may be represented by formula I wherein the terminal amino group is substituted by an additional group as depicted below
Figure imgf000009_0001
wherein R3 and R4 alone or taken together with the nitrogen atom to which each is attached have the meanings defined above; R8 is a lower alkyl group of from 1 to 4 carbon atoms, preferably methyl or ethyl; and X' represents an anion, e.g. X is I, Br, Cl, CH3SO3 or CH3COO. DETAILED DESCRIPTION OF THE INVENTION
As stated above, D in formula I represents the dehydro-genated residue of any drug or medicament having one or more hydroxyl groups (m=0 in formula I) or D represents the dehydrogenated residue of a drug containing one or more NH-acidic functions (m=1 in formula I). In the present context, an NH-acidic function, group or moiety is defined as a structure with the formula -NH-CO- or -NH-SO2- or as a heterocyclic nitrogen structure. Examples of NH-acidic structures encompassed within the present invention include the following: Secondary carboxamides
Secondary sulfonamides
Secondary carbamates
Imides
N-alkyl ureas
N-acyl N' -alkyl ureas
Cyclic structures containing such moieties like
Uracils (2,4-pyrimidinediones)
Thiouracils
Pyrimidinones
Barbituric acids (2,4,6-pyrimidinetriones)
Hydantoins (2,4-imidazolidinediones)
Oxazolinones
Benzoxazolinones
Oxazolidinediones
Imidazoles
Benzimidazoles
Pyrazoles
Benzopyrazoles
Triazoles
Benzotriazoles
Xanthines
Isatins
Such structures may contain more than one NH-acidic function. For example, the uracil ring contains two NH-acidic funtions. In such cases prodrug derivatives formed at both NH-acidic functions are also part of the present invention.
For drugs containing NH-acidic functions it will be appreciated that it is a critical feature of the present invention that m=1 in the formula I. If, for example, m=2, such compounds would not facilely be converted in-vivo to the parent active NH-acidic drug. For compounds with m=l cleavage in-vivo proceeds via two steps, an enzymatic ester hydrolysis to produce
I
Rj_
Figure imgf000011_0001
followed by a fast and spontaneous decomposition of this N-α-hydroxyalkyl derivative as follows:
D - CHOH > D - H + RL - CHO
I
Figure imgf000011_0002
Examples of drugs or pharmaceuticals from which the instant prodrugs may be derived are listed below. Those skilled in the art will realize that the list is not exhaustive and the invention is applicable to other drugs containing a hydroxyl group or an NH-acidic function as well. a Drugs containing an OH-group:
Aciclovir
Clavulanic acid
Cromolyn and cromolyn esters
Aclarubicin
Doxorubicin
Ivermectin
Benzyl alcohol
Alfacalcidol
Erythromycin A
2' -Deoxy-5-trifluoromethyluridine
Amphotericin B Cyclocytidine
Arbaprostil
Atropine
Azacitidine
Chloramphenicol
Azidamfenicol
Carboprost
Metronidazole
Cefamandole
Cetophenicol
Chlorphenesin
Chlorphenesin carbamate
Cycloheximide
Clindamycin
Cytarabine
Digoxine
Dinoprostone
Ribavirine
Temazepam
Thiamphenicol
Trifluridine
Vidarabine
Doxifluridine
Compactin
Mevinolin
Floxuridine
3' -Azido-3' -deoxythymidine (zidovudine)
Cyclaradine
Camptothecin
Dipyridamole
Diprophylline
Doxefazepam
Oxazepam
Lorazepam
Epirubicine
Ergometrine
Ergotamine
Etofylline Etoposide
Fenyramidol
Forskolin
Guaifenesine
Idoxuridine
Imipenem
Isometronidazole
Lormetazepam
Mazindol
Nandrolone
Naproxol
Nicotinyl alcohol
Novobiocin
Oleandomycin
Ornidazole
Phenylpropanolamine
Proxyphylline
Pseudoephedrine
Quinidine
Retinol
Secnidazole
Budesonide
9α-Fluorohydrocortisone
Triamcinolone
Corticosterone
Prednisone
Prednisolone
6α-Methylprednisolone
Fluclorolone acetonide Fluocinolone acetonide
Alclometasone
Aldosterone
Alfadolone
Alfaxalone
Amcinafal
Beclomethasone
Betamethasone
Betamethasone 17-valerate Chlorprednisone Clobetasol Clobetasone Cortisone Hydrocortisone Dexamethasone Fludroxycortide Flumethasone Flunisolide Fluocortolone
Fluprednisolone Pregnanolone Hydroxydione Paramethasone Prednylidene Propranolol Metoprolol Fluorometholone Timolol
Cetamolol Celiprolol Acebutolol Albuterol Alprenonol Atenolol
Bucindolol Levobunolol Butopamine Carbuterol Cartelolol Nadolol
Oxprenolol Labetalol Pindolol Pirbuterol Prenalterol Sotarol
Metipranolol Betaxolol
Minaxolone
7-Deacetylforskolin
Prostacyclin
Silybin
Estramustine
Ganciclovir
Bromperidol
Thymidine
Rapamycin
Sydnocarb
Digitoxigenin
Dyphyllin
4-Acetyl-2-(2-hydroxyethyl)-5,6-bis(4-chlorophenyl) -2-¥-pyridazin-3- one
Nystatin
Aureofacin
Perimycin
Testosterone
Acenocoumarol
Paracetamol
Salicylic acid
Salicylsalicylic acid
Tetracycline
Bamethan
Diflunisal
Dicoumarol
Carbidopa
Dienostrol
Diethylstilbestrol
Dithranol
Dobutamine
Levodopa
Methyldopa
Estradiol
Estriol
Estrone
Ethinylestradiol Etilefrine
Fenoterol
Furodazole
Hydromorphone
Isoprenaline
Levallorphane
Metaraminol
Metazocine
Morphine
Naloxone
Naltrexone
Nalorphine
Nalmexone
Levorphanol
Olsalazine
Orciprenaline
Adrenaline
Oxilorphane
Oximetazoline
Oxymorphone
Oxyphenbutazone
Pentazocine
Ketobemidone
Phenprocoumon
Phenylephrine
Rimiterol
Salbutamol
Salicylamide
Serotonin
Terbutaline
Tocopherol
Tyrosine
Warfarin
5-aminosalicylic acid and esters thereof Dopamine
Ethylmorphine
Fenoldopam
N-t-Butylarterenol Isoproterenol
2-Amino-6,7-dihydroxytetrahydronaphthalene (ADTN)
2-(m-Hydroxyphenyl)imidazo[2,1-b]benzothiazole
Isoxsuprine
Apomorphine
Nalbufine
Cyclazocine
Oxytetracycline
Doxycline
Raclopride
Eticlopride
Ethyldeoxyuridine
5-(2-Bromovinyl)-2'-deoxyuridine
Dehydroepiandrosterone
5-Vinyl-1-β-D-arabinofuranosyluracil
Doxefazepam
Desciclovir
17β-Hydroxy-11-(4-dimethylaminophenyl)-17α-prop-1-ynyl-estra-4,9-dien-3-one
2,3-Dihydro-6-[3-(2-hydroxymethyl)phenyl-2-propenyl]-5-benzofuranol
Levonorgestrel
Propofol
1,3-Dipropyl-8-(p-hydroxyphenyl)xanthine b NH-Acidic agents like:
Allopurinol
5-Fluorouracil
Cimetidine
Theophylline
Phenytoin
Mephenytoin
Albendazole
Phenobarbital
Alonimide
Aminoglutethimide
Azathioprine
Mercaptopurine
Bemegride Bendazol
Chlorzoxazone
Bromchlorenone
5' -Deoxy-4' ,5-difluoruridine
1,3-Diphenylxanthine
Cambendazole
4-Ethyl-1,3-dihydro-5-[4-(2-methyl-1H-imidazol-1-yl)benzoyl]-2H- imidazol-2-one
N-Methylacetazolamide
Pyridoglutethimide
Carbamazepine
Cyclobendazole
Dantrolene
Enprofylline
Ethotoin
Fenbendazole
Flubendazole
Flueytosine
Ketoconazole
Lobendazole
Methylthiouracil
Methiamide
Miconazole
Mebendazole
Niridazole
Nocodazole
Oxfendazole
Oxibendazole
Parbendazole
Parconazole
Thiabendazole
Nitrofurantoin
Mifentidine
Mitindomide
Domperidone
Ethosuximide
Lixazinone
Spiro-(2-fluoro-9H-fluorene-9,4'-imidazolidine)-2',5'-dione 6-Fluoro-2-methyl-spiro[chroman-4,4'-imidazoline]-2' 5'-dione
All of the above compounds are known in the art.
While all of the compounds encompassed by formula I essentially satisfy the obj ectives of the present invention, preferred compounds include those derived from the following bio-affecting agents (compounds A):
Aciclovir
Cromolyn and cromolyn esters
Erythromycin A
Chloramphenicol
Metronidazole
Cefamandole
Cytarabine
Vidarabine
Testosterone
Doxifluridine
Floxuridine
Zidovudine
Oxazepam
Lorazepam
Etoposide
Forskolin
Idoxuridine
Hydrocortisone
Cortisone
5-Aminosalicylic acid and esters thereof
Corticosterone
Prednisone
Prednisolone
6α-Methylprednisolone
Triamcinolone
Dexamethasone
Desciclovir
Flumethasone
Chlorprednisone Betamethasone
Betamethasone 17-valerate
Fluprednisolone
9α-Fluorohydrocortisone Pregnanolone
Propranolol
Timolol
Alprenolol
Atenolol
Labetalol
Metoprolol
Oxprenolol
Levobunolol
Betaxolol
Ganciclovir
Rapamycin
Paracetamol
Levodopa
Methyldopa
Dopamine
Dobutamine
Morphine
Naloxone
Naltrexone
Nalorphine
Oximetazoline
Ketobemidone
Phenylephrine
Salbutamol
Terbutaline
Fenoldopam
Allopurinol
5-Fluorouracil
Theophylline
Cimetidine
Phenytoin
Aminogluthethimide
Mercaptopurine Chlorzoxazone
Mebendazole
Thiabendazole
Mitindomide
Domperidone
Ketoconazole
Mifentidine
1,3-Diphenylxanthine
1,3-Dipropyl-8-(p-hydroxyphenyl)xanthine Particularly preferred compounds of the invention include those wherein D in formula I is derived from one of the specific bio-affecting agents named above (compounds A) , R1 is hydrogen or methyl (when m = 1), p =0, R2 is hydrogen, n is 1 or 2, and m and R3 and R4 are as defined in connection with the general formula I. In especially preferred compounds of the formula I, D
is derived from one of the compounds A above, R1 is hydrogen (when m = 1), p - 0, R2 is hydrogen, n =1, and m and R3 and R4 are the same or different and are
- H
- CH3
- C2H5
- CH2CH2CH3
- CH2CH2OH
- CH2CONH2
- CH2CH2NH2
- CH2CH2NHCH3
- CH2CH2N(CH3)2
- CH2CH2N(C2H5)2 or
- CH2CH2OCH3 or - NR3R4 is ,
Figure imgf000022_0001
It will be appreciated that in the especially preferred compounds defined immediately above, each and every possible combination between the given examples of R3 and R4 in the
formula D
Figure imgf000022_0002
course, be combined with each and every group D derived from the compounds A listed above, and that the above definition is equivalent to listing each and every possible combination of the listed examples of D, m, R3 and R4.
Specific examples of especially preferred compounds of the formula I are the following compounds of formula la - Is:
Figure imgf000022_0003
Figure imgf000022_0004
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000023_0003
Figure imgf000024_0001
Figure imgf000024_0002
Figure imgf000025_0001
Figure imgf000025_0002
Figure imgf000026_0001
Figure imgf000026_0002
Figure imgf000026_0003
and the corresponding 2-substituted, 2,5- and 1,5-disubstituted allopurinol derivatives
Figure imgf000027_0001
Figure imgf000027_0002
Figure imgf000027_0003
Figure imgf000028_0001
Figure imgf000028_0002
Figure imgf000029_0001
Figure imgf000029_0002
Figure imgf000030_0002
Figure imgf000030_0001
wherein the substituents in the phenyl ring of the benzoate ester moiety are in either meta- or para-position to each other and wherein R3 and R4 are the same or different and are
- H
- CH3
- C2H5
- CH2CH2CH3
- CH2CH2OH
- CH2CONH2
- CH2CH2NH2
- CH2CH2NHCH3
- CH2CH2N(CH3)2
- CH2CH2N(C2H5)2 or
- CH2CH2OCH3 or - NR3R4 is ,
Figure imgf000031_0001
A most important characteristic of the novel prodrug derivatives of the formula I is their combination of high water solubility, high stablity in aqueous solution at pH values affording the high water solubility (i.e., weakly acidic pH values) and facile enzymatic cleavage in the body with quantitative release of the parent drug.
The solution stability of these compounds is markedly higher than that of other amino-containing ester prodrugs such as esters formed with α-amino acids. Normally, a protonated amino group in the acyl part of an ester strongly activates or catalyzes the ester bond toward hydroxide ion-catalyzed or water-catalyzed hydrolysis (e.g. Bundgaard et al., 1984). In the compounds of formula I the amino group is, however, structurally incapable of exhibiting such catalytic effect on cleavage of the ester bond due to the incorporation of a phenyl group between the ester moiety and the amino group. It can also be said that the phenyl moiety functions as a spacer group hindering any instability-causing interactions between the ester moiety and the solubilizing amino function.
These characteristics of the novel compounds of the present invention make them particularly suitable for administration as sterile aqueous solutions by intravenous injection, intravenous infusion, or intramuscular or subcutaneous injection, or for topical administration to the eye. However, due to their ready solubility at acidic pH values and high chemical stability, the prodrugs of this invention are also highly useful for peroral administration, e.g. to improve the bioavailability of slightly water soluble parent drugs containing a hydroxyl group or an NH-acidic group. Similarly, the solubility and stability charateristics of the novel prodrugs make them highly suitable for rectal or dermal administration.
It will be appreciated that the lipophilicity of the prodrug derivatives of the formula I can be readily modified or controlled by the appropriate selection of the amino group (-NR3R4 in formula I) in the compounds both in terms of amine basicity, and hence degree of ionization at physiological pH values, and in terms of hydrophobicity of the substituents (R3 and R4) on the nitrogen atom. Thus, it is readily feasible to select prodrug derivatives of the formula I which through a combination of improved water solubility and lipophilicity are capable of providing increased biomembrane transport so that the parent drugs are more bioavailable from the site of administra-tion such as the gastro-intestinal tract, the rectum, the skin or the eye of the human body. Likewise, for phenolic drugs, for example, the prodrug derivatization of the present invention makes it feasible to protect the phenolic group in the parent drug against metabolic inactivation processes during or following e.g. peroral or rectal absorption.
Dosage forms and dose
The prodrug compounds of formula I of the present invention can be used to treat any condition for which the parent hydroxyl or NH-acidic group containing drug, medicament or pharmaceutical is useful. For example, if metronidazol is the parent drug of choice, the ester prodrug can be used for any condition or treatment for which metronidazole would be administered. Thus, the prodrug compounds of formula I may be administered orally, topically, parenterally, rectally or by inhalation spray in dosage forms or formulations containing conventional, non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The formulation and preparation of any of this broad spectrum of dosage forms into which the subject prodrugs can be disposed is well-known to those skilled in the art of pharmaceutical for-mulation. Specific information can, however, be found in the text entitled "Remington' s Pharmaceutical Sciences" , Sixteenth Edition, 1980.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous suspensions, or solutions, dispersible powders og granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide a pharmaceutically elegant and palatable preparation.
Formulations for oral use include tablets which contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium chloride, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, potato starch, or algi-nic acid, binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
Formulations 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 as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. For the rectal application of the compounds of formula I of this invention, typical dosage forms include suppositories, rectal gelatin capsules (solutions and suspensions), and enemas or micro-enemas (solutions and suspensions). Thus, in a typical suppository
formulation, any one of the compounds of this invention is combined with any pharmaceutically acceptable suppository base such as cocoa butter, esterified fatty acids (C10-C18), glycerinated gelatin, and various water-soluble or dispersible bases like polyethylene glycols and polyoxyethylene sorbitan fatty acid esters. Various additives like salycilates or surfactant materials may be incorporated. Enemas or micro-enemas of the solution type may simply be prepared by dissolving the water-soluble prodrugs of this invention in water or in water containing e.g. 0.5% methylcellulose or another viscosity-in-creasing agent.
For topical use, creams, ointments, gels, solutions or the like containing the prodrugs are employed according to methods recognized in the art.
Sterile aqueous solutions of the compounds of Formula I for parenteral administration or ophthalmic use typically will contain other components such as preservatives, anti-oxidants, chelating agents, buffer substances, or other stabilizers.
Naturally, therapeutic dosage range for the compounds of the present invention will vary with the size and needs of the patient and the particular pain or disease symptom being treated. However, generally speaking, the following dosage guide-lines will suffice. For oral administration, the therapeutic dose required for a compound of the present invention will generally, on a molecular basis, mimic that for the parent hydroxyl- or NH-acidic drug. On a topical basis, application of an 0.01% to 5% concentration of a compound of the present invention (in a suitable topical carrier material) to the affected site should suffice.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration to humans may contain from 5 mg to 5 g of the active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total composition. Other dosage forms such as ophthalmic dosage forms contain less active ingredient such as for example from 0.1 mg to 5 mg. Dosage unit forms will generally contain between from about 0.1 mg to about 500 mg of active ingredient. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors
including the activity of the specific compund employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and severity of the particular disease undergoing therapy.
From the foregoing description, one of ordinary skill in the art can easily ascertain the essential characteristics of the present invention and, without departing from the spirit and scope thereof, can make various changes and/or modifications of the invention to adapt it to various usages and conditions. As such, these changes and/or modifications are properly, equitably and intended to be within the full range of equivalence of the following claims.
Preparation of the prodrugs of formula I
The compounds of the present invention may be prepared by various means, and it will be apparent from the following that the aminecontaining ester moiety attached to the OH-group of the parent OH- containing drug or to the -CHOH
I group of the parent NH-acidic drug may be introduced by reaction with an appropriate starting material amino acid which provides the entire moiety, or said ester moiety may be introduced by a sequence of two or more reactions.
One method (method A) for preparing compounds of the formula I comprises reacting the OH-containing drug of the formula A
D-H (A) or the N-α-hydroxyalkylated NH-acidic drug of the formula B
Figure imgf000036_0002
wherein D and R1 are as defined above in connection with formula I, with a compound having the formula C:
Figure imgf000036_0001
wherein p, n, and R2 are as defined above and Y is a leaving group or a hydroxy group (when p = 0) and Z is a halogen (chlorine, bromide or iodide), and then reacting the so produced compound of the formula D
Figure imgf000037_0001
with an amine of the formula E
HNR3R4 (E)
wherein R3 and R4 are as defined above.
As examples of leaving groups Y may be mentioned chlorine, bromide and iodine. Group Y may also be an acyloxy group, i.e. the reacting compound of formula C may be an anhydride or a mixed anhydride. When Y is a hydroxy group (then p = 0 in Formula C), a dehydrating agent (e.g. a carbodiimide) has to be present and normally, a sulfonic acid or '4- (N,N-dimethylamino)pyridine is added as a catalyst. The reaction utilizing compound C in which Y is hydroxy is conveniently carried out in an inert solvent such as dichloromethane, dioxane, pyridine, N,N-dimethylformamide or the like, at a temperature of from -10ºC to 60ºC, for from 1 to 72 h. When the reaction utilizes an acid halogenide starting material (e.g. Y in formula C is chlorine), the process leading to compounds of formula D can be conveniently carried out in an inert solvent such as benzene, dichloromethane, acetone, N,N- dimethylformamide, dioxane, acetonitrile or the like, at from -10C° to reflux temperature, for from 1 to 24 h, in the presence of an acid scavenger such as an alkali metal carbonate, or an organic base such as triethylamine or pyridine.
Several compounds of formula C in which p = 0, Z is Cl or
Br and Y is OH, Cl or Br and methods for preparing them are known from the literature, see e.g. Blicke & Lilienfeld (1943); Smith & Menger (1969); Day & Gohil (1976).
The process of reacting a compound of formula D with an amine of formula E can be conveniently carried out in the absence of a solvent or in an inert solvent such as acetone, acetonitrile, tetrahydro furan, ethanol, dichloromethane, N,N-dimethylformamIde, or the like, at from -10C° to reflux temperature, for from 1 to 72 h. When Z in a reacting compound of formula D is chlorine, sodium iodide may be added as a catalyst to the reaction mixture. Another method (method B) for preparing compounds of formula I comprises reacting a compound of formula A or B with a compound having the formula F
Figure imgf000038_0001
wherein Y, p, n, R2, R3 and R4 are as defined above with the proviso that when Y is hydroxy, p is zero.
If either R3 or R4 is hydrogen, the reaction may preferably be carried out by using a compound of formula F in which the amino group is suitably protected with a protecting group such as a carbobenzoxycarbonyl or a tert-butyloxycarbonyl group. Deprotection is subsequently performed by known methods, e.g. by hydrogenation or hydrolysis. The reaction is performed under the same conditions as those used to prepare compounds of formula D.
Several compounds of formula F in which p = 0 and Y is a halogen or hydroxy and methods for preparing them are known from the literature, see e.g. Markwardt et al. (1966); Kasmirowski et al. (1967);
Kuhn et al. (1950); Blicke & Lilienfeld (1943); Fujii et al. (1977).
A third method (method C) for preparing compounds of the formula I, wherein p = 0, comprises reacting a compound of formula G D' -Z (G) in which the hydroxy group of the parent drug DH is replaced by Z, so that D' is the dehydroxylated residue of a hydroxyl group- containing drug, or a compound of formula H )
Figure imgf000039_0002
wherein Z is as defined above, with a compound of formula J
Figure imgf000039_0001
wherein n, R2 , R3 and R4 are as defined above and N+ is a counter ion such as Na+, K+, Ag+ or trialkylammonium. The reaction can be conveniently carried out in an inert solvent such as ethyl acetate, acetone, dimethylformamide or the like, at from room temperature to reflux, for from 0.5 to 48 h. If Z in formula G and H is chlorine, sodium iodide may be added as a catalyst to the reaction mixture.
The starting materials of formula B may be prepared by reacting the NH-acidic drug with an aldehyde, preferably formaldehyde, of formula K
R1 - CHO (K)
Several N-α-hydroxyalkyl or N-hydroxymethyl derivatives of formula B and methods for their preparation are known in the literature, e.g. for allopurinol (Bansal et al., 1981 b; Bundgaard & Falch, 1987); phenytoin and other hydantoins (Zejc, 1968; Bundgaard & Johansen, 1980); 5-fluorouracil (Buur et al., 1986; Ahmad et al., 1987); benzimidazoles (Hideg & Hanskovsky, 1967; Varma et al., 1980); chlorzoxazone (Varma & Nobles, 1968), theophylline (Bodor & Sloan, 1977); various imides (Vail & Pierce, 1972; Buc, 1947); mitindomide (Deutsch et al., 1986; Haugwitz et al., 1987); barbituric acids (Bansal et al., 1981 b); uracils (Bansal et al., 1981 a); and secondary carboxamides (Bόhme et al., 1961). Compounds of formula B derived from other NH-acidic drugs may be prepared by methods similar to those described in these references. Several compounds of formula H and methods for their preparation are also known in the literature, see e.g. Zaugg & Martin (1965) and references cited therein. A convenient method of their preparation is treatment of a compound of formula B with thionyl chloride, phosphorous pentachloride, phosphorous trichloride or the like.
An alternative method (method D) for preparing compounds of the formula I, wherein m - 1, comprises reacting a parent NH-acidic drug with a compound of the formula L.
Figure imgf000040_0001
wherein R1, R2, p, n and Z are as defined above, and then reacting the resultant compound of formula D with an amine of the formula E as described above. Compounds of formula L are prepared by known means e.g. by the procedures described by Bigler et al. (1978), Waranis & Sloan (1987), Binderup & Hansen (1984), Barcelo et al. (1986) and Senet et al. (1988).
An additional method (method E) for preparing compounds of the formula I, wherein p = 1, comprises reacting a compound of formula M
Figure imgf000040_0002
or of formula N
Figure imgf000040_0003
wherein R1 and Z are as defined above, with a compound of formula 0
.
Figure imgf000040_0004
wherein n, R2, R3 and R4 are as defined above. If either R3 or R4 is hydrogen, the reaction is preferably carried out by using a compound of formula 0 in which the amino group is suitably protected such as described above. Compounds of formula M and N may conveniently be prepared by treating compounds of formula A and B, respectively, with phosgene or a phosgene-releasing agent. Several compounds of formula 0 and methods for their preparation are known from the literature, see e.g. Lumma et al. (1984).
While the basic methods described above can be used to prepare any of the compounds of the invention, certain con-ditions and/or modifications therein are made in specific instances. Thus, for example, the basic methods may be modified in the cases where the parent drug contains a free primary or secondary amino group. In such cases, it is preferable to block this amino group before reacting the parent compound as described above. The protected ester prodrug thus obtained is then deprotected by known methods, e.g. by
hydrogenation or hydrolysis.
To form acid addition salts of the compounds of formula I said compounds are treated with suitable pharmaceutically acceptable inorganic or organic acids by standard procedures . The quaternary ammonium salts of the compounds of formula I are formed by reacting said compounds with a suitable alkylating agent such as dimethyl sulphate, diethyl sulphate, methyl bromide, methyl iodide or ethyl iodide.
The present invention is further illustrated by the following examples which, however, are not construed to be limiting. The derivatives described all had spectroscopic properties (IR and 1H NMR) and elemental analysis in agreement with their structures. Brief description of the drawings
Fig. 1
Time-courses for 1-(4-morpholinomethylbenzoyloxymethyl)-allopurinol (•) and allopurinol (0) during hydrolysis of the prodrug derivative in 80% human plasma at 37ºC. The initial prodrug concentration was 10-4M.
Fig. 2
Plots of the first-order kinetics of hydrolysis of various prodrug derivatives in 80% human plasma at 37°C.
Key: (0), hydrocortisone 21-(3-[4-methylpiperazin-1-yl]methyl)-benzoate; (•), metronidazole 4-(morpholinomethyl)benzoate;
(Δ), 7-(3-morpholinomethylbenzoyloxymethyl)theophylline.
Fig. 3
The pH-rate profile for the degradation of hydrocortisone
21-(3-[4-methylpiperazin-1-yl]methyl)benzoate dihydrochloride in aqueous solution at 60°C; k denotes the pseudo-first-order rate constant for the degradation of the ester.
EXAMPLE 1
Hydrocortisone 21- (3-Chloromethyl)benzoate
To a suspension of hydrocortisone (9.05 g, 25 mmol) in dichloromethane (200 ml) was added triethylamine (8.4 ml, 60 mmol) followed by 3-chloromethylbenzoyl chloride (27 mmol, 3.83 ml). The reaction mixture was stirred at room temperature for 4 h. The clear solution obtained was washed with water and a 2% aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was recrystallized from methanolwater to give 9.2 g of the title compound as the monohydrate. Mp 175176°C.
Anal . : Calc. for C29H35CIO6, H2O:
C, 65.34; H, 6.99; Cl, 6.65.
Found: C, 65.57; H, 7.05; Cl, 6.48.
***
EXAMPLE 2
Hydrocortisone 21- (4-chloromethyl)benzoate
To a solution of hydrocortisone (9.05 g, 25 mmol) in pyridine (50 ml) was added with stirring 4-chloromethyl-benzoyl chloride (4.61 g, 27 mmol). The reaction mixture was stirred at room temperature for 4 h and concentrated in vacuo. The residue was slurried with water and the solid obtained filtered off and recrystallized from methanolacetone to give 8.5 g of the title compound as the monohydrate. Mp 189-190°C.
Anal . : Calc. for C29H35ClO6, H2O:
C, 65.34; H, 6.99; Cl, 6.65.
Found: C, 65.43; H, 7.05; Cl, 6.55.
*** EXAMPLE 3
Hydrocortisone 21- (A-N,N-diethylaminomethyl)benzoate
A mixture of hydrocortisone 21-(4-chloromethyl)benzoate (533 mg, 1 mmol), sodium iodide (150 mg, 1 mmόl) and diethyl-amine (0.83 ml, 8 mmol) in 10 ml of acetone was stirred at 60°C for 5 h. The reaction solution was cooled to about 25°C, filtered and evaporated in vacuo. The residue obtained was stirred with water (30 ml) for about 1 h and the precipitate filtered off, washed with water and recrystallized from acetone-water to give 475 mg of the title compound.
Mp 209-211°C .
Anal . : Gale . for C33H45NO6:
C, 71.84; H, 8.22; N, 2.54.
Found: C, 71.88; H, 8.26; N, 2.48.
EXAMPLE 4
Hydrocortisone 21- (3-imidazolylomethyl)benzoate
The compound was prepared from hydrocortisone 21-(3-chloromethyl)-benzoate and imidazole by essentially the same procedure as described in Example 3. After recrystallization from ethanol-water, the yield was 80%. Mp 203-205°C (dec).
Anal . : Calc. for C32H38N2O6, H2O:
C, 68.05; H, 7.14; N, 4.96.
Found: C, 67.95, H, 7.16; N, 4.85.
*** EXAMPLE 5
Hydrocortisone 21 - [3- (4-methylpiperazin-1 -yl)methyl]benzoate, dihydrochloride
A mixture of hydrocortisone 21- (3-chloromethyl)benzoate (2.67 g, 5 mmol), sodium iodide (0.75 g, 5 mmol) and 1-methylpiperazine (5.0 ml, 45 mmol) in 50 ml of acetone was stirred at 60°C for 5 h. Upon cooling to room temperature, the mixture was filtered and evaporated in vacuo. The residue obtained was slurried with 90% ethanol (10 ml) and the precipitate filtered off. Recrystallization from ethanol afforded 2.0 g of the title compound as the monohydrate. Mp 173-175°C.
A dihydrochloride salt was prepared by dissolving 1 g of the free base in a mixture of hot ethanol (40 ml) and acetone (10 ml) and adding an excess of 2.5 M methanolic HCl following by the addition of ether. Upon standing at 4°C overnight the precipitate formed was filtered off and re-crystallized from methanol to give 0.85 g of the title compound as the dihydrochloride. Mp 235-236°C (dec).
Anal . : Calc. for C34H48Cl2N2O6 , 2 HCl, 2 H2O:
C, 59.38; H, 7.33; Cl, 10.31; N, 4.07.
Found: C, 59.20; H, 7.50; Cl, 10.02; N, 3.95.
***
EXAMPLE 6
21- [3 - (N-ethyl-N[2-diethylaminoethyl]aminomethyl)]benzoate, dihydrochloride
A mixture of hydrocortisone 21-(3-chloromethyl)benzoate (533 mg, 1 mmol), sodium iodide (150 mg, 1 mmol) and N,N,N' -triethylethylenediamine (1 ml) in 10 ml of acetone was stirred at 60°C for 5 h. The mixture was cooled to 20°C and filtered. The filtrate was evaporated in vacuo and the residue taken up in ethyl acetate (50 ml) . The solution was washed with water (2 × 25 ml), dried over anhydrous sodium sulphate and evaporated in vacuo to give the title compound as the base. This was dissolved in ether and 2.5 M methanolic HCl (1 ml) added. The precipitate formed upon standing at 4°C for 5 h was fil tered off and recrystallized from ethanol to give 390 mg of the title compound.
Anal . : Calc. for C37H54N2O6, 2 HCl, H2O:
C, 62.26; H, 8.19; Cl, 9.93; N, 3.92.
Found: C, 62.01; H, 8.33; Cl, 9.90; N, 3.87.
***
EXAMPLE 7
Prednisolone 21- (3-chloromethyl)benzoate
To a solution of prednisolone (5.6 g, 15.5 mmol) in pyridine (40 ml) was added with stirring 3-chloromethylbenzoyl chloride (2.41 ml, 17 mmol) . The reaction mixture was stirred at room temperature for 4 h and concentrated in vacuo. The residue was slurried with water and the solid obtained filtered off, washed with water and recrystallized from methanol-water to give 6.3 g of the title compound.
Mp 226-228°C.
Anal . : Calc. for C29H33ClO6:
C, 67.89; H, 6.48; Cl, 6.91.
Found: C, 67.72; H, 6.62; Cl, 6.81.
***
EXAMPLE 8
Prednisolone 21-[3- (4-methylpiperazin-1-yl)methyl]benzoate, dihydrochloride
The compound was prepared from prednisolone 21-(3-chloromethyl)benzoate and 1-methylpiperazine by essentially the same procedure as described in Example 5. After recrystallization from methanol-ether, the yield was 77%.
Anal . : Calc. for C34H44N2O6, 2 HCl:
C, 62.86; H, 7.14; Cl, 10.91; N, 4.31.
Found: C, 62.74; H, 7.18; Cl, 10.87; N, 4.28.
*** EXAMPLE 9
Chloramphenicol 3- (3-chloromethyl)benzoate
To a suspension of chloramphenicol (6.46 g, 20 mmol) in dichloromethane (100 ml) was added triethylamine (3.2 ml, 22 mmol) followed by 3-chloromethylbenzoyl chloride (3.14 ml, 22 mmol). The mixture was stirred overnight at room temperature, washed with a 2% aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulphate and evaporated in vacuo. The solid residue obtained was recrystallized from ethanol-water to give 6.5 g of the title compound.
Anal . : Calc. for C19H17Cl3N2O6 :
C, 47.97; H, 3.60; Cl, 22.36; N, 5.89.
Found: C, 47.95; H, 3.75; Cl, 22.23; N, 5.80.
***
EXAMPLE 10 Chloramphenicol 3- (3-N,N-diethylaminomethyl)benzoate, hydrochloride
A mixture of chloramphenicol 3- (3-chloromethyl)benzoate (0.48 g, 1 mmol), sodium iodide (0.15 g, 1 mmol) and diethyl-amine (0.83 ml, 8 mmol) in 10 ml of tetrahydrofurane was stirred at 50°C for 16 h. The mixture was filtered and eva-porated in vacuo. The residue was taken up in ethyl acetate (50 ml) and water (40 ml) and the organic phase was sepa-rated, washed with water, dried and evaporated in vacuo. The residue was dissolved in ether and ethanol and 0.5 ml of a 2.5 M methanolic HCl solution added. Upon standing at 4°C for 20 h the precipitate formed was filtered off and recrystallized from ethanol to yield 0.38 g of the title compound. Mp 210-211°C.
Anal . : Calc. for C23H28CI3N3O6:
C, 50.33; H, 5.14; Cl, 19.38; N, 7.66.
Found: C, 50.31; H, 5.27; Cl, 19.29; N, 7.48. EXAMPLE 11
Benzyl 4-(N,N-dimethylaminomethyl)benzoate, hydrochloride
To a solution of benzyl alcohol (0.43 ml, 4 mmol) and triethylamine (1.84 ml, 13 mmol) in dichloromethane (25 ml) was added 4-(N,N-dimethylaminomethyl)benzoyl chloride hydrochloride (1.07 g, 4.6 mmol). The mixture was stirred at 20-25ºC for 45 h and then washed with water, a 2% aqueous solution of potassium carbonate and water, dried and evaporated in vacuo. The residue obtained was dissolved in a mixture of ether and ethyl acetate. Upon addition of a 2.5 M HCl solution in methanol the title compound precipitated. It was filtered off and recrystallized from acetonitrile-ether to provide 0.85 g. Mp 184-185°C.
Anal . : Calc. for C17H20ClNO2 :
C, 66.77; H, 6.59; N, 4.58.
Found: C, 66.42; H, 6.64; N, 4.65.
***
EXAMPLE 12
Methylprednisolone 21- (3-chloromethyl)benzoate
To a suspension of methylprednisolone (3.74 g, 10 mmol) and triethylamine (3.4 ml, 24 mmol) in dichloromethane (100 ml) was added 3-chloromethylbenzoyl chloride (1.56 ml, 11 mmol). The mixture was stirred at 40°C for 24 h and then washed with water and a 2% aqueous solution of sodium bicar-bonate. The dichloromethane phase was dried over anhydrous sodium sulphate and evaporated in vacuo to give the title compound, which was purified by recrystallization from methanol. Mp 214-215°C.
Anal . : Calc. for C30H35ClO6, 0.5 H2O:
C, 67.22; H, 6.77; Cl, 6.63.
Found: C, 67.34; H, 6.78; Cl, 6.68.
*** EXAMPLE 13
Methylprednisolone 21 - [3- (4-methylpiperazin-l -yl)methyl]benzoate
A mixture of methylprednisolone 21-(3-chloromethyl)-benzoate (527 mg, 1 mmol), sodium iodide (150 mg, 1 mmol) and 1-methylpiperazine (0.89 ml, 8 mmol) in 10 ml of acetone was stirred at 60°C for 5 h. The reaction mixture was filtered and evaporated in vacuo. The residue obtained was triturated with water, filtered off, washed with water and recrystallized from ethanol to yield 470 mg of the title compound. Mp 127-128°C.
Anal . : Calc . for C35H45N2O6, 2 H2O:
C, 67.15; H, 7.88; N, 4.48.
Found: C, 67.40, H, 8.00; N, 4.32.
The dihydrochloride salt was obtained as described in Example 10 , mp 212-215°C(dec).
***
EXAMPLE 14
Methylprednisolone 21- [3- (N-methyl-N- [2-dimethylaminoethyl]-aminomethyl)] benzoate, dihydrochloride
The compound was prepared from methylprednisolone 21-(3-chloromethyl)benzoate and N,N,N' -trimethylethylenediamine by essentially the same procedure as described in Example 6. After recrystallization from acetonitrile-ether, the yield was 81%.
Anal . : Calc. for C35H48N2O6, 2 HCl:
C, 63.15; H, 7.57; N, 4.21.
Found: C, 63.05; H, 7.66; N, 4.23.
*** EXAMPLE 15
4-Acetamidophenyl 3 - chloromethylbenzoate
To a stirred mixture of paracetamol (4.57 g, 30 mmol) and pyridine (10 ml) was added 3-chloromethylbenzoyl chloride (4.6 ml, 33 mmol) dropwise. The resultant solution was stirred at 20-25°C for 3 h and evaporated in vacuo. The residue obtained solidified by trituration with water and was filtered off and recrystallized from ethanolacetone to yield 6.5 g of the title compound. Mp 159-160°C.
Anal . : Calc. for C16H14ClNO3:
C, 63.27; H, 4.65; N, 4.61.
Found: C, 63.18; H, 4.63; N, 4.71.
EXAMPLE 16
4-Acetamidophenyl 3-[4-methylpiperazin-1-yl)methyl]benzoate, dihydrochloride
A mixture of 4-acetamidophenyl 3-chloromethylbenzoate (1.21 g, 4 mmol), sodium iodide (0.30 g, 2 mmol), 1-methyl-piperazine (1.11 ml, 10 mmol) and 20 ml of acetone was stirred at 40°C for 16 h and filtered. The filtrate was evaporated in vacuo and the residue taken up in ethyl acetate (50 ml) and water (40 ml). The organic phase was separated, washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was dissolved in ether and ethyl acetate. A 2.5 M methanolic solution of HCl (4 ml) was added and the mixture allowed to stand at 4°C for 1 h. The crystalline precipitate formed was filtered off and recrystallized from methanol to yield 0.94 g of the title compound as monohydrate. Mp
228-230βC.
Anal. : Calc. for C21H25N3O3, 2 HCl, H2O:
C, 55.03; H, 6.37; Cl, 15.47; N, 9.17.
Found: C, 55.20; H, 6.40; Cl, 15.53; N, 9.31.
*** EXAMPLE 17
4-Acetamidophenyl 3- (N ,N-diethylaminomethyl)benzoate, fumarate
A mixture of 4-acetamidophenyl 3-chloromethylbenzoate (1.21 g, 4 mmol), sodium iodide (0.30 g, 2 mmol), diethyl-amine (1.04 ml, 10 mmol) and 20 ml of acetone was stirred at 60°C for 5 h and then filtered. The filtrate was evaporated in vacuo and the residue taken up in ethyl acetate (50 ml) and water (40 ml). The ethyl acetate layer was separated, washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was dissolved in ether and 2-propanol. A solution of fumaric acid (0.40 g) in 2-propanol (10 ml) was added followed by ether (50 ml) . The precipitate formed upon standing at 4°C for 20 h was filtered off and recrystallized from ethanol-ether to give 1.3 g of the title compound. Mp 132-133°C.
Anal . : Calc. for C20H24N2O3, C4H4O4:
C, 63.15; H, 6.18; N, 6.14.
Found: C, 62.99; H, 6.28; N, 6.02.
***
EXAMPLE 18 N-(3 -Chloromethylbenzoyloxymethyl)chlorzoxazone
To a stirred mixture of N-(hydroxymethyl)chlorzaxone (4.94 g, 30 mmol) [prepared as described by Varma & Nobles (1968)] in 20 ml of pyridine was added 3-chloromethylbenzoyl chloride (4.76 ml, 33 mmol) The mixture was kept at room temperature for 3 h and evaporated in vacuo. The residue obtained was recrystallized twice from ethanolwater, yielding 5.9 g of the title compound. Mp 107-108°C.
Anal . : Calc. for C16H11Cl2NO4:
C, 54.57; H, 3.15; Cl, 20.13; N, 3.98.
Found: C, 54.47, H, 3.13; Cl, 20.19; N, 3.87.
*** EXAMPLE 19
N- (3-N,N-Diethylaminomethylbenzoyloxymethyl)chlorzoxazone, hydrochloride
A mixture of N-(3-chloromethylbenzoyloxymethyl)chlor-zoxazone (0.70 g, 2 mmol), sodium iodide (0.30 g, 2 mmol), diethylamine (1.04 ml, 10 mmol) and 20 ml of acetone was stirred at 60°C for 5 h. Upon cooling to room temperature the mixture was filtered and evaporated in vacuo. The residue obtained was taken up in ethyl acetate. The solution was washed with water, dried and evaporated in vacuo. The residue of evaporation was dissolved in ether wherupon 1 ml of 2.5 M methanolic HCl was added. The precipitate formed was recrystallized from ethanol to give 0.65 g of the title compound. Mp 202-203°C.
Anal. : Calc . for C20H21ClN2O4, HCl:
C, 56.48; H, 5.21; Cl, 16.67; N, 6.59.
Found: C, 56.35; H, 5.23; Cl, 16.70; N, 6.49.
***
EXAMPLE 20
Erythromycin 2 '- (3-chloromethyl) benzoate
To a solution of erythromycin (2.20 g, 3 mmol) in 10 ml of acetone was added sodium bicarbonate (1.5 g) followed by 3-chloromethylbenzoyl chloride (0.53 ml, 3.75 mmol). The suspension was stirred at room temperature for 4 h and then poured into 100 ml of 0.1 M phosphate buffer (pH 7.0). The precipitate formed was filtered off, washed with water and recrystallized from acetone-water to give 1.8 g of the title compound. Mp 128-131°C.
Anal . : Calc . for C45H72ClNO14:
C, 60.97; H, 8.19; N, 1.58.
Found: C, 60.82; H, 8.25; N, 1.65.
*** EXAMPLE 21
Erythromycin 2 ' - [3- (4-methylpiperazin-1-yl)methyl]benzoate
A mixture of erythromycin 2' - (3-chloromethy1)benzoate (0.89 g, 1 mmol), sodium iodide (0.15 g, 1 mmol), 1-methyl-piperazine (0.89 ml, 8 mmol) and acetone (10 ml) was stirred at 60°C for 5 h and filtered. The filtrate was evaporated in vacuo and the residue obtained washed with water and recrystallized from ethanol to give 0.62 g of the title compound. Mp 119-121°C.
Anal . : Calc. for C50H83N3O14:
C, 63.20; H, 8.80; N, 4.42. '
Found: C, 63.43; H, 8.75; N, 4.48.
EXAMPLE 22
7-(3 -Chloromethylbenzoyloxymethyl) theophylline To a stirred suspension of 7- (hydroxymethyl)theophylline (4.18 g,
20 mmol) , prepared as described by Sloan and Bodor (1982) , and triethylamine (4.2 ml, 30 mmol) in 60 ml of di-chloromethane was added 3-chloromethylbenzoyl chloride (3.12 ml, 22 mmol). The mixture was stirred for 5 h at 20-25°C, washed with a 2% aqueous solution of sodium bicarbonate, dried and concentrated in vacuo to yield a white solid which was recrystallized from dicloromethane-petroleum ether, giving 5.5 g of the title product. Mp 150-151°C.
Anal . : Calc. for C16H15ClN4O4:
C, 52.97; H, 4.17; N, 5.44.
Found C, 52.85; H, 4.20; N, 15.33.
*** EXAMPLE 23
7-(3-N ,N -Diethylaminomethylbenzoyloxymethyl)theophylline
A mixture of 7-(3-chloromethylbenzoyloxymethyl)theo-phylline (0.72 g, 2 mmol), sodium iodide (0.30 g, 2 mmol), diethylamine (1 ml) and 20 ml of acetone was stirred at 60°C for 5 h. The mixture was filtered and evaporated in vacuo. The residue obtained was washed with water and recrystallized from ethanol to give 0.51 g of the title compound. Mp 118-119°C.
Anal . : Calc. for C20H25N5O4:
C, 60.14; H, 6.31; N, 17.53.
Found: C, 60.20; H, 6.28; N, 17.48.
***
EXAMPLE 24
7-[3- (4-Methylpiperazin-1-yl)methylbenzoyl-oxymethyl]theophylline The compound was prepared from 7(3-chloromethylbenzoyl-oxymethyl)-theophylline and 1-methylpiperazine by essentially the same procedure as described in Example 23. After recrystallization from water-ethanol, the yield was 60%. Mp 149-151°C.
Anal . : Calc. for C21H24N6O4:
C, 59.42; H, 5.70; N, 19.80.
Found: C, 59.59; H, 5.65; N, 19.73.
EXAMPLE 25
7-(3-Morpholinomethylbenzoyloxymethyl)theophylline The compound was prepared from 7-(3-chloromethylbenzoyl-oxymethyl) theophylline and morpholine by essentially the same procedure as described in Example 23. After reerystallation from ethanol, the yield was 75%. Mp 126-127°C. Anal . : Calc . for C20H23N5O5 :
C, 58.10; H, 5.61; N, 16.94.
Found: C, 58.15; H, 5.60; N, 16.92.
***
EXAMPLE 26
7-(3-Imidazolylmethylbenzoyloxymethyl) theophylline
The compound was prepared from 7-(3-chloromethyl-benzoyloxymethyl)- theophylline and imidazole by essentially the same procedure as described in Example 23. After recrystallization from ethanol-water, the yield was 71%.
Anal . : Calc. for C19H18N6O4:
C, 57.86; H, 4.60; N, 21.31.
Found: C, 57.72; H, 4.65; N, 21.21.
The hydrochloride salt was formed with HCl in methanol-ether. Mp 211-212°C (dec).
***
EXAMPLE 27
Phenyl 3 -chloromethylbenzoate
3-Chloromethylbenzoyl chloride (7.09 ml 50 mmol) was added dropwise with stirring to a solution of phenol (4.7 g, 50 mmol) and pyridine (4.03 ml, 50 mmol) in benzene (30 ml). The mixture was stirred at 60°C for 1 h, cooled to room temperature and filtered. The filtrate was evaporated in vacuo. The residue obtained solidified after storage at -20°C overnight and was recrystallized from dichloromethaneether to give 9.2 g of the title compound. Mp 59-60°C.
Anal . : Calc . for C14H11ClO2 :
C, 68.16; H, 4.49; Cl, 14.37.
Found: C, 68.08; H, 4.48; Cl, 14.39.
*** EXAMPLE 28
Phenyl 3- (N,N-diethylaminomethyl)benzoate, hydrochloride
A mixture of phenyl 3-chloromethylbenzoate (1.23 g, 5 mmol), sodium iodide (0.38 g, 2.5 mmol), diethylamine (1.04 ml, 10 mmol) and acetone (25 ml) was stirred at 60ºC for 5 h. After cooling to room temperature the mixture was filtered and evaporated in vacuo. The residue obtained was dissolved in ethyl acetate (50 ml) and the solution washed with water (2 × 25 ml), dried over anhydrous sodium sulphate and eva-porated in vacuo. The residue was dissolved in a mixture of ethyl acetate and ether and a 2.5 M methanolic HCl solution (2.5 ml) was added. The precipitate formed upon storage at 4°C for 4 h was filtered off and recrystallized from ethanol-ether to give 1.2 g of the title compound. Mp 141-142°C.
Anal . : Calc for C18H21NO2, HCl:
C, 67,60; H, 6.93; Cl, 11.08; N, 4.38.
Found: C, 67.50; H, 6.97; Cl, 11.02; N, 4.36.
***
EXAMPLE 29
Phenyl 3-[4-methylpiperazin-1-yl)methyl]benzoate, dihydrochloride The compound was prepared from phenyl 3-chloromethyl-benzoate and 1-methylpiperazine by essentially the same procedure as described in Example 28. After recrystallization from methanol, the yield was 75%. Mp 259-261°C.
Anal . : Calc. for C19H22N2O2 2 HCl:
C, 59.69; H, 6.33; Cl, 18.55; N, 7.33.
Found: C, 59.57; H, 6.40; Cl, 18.53; N, 7.31.
*** EXAMPLE 30 β-Estradiol 3- (3-chloromethyl)benzoate
To a stirred mixture of β-estradiol (2.72 g, 10 mmol) and triethylamine (1.6 ml, 11 mmol) in acetone (50 ml) was added 3-chloromethylbenzoyl chloride (1.57 ml, 11 mmol). The mixture was stirred at 20-25°C for 20 h, filtered and evaporated in vacuo. The solid residue obtained was recrystallized from ethanol-acetone-water to yield 3.2 g of the title compound. Mp 144-145ºC .
Anal . : Calc. for C26H29CIO3:
C, 73.48; H, 6.88; Cl, 8.34.
Found: C, 73.28; H,'6.86; Cl, 8.45.
EXAMPLE 31 β-Estradiol 3- (3-N,N-diethylaminomethyl)benzoate, hydrochloride
A mixture of β-estradiol 3-(3-chloromethyl)benzoate (425 mg, 1 mmol), sodium iodide (150 mg, lmmol), diethylamine (0.83 ml, 8 mmol) and acetone (10 ml) was stirred at 60°C for 5 h. The reaction solution was cooled to room temperature, filtered and evaporated in vacuo. The residue obtained was taken up in ethyl acetate (50 ml) and the solution washed with water (2 × 25 ml), dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was dissolved in ethyl acetate and ether and a 2.5 M methanolic HCl solution (0.5 ml) was added. The precipitate formed upon storage at 4°C for 4 h was filtered off and recrystallized from ethanol-ether to give 0.38 g of the title compound. Mp 240-241°C.
Anal . : Calc. for C30H39NO3, HCl:
C, 72.34; H, 8.09; Cl, 7.12; N, 2.81.
Found: C, 72.44; H, 8.12; Cl, 7.10; N, 2.78.
*** EXAMPLE 32 β-Estradiol 3-[3- (4-methylpiperazin-1-yl)methyl]benzoate, dihydrochloride
The compund was prepared from β-estradiol 3-(3-chloro-methylbenzoate and 1-methylpiperazine by essentially the same procedure as described in Example 31. After recrystallization from ethanol-ether, the yield was 55%. Mp 254-255°C.
Anal . : Calc for C31H40N O3, 2 HCl:
C, 66.30; H, 7.54; Cl, 12.63; N, 4.99.
Found: C, 66.20, H, 7.60; Cl, 12.55; N, 4.92.
***
EXAMPLE 33
3- (3-Chloromethylbenzoyloxymethyl)phenytoin
3-Chloromethylbenzoyl chloride (3.12 ml, 22 mmol) was added to a solution of 3-(hydroxymethyl)phenytoin (5.65 g, 20 mmol) (prepared as described by Zejc (1968)) and triethylamine (4.2 ml, 30 mmol) in 60 ml of dichloromethane. The mixture was stirred for 5 h at 20 °C, washed with a 2% aqueous solution of sodium bicarbonate and water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was recrystal-lized from ether-ethanol-petroleum ether to give 6.8 g of the title compound. Mp 117-118βC.
Anal . : Calc. for C24H19ClN2O4:
C, 66.29; H, 4.40; Cl, 8.15; N, 6.44.
Found: C, 66.28, H, 4.30; Cl, 8.10; N, 6.51.
*** EXAMPLE 34
3- (3-N,N-Diethylaminomethylbenzoyloxymethyl)phenytoin, hydrochloride
A mixture of 3-(3-chloromethylbenzoyloxymethyl)phenytoin (0.87 g, 2 mmol), sodium iodide (150 mg, 1 mmol), diethylamine (0.83 ml, 10 mmol) and acetone (20 ml) was stirred at 60°C for 6 h. The mixture was cooled to room temperature, filtered and evaporated in vacuo. The residue obtained was dissolved in ethyl acetate (50 ml) and the solution washed with water (2 × 30 ml) , dried over anhydrous sodium sulphate and evaporated in vacuo. The residue of the evaporation was dissolved in ethyl acetate and ether and a 2.5 M methanolic HCl solution (0.5 ml) added. The precipitate formed upon storage at -20°C for 20 h was filtered off and recrystallized from acetone-ether to give 0.62 g of the title compound. Mp 113-115°C (dec).
Anal . : Calc. for C28H29N3O4, HCl:
C, 66.20; H, 5.95; Cl, 6.98; N, 8.27.
Found: C, 66.22; H, 5.90; Cl, 6.93; N, 8.24
***
EXAMPLE 35
Pregnanolone 3- (3-N,N-diethylaminomethyl)benzoate, hydrochloride A mixture of pregnanolone 3-(3-chloromethyl)benzoate (471 mg, 1 mmol), sodium iodide (150 mg, 1 mmol), diethylamine (0.83 ml, 8 mmol) and 10 ml of acetone was stirred at 60°C for 6 h. It was cooled to 25°C, filtered and evaporated in vacuo. The residue obtained was taken up in ethyl acetate (50 ml) and the solution washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was dissolved in ethyl acetate and ether and a 2.5 M methanolic HCl solution (0.5 ml) added. The precipitate formed upon storage at -20°C for 24 h was filtered off and recrystallized from ethanol-ether to give 0.37 g of the title compound.
Anal . : Calc. for C33H49NO3, HCl:
C, 72.83; H, 9.26; Cl, 6.51; N, 2.57
Found: C, 72.76; H, 9.35; Cl, 6.48, N, 2.58. The starting material, pregnanolone 3-(3-chloromethyl) -benzoate was prepared from pregnalonone (pregnan-3α-ol-20-one) and 3-chloromethylbenzoyl chloride by essentially the same procedure as described in
Example 1.
***
EXAMPLE 36
Pregnanolone 3- [3- (4-methylpiperazin-1-yl)methylJbenzoate, dihydrochloride
The compound was prepared from pregnanolone 3-(3-chloromethyl)benzoate and 1-methylpiperazine by essentially the same procedure as described in Example 35. After recrystallization from ethanol-ether, the yield was 67%.
Anal . : Calc. for C28H50N2O3, 2 HCl:
C, 62.79; H, 9.79; Cl, 13.24; N, 5.23.
Found: C, 62.55, H, 9.89; Cl, 13.20; N, 5.20.
***
EXAMPLE 37
1- (3-Chloromethylbenzoyloxymethyl)allopurinol
A mixture of 1-(hydroxymethyl)allopurinol (1.6 g, 10 mmol) (prepared as described by Bansal et al. (1981 b)) and
3-chloromethylbenzoyl chloride (1.85 ml, 13 mmol) in pyridine (20 ml) was stirred at room temperature for 3 h. Water (100 ml) was added, and after standing for 3 h at 5°C the precipitate was collected, washed with water and recrystallized from ethanol to give 2.0 g of the title compound. Mp 201-202βC.
Anal. : Calc. for C14H11ClN4O3:
C, 52.76; H, 3.48; Cl, 11.12; N, 17.58.
Found: C, 52.66, H, 3.49; Cl, 11.12; N, 17.56.
*** EXAMPLE 38
1 - (3 -Imidazolylmethylbenzoyloxymethyl)allopurinol
A mixture of 1-(3-chloromethylbenzoyloxymethyl)-allopurinol (319 mg, 1 mmol) , sodium iodide (150 mg, 1 mmol) , imidazole (340 mg, 5 mmol) and 15 ml of acetone was stirred at 60°C for 5 h. The mixture was cooled to room temperature, filtered and evaporated in vacuo. The residue obtained was stirred with water (20 ml) for 2 h and the precipitate formed filtered off, washed with water and
recrystallized from ethanol-water to give 280 mg of the title compound.
Mp 148-150°C.
Anal . : Calc. for C17H14N6O3:
C, 58.28; H, 4.03; N, 23.99.
Found: C, 58.35; H, 4.04; N, 23.95.
***
EXAMPLE 39
3 - [3- (4-Methylpiperazin-1-ylmethyl)benzoyloxymethyl]phenytoin, dihydrochloride
The compound was prepared from 3-(3-chloromethyl-benzoyloxymethyl)phenytoin and 1-methylpiperazine by essentially the same procedure as described in Example 34.
After recrystallization from ethanol-ether, the yield was 65%. Mp 205-206°C.
Anal . : Calc. for C29H30N4O4, 2 HCl, H2O:
C, 59.09; H, 5.81; Cl, 12.03; N, 9.50.
Found: C, 59.11; H, 5.88; Cl, 12.00; N, 9.43
*** EXAMPLE 40
N- [3- (4-Methylpiperazin-1-ylmethyl)benzoyloxy-methyl]chlorzoxazone, dihydrochloride
The compound was prepared from N-(3-chloromethyl-benzoyloxymethyl)chlorzoxazone and 1-methylpiperazine by essentially the same procedure as described In Example 19. After recrystallization from methanol, the yield was 70%.
Mp 240-241°C.
Anal . : Calc. for C21H22CIN3O4, 2 HCl, H2O:
C, 49.77; H, 5.17; Cl, 20.99; N, 8.29.
Found: C, 49.62; H, 5.32; Cl, 20.90; N, 8.36.
EXAMPLE 41
Metronidazole 3-chloromethylbenzoate A solution of 3-chloromethylbenzoyl chloride (1.42 ml, 10 mmol) in methylene chloride (30 ml) was added dropwise to a mixture of metronidazole (1.71 g, 10 mmol), pyridine (1 ml), and methylene chloride (40 ml) . The resulting clear solution was stirred at room temperature for 20 h and evaporated in vacuo. The residue was stirred with 1M sodium carbonate for 15 min and the resulting solid was filtered off and washed with water to give 2.76 g (85%) of the title compound. After recrystallization from ethyl acetate-petroleum ether the compound melted at 78-80βC.
Anal . : Calc. for C14H14ClN3O4:
C, 51.94; H, 4.36; Cl, 10.95; N, 12.98.
Found: C, 51.73; H, 4.38; Cl, 11.14; N, 13.06.
*** EXAMPLE 42
Metronidazole 4-chloromethylbenzoate
The compound was prepared by a method analogous to that described in Example 41, starting from 2.57 g (15 mmol) of metronidazole and 4-chloromethylbenzoyl chloride (15 mmol). The crude product was purified by flash chromatography on silica gel (eluent: toluene containing ethyl acetate). Yield (from cyclohexane) : 3.01 g (62%). Mp 112-115°C. Anal . : Calc. for C14H14CIN3O4:
C, 51.94; H, 4.36; Cl, 10.95; N, 12.98.
Found: C, 51.77; H, 4.38; Cl, 11.25; N, 13.13
***
EXAMPLE 43
Metronidazole 3- (morpholinomethyl)benzoate
To a solution of metronidazole 3-chloromethylbenzoate (0.648 g, 2 mmol) in acetone (25 ml) were added morpholine (0.88 ml, 10 mmol) and sodium iodide (20 mg) . The mixture was stirred at room temperature for 20 h, filtered and evaporated in vacuo. Water (10 ml) was added to the residue and the mixture was extracted with methylene chloride (3 × 20 ml). The combined extracts were dried and evaporated in vacuo. Flash chromatography of the residue on silica gel (eluent: methylene chloride containing acetone) gave 0.59 g (79%) of the title compound as an oil. The difumarate was prepared by adding a solution of fumaric acid in 2-propanol and preci-pitating the salt with ether. Mp (from 2-propanol-ether) : 169-170°C.
Anal . : Calc. for C26H30N4O13 :
C, 51.49; H, 4.99; N, 9.24.
Found: C, 51.52; H, 4.92; N, 9.22.
*** EXAMPLE 44
Metronidazole 4- (morpholinomethyl)benzoate
A mixture of metronidazole 4-chloromethylbenzoate (648 mg, 2 mmol) , morpholine (0.88 ml, 10 mmol), sodium iodide (20 mg) and acetone (20 ml) was refluxed for 20 h. The reaction mixture was filtered and the filtrate was evaporated in vacuo. Water (20 ml) was added to the residue and the solid formed was collected and washed with water, yielding 625 mg (83%) of the title compound. Mp (from cyclohexane) : 98-99ºC.
Anal. : Calc. for C18H22N4O5:
C, 57.74; H, 5.92; N, 14.96
Found: C, 57.93; H, 5.96; N, 14.88.
The fumarate of the title compound melted at 144-146°C.
Anal.: Calc for C22H26N4O9:
C, 53.87; H, 5.34; N, 11.42.
Found: C, 53.57; H, 5.51; N, 11.21.
***
EXAMPLE 45
Metronidazole 3-dimethylaminomethylbenzoate The compound was prepared by a method analogous to that described in Example 43, from metronidazole 3-chloromethyl-benzoate (456 mg, 1.5 mmol), dimethylamlne (0.82 ml of a 33% solution in ethanol, 6 mmol), sodium iodide (20 mg) and ace-tone (20 ml). Treatment of the title compound with fumaric acid yielded the salt with 1.5 equivalent fumaric acid which crystallized from 2-propanol-ether with 0.25 mole of water: Mp 141-143°C.
Anal . : Calc for C22H26N4O10, 0.25 H2O:
C, 51.71; H, 5.22; N, 10.96.
Found: C, 51.64; H, 5.26; N, 10.94.
*** EXAMPLE 46
Metronidazole 4-dimethylaminomethylbenzoate
The compound was prepared by a method analogous to that described in Example 43. The title compound was recrystallized from etherpetroleum. Mp 73-74°C.
Anal . : Calc. for C16H20N4O4:
C, 57.82; H, 6.07; N, 16.86.
Found: C, 57.73; H, 6.10; N, 16.75.
EXAMPLE 47
Metronidazole 3- [ (4-methylpiperazin-1-yl)methyl]benzoate
A mixture of metronidazole 3-chloromethylbenzoate (648 mg, 2 mmol), N-methylpiperazine (1.12 ml, 10 mmol), sodium iodide (20 mg) and methylene chloride (25 ml) was refluxed for 20 h. The reaction mixture was washed with water (2 × 25 ml), dried and evaporated in vacuo. To the residue was added a solution of 464 mg (4 mmol) of fumaric acid in 2-propanol (12 ml) followed by ether precipitating the difumarate of the title compound with 0.5 equivalent of water. Yield: 754 mg (60%). Mp 179-182°C.
Anal . : Calc . for C27E33N5O12 , 0.5 H2O:
C, 51.59; H, 5.45; N, 11.14;
Found: C, 51.56; H, 5.60; N, 11.15.
***
EXAMPLE 48
Metronidazole 4- [(4-methylpiperazin-1-yl)methyl]benzoate
The compound was prepared by a method analogous to that described in Example 47. The yield of the difumarate of the title compound was 52%. Mp 193-194ºC.
Anal. : Gale, for C27H33N5O12:
C, 52.34; H, 5.37; N, 11.30.
Found: C, 52.10; H, 5.57; N, 11.12.
***
EXAMPLE 49
4-Acetamidophenyl 4-Chloromethylbenzoate
A mixture of 4-chloromethylbenzoic acid (2.6 g, 15 mmol) and thionyl chloride (12 ml) was refluxed for 90 min. The solution was evaporated in vacuo and the residue dissolved in methylene chloride (45 ml). This solution was added dropwise to a mixture of paracetamol
(2.27 g, 15 mmol), pyridine (1.5 ml, 19 mmol) and methylene chloride (60 ml). After stirring at room temperature for 20 h, the reaction mixture was evaporated in vacuo. Water (20 ml) was added to the residue and the precipitate collected. Recrystallization from ethyl acetate yielded 2.6 g (57%) of the title compound. Mp 217-218ºC. Anal . : Calc for C16H14ClNO3:
C, 63.27; H, 4.65; Cl, 11.67; N, 4.61.
Found: C, 63.33; H, 4.79; Cl, 11.63; N, 4.66.
EXAMPLE 50
4-Acetamidophenyl 4- (morpholinomethyl)benzoate
A mixture of 4-acetamidophenyl 4-chloromethylbenzoate (304 mg, 1.0 mmol), morpholine (0.44 ml, 5.0 mmol) and acetone was refluxed for 4 h. After filtration, the reaction mixture was evaporated in vacuo. Water (20 ml) was added to the residue and the precipitate collected. Yield of the title compound: 294 mg (83%). Mp (from toluene-eyelohexane) : 161-164°C. The hydrochloride of the title compound was prepared by adding a solution of HCl in ethyl acetate to a solution of the title compound in ethyl acetate. Mp (from methanol-ether): 252-256°C (dec).
Anal . : Calc . for C20H23CIN2O4:
C, 61.46; H, 5.93; Cl, 9.07; N, 7.17.
Found: C, 61.08; H, 5.86; Cl, 9.06; N, 7.04.
EXAMPLE 51
4-Acetamidophenyl 4-dimethylaminomethylbenzoate
A mixture of 4-acetamidophenyl 4-chloromethylbenzoate (456 mg, 1,5 mmol), dimethylamine (1.0 ml of a 33% solution in ethanol, 7.3 mmol), sodium iodide (20 mg) and acetone (20 ml) was stirred for 20 h at room temperature. The reaction mixture was filtered and the filtrate evaporated in vacuo. Water (10 ml) was added to the residue and the precipitate was collected, dried and suspended in ethyl acetate. A solution of HCl in ethyl acetate was added to give the hydrochloride of the title compound [306 mg (58%)]. Mp (from methanol): 256-259°C.
Anal . : Calc. for C18H21ClN2O3 :
C, 61.98; H, 6.07; Cl, 10.17; N, 8.03.
Found: C, 62.05; H, 6.05; Cl, 10.07; N, 7.98.
The title compound was also prepared by the following method:
A mixture of 4-(N,N-dimethylaminomethyl)benzoic acid hyd-rochloride (562 mg, 2.6 mmol), paracetamol (395 mg, 2.6 mmol), p-toluenesulfonic acid (40 mg), N,N' -dicyclohexyl-carbodiimide (622 mg, 3 mmol) and pyridine (10 ml) was stirred at room temperature for 20 h. Metylene chloride (20 ml) was added to the reaction mixture. The mixture was filtered and the filtrate evaporated in vacuo. Ethyl acetate (20 ml) was added to the residue , and after filtration a solution of HCl in ethyl acetate was added to the filtrate. The precipitate (348 mg, 37%) was shown to be Identical (IR-spectrum and mp) with the compound prepared in the example above.
***
EXAMPLE 52
4-Acetamidophenyl 4-[(4-methylpiperazin-1-yl)methyl]benzoate
The compound was prepared by a method analogous to that described in Example 51 (1st part). The yield of the title compound was 80% , mp (from ethyl acetate-petroleum):
181-183°C.
Anal . : Calc. for C21H25N3O3 :
C, 68.64; H, 6.86; N, 11.44.
Found: C, 68.35; H, 6.85; N, 11.31.
***
EXAMPLE 53
4-Acetamidophenyl 4- trimethylammoniomethylbenzoate iodide
A mixture of 4-acetamidophenyl 4-dimethylaminomethyl-benzoate (0.23 g, 0.74 mmol), methyl iodide (0.5 ml, 7 mmol) and methanol (5 ml) was stirred at 50°C for 4 h. After cooling ether (10 ml) was added and the title compound was collected [0.31 g (92%)].
Mp (from ethanol): 231-235°C (dec).
Anal. : Calc. for C19H23IN2O3:
C, 50.23; H, 5.10; N, 6.17.
Found: C, 50.36; H, 5.20; N, 6.15.
*** EXAMPLE 54
Metronidazole 4- trimethylammoniomethylbenzoate iodide
The compound was prepared from metronidazole 4-dimethylaminomethylbenzoate (60 mg, 0.18 mmol) by the method described above in Example 53. Yield: 76 mg. Mp 203-206°C (dec.)
EXAMPLE 55
1 - (4-Chloromethylbenzoyloxymethyl)allopurinol
A solution of 4-chloromethylbenzoyl chloride (prepared from 4-chloromethylbenzoic acid (5.12 g, 30 mmol) by refluxing with thionylchloride) in methylene chloride (6 ml) was added to a suspension of 1-(hydroxymethyl)allopurinol (3.84 g, 24 mmol) in pyridine (60 ml). The mixture was stirred at room temperature for 3 h and filtered. The filtrate was evaporated in vacuo to half-volume and water (100 ml) was added. The precipitate formed (5.97 g, 62%) was collected and recrystallized from 2-propanol-DMF to give the pure title compound. Mp 245-247°C.
Anal . : Calc . for C14H11ClN4O3 :
C, 52.76; H, 3.48; Cl, 11.13; N, 17.58
Found: C, 52.70; H, 3.63; Cl, 11.00; N, 17.42
***
EXAMPLE 56
1- (4-Morpholinomethylbenzoyloxymethyl)allopurinol , hydrochloride
A mixture of 4-morpholinomethylbenzoic acid hydrochloride (1.29 g, 5.0 mmol) and thionylchloride (10 ml) was refluxed for 1 h and then evaporated in vacuo. Pyridine (25 ml) and 1- (hydroxymethyl)allopurinol (0.83 g, 5.0 mmol) were added to the residue and the mixture was stirred at room temperature for 30 h. The precipitate was collected and suspended in water (20 ml). Hydrochloric acid was added to pH 4 and after stir-ring for 30 min. the mixture was filtered and the filtrate evaporated in vacuo. The residue (0.80 g, 38%) was recrystallized from methanol-ethanol (1:1) to give the monohydrate of the title compound. Mp 210-213ºC.
Anal . : Calc for C18H19N5O4, HCl, H2O:
C, 51.01; H, 5.23; Cl, 8.37; N, 16.52
Found: C, 50.68; H, 5.40; Cl, 8.31; N, 16.55.
The title compound was also prepared by the following method: A mixture of 1-(hydroxymethyl)allopurinol (448 mg, 3 mmol), 4-morpholinomethylbenzoic acid hydrochloride (771 mg, 3 mmol), N,N'-dicyclohexylcarbodiimide (618 mg, 3 mmol) , p-toluene-sulfonic acid (40 mg) and pyridine (10 ml) was stirred at room temperature for 20 h. Methylene chloride (20 ml) was added to the reaction mixture. After stirring for 2 h the mixture was filtered, and the filtrate evaporated in vacuo. The residue was dissolved in ethanol (10 ml) and excess of hydrochloric acid in ethyl acetate was added, precipitating the title compound (138 mg, 33%) . It was identical (IR-spectrum, mp and TLC) with the compound described above. A third method of preparing the title compound is the following:
A mixture of 1-(4-chloromethylbenzoyloxymethyl)allopurinol (478 mg, 1.5 mmol), morpholine (0.53 ml, 6 mmol), sodium iodide (10 mg) and N,N-dimethylformamide (5 ml) was stirred at 50°C for 5 h. The mixture was filtered and the filtrate evaporated in vacuo. The residue was dissolved in methylene chloride (50 ml) and the solution was washed twice with water, dried and evaporated. The residue was recrystallized from ethanol to give the title compound (409 mg, 74%) as the base. Mp 174-176°C.
The hydrochloride was prepared by adding a solution of hydrochloric acid in ethyl acetate to a solution of the base in ethanol. The precipitate was shown to be identical (IR-spectrum, mp and TLC) to the compounds prepared by the two other methods above. EXAMPLE 57
1 - (3 -Morpholinomethylbenzoyloxymethyl)allopurinol
Morpholine (0.53 ml, 6 mmol) and sodium iodide (10 mg) were added to a solution of 1-(3-chloromethylbenzoyloxymethyl)-allopurinol (478 mg, 1.5 mmol) in N,N-dimethylformamide (5 ml). The mixture was stirred at 50°C for 5 h and left at room temperature for 20 h. After evaporation in vacuo methylene chloride (30 ml) was added to the residue and the solution was washed twice with water, dried and evaporated. The residue was crystallized from ethyl acetate to give the title compound (307 mg, 55%). Mp 126-128°C.
Anal . : Calc. for C18H19N5O4:
C, 58.53; H, 5.18; N, 18,96.
Found: C, 58.14; H, 5.20; N, 18.72.
***
EXAMPLE 58
1- [3- (4-Methylpiperazin-1-yl)methylbenzoyloxymethyl] -allopurinol
The compound was prepared from 1-(3-chloromethylbenzoyl-oxymethyl)allopurinol (1.5 mmol) and 1-methylpiperazine (6 mmol) by essentially the same procedure as described in Example 57. The compound crystallized from ethyl acetate with 2/3 mol of ethyl acetate. The yield was 46%. Mp 129-131°C.
Anal.: Calc. for C19H22N6O3 2/3 C4H8O2:
C, 58.99; H, 6.24; N, 19.05.
Found: C, 59.08; H, 6.25; N, 19.17. The fumarate was prepared by adding a solution of fumaric acid in 2-propanol. The salt was recrystallized from 2-propanol-ethanol. Mp 212-214°C. Anal.: Calc. for C23H26N6O7. 0.25 H2O:
C, 54.92; H, 5.31; N, 16.71.
Found: C, 55.05; H, 5.39; N, 16.53.
***
EXAMPLE 59
1-[4- (4-Methylpiperazin-1-yl)methylbenzoyloxymethyl]-allopurinol
The compound was prepared from 1-(4-chloromethylbenzoyl-oxymethyl)allopurinol (3 mmol) and 1-methylpiperazine (12 mmol) by essentially the same procedure as described in Example 57. The compound was crystallized from 2-propanol-ethyl acetate. The yield was 29%.
Mp 190-192°C.
Anal . : Calc. for C19H22N6O3:
C, 59.67; H, 5.80; N, 21.98.
Found: C, 59.42; H, 5.88; N, 21.87.
***
EXAMPLE 60
2 ,5- [bis- (3 -Chloromethylbenzoylmethyl)]allopurinol
A mixture of 2, 5-bis(hydroxymethyl)allopurinol (4.0 g, 20 mmol) (prepared as described by Bansal et al. (1981b)) and 3-chloromethylbenzoyl chloride (3.70 ml, 26 mmol) In pyridine (40 ml) was stirred at room temperature for 4 h. Water (200 ml) was added, and after standing for 20 h at 5°C the preei-pitate was collected, washed with water and recrystallized from ethanol to give 5.9 g of the title compound. Mp 198-199°C.
Anal. : Calc. for C23H18Gl2N4O5 :
C, 55.10; H, 3.62; Cl, 14.14; N, 11.18.
Found: C, 55.15; H, 3.55; Cl, 14.17; N, 11.17.
*** EXAMPLE 61
2 ,5- [bis-(3-Morpholinomethylbenzyloxymethyl)]allopurinol
A mixture of 2,5-[bis-(3-chlormethylbenzoyloxymethyl)]-allopurinol (501 mg, 1 mmol), morpholine (0.53 ml, 6 mmol), sodium iodide (10 mg) and acetone (20 ml) was refluxed for 6 h. After filtration and evaporation of the filtrate methylene chloride (25 ml) was added to the residue. The solution was washed with water, dried and evaporated. The residue was crystallized from ethyl acetate to give the title compound (371 mg) as the monohydrate. Mp 88-90°C.
Anal . : Calc. for C31H34N6O7, H2O:
C, 60.00; H, 5.85; N, 13.54.
Found: C, 60.24; H, 5.98; N, 13.48.
***
EXAMPLE 62 9- [[2- (4-Morpholinomethylbenzoyl)oxy]ethoxymethyl]quanine, hydrochloride
To a solution of 4-morpholinomethylbenzoyl chloride hydrochloride (prepared from 4-morpholinomethylbenzoic acid hydrochloride (514 mg, 2.0 mmol)) in pyridine (15 ml) was added aciclovir (480 mg, 2.0 mmol) and the mixture was stirred at room temperature for 20 h. The reaction mixture was filtered and the filtrate evaporated in vacuo.
Fractional crystalli-zations of the residue from methanol containing increasing amounts of acetonitrile afforded the title compound. Thinlayer chromatography on silica gel (Merck) :
Rf = 0.19 (butanol -acetic acid -water [4:1:1]).
*** EXAMPLE 63
9-[[2- (4-Morpholinomethylbenzoyl)oxy]ethoxymethyl]guanine
To a mixture of aciclovir (1.92 g, 8 mmol) in 65 ml of pyridine was added 4-morpholinomethylbenzoyl chloride hydrochloride (12 mmol) in four portions over 10 min. The mixture was stirred at room temperature for 20 h and then evaporated in vacuo. The residue obtained was slurried in 25 ml of water and the mixture filtered. Sodium hydroxide (2 M) was added to the filtrate to pH 9±0.2. Upon standing at 4°C for 5 h, the precipitate formed was filtered off, washed with water and recrystallized from ethanol-water to give 1.8 g of the title compound as the monohydrate. Mp 218-220βC.
Anal . : Calc. for C20H24N6O5, H2O:
C, 53.81; H, 5.87; N, 18.82
Found: C, 54.01; H, 5.93; N, 18.92
***
EXAMPLE 64
9-[[2- (4-Dimethylaminomethylbenzoyl)oxy]ethoxymethyl]guanine
The compound was prepared from aciclovir and 4-dimethylaminomethylbenzoyl chloride hydrochloride by the method described above in Example 63. Yield: 75%. Mp 185-186ºC (from ethanol-water).
Anal . : Calc. for C18H22N6O4, 1-5 H2O:
C, 52.30; H, 6.08; N, 20.33
Found: C, 52.48; H, 5.99; N, 20.33
*** EXAMPLE 65
9-[[2- (3-Dipropylaminomethylbenzoyl)oxy]ethoxymethylguanine
The compound was prepared from aciclovir and 3-diρropylaminomethyl benzoyl chloride hydrochloride by the method described in Example 63. Yield: 79%. Mp 195-197°C (from ethanol-water).
Anal . : Gale , for C22H30N6O4, 0.75 H2O:
C, 57.94; H, 6.96; N, 18.43
Found: C, 57.80; H, 7.02; N, 18.41
***
EXAMPLE 66
9- [1 ,3 - (Dimorpholinomethylbenzoyloxy) -2-proproxy)methylguanine
To a mixture of ganciclovir (1.18 g, 5 mmol) in 50 ml of pyridine was added 4-morpholinomethylbenzoyl chloride hydrochloride (15 mmol) in four portions over 10 min. The mixture was stirred at room temperature for 20 h and then evaporated in vacuo. The residiue obtained was slurried in 50 ml of water and the mixture filtered. Sodium hydroxide (2 M) was added to the filtrate to pH 8.5. Upon standing at 4ºC for 5 h the precipitate formed was filtered off, washed with water and recrystallized from ethanol-water to give 1.4 g of the title compound as the hemihydrate. Mp 204-205°C.
Anal . : Calc. for C33H39N7O8 0.5 H2O:
C, 59.10; H, 6.01; N, 14.62
Found: C, 59.09; H, 6.11; N, 14.70
***
EXAMPLE 67
9- [ (1 ,3 - [4-Dimethylaminomethylbenzoyl)oxy-2-propoxy)methyl]guanine
The compound was prepared from ganciclovir and 4-dimethylaminomethylbenzoyl chloride hydrochloride by the method described above in Example 66. Yield: 70%. Mp 109-110°C (from ethanol-water). Anal . : Calc for C29H35N7O6 , 2.5 H2O:
C , 55.94; H, 6.47 ; N, 15.75
Found: C, 56.04; H, 6.44; N, 15.65
***
EXAMPLE 68
9 - [ (1 ,3 - (4-Diethylaminomethylbenzoyl)oxy-2-proproxy)methyl]guanine
The compound was prepared from ganciclovir and 4-diethylaminomethylbenzoyl chloride hydrochloride by the method described in Example 66. Yield: 65%. Mp 150-152°C.
Anal. : Calc. for C33H43N7O6, 0.75 H2O:
C, 61.24; H, 6.93; N, 15.15
Found: C, 61.14; H, 7.02; N, 15.11
***
EXAMPLE 69 1 ,3-Dipropyl-8(-p- (4-dimethylaminomethylbenzoyl)oxyphenyl)xanthine
To a suspension of 1,3-dipropyl-8(p-hydroxyphenyl)xanthine (1.65 g, 5 mmol) in pyridine (30 ml) was added with stirring 4-(N,N-dimethylaminomethyl)benzoyl chloride hydrochloride (7 mmol). The mixture was stirred at room temperature for 20 h and then evaporated in vacuo. The residue was dissolved in water (50 ml) and sodium hydroxide (2 M) was added to pH 8.5-9. Upon standing at 4ºC for 4 h the precipitate formed was filtered off, washed with water and recrystallized from acetone-water to give 1.96 g (80% yield) of the title compound. Mp 255-256°C.
Anal. : Calc for C27H31N5O4:
C, 66.24; H, 6.38; N, 14.31
Found: C, 66.15; H, 6.34; N, 14.24. The hydrochloride salt of the title compound was prepared as follows : To a solution of the title compound (490 mg, 1 mmol) in acetone (30 ml) was added 0.5 ml of a 2.5 M methanolic HCl solution. The solution was evaporated in vacuo and the residue obtained recrystallized from ethanol (about 30 ml) with the addition of two drops of water. Mp 247-249°C.
Anal . : Calc for C27H32ClN5O4, 0.25 H2O:
C, 61.13; H, 6.17; N, 13.20
Found: C, 61.15; H, 6.24; N, 13.14 ***
EXAMPLE 70
1 ,3 -Dipropyl -8 (-p- (3 - dipropylaminomethylbenzoyl)oxyphenyl)zanthine
The compound was prepared from 1 , 3-dipropyl-8-(p-hydroxyphenyl)xanthine and 3(N,N-dipropylaminomethyl)benzoyl chloride hydrochloride by the method described above in Example 69. Yield: 73%. Mp 194-195°C (from N,N-dimethylformamide-ethanol).
Anal . : Calc for C31H39N5O4:
C, 68.23; H, 7.20; N, 12.83
Found: C, 68.20; H, 7.12; N, 12.82 The hydrochloride salt was prepared as described in Example 69. Mp 151-153°C (from ethanol).
Anal . : Calc. for C31H40ClN5O4, H2O:
C, 62.04; H, 7.05; N, 11.67
Found: C, 61.96; H, 7.19; N, 11.51
***
EXAMPLE 71
N -Methyl -N- (4-morpholinomethylbenzoyl)acetazolamide , hydrochloride
To a suspension of N-methylacetazolamide (0.95 g, 4 mmol) in pyridine (10 ml) was added 4-(morpholinomethyl)benzoyl chloride hydrochloride (5 mmol). The mixture was stirred at 70°C for 4 h and then evaporated in vacuo. Water (50 ml) was added to the residue followed by sodium hydroxide (2 M) to give a pH of 8-8.5. The precipitate formed was filtered off, washed with water and recrystallized from acetone- water. The compound (0.64 g, 1.45 mmol) was slurried in acetone (30 ml) and 1 ml of 2.5 M methanolic HCl was added. Ether was added to the solution to slight turbidity. Upon standing at -18°C overnight the precipitate formed was filtered off and washed with ether to give 0.59 g of the title compound as the monohydrate. Mp. 116-117°C.
Anal . : Calc for C17H22ClN5O5S2,H2O:
C, 41.34; H, 4.89; N, 14.18
Found: C, 41.49; H, 5.01; N, 14.01
***
EXAMPLE 72 4-Acetamidophenyl 4- (tert. -butoxycarbonylaminomethyl)benzoate
A mixture of 4-(tert. -butoxycarbonylaminmethyl)benzoic acid (2.58 g, 10 mmol) cf. J.Med.Chem.29 (1986) 448), paracetamol (1.5 g, 10 mmol), p-toluensulfonic acid (150 mg), N,N' -dicyclohexylcarbodiimide (2.06 g, 10 mmol) and pyridine (30 ml) was stirred at room temperature for 24 h. Methylene chloride (60 ml) was added to the reaction mixture. The mixture was filtered and the filtrate evaporated in vacuo. The residue was extracted with two 60 ml portions of warm methylene chloride and the extracts were evaporated. The residue was recrystallized from methanol to give 0.73 g (19%) of the title compound. Mp. 205-208°C.
Anal . z Calc. for C21H24N2O5 :
C, 65.61; H, 6.29; N, 7.29
Found: C, 65.71; H, 6.31; N, 7.23 EXAMPLE 73
4-Acetamidophenyl 4-aminomethylbenzoate, hydrobromide
A mixture of 4-acetamido 4-(tert.-butoxycarbonylaminomethyl)benzoate (190 mg, 0.5 mmol) and a 48% solution of hydrobromic acid in glacial acetic acid (2.0 ml) was stirred at room temperature for 2 min. Ethyl acetate (20 ml) was added and the stirring was continued for 5 min. The mixture was evaporated in vacuo and the residue recrystallized from methanol to give 130 mg (71%) of the title compound. Mp 273-276°C.
Anal . : Calc. for C16H16N2O3HBr:
C, 52,62; H, 4.69; N, 7.67; Br 21.88
Found: C, 52,64; H, 4.82; N, 7.65; Br, 21.77
EXAMPLE 74
4- [2- (Morpholino) ethyl]benzoic acid, hydrochloride A mixture of 4-(2-chloroethyl)benzoic acid (1.84 g, 10 mmol), morpholine (4.36 ml, 50 mmol), sodium iodide (0.1 g) and N,N-dimethylacetamide was heated at 125°C for 48 h. The mixture was evaporated in vacuo. The residue was dissolved in 2 M sodium hydroxide (25 ml) and the solution was washed with ether (3 × 25 ml) . The aqueous solution was acidified with hydrochloric acid and evaporated. The residue was extracted with boiling ethanol (2 × 50 ml) and the ethanol was evaporated. Recrystallization of the residue from ethanol gave 0.71 g (26%) of the title compound. Mp 267-270°C.
Anal . : Calc. for C13H17NO3, HCl:
C, 57.46; H, 6.68; N, 5.16; Cl. 13.05
Found: C, 57.42; H, 6.81; N, 5.15; Cl. 12.93 *** EXAMPLE 75
4-Acetamidophenyl 4- [2- (morpholino) ethyl] benzoate, hydrochloride
A mixture of 4- [2-(morρholino)ethyl]benzoic acid (544 mg, 2.0 mmol) and thionyl chloride (5 ml) was refluxed for 1 h. The mixture was evaporated In vacuo. Pyridine (15 ml) was added dropwise to the residue followed by paracetamol (302 mg, 2.0 mmol). The mixture was stirred at room temperature for 20 h and evaporated in vacuo. The residue was triturated with 50% aqueous ethanol (5 ml) . The insoluble solid was recrystallized from methanol to give 480 mg (59% of the title compound. Mp 273-277°C.
Anal . : Calc. for C21H24N2O4, HCl:
C, 62.29; H, 6.22; N, 6.92; Cl, 8.76
Found: C, 62.32; H, 6.24; N, 6.88; Cl. 8.65
***
EXAMPLE 76
N ,N-Diethylcarbamoγlmethyl 2 -hydroxy-5-nitrobenzoate
A mixture of 2-hydroxy-5-nitrobenzoic acid (9.16 g, 50 mmol), 2-chloro-N,N-diethylacetamide (7.55 ml, 55 mmol), triethylamine (7.7 ml, 55 mmol), sodium iodide (0.75 g, 5 mmol) and N,N-dimethylformamide (40 ml) was stirred at 60ºC for 20 h. The mixture was poured into water (200 ml) and the precipitate formed filtered off, washed with water and recrystallized from ethyl acetate-light petroleum to give 8.0 g of the title compound. Mp 85-86°C.
Anal. : Calc . for C13H16N2O6:
C, 52.70; H, 5.44; N, 9.45
Found: C, 52.74; H, 5.47; N, 9.40.
*** EXAMPLE 77
N ,N-Diethylcarbamoylmethyl 2- [4- (morpholinomethyl)benzoyloxy] -5- nitrobenzoate
A mixture of 4-(morρholinomethyl)benzoic acid hydrochloride (1.42 g, 5.5 mmol) and thionyl chloride (10 ml) was refluxed for 1 h. The solution was evaporated in vacuo. Methylene chloride (35 ml), N,N- diethylcarbamoylmethyl 2-hydroxy-5-nitro-benzoate (1.48 g, 5.0 mmol) and triethylamine (2.1 ml, 15 mmol) were added to the residue and the resulting solution was stirred at room temperature for 20 h. The reaction mixture was washed with water (30 ml), a 5% aqueous solution of sodium hydrogen carbonate (30 ml) and water (30 ml). After drying, the methylene chloride was evaporated in vacuo. The residue was triturated with ether (20 ml) and the solid compound formed was collected. Recrystallization from ethyl acetate-light petroleum gave 2.23 g (89%) of the title compound. Mp 119-121°C.
Anal . : Calc. for C25H29N3O8:
C, 60.11; H, 5.85; N, 8.41
Found: C, 60.00; H, 5.88; N, 8.31
*** EXAMPLE 78
N ,N -D iethylcarbamoylmethyl 2-[4- (morpholinomethyl)benzoyloxy] -5-aminobenzoate, hydrochloride
To a solution of N,N-diethylcarbamoylmethyl 2-[4-(morpholinomethyl)-benzoyloxy]-5-nitrobenzoate (500 mg, 1.0 mmol) in 0.05 N hydrochloric acid (20 ml) and ethanol (15 ml) was added platinium oxide (25 mg) and the mixture was hydrogenated for 1 h. The reaction mixture was filtered and evaporated in vacuo. The residue was recrystallized from acetonitrile-ethanol-ether to give 294 mg (57%) of the title compound. Mp 209-213°C.
Anal . : Calc. for C25H31N3O6, HCl, 0.5 H2O:
C, 58.30; H, 6.46; N, 8.16; Cl, 6.89
Found: C, 58.49; H, 6.44; N, 8.28; Cl, 6.99 EXAMPLE 79
Pregnanolone 3- (3-morpholinomethyl)benzoate, hydrochloride
A mixture of 3-(morpholinomethyl)benzoic acid hydrochloride (445 mg, 1.73 mmol) and thionyl chloride (4 ml) was refluxed for 45 min. The solution was evaporated in vacuo. Pyridine (15 ml) and pregnanolone (500 mg, 1.57 mmol) were aded to the residue and the mixture was stirred at room temperature for 20 h. The reaction mixture was evaporated in vacuo. Water (15 ml) was added to the residue and the mixture was extracted with ethyl acetate (3 × 20 ml). The organic extracts were dried and concentrated in vacuo. Ether (25 ml) was added followed by a solution of hydrochloric acid in ethyl acetate to precipitate the title compound. Recrystallization from methanol-ether gave 212 mg (24%) of the title compound. Mp 263-266°C.
Anal . : Calc. for C32H47NO4, HCl:
C, 71.00; H, 8.67; N, 2.51; Cl, 6.35
Found: C, 70.88; H, 8.67; N, 2.50; Cl, 6.15
***
OTHER EXAMPLES By following the procedures of the foregoing examples several more esters according to the invention are obtained. The structure of these derivatives are shown in Table 1 and 2.
BIOCONVERSION OF THE PRODRUGS To demonstrate the bioconversion of the compounds of formula I to the parent drug in plasma, samples of human plasma were diluted to 80% with 0.05 M phosphate buffer (pH 7.4) and warmed to 37°C in a water bath. Aliquots of 100 μl of aqueous or ethanolie solutions of the prodrug derivatives were added to 5.00 ml of the plasma samples , the initial concentration of the derivatives being about 10-4M. At various times aliquots of 250 μl of the solutions were withdrawn and deproteinized by mixing with methanol, acetonitrile or a 1% ZnSO4 solution (methanol-water 1:1). After centrifugation, the clear supernatant was analyzed by HPLC for remaining derivative as well as for parent drug .
In the HPLC method a reversed-phase Supelcosil LC-8DB column (3.3 x 4.6 mm) was eluted at ambient temperature with mixtures of 0.1% phosphoric acid, methanol and acetonitrile, the composition of the eluent being adjusted for each compound to provide an appropriate retention time and separation of the prodrug and the parent drug. Occasionally, triethylamine was added to the eluent in a concentration of 10-4 M in order to improve peak shape. The flow-rate was 1.0 ml/min and the column effluent was monitored spectrophotometrically at an appropriate wavelength. Quantitation of the compounds was done by measurement of the peak heights in relation to those of standards chromatographed under the same conditions.
The various prodrug derivatives were found to be cleaved quantitatively to the parent drugs in human plasma solutions. An example is shown in Fig. 1. In all cases, the cleavage of the derivatives displayed strict first-order kinetics. An example is shown in Fig. 2. The half-lives of hydrolysis of various derivatives in 80% human plasma solutions at 37°C are given in Table 1 and 2. As can be seen from the data thederivatives are readily converted to the parent drugs at conditions similar to those prevailing in-vivo.
A demonstration of the enzymatic conversion of the derivatives in plasma is provided by the fact that the half-lives of hydrolysis of the derivatives in Table 1 and 2 in the absence of plasma, i.e. in a pH 7.4 phosphate buffer at 37°C, exceeded 200-400 h. The results in Tables 1 and 2 show that it is quite feasible to select prodrug derivatives of the present inven-tion with varying rates of plasma-catalyzed regeneration of a certain parent drug. If the aim is to obtain a very rapid rate of hydrolysis in-vivo for e . g . metronidazole prodrugs , the 4- (morpholinomethyl)benzoate ester of metronidazole is a preferred derivative since its half-life of hydrolysis in plasma is only 0.4 min.
Stability in aqueous solution
The novel compounds of the present invention were found to exhibit at very high stability in aqueous solutions of pH 3-5, thus affording long term storage af solutions of said novel compounds. The stability of the compounds was assessed by keeping aqueous buffer solutions of the compounds at constant temperatures and analyze the solutions for intact prodrug derivative as well as parent drug formed by the HPLC methods mentioned above. The pH of the solution was found to have a marked impact on the stability as seen from the pH-rate profile for a hydrocortisone prodrug in Fig. 3. Maximal stability for the compounds of the present invention generally occurs in the pH-range 3-5 at which pH values high solubilities of the compounds also are achieved due to protonation of their amino function(s) .
By performing stability studies at these pH values at dif-ferent temperatures shelf-lives in excess of two years at 25°C were predicted. For example, the hydrocortisone prodrug the pH-rate for degradation of which is shown in Fig. 3 was to possess a shelf-life in aqueous solutions of pH 4.0 of 6.0 and 10.2 years at 25 and 20°C, respectively. The stability or shelf-life of solutions of compounds of the present invention can be prolonged by decreasing the storage temperature, e.g. to temperatures from 4 to 20ºC.
A remarkable feature of the compounds of the present invention with regard to providing highly stable aqueous solutions is the solubilizing capacity of the compounds for their parent drugs. Thus, whereas the solubility of hydro-cortisone in water is 0.40 mg/ml at 21°C, the solubility was found to be increased to 3.5 mg/ml in a 10% w/v solution of the prodrug hydrocortisone 21-[3-(4-methylpiperazin-1-ylmethyl)]benzoate dihydrochloride. This unexpected behaviour greatly prolongs the shelf-life of aqueous prodrug solutions in cases where the shelf-life is limited by precipitation of parent drug formed upon hydrolysis rather than loss in prodrug. As indicated above, the compounds of Formula I exhibit the highest stability in water when pH of their solution is maintained in the range 3-5. Most advantageously, buffers can be employed to maintain the pH at or near the desired level throughout the shelf-life of the formulation. Suitable buffers are those which are physiologically acceptable and exhibit sufficient buffer capacity in the pH range 3-5, e.g. acetate, citrate, succinate or phthalate buffers. The quantity of buffer used is determined by means known in the art and will depend on the pH desired, the concentration of the solution, and the buffering capacity of the buffer.
Water solubility and lipophilicity of the prodrugs
of this invention
The amine-containing prodrugs of this invention were found to be highly soluble in water when present in salt forms. Solubilities of hydrochloride or fumarate salts were generally found to exceed 15% w/v. The solubilities were assessed by rotating mixtures of excess amounts of the compounds in water for 24-28 h and analyzing an aliquot of the filtered saturated solutions for prodrug derivative by HPLC. The lipophilicity of the derivatives of the present invention was assessed by measuring the apparent partition coefficients (P) of the compounds between octanol and 0.02M phosphate buffer of pH 7.4. The log P values for some compounds of the present invention are shown in Table 3. The results obtained show clearly that it is readily feasible to obtain prodrug derivatives according to the present invention which at the same time possess both a much higher water solubility and a higher lipophilicity than the parent compound. Such improved properties are quite advantageous for enhanced delivery through various biomenbranes as stated before.
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
TABLE 3 .
Water solubilities (S) and partition coefficients (P) for allupurinol, aciclovir and various prodrugs.
Compound Sa log Pb
(mg/ml)
Allopurinol 0.50 - 0.55
1-(4-Morpholinomethylbenzoyloxymethyl)allopurinol, > 100 1.13 fumarate
1- (4-N,N-Dimethylaminomethylbenzoyloxymethyl)allopurinol, > 100 0.53 fumarate 1- [3-(4-Methylpiperazin-l-yl)- methyl)benzoyloxymethyl] allo> 100 0.97 purinol, fumarate
1-(3-Imidazolylmethylbenzo- yloxymethyl)allopurinol 0.97
Aciclovir 1.2 - 1.47
Aciclovir 4-morpholinomethylbenzoate, hydrochloride > 100 - 0.05 aAt 21°C.
Aciclovir 3-dipropylaminomethylbenzoate nitrate > 50 0.60
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Claims

Compounds of the formula I C
Figure imgf000095_0001
wherein D represents the dehydrogenated residue of a hydroxyl group- containing drug or D represents the dehydrogenated residue of an NH- acidic group-containing drug; the substituents in the phenyl ring
Figure imgf000095_0002
are in either meta- or para- position to each other;
the phenyl ring additionally may be substituted with one, two, three or four substituents selected from the group consisting of an alkyl group, a halogen, a hydroxyl group or an alkoxy group; m is an integer 0 or 1 ;
p is an integer of 0 or 1;
n is an integer from 1 to 4;
R1 is selected from the group consisting of hydrogen, an alkyl
group, an aryl group, an aralkyl group, a group having the formula -COOR5, wherein R5 is an alkyl or aralkyl group, or a carbamoyl group of the formula -CONR6R7, wherein R6 and R7 are the same or different and are hydro-gen, an alkyl group, or together with the adjacent nitrogen atom form a 4- , 5-, 6- or 7- membered heterocyclic ring, which in addition to the nitrogen may contain one or two further hetero-atoms selected from the group consisting of nitrogen, oxygen, and sulfur;
R2 is hydrogen or an alkyl group;
R3 and R4are the same or different and are selected from the group consisting of hydrogen, an alkyl group, an aralkyl, an alkenyl group, a cycloalkyl group, in which the alkyl, aralkyl, alkenyl or
cycloalkyl group is unsubstituted or substituted with one or more substituents selected from: a hydroxyl group
a straight or branched-chain alkoxy group
a carbamoyl group having the formula -CONR6R7 as defined above
an amino group having the formula -NR6R7, wherein R6 and R7 are as defined above; or R3 and R4 are combined so that -NR3R4 forms a 4- , 5-, 6- or 7-membered heterocyclic ring, which in addition to the nitrogen atom may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and which hetero-cyclic ring may be substituted with a hydroxyl group, a carbonyl group, an alkyl group, an alkyl group substituted with a hydroxyl group or an acyloxy group having the formula R5COO-, wherein R5 is as defined above, an alkoxycarbonyl group having the formula -COOR5 as defined above, or a carbamoyl group of the formula -CONR6R7 as defined above;
with the proviso that m is 0 when D represents the dehydrogenated residue of a hydroxyl group-containing drug and m is 1 when D represents the dehydrogenated residue of an NH-acidic group-containing drug;
and the pharmaceutically acceptable acid addition salts or quaternary ammonium salts thereof.
2. Compounds according to claim 1 wherein D is the dehydrogenated residue of a hydroxyl group-containing drug (m is zero) or of an NH-acidic group-containing drug (m is 1) selected from
Aciclovir
Cromolyn and cromolyn esters
Erythromycin A
Chloramphenicol
Metronidazole
Cefamandole
Cytarabine
Vidarabine
Testosterone
Doxifluridine
Floxuridine
Zidovudine
Oxazepam
Lorazepam
Etoposide
Forskolin
Idoxuridine
Hydrocortisone
Cortisone
Corticosterone
Prednisone
Prednisolone
6α-Methylprednisolone
Triamcinolone
Dexamethasone
Desciclovir
Flumethasone
Chlorprednisone
Betamethasone
Betamethasone 17-valerate
Fluprednisolone
9α-Fluorohydrocortisone
Pregnanolone
Propranolol Timolol
Alprenolol
Atenolol
Labetalol
Metoprolol
Oxprenolol
Levobunolol
Betaxolol
Ganciclovir Rapamycin
Paracetamol
Levodopa
Methyldopa
Dopamine
Dobutamine
Morphine
Naloxone
Naltrexone
Nalorphine
Oximetazoline
Ketobemidone
Phenylephrine
Salbutamol
Terbutaline Fenoldopam
Allopurinol
5-Fluorouracil
Theophylline
Cimetidine
Phenytoin
Aminogluthethimide
Mercaptopurine
Chlorzoxazone
Mebendazole Thiabendazole
Mitindomide
Domperidone
Ketoconazole Mifentidine
1,3-Diphenylxanthine
3. Compounds according to claim 1 or 2 wherein R1 is hydrogen or methyl, p is zero, R2 is hydrogen, m is zero or 1 and n is 1 or 2.
4. Compunds according to claim 2 wherein R1 is hydrogen, m is zero or 1, p is zero, R2 is hydrogen, n is 1 and R3 and R4 are the same or different and are
- H
- CH3
- C2H5
- CH2CH2CH3
- CH2CH2OH
- CH2CONH2
- CH2CH2NH2
- CH2CH2NHCH3
- CH2CH2N(CH3)2
- CH2CH2N(C2H5)2 or
- CH2CH2OCH3 or - NR3R4 is
Figure imgf000099_0001
2
5. Compounds of the formula I
Figure imgf000100_0001
wherein R1 is hydrogen, R2 is hydrogen, p is zero, m is zero or 1, n is 1, R3 and R4 are the same or different and are
- H
- CH3
- C2H5
- CH2CH2CH3
- CH2CH2OH
- CH2CONH2
- CH2CH2NH2
- CH2CH2NHCH3
- CH2CH2N(CH3)2
- CH2CH2N(C2H5)2 or
- CH2CH2OCH3 or - NR3R4 is
Figure imgf000100_0002
and D is the dehydrogenated residue of a hydroxyl group-containing drug (then m is zero) or of an NH-acidic group-containing drug (then m is 1) selected from aciclovir, metronidazole, chloramphenicol, paracetamol, ganciclovir, hydrocortisone, prednisolone, methylpred-nisolone, pregnanolone, β-estradiol, phenytoin, chlor-zoxazone, allopurinol, theophylline, 5-fluorouracil, testosterone, oxazepam, idoxuridine and vidarabine.
6. A pharmaceutical composition comprising a pharma-ceutically
acceptable execipient and a pharmaceutically effective amount of a compound according to any of claims 1-5.
7. A process for preparing a compound of the formula I as defined in claims 1-5 comprising a) reacting the OH-containing drug of the formula A
D-H (A) or the N-α-hydroxyalkylated NH-acidic drug of the formula B
Figure imgf000101_0003
wherein D and R1 are as defined above in connection with formula I , with a compound having the formula C :
Figure imgf000101_0002
wherein p, n, and R2 are as defined above and Y is a suitable leaving group, and then reacting the so produced compound of the formula D
Figure imgf000101_0001
with an amine of the formula E HNR3R4 (E) wherein R3 and R4 are as defined above; or
b) reacting a compound of formula A or B with a compound having the formula F
Figure imgf000102_0001
wherein Y, p, n, R2, R3 and R4 are as defined above with the proviso that when Y is hydroxy, p is zero; or
c) reacting a compound of formula G -
D' - Z (G) in which the hydroxy group of the parent drug DH is replaced by Z, so that D' is the dehydroxylated residue of a hydroxyl group- containing drug, or a compound of formula H
Figure imgf000102_0002
wherein Z is as defined above, with a compound of formula J
Figure imgf000102_0003
wherein n, R2, R3 and R4 are as defined above and N+ is a counter ion such as Na+, K+, Ag+ or trialkylammonium.
8. A compound as defined in claims 1-5 for use in therapy.
9. The use of a compound according to any of claims 1-5 for preparing a pharmaceutical composition for use in therapy.
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