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WO1990008128A1 - Nouveaux derives promedicamenteux d'agents biologiquement actifs contenant des groupes hydroxyle ou des groupes a fonction acide nh - Google Patents

Nouveaux derives promedicamenteux d'agents biologiquement actifs contenant des groupes hydroxyle ou des groupes a fonction acide nh 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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Hans Bundgaard
Erik Falch
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; 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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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/38—Compounds 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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    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic 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
    • C07C233/17—Carboxylic 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
    • C07C233/18—Carboxylic 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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    • C07C233/16—Carboxylic 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
    • C07C233/24—Carboxylic 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
    • C07C233/25—Carboxylic 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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    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic 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
    • C07C235/04—Carboxylic 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
    • C07C235/06—Carboxylic 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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    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters 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
    • C07C271/22—Esters 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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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic 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
    • C07D233/66—Heterocyclic 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
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/74—Two 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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    • C07D233/54—Heterocyclic 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
    • C07D233/66—Heterocyclic 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
    • C07D233/91—Nitro radicals
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    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-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
    • C07D285/135—Nitrogen atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by 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
    • C—CHEMISTRY; METALLURGY
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    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic 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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    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic 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
    • C07D473/08—Heterocyclic 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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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic 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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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic 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
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
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    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
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    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C—CHEMISTRY; METALLURGY
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    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
    • C07J1/007—Estrane 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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    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
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    • C07J41/005—Normal 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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    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
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    • C07J5/00—Normal 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
    • C07J5/0046—Normal 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
    • C07J5/0053—Normal 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.

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Abstract

La présente invention se rapporte à des composés représentés par la formule (I); où D représente le résidu déshydrogéné d'un médicament contenant des groupes hydroxyle ou le résidu hydrogéné d'un médicament contenant des groupes à fonction acide NH; les substituants présents dans le noyau phényle α et β se trouvent soit en position méta- ou para- l'un par rapport à l'autre; et le noyau phényle peut en outre être substitué; m est égal au nombre entier 0 ou 1, p est égal au nombre entier 0 ou 1; n représente un nombre entier compris entre 1 et 4; R1 est choisi dans le groupe composé d'un hydrogène, d'un alkyle, d'un aryle, d'un aralkyle, d'un groupe ayant la formule -COOR5 où R5 représente un groupe alkyle ou aralkyle, ou d'un groupe carbamoyle ayant la formule -CONR6R7, où R6 et R7 sont identiques ou différents et représentent un hydrogène, un groupe alkyle ou forment ensemble, avec l'atome d'azote adjacent, un noyau hétérocyclique à 4, 5, 6 ou 7 éléments; R2 représente un hydrogène ou un groupe alkyle; R3 et R4 sont identiques ou différents et représentent un hydrogène ou un alkyle, un aralkyle, un alkényle ou un cycloalkyle éventuellement substitués; ou R3 et R4 sont combinés de sorte que -NR3R4 forme un noyau hétérocyclique à 4, 5, 6 ou 7 éléments éventuellement substitués, qui, en plus de l'atome d'azote, peut contenir un ou deux autres hétéroatomes choisis parmi l'azote, l'oxygène et le soufre; à condition que m soit égal à 0 lorsque D représente le résidu déshydrogéné d'un médicament contenant des groupes hydroxyle, et que m soit égal à 1 lorsque D représente le résidu déshydrogéné d'un médicament contenant des groupes à fonction acide NH; ainsi qu'aux sels d'addition d'acide ou aux sels d'ammonium quaternaire pharmaceutiquement acceptables desdits composés.
PCT/DK1990/000020 1989-01-20 1990-01-19 Nouveaux derives promedicamenteux d'agents biologiquement actifs contenant des groupes hydroxyle ou des groupes a fonction acide nh Ceased WO1990008128A1 (fr)

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