WO1998004547A1 - Derives cristallins de pyridinium en tant qu'antagonistes du facteur d'activation des plaquettes - Google Patents

Derives cristallins de pyridinium en tant qu'antagonistes du facteur d'activation des plaquettes Download PDF

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WO1998004547A1
WO1998004547A1 PCT/JP1997/002522 JP9702522W WO9804547A1 WO 1998004547 A1 WO1998004547 A1 WO 1998004547A1 JP 9702522 W JP9702522 W JP 9702522W WO 9804547 A1 WO9804547 A1 WO 9804547A1
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group
crystals
alkyl
compound
formula
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PCT/JP1997/002522
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Yukio Mizuno
Takahiro Konishi
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Takeda Chemical Industries, Ltd.
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Priority to AU34633/97A priority Critical patent/AU3463397A/en
Publication of WO1998004547A1 publication Critical patent/WO1998004547A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to crystals of pyridinium derivatives, which show very satisfactory antagonizing activity against septic shock due to PAF (platelet activating factor) antagonism and endotoxin- induced pancreatitis and, as such, are of value as prophylactic and treating drugs for various diseases such as PAF-associated gastrointestinal diseases, PAF- associated circulatory diseases (e.g. serious infections, postoperative endotoxin shock, etc.), hyperendothelinism (e.g.
  • European Patent Publication EP-A-382 , 380 which corresponds to Japanese Patent Application Laid-open No. 2-275876/1990, describes a production technology which comprises N-propylating 3-bromo-5-[N-phenyl-N-[ 2- [ f 2-( l,2,3,4-tetrahydro-2-isoquinolylcarbonyloxy)- ethyl ]carbamoyl Jethyl ]carbamoyl]pyridine with 1- iodopropane, treating the resulting compound with an anion exchange resin, fractionating it by column chro atography, and drying the necessary fraction to provide a non-crystalline pyridinium derivative, namely 3-bromo-5- [N-phenyl-N- [ 2- [ [ 2- ( 1 , 2 , 3 , 4-tetrahydro-2- isoquinolylcarbonyloxyJethyl Jcarbaraoyl ]ethyl Jcarbamoyl ] -1-propy
  • the object pyridinium derivative (nitrate) is sparingly soluble in water (81 mg/ml at 25°C) so that when it is to be freeze-dried by the known lyophilization procedure, water must be used in a large quantity, i.e. 12 or more times the amount of the derivative, thus making the production line remarkably complicated.
  • the end product amorphous pyridinium derivative is so highly hygroscopic that it absorbs moisture and melts readily even if handled in a nitrogen atmosphere, thus making its handling extremely difficult.
  • freeze-drying in a highly concentrated state with a reduced amount of water is essential but because the water solubility of this pyridinium derivative is very low as mentioned above, lyophilization takes place in a heterogeneous state, that is the state in which the lipophilic fraction is discrete so that, as a serious problem, the product pyridinium derivative is obtained as non-homogeneous powders .
  • the inventors of the present invention did much research for overcoming the above-mentioned disadvantages of the commercial production technology for the pyridinium derivative of value as a prophylactic and treating drug for the above-mentioned diseases. As a consequence, they discovered that they can obtain crystals of the pyridinium derivatives by solvating it with ethanol, and subjecting the isolated solvate to desolvation.
  • the crystalline pyridinium derivative obtained by the method of the invention is considerably less hygroscopic, quite easier to handle, more stable and more uniform than the conventional amorphous pyridinium derivative obtained by the freeze-drying technique or the like. Furthermore, by preparing crystals of the pyridinium derivatives, the compound is obtained in a high purity and a high yield. Disclosure of Invention
  • the present invention is directed to (1). Crystals of pyridinium derivatives or crystals of solvate of pyridinium derivatives, the pyridinium derivatives being a compound of the formula:
  • R , 1b represents an alkyl group or an aralkyl group
  • R represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a hydroxyl group, an amino group, a nitro group, a carbamoyl group, a mercapto group or a cyano group
  • R represents (1) a hydrogen atom, (2) an alkyl group, (3) an aryl group which may optionally be substituted with alkyl, alkoxy, halogen, amino, hydroxy or nitro groups
  • m is an integer of 0 to 3
  • each of R ' and R is a hydrogen atom, an alkyl group or an aralkyl group, or R 4b and R b may be combined to form a nitrogen- containing heterocyclic group together with the adjacent nitrogen atom or its condensed-heterocyclic group
  • W ⁇ represents an anion
  • Fig. 1 shows the powder X-ray diffraction pattern of crystals of the 3-bromo-5-[N-phenyl-N-[ 2- [ [ 2- (1,2,3, 4-tetrahydro-2-isoquinolylcarbonyloxy) ethyl Jcarbamoyl Jethyl Jcarbamoyl J -1-propylpyridinium nitrate ethanol solvate obtained in Example 1.
  • Fig. 2 shows the powder X-ray diffraction pattern of crystals of the 3-bromo-5-[N-phenyl-N-[2- [ [ 2 - (1,2,3, 4-tetrahydro-2-isoquinolylcarbonyloxy) ethyl Jcarbamoyl Jethyl Jcarbamoyl ] -1-propylpyridinium nitrate obtained in Example 2.
  • Fig. 3 shows the powder X-ray diffraction pattern of crystals of the 3-bromo-5-[N-phenyl-N- [2- [ [ 2- (1,2,3, 4-tetrahydro-2-isoquinolylcarbonyloxy) ethyl Jcarbamoyl Jethyl Jcarbamoyl ]-l-propylpyridinium chloride ethanol solvate obtained in Example 3.
  • Fig. 4 shows the powder X-ray diffraction pattern of crystals of the 3-bromo-5-[N-phenyl-N- [ 2- [ [ 2- (1,2,3, 4-tetrahydro-2-isoquinolylcarbonyloxy ) ethyl Jcarbamoyl Jethyl Jcarbamoyl J -1-propylpyridinium chloride obtained in Example 4.
  • Fig. 4 shows the powder X-ray diffraction pattern of crystals of the 3-bromo-5-[N-phenyl-N- [ 2- [ [ 2- (1,2,3, 4-tetrahydro-2-isoquinolylcarbonyloxy ) ethyl Jcarbamoyl Jethyl Jcarbamoyl J -1-propylpyridinium chloride obtained in Example 4.
  • Fig. 4 shows the powder X-ray diffraction pattern of crystals of the 3-bromo-5-[N-phenyl-N- [ 2- [ [ 2- (1
  • Fig. 6 shows the powder X-ray diffraction pattern of crystals of the 3-bromo-5- [N-phenyl-N- [ 2-[ [ 2- (1,2,3, 4-tetrahydro-2-isoquinolylcarbonyloxy) ethyl ]- carbamoyl Jethyl Jcarbamoyl ]-l-propylpyridinium chloride isopropylalcohol solvate obtained in Example 8.
  • Fig. 7 shows the powder X-ray diffraction pattern of crystals of the 3-bromo-5- [N-phenyl-N- [ 2- [[ 2- (1,2,3, 4-tetrahydro-2-isoquinolylcarbonyloxy)ethyl J- carbamoyl Jethyl Jcarbamoyl ]-l-propylpyridinium nitrate dioxane solvate obtained in Example 9. Best mode for Carrying Out the Invention
  • the compound employed in the present invention is exemplified by a compound represented by the formula:
  • R represents a lower alkyl group or an aralkyl groupl; R and R independently represent a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group; ? represents 0 or 1; R represents a phenylene group or an optionally substituted alkylene group; R represents an alkyl group or an aryl groupl; X represents a group represented by the formula: -CH 2 OCH 2 - or the formula:
  • R represents a hydrogen atom, a lower alkyl group or a lower alkoxy group
  • m represents an integer from 0 to
  • R represents a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group
  • Y and Z independently represent a divalent chain group consisting of 1 to 6 groups selected from the groups represented by the formulas:
  • R represents a hydrogen atom, a lower alkyl group, an acyl group or an aryl group), and at least one of which is a group represented by the formula: -0- or -N- , with
  • R may be the same or different from each other, or may form a ring together when two or more groups of the formula: -N- are contained, that R
  • I R may be bonded to R when Y contains a group of the formula: -N- and that R may be bonded to R 11 when Z contains a group of the formula: -N-; and W e represents an anion.
  • R .lb represents an alkyl group or an aralkyl group
  • R represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a hydroxyl group, an amino group, a nitro group, a carbamoyl group, a mercapto group or a cyano group
  • R represents (1) a hydrogen atom, (2) an alkyl group, (3) an aryl group which may optionally be substituted with alkyl, alkoxy, halogen, amino, hydroxy or nitro
  • m is an integer of 0 to 3
  • each of R and R is a hydrogen atom, an alkyl group or an aralkyl group or R and R may be combined to form a nitrogen containing heterocyclic group together with the adjacent nitrogen atom or its condensed-heterocyclic group, a compound of the formula (I) wherein R is a Cj_ 6 alkyl group, R is
  • aryl group which may optionally be substituted with halogen atom(s) m is an integer of 0 to 2 , each of R and R is piperidino, piperadino, morpholino, thiomorpholino, quinolyl, isoquinolyl, indolyl or isoindolyl together with the adjacent nitrogen atom, a compound of the formula (I), wherein R in the derivative is a Cj-s alkyl, R is a halogen atom, R is a C 6 _ u aryl group which may optionally be substituted with halogen atom(s), m is an integer of 0 to 2, each of R and R is piperidino, piperadino, morpholino, thiomorpholino, quinolyl, isoquinolyl, indolyl or isoindolyl together with the adjacent nitrogen atom, and ⁇ represents an anion, a compound of the formula:
  • R a represents a lower alkyl group; R a represents a phenyl group which may be substituted by a halogen; R a represents an alkyl group; R a represents a hydrogen atom or a group represented by the formula:
  • R ⁇ a *"" - f ormed between R a and R a represents a
  • R represents a halogen
  • X represents a group represented by the formula: -(CH 2 )m' ⁇ (m' represents 0 or 1)
  • Y represents a group represented by the formula: -NH-C-
  • W ⁇ represents an anion, or a compound of the formula:
  • the pyridinium ring may have 1 to 4 (preferably 1 or 2) substituents such as halogen, lower alkyl, lower alkoxy, nitro, cyano, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, etc. as well as an aromatic ring.
  • the side chain is preferably in one of the 2- through 4-positions of the pyridinium ring, preferably in the 3-position.
  • the substituent group or groups are preferably situated in one or two of the 3- through 5-positions of the pyridinium ring, more preferably in the 5-position.
  • the lower alkyl mentioned for R , R , R , R , or R , or as a nuclear substituent group for the pyridinium ring includes straight-chain or branched alkyl groups of 1 through 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, and hexyl .
  • This lower alkyl may contain unsaturation and as examples of such unsaturated lower alkyl there can be mentioned lower alkenyl groups of 2 through 6 carbon atoms, such as vinyl, allyl, 2-butenyl, 3-butenyl, etc.
  • the lower alkoxy mentioned for R or as a nuclear substituent group for the pyridinium ring includes straight-chain or branched alkoxy groups of 1 through 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, etc.
  • the lower alkoxy for R may have a substituent or substituents and the substituent groups may jointly form a 5- through 7-membered heterocycle (e.g. imidazolyl, oxazolyl, isoxazolyl, thiazolyl, etc.), which may be substituted by lower alkyl, acyl, aryl, aralkyl, etc.
  • the lower alkyl mentioned as a substituent for the heterocycle formed by substituents on lower alkoxy R may be similar to the lower alkyl mentioned for R .
  • the acyl mentioned as a substituent for the heterocycle formed by substituents on lower alkoxy R includes alkanoyl groups of 2 through 6 carbon atoms, such as acetyl, propanoyl, butyryl, pivaloyl, etc., and benzoyl .
  • the aryl mentioned as a substituent for the heterocycle formed by substituents on lower alkoxy R may be similar to the aryl mentioned below for R ' .
  • the aralkyl mentioned as a substituent for the heterocycle formed by substituents on lower alkoxy R may be similar to the aralkyl mentioned below for R .
  • the halogen as a substituent for the pyridinium ring includes fluoro, bromo, chloro, and iodo .
  • the lower alkoxycarbonyl as a substituent for the pyridinium ring includes alkoxycarbonyl groups each containing 1 through 6 carbon atoms in the alkyl moiety, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl , etc.
  • the lower alkylcarbamoyl as a substituent for the pyridinium ring includes N-alkylcarbamoyl groups each containing 1 through 6 carbon atoms in the alkyl moiety, such as methylcarba oyl , ethylcarbamoyl , propylcarbamoyl, butylcarbamoyl , etc., and N,N- dialkylcarba oyl groups each containing 1 through 6 carbon atoms in the alkyl moiety, such as dimethylcarbamoyl , diethylcarbamoyl, dibutylcarbamoyl , methylethylcarbamoyl, etc.
  • the aryl for R , R or R includes aromatic mono- cyclic, dicyclic or tricyclic hydrocarbyl groups such as phenyl, 1-naphthyl, 2-naphthyl, phenanthryl , anthryl , etc. and aromatic monocyclic or dicyclic heterocyclic groups such as thienyl, furyl, benzothienyl , benzofuranyl , etc.
  • This aryl group may have 1 through 4 (preferably 1 or 2 ) substituents such as halogen, lower alkyl, lower alkoxy, nitro, cyano, oxo, hydroxy, amino, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, etc.
  • the halogen includes fluoro, bro o, chloro, and iodo.
  • the lower alkyl includes alkyl groups of 1 through 6 carbon atoms and this lower alkyl may contain unsaturation . Such unsaturated lower alkyl includes lower alkenyl groups of 2 through 6 carbon atoms.
  • the C x ⁇ 6 alkyl and C 2 . 6 lower alkenyl mentioned just above include the same species as those mentioned for the lower alkyl for the substituent on the pyridinium ring.
  • the lower alkoxy includes alkoxy groups of 1 through 6 carbon atoms and the lower alkoxycarbonyl includes alkoxycarbonyl groups containing 1 through 6 carbon atoms in the alkyl moiety.
  • the lower alkylcarbamoyl includes N- alkylcarbamoyl groups each containing 1 through 6 carbon atoms in the alkyl moiety and N,N-di- alkylcarbamoyl groups each containing 1 through 6 carbon atoms in each alkyl moiety. Those groups include the same species as those mentioned for the lower alkoxy, lower alkoxycarbonyl, and lower alkylcarbamoyl as the substituents on the pyridinium ring.
  • the aryl having oxo includes but is not limited to benzoquinonyl , naphthoquinonyl , and anthraquinonyl .
  • the aralkyl mentioned above for R , R , R , or R includes phenyl-lower alkyl groups each containing 1 through 6 carbon atoms in the alkyl moiety, such as benzyl, phenethyl , 3-phenylpropyl , 4-phenylbutyl , etc., and naphthyl-lower alkyl groups each containing 1 through 6 carbon atoms in the alkyl moiety, such as (1- naphthyl)methyl, 2- ( 1-naphthyl ) ethyl , 2- (2- naphthyl ) ethyl , etc.
  • the phenyl moieties of said phenyl-lower alkyl groups and the naphthyl moieties of said naphthyl-lower alkyl groups may each have 1 through 4 (preferably 1 or 2 ) substituents selected from among, for example, halogen, lower alkyl, lower alkoxy, nitro, cyano, oxo, hydroxy, amino, lower alkoxycarbonyl, carbamoyl, and lower alkylcarbamoyl.
  • substituent groups may be similar to the substituent groups mentioned for the aryl R , R , or
  • the phenylene mentioned for R includes o- phenylene ( 1 , 2-phenylene) , m-phenylene ( 1, 3-phenylene) , and p-phenylene ( 1 , 4-phenylene) .
  • the alkylene for R includes alkylene groups of 1 through 6 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene and those alkylene groups may each have a substituent or substituents such as C 5 lower alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl, etc.).
  • the alkyl for R ' includes straight-chain or branched alkyl groups of 1 through 30 carbon atoms (preferably C ⁇ _ 18 alkyl), such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, tridecyl , tetradecyl, pentadecyl, hexadecyl , heptadecyl , octadecyl, nonadecyl , eicosanyl, heneicosanyl, docosanyl, tricosanyl, tetracosanyl , pentacosanyl, hexacosanyl, heptacosanyl, octacosanyl, nonacosanyl, triacontanyl , farnesyl , dihydro
  • the above- mentioned alkyl group may contain unsaturation and such unsaturated alkyl group includes C 2 - 30 alkenyl such as vinyl, allyl, 9-octadecenyl, etc.; C 5 . 8 cycloalkenyl such as cyclopentenyl , cyclohexenyl , etc.; C 7 .
  • bicycloalkenyl such as bicyclo[2 , 2 ,2 Joct-2-enyl etc.; bicyclic hydrocarbyl groups available upon condensation of a benzene ring with 5- through 8-membered rings, such as indanyl (1-indanyl, 2-indanyl, etc.), indenyl ( lH-inden-1-yl, lH-inden-2-yl , lH-inden-3-yl, etc.), dihydronaphthyl ( 1 , 2-dihydro-l-naphthyl , 1 , 2-dihydro-2- naphthyl , etc.), tetrahydronaphthyl (5,6,7,8- tetrahydro-1-naphthyl , 5,6,7, 8-tetrahydro-2-naphthyl , etc.), 5H-benzocycloheptenyl (5H-5-benzo
  • the Ci. 30 alkyl and C 2 . 30 alkenyl mentioned above for the alkyl R may each have 1 through 4 (preferably 1 or 2 ) substituents selected from among, for example, C 3 _ 8 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), phenyl, naphthyl, quinonyl, naphthoquinonyl , halogen (e.g. chloro, fluoro, bromo, iodo), cyano, oxo, and C,. fi lower alkoxy (e.g.
  • C 3 _ 8 cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl
  • the phenyl, naphthyl, quinonyl, and naphthoquinonyl as substituents for the alkyl or alkenyl mentioned above may have 1 through 5 substituents selected from among, for example, C,_ 6 lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), C ⁇ lower alkoxy (e.g.
  • halogen e.g. chloro, fluoro, bromo, iodo
  • the cycloalkyl, bicycloalkyl, tricycloalkyl , bicyclic hydrocarbyl, tricyclic hydrocarbyl, inclusive of the corresponding unsaturated groups, as mentioned for the alkyl R may each have 1 through 4 (preferably 1 or 2 ) substituents selected from among, for example, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl-lower alkoxy, lower alkenyloxy, aralkyloxy, lower alkoxy- lower alkoxy, lower alkoxycarbonyl, carboxy, carba oyl , N,N-di-lower alkylcarbamoyl, N-lower alkylcarbamoyl, halogen, cyano, nitro, hydroxy, acyloxy, amino, lower al
  • the lower alkyl mentioned as a substituent for the cycloalkyl, bicycloalkyl , tricycloalkyl, bicyclic hydrocarbyl and tricyclic hydrocarbyl, inclusive of the corresponding unsaturated groups, all of which have been mentioned for the alkyl R includes alkyl groups of 1 through 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, etc.
  • the halo-lower alkyl similarly mentioned above includes C ⁇ alkyl groups substituted by 1 through 3 halogen atoms, such as trifluoromethyl , fluoromethyl, chloromethyl, chloroethyl, fluoroethyl, etc.
  • the hydroxy-lower alkyl includes hydroxyalkyl groups each containing 1 through 6 carbon atoms, such as hydroxymethyl , hydroxyethyl , hydroxypropyl , hydroxybutyl , etc.
  • the acyloxy-lower alkyl includes C 2 . 6 lower alkanoyloxy groups such as acetoxyethyl , benzoyloxyethyl, etc. and C ⁇ alkyl substituted by benzoyloxy.
  • the lower alkoxy-lower alkyl includes C, ⁇ alkyl substituted by C-_ 6 alkoxy, such as methoxyethyl , ethoxyethyl, propoxyethyl , butoxyethyl , methoxypropyl , methoxybutyl, ethoxypropyl , ethoxybutyl , etc.
  • the lower alkoxy includes C-_ 6 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, tert-butoxy, etc.
  • the halo-lower alkoxy includes C ⁇ alkoxy substituted by 1 through 3 halogen atoms, such as chloroethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, chloropropoxy, chlorobutoxy, etc.
  • the lower alkoxycarbonyl-lower alkoxy includes C-_ 6 alkoxy substituted by alkoxycarbonyl containing 1 through 6 carbon atoms in the alkyl moiety, such as methoxycarbonylmethoxy, ethoxycarbonylmethoxy, butoxycarbonylmethoxy, methoxycarbonylpropoxy, ethoxycarbonylethoxy, etc.
  • the lower alkenyloxy includes C 2 .
  • the aralkyloxy includes phenyl-lower alkyloxy groups each containing 1 through 6 carbon atoms in the lower alkyl moiety, such as benzyloxy, phenethyloxy, 3-phenylpropyloxy, ⁇ - methylphenethyloxy, ⁇ -methylbenzyloxy, - ethylbenzyloxy, ⁇ -ethylphenethyloxy, ⁇ - methylphenethyloxy, etc .
  • the lower alkoxy-lower alkoxy includes C ⁇ alkoxy substituted by C ⁇ alkoxy, such as ethoxymethoxy, methoxyethoxy, butoxyethoxy, ethoxypropoxy, etc.
  • the lower alkoxycarbonyl includes alkoxycarbonyl groups each containing 1 through 6 carbon atoms in the alkoxy (alkyl) moiety, such as methoxycarbonyl , ethoxycarbonyl, propoxycarbonyl , butoxycarbonyl, etc.
  • the N,N-di-lower alkylcarbamoyl includes N,N-dialkylcarbamoyl groups each containing 1 through 6 carbon atoms in the alkyl moiety, such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl , N,N- dipropylcarbamoyl , N,N-dibutylcarbamoyl , N-ethyl-N- ethylcarbamoyl, etc. and groups such that the two alkyl moieties form a 5- or 6-membered cyclic system (e.g.
  • the N-lower alkylcarbamoyl includes N- alkylcarbamoyl containing 1 through 6 carbon atoms in the alkyl moiety, such as N-methylcarbamoyl , N- ethylcarbamoyl, N-propylcarbamoyl, N-butylcarbamoyl , etc.
  • the halogen includes chloro, fluoro, bromo, and iodo.
  • the acyloxy includes C 2 _ 6 alkanoyloxy such as acetoxy, propanoyloxy, butyryloxy, pivaloyloxy, etc.
  • the lower alkylsulfonylamino includes Ci-e alkylsulfonylamino groups such as methanesulfonylamino, ethanesulfonylamino, etc.
  • the acylamino includes C 2 _ 6 alkanoylamino such as acetamido, propanoylamino, butyrylamino, pivaloylamino, etc. and benzamido.
  • the lower alkoxycarbonylamino includes alkoxycarbonylamino groups each containing 1 through 6 carbon atoms in the alkoxy moiety, such as methoxycarbonylamino , ethoxycarbonylamino , propoxycarbonylamino, butoxycarbonylamino, etc.
  • the acyl includes C 2 . 6 alkanoyl such as acetyl , propanoyl , butyryl, pivaloyl , etc. and benzoyl .
  • the lower alkylthio includes C ⁇ alkylthio such as ethylthio, ethylthio, propylthio, butylthio, etc.
  • the lower alkylsulfinyl includes C ⁇ _ 6 alkylsulfinyl such as methylsulfinyl, ethylsulfinyl , propylsulfinyl , butylsulfinyl , etc.
  • the lower alkylsulfonyl includes Ci.e alkylsulfonyl such as methylsulfonyl , ethylsulfonyl , propylsulfonyl , butylsulfonyl , etc.
  • the aryl mentioned for R includes phenyl, aromatic bicyclic or tricyclic hydrocarbyl groups available upon condensation of 5- through 8-membered rings, such as naphthyl (1-naphthyl, 2-naphthyl), azulenyl, heptalenyl, indacenyl (as, s), acenaphthylenyl, phenanthryl, anthryl, benzocyclooctenyl , etc., monocyclic hetero systems such as thienyl, furyl , etc., and bicyclic hetero systems such as benzothienyl , isobenzothienyl , benzofuranyl, isobenzofuranyl, benzoxepinyl, benzothiepinyl, etc.
  • aryl groups may each be partially saturated and such partially saturated aryl group includes indanyl (4-indanyl, 5-indanyl, etc.), indenyl ( lH-inden-4-yl , lH-inden-5-yl, etc.), dihydronaphthyl ( 5 , 6-dihydro-l - naphthyl, 5 , 6-dihydro-2-naphthyl, 7 , 8-dihydro-l- naphthyl , 7 , 8-dihydro-2-naphthyl , etc .
  • tetrahydronaphthyl (5,6,7, 8-tetrahydro- 1-naphthyl , 5,6,7,8-tetrahydro-2-naphthyl, etc.), 1,2,3,4- tetrahydro-1-quinolyl, and 1 , 2 , 3, 4-tetrahydro-2- isoquinolyl, among other groups.
  • the aryl group and partially saturated aryl group mentioned above for R may each have 1 through 4 (preferably 1 or 2 ) substituents selected from among, for example, lower alkyl, halo-lower alkyl, hydroxy- lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl-lower alkoxy, lower alkenyloxy, aralkyloxy, lower alkoxy-lower alkoxy, lower alkoxycarbonyl, carboxy, carbamoyl, N,N-di-lower alkylcarbamoyl, N-lower alkylcarbamoyl, halogen, cyano, nitro, hydroxy, acyloxy, amino, lower alkylsulfonylamino, acyla ino, lower alkoxycarbonylamino, acyl, mercapto, lower alkylthio,
  • the substituent groups may be similar or dissimilar.
  • the substituent mentioned above includes the same species as the substituent groups mentioned for the cycloalkyl, bicycloalkyl, tricycloalkyl, bicyclic hydrocarbyl, and tricyclic hydrocarbyl, inclusive of the corresponding unsaturated groups, all of which have been mentioned hereinbefore for R 11 .
  • the divalent chain group represented by Y is exemplified by divalent functional group represented by the formula:
  • n 1 or 2; R and R independently represent a hydrogen atom, a lower alkyl group, an acyl group or an aryl group; R and R may bind together to form a ring.
  • the divalent chain group represented by Z is exemplified by divalent functional groups represented by the formula:
  • R and R 9 independently represent a hydrogen atom, a lower alkyl group, an acyl group or an aryl groupl R and R may bind together to form a ring.
  • the lower alkyl mentioned for R, R , R , R , or R includes straight-chain or branched Cj.g alkyl such as methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
  • This lower alkyl may contain unsaturation and such unsaturated lower alkyl includes C 2 . 6 lower alkenyl such as vinyl, allyl, 2- butenyl, 3-butenyl, etc.
  • the acyl mentioned for R, R 2 , R 3 , R 8 , or R 9 includes C 2 .
  • R, R , R , R , or R includes aromatic monocyclic, bicyclic or tricyclic hydrocarbyl groups such as phenyl, 1-naphthyl, 2- naphthyl, phenanthryl , anthryl, etc. and aromatic monocyclic or bicyclic hetero systems such as thienyl, furyl, benzothienyl, benzofuranyl , etc.
  • This aryl group may have 1 through 4 (preferably 1 or 2 ) substituents selected from among, for example, halogen, lower alkyl, lower alkoxy, nitro, cyano, oxo, hydroxy, amino, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, etc.
  • the halogen mentioned above includes fluoro, bromo, chloro, and iodo.
  • the lower alkyl includes Cj. 6 alkyl and this lower alkyl may contain unsaturation. Such unsaturated lower alkyl includes C 2 . 6 lower alkenyl.
  • lower alkenyl mentioned above include the same species as the lower alkyl mentioned as substituents for the pyridinium ring.
  • the lower alkoxy includes C ⁇ alkoxy
  • the lower alkoxycarbonyl includes alkoxycarbonyl groups each containing 1 through 6 carbon atoms in the alkoxy moiety.
  • the lower alkylcarbamoyl includes N- alkylcarbamoyl groups each containing 1 through 6 carbon atoms in the alkyl moiety and N,N- dialkylcarbamoyl groups each containing 1 through 6 carbon atoms in each alkyl moiety.
  • R and R may bind together to form
  • R I * R I a ring.
  • -Y-R -N- is exemplified by
  • R 9 and R11 may combinedly form a ring.
  • A' includes 3- through 8-membered monocyclic heterocyclic groups such as 1-aziridinyl , 1-azetidinyl, piperidino, perhydro-1-azepinyl, perhydro-1-azocinyl, morpholino, thiomorpholino, 1-piperazinyl , 3-thiazolidinyl , etc.; condensed bicyclic or bridged bicyclic heterocyclic groups such as 1-indolyl, perhydro-1-indolyl, 2-is ⁇ indolyl, perhydro-2-isoindolyl, 1,2,3 ,4-tetrahydro-l-quinolyl, 1,2,3, 4-tetrahydro-2-isoquinolyl, perhydro-1-quinolyl, perhydro-2-isoquinolyl , 3-azabicyclo[ 3.2.2 ]non-3-yl, etc . ; and condensed tricyclic heterocyclic groups such as 9- carbazolyl, 10-
  • heterocyclic groups may each have 1 through
  • substituents selected from among, for example, lower alkyl, halo-lower alkyl, hydroxy- lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy, halo-lower alkoxy, lower alkoxycarbonyl-lower alkoxy, lower alkenyloxy, aralkyloxy, lower alkoxy-lower alkoxy, lower alkoxycarbonyl, carboxy, carbamoyl, N,N-di-lower alkylcarbamoyl, N-lower alkylcarbamoyl, halogen, cyano, nitro, hydroxy, acyloxy, amino, lower alkylsulfonylamino, acylamino, lower alkoxycarbonylamino, acyl, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, and
  • the substituent groups may be similar or dissimilar.
  • the lower alkyl as a substituent group for said heterocyclic groups includes C-_ 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.
  • the halo-lower alkyl mentioned above includes C ⁇ alkyl substituted by 1 through 3 halogen atoms, such as trifluoromethyl, fluoromethyl, chloromethyl, chloroethyl, fluoroethyl, etc.
  • the hydr ⁇ xy-lower alkyl includes hydroxyalkyl containing 1 through 6 carbon atoms, such as hydroxymethyl , hydr ⁇ xyethyl , hydroxypropyl , hydroxybutyl , etc .
  • the acyloxy-lower alkyl includes C-_ 6 alkyl substituted by either C 2 . 6 lower alkanoyloxy or benzoyloxy, such as acetoxyethyl , benzoyloxyethyl, etc.
  • the lower alkoxy- lower alkyl includes C ⁇ alkyl substituted by C[.
  • alkoxy such as methoxyethyl , ethoxyethyl, propoxyethyl, butoxyethyl, methoxypropyl , methoxybutyl, ethoxypropyl, ethoxybutyl, etc.
  • the lower alkoxy includes C ⁇ alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.
  • the halo-lower alkoxy includes C ⁇ alkoxy substituted by 1 through 3 halogen atoms, such as chloroethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, chloropropoxy, chlorobutoxy, etc.
  • the lower alkoxycarbonyl-lower alkoxy includes C-_ 5 alkoxy substituted by alkoxycarbonyl containing 1 through 6 carbon atoms in the alkyl moiety, such as methoxycarbonylmethoxy, ethoxycarbonylmethoxy, butoxycarbonylmethoxy, methoxycarbonylpropoxy, ethoxycarbonylethoxy, etc.
  • the lower alkenyloxy includes C 2 _ 6 alkenyloxy such as vinyloxy, allyloxy, butenyloxy, etc.
  • the aralkyloxy includes phenyl-lower alkyloxy groups each containing 1 through 6 carbon atoms in the lower alkyl moiety, such as benzyloxy, phenethyloxy, 3-phenylpropyloxy, ⁇ -methylphenethyloxy, ⁇ -methylbenzyloxy, -ethylbenzyloxy, ⁇ - ethylphenethyloxy, ⁇ -methylphenethyloxy, etc.
  • the lower alkoxy-lower alkoxy includes C ⁇ alkoxy substituted by C ⁇ alkoxy, such as ethoxymethoxy, methoxyethoxy, butoxyethoxy, ethoxypropoxy, etc.
  • the lower alkoxycarbonyl includes alkoxycarbonyl groups each containing 1 through 6 carbon atoms in the alkyl moiety, such as methoxycarbonyl, ethoxycarbonyl , propoxycarbonyl , butoxycarbonyl, etc.
  • the N,N-di-lower alkylcarbamoyl includes N,N-dialkylcarbamoyl groups containing 1 through 6 carbon atoms in each alkyl moiety, such as N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl , N,N-dipropylcarbamoyl , N,N- dibutylcarbamoyl, N-ethyl-N-methylcarbamoyl, etc. and groups such that the two alkyl groups of said dialkyl moiety are combined to form a 5- or 6-membered cyclic system (e.g.
  • the N-lower alkylcarbamoyl includes N-alkylcarbamoyl groups each containing 1 through 6 carbon atoms in the alkyl moiety, such as N- methylcarba oyl , N-ethylcarbamoyl , N-propylcarbamoyl , N-butylcarbamoyl, etc.
  • the halogen includes chloro, fluoro, bromo, and iodo.
  • the acyloxy includes C 2 . 6 alkanoyloxy such as acetoxy, propanoyloxy, butyryloxy, pivaloyloxy, etc.
  • the lower alkanesulfonylamino includes C-_ 6 alkanesulfonylamino such as methanesulfonylamino, ethanesulfonylamino, etc.
  • the acylamino includes C 2 . 6 alkanoylamino such as acetamido, propanoylamino, butyrylamino, pivaloylamino, etc. and benzamido.
  • the lower alkoxycarbonylamino includes alkoxycarbonylamino groups each containing 1 through 6 carbon atoms in the alkyl moiety, such as methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, etc.
  • the acyl includes C 2 . 6 alkanoyl such as acetyl , propanoyl, butyryl, pivaloyl, etc. and benzoyl .
  • the lower alkylthio includes C-_ 6 alkylthio such as methylthio, ethylthio, propylthio, butylthio, etc.
  • the lower alkanesulfinyl includes C ⁇ alkanesulfinyl such as methanesulfinyl, ethanesulfinyl , propanesulfinyl , butanesulfinyl , etc.
  • the lower alkanesulfonyl includes C-_ 6 alkanesulfonyl such as methanesulfonyl , ethanesulfonyl, propanesulfonyl, butanesulfonyl , etc.
  • quinoliniu ring includes but is not limited to quinoliniu ring and isoquinolinium ring.
  • the anion represented by W ⁇ may be a pharmacologically acceptable anion.
  • the pharmaceutically acceptable anion includes hydroxy ion, inorganic acid anions such as halogen ion (e.g. chloride ion, bromide ion, iodide ion), sulfate ion, nitrate ion, phosphate ion, etc. and organic acid anions such as acetate ion, tosylate ion, mesylate ion, etc.
  • the inorganic acid anions are preferred and, among them, halogen ion especially chloride ion, nitrate ion and sulfate ion are more preferred. Particularly preferred is nitrate ion.
  • ? is preferably 1;
  • U is preferably a group represented by the formula: -N - C-;
  • X is preferably X , Y is preferably Y ;
  • Y is
  • O II preferably an ethylene group
  • Z is preferably a group represented by
  • R is preferably a hydrogen atom; R is preferably a hydrogen atom; R is preferably R a ;
  • the alkyl group and the aralkyl group of R in the formula (I) concrete examples of the halogen, the alkyl and the alkoxy of R , concrete examples of (i) the alkyl group, (ii) the aryl group, (iii) the alkyl group, the alkoxy group and the halogen as the substituent on the aryl group, and (iv) the aralkyl group of R , the alkyl group and the aralkyl group of R and/or R , mention is made of those described hereinbefore.
  • the aryl group represented by R may have 1 to 4 , preferably 1 or 2 , substituents .
  • the nitrogen containing heterocyclic group or its condensed- heterocyclic group mention is made of those described hereinbefore .
  • a C ⁇ 6 alkyl group is preferable.
  • a halogen atom is preferable.
  • a C 6 . 14 aryl group which may optionally be substituted is preferable.
  • m an integer of 0 to 2 is preferable.
  • piperidino, piperazinyl, morpholino, thiomorpholino, quinolyl, isoquinolyl, indolyl and isoindolyl are preferable.
  • the group R is preferably at 3-position of the pyridine ring.
  • the lower alkyl for R includes the same lower alkyl groups mentioned for R 1 .
  • the preferred species of R a is propyl.
  • halogen of the phenyl that may be substituted by halogen as mentioned for R a includes fluoro, bromo, chloro, and iodo.
  • the preferred species of R* a is unsubstituted phenyl .
  • the alkyl for R a includes the same C ⁇ -, alkyl groups as mentioned for the alkyl R 11 .
  • I ' is preferably a 1 , 2 , 3 , 4-tetrahydro-2-
  • the halogen for R includes fluoro, bromo, chloro, and iodo.
  • the preferred species of R 17 is bromo .
  • m is preferably 0.
  • the compounds of the formula ( I ) , ( I ' ) , ( I " ) emloyed in the present invention can be produced by any of the methods described in European Patent Publications EP-A-301751 (Japanese Patent Application Laid-open No. 2-76854/1990), EP-A-369810 (Japanese Patent Application Laid-open No. 2-231433/1990), EP-A- 382380 (Japanese Patent Application Laid-open No. 2- 275876/1990), or methods analogous thereto.
  • Ph represents phenyl
  • X represents halogen
  • R represents C ⁇ . 5 alkyl or phenyl that may optionally be substituted (the substituent group or groups may be the same as those mentioned for the pyridinium ring);
  • R represents C ⁇ alkyl that may optionally be substituted.
  • the objective pyridinium derivative (la) is chemically made up of an amidocarboxylic acid moiety, two amino groups and a quaternized N moiety as shown by the following formula, suggesting that it can be synthetically constructed by the integration of 6 segments. To achieve this synthesis in an industrially efficient way, use of protective groups should be avoided as far as possible. Therefore, the above production process involving a serial extension of the C-terminus of 5-bromonicotinic acid is preferred.
  • the starting material 3-anilinopropionic acid (VII) can be synthesized by subjecting the known compound 3-anilinopropionitrile (available from many commercial sources including Wako Pure Chemical Industries) to acid or alkaline hydrolysis.
  • 5-bromonicotinyl chloride [VI] can be synthesized by chlorinating the known compound 5- bromonicotinic acid (available from many commercial sources including Wako Pure Chemical Industries) with phosphorus pentachloride, thionyl chloride, oxalyl chloride, or the like.
  • 3-Bromo-5-[N- ( 2-carboxyethyl ) -N-phenyl Jcarbamoyl- pyridine (V) can be prepared by subjecting 3- anilinopropionic acid (VII) and 5-bromonicotinyl chloride (VI) to condensation reaction.
  • This condensation reaction is carried out in an organic solvent with stirring at 0°-50°C, preferably around room temperature (15-30°C).
  • the organic solvent that can be used for this reaction includes halogenated hydrocarbons (e.g. methylene chloride, chloroform, etc.), ethers (e.g. tetrahydrofuran, dioxane, diethyl ether, etc.), esters (e.g.
  • ethyl acetate etc. aromatic hydrocarbons (e.g. toluene etc.), and amides (e.g. N,N-dimethylformamide, N,N-dimethylacetamide, etc.).
  • Preferred is a mixture of a halogenated hydrocarbon and N,N-dimethylacetamide .
  • the ratio of halogenated hydrocarbon to N,N-dimethylacetamide in such a solvent mixture is generally about 3 through 5/1 and preferably about 4/1.
  • the reaction time depends much on reaction temperature but when conducted around room temperature, the reaction goes to completion generally in 2-3 hours.
  • the condensation reaction is carried out by the acid chloride method which is one of the known amide bond-forming reaction techniques
  • this method is not an exclusive choice but other amide- forming methods (i.e. the azide method, DCC (dicyclohexylcarbodiimide) method, active ester method, mixed acid anhydride method, etc.) can likewise be employed.
  • 3-Bromo-5-[N-[2-[ ( 2-hydroxy) ethyl Jcarbamoyl Jethyl- N-phenyl J carbamoylpyridine (IV) can be synthesized by subjecting the C-terminus of 3-bromo-5-[N-( 2- carboxyethyl) -N-phenyl]carbamoylpyridine (V) to amide- forming reaction with 2-aminoethanol .
  • This amide- forming reaction can be carried out by any of the azide, DCC, active ester, mixed acid anhydride, acid chloride, and other methods but the DCC method is especially preferred.
  • compound (V) is isolated as the hydrochloride.
  • compound (V) is suspended in an organic solvent such as a halogenated hydrocarbon (e.g. ethylene chloride, chloroform, etc.), ether (e.g. tetrahydrofuran, dioxane, diethyl ether, etc.), ester (e.g. ethyl acetate etc.), aromatic hydrocarbon (e.g.
  • a halogenated hydrocarbon e.g. ethylene chloride, chloroform, etc.
  • ether e.g. tetrahydrofuran, dioxane, diethyl ether, etc.
  • ester e.g. ethyl acetate etc.
  • aromatic hydrocarbon e.g.
  • condensation reaction is carried out by the DCC method which is one of the known amide bond-forming reaction methods
  • this is not an exclusive choice but other amide-forming methods (i.e. the azide method, acid chloride method, active ester method, mixed acid anhydride method, etc.) can likewise be employed.
  • the reaction for introducing carbonyl to the hydroxyl group of (IV) is carried out by permitting XC0 2 R , X represents halogen, R represents lower alkyl (C-_ 5 alkyl) or phenyl that may optionally be substituted, to act on compound (IV) in the presence of a base in an organic solvent.
  • a base in an organic solvent.
  • an amine e.g. pyridine, triethylamine, etc.
  • an inorganic base e.g. potassium carbonate, sodium carbonate, etc.
  • a hydride e.g. sodium hydride etc.
  • the organic solvent mentioned above includes halogenated hydrocarbons (e.g. methylene chloride, chloroform, etc.), ethers (e.g. tetrahydrofuran, dioxane, diethyl ether, etc.), esters (e.g. ethyl acetate etc.), aromatic hydrocarbons (e.g. toluene etc.), N,N-dimethylformamide, and acetonitrile. Particularly preferred is ethyl acetate.
  • the ester (III) produced by this reaction can be purified by recrystallization from toluene or toluene-hexane and recovered generally in a yield of not less than 70%.
  • the reaction between this ester (III) and 1,2,3,4- tetrahydroisoquinoline can be carried out by admixing the two reactants in an organic solvent such as a halogenated hydrocarbon (e.g. methylene chloride, chloroform, etc.), an ether (e.g. tetrahydrofuran, dioxane, diethyl ether, etc.), an ester (e.g. ethyl acetate etc.), an aromatic hydrocarbon (e.g.
  • a halogenated hydrocarbon e.g. methylene chloride, chloroform, etc.
  • an ether e.g. tetrahydrofuran, dioxane, diethyl ether, etc.
  • an ester e.g. ethyl acetate etc.
  • aromatic hydrocarbon e.g.
  • Pyridinium derivative (la) e.g. 3-bromo-5-[N- phenyl-N-[2-[ [2-( 1,2, 3 , 4-tetrahydro-2-isoquinolyl- carbonyloxy) ethyl Jcarbamoyl Jethyl ]carbamoyl J-l- propylpyridinium nitrate] can be produced by N- alkylating the pyridine ring of compound (II).
  • This N-alkylation reaction can be carried out by mixing compound (II) with a stoichiometric excess of RX, wherein R represents C ⁇ _ b lower alkyl that may be substituted; X represents halogen, preferably iodine which is highly reactive, and causing the mixture to react at 100-150°C or reflux temperature under atmospheric pressure or is a higher pressure (1-3 kg/cm ) .
  • RX may be expected to double as a reactant and a solvent but the reaction may be conducted in a dilute system by adding an organic solvent.
  • the iodide ion which is the counter anion of the product pyridinium derivative (la) can be replaced with the desired other anion (the preferred species of X is chloride ion or nitrate ion) by passing compound (la) through an anion exchange resin carrying the objective anion (e.g. chloride ion, nitrate ion, etc.) [for example IRA-410, N0 " -form or Cl " -form] , whereby compound (la) can be converted to the pyridinium derivative having the desired anion.
  • anion exchange resin is Amberlite IRA-410 (Cl ) (Tokyo Organic Chemical Industries, Ltd.). Production of crystals of the present pyridinium derivatives :
  • the solvate of the compounds (I'), (I) and (I") i.e. crystal form, can be produced by the manner mentioned below.
  • the compounds (I'), (I) and (I") are called “the present pyridinium derivatives " .
  • a solution containing the present pyridinium derivatives is purified by, for example, an anion exchange resin.
  • an anion exchange resin As the resin, mention is made of those having a counter anion such as an inorganic anion, e.g. N0 3 " , S0 4 " , OH " , which has been prepared from Amberlite IRA-410 (Cl " ).
  • the solution containing the present pyridinium derivatives is then concentrated, if necessary, by a per se conventional method.
  • organic solvent mention is made of alcohols (e.g. C-_ 6 alcohols such as methanol, ethanol, isopropyl alcohol, etc.), ethers (e.g. diethyl ether, dioxane, etc. especially dioxane is preferable), halogenated hydrocarbons (e.g. methylene chloride etc.), ketones (e.g. acetone etc.), aromatic hydrocarbons (e.g. toluene, benzene, etc.), esters (e.g. ethyl acetate etc.), N,N-dimethylformamide, etc. Among them, alcohols especially methanol, ethanol and isopropanol, ketones and ethers are preferred.
  • the organic solvent is used in an amount of about 2 to 20 times the volume, preferably about 5 to 8 times the volume of the present pyridium derivatives .
  • the crystals thus formed are collected by a known method, e.g. filtration, centrifugation.
  • the crystals of solvate, e.g. ethanol solvate, of the present pyridinium derivative is subjected to de-solvent treatment to give crystals of the present pyridinium derivatives .
  • the de-solvent treatment are exemplified by (1) humidified de-solvent treatment, in which a solvent in crystal grating is replaced with water molecule; (2) supercritical de-solvent treatment, in which a solvent is replaced with carbon dioxide which is in a supercritical state; and (3) de-solvent treatment wherein the sample is treated under reduced pressure in a warm temperature.
  • the bondage between the pyridinium derivative and ethanol is not strong. Therefore, the ethanol can be easily eliminated by the de-solvent treatment, which is well established in organic chemistry, i.e. heating under reduced pressure.
  • the ethanol solvate is dried in vacuo at room temperature (15-30°C) to 100°C, preferably 60 to 70°C, for about 5 to 100 hours, preferably about 40 to 60 hours, whereby the residual amount of the solvent (ethanol) is usually reduced to 1000 ppm or less, thus giving sparingly hygroscopic, stable crystals of the present pyridinium derivatives.
  • a crystal of the pyridinium derivative can be obtained by subjecting the solvate to de-solvent treatment.
  • de-solvent treatment it can be carried out by a similar manner as those mentioned above .
  • the crystals of the present pyridinium derivatives obtained by de-solvent of crystals of ethanol solvate of the present pyridinium derivatives remains crystal forms .
  • the crystals of solvate of the present pyridinium derivatives and the crystals of pyridinium derivatives of the present invention are of very low hygroscopicity compared with the conventional lyophilizate, are very easy to handle and have characteristics of high stability and high uniformity.
  • the crystals of the present pyridinium derivatives in accordance with the present invention are effective in the prevention and treatment of the various diseases mentioned hereinbefore, without eliciting adverse reactions or toxic responses.
  • the crystals can be administered either as such, i.e. as powders, or in suitable pharmaceutical dosage forms to mammals (e.g. man, rabbit, dog, cat, rat, mouse, guinea pig, etc.), whether orally or by any other suitable route.
  • mammals e.g. man, rabbit, dog, cat, rat, mouse, guinea pig, etc.
  • the dosage depends on the characteristics and clinical status of the recipient, route of administration, dosing frequency, and other factors.
  • the recommended dosage in terms of the crystals of the present pyridinium derivatives is usually 0.001 to 10 g/kg body weight, preferably 0.01 to 2.0 mg/kg b. wt., and more preferably 0.1 to 2.0 mg/kg b. wt., which dose is to be administered 1 to about 5 times daily, preferably 1 to about 3 times daily.
  • the crystals of the present pyridinium derivatives can be administered by drip injection in a dose of 0.01 to 2.0 mg/kg body weight/minute over about 2 hours, once to 5 times daily, preferably once to 3 times daily.
  • the above dosage may be used as a reference.
  • crystals of the present pyridinium derivatives can be administered in a dose of about 0.01 to 100 mg/kg, preferably 0.1 to 10 mg/kg, once or up to 4 divided doses daily.
  • composition for administration by the oral route or otherwise can be manufactured, for example by the following known procedures.
  • the composition for oral administration can be typically provided in a solid or a liquid dosage form.
  • the solid dosage form for oral administration includes tablets (including dragees and film-coated tablets), pills, granules, fine granules, powders, capsules (including soft capsules), and others.
  • the liquid dosage form for oral administration includes an elixir, syrup, emulsion, suspension, etc. Those compositions can be prepared by known pharmaceutical procedures using the common carrier or excipient in a suitable amount .
  • composition for non-oral administration can also be provided in a variety of dosage forms such as injections, suppositories, ointments, plasters, liniments, and others.
  • Typical injections are intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, drip injection, etc.
  • Solid dosage forms can be manufactured using the routine formulating components, e.g.
  • saccharides such as starch, lactose, sucrose, annitol, corn starch, etc.; excipients such as crystalline cellulose, carboxymethylcellulose, light silicic anhydride, etc.; binders such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl ether, ethylcellulose, arabic gum, tragacanth gum, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin, pectin, etc.; lubricants such as magnesium stearate, calcium stearate, talc, polyethylene glycol, colloidal silica, etc.; disintegrators such as starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, etc.; disintegration aids, humectants, surfactants, etc . in suitable proportions .
  • Liquid dosage forms can be manufactured by using suitable amounts of the conventional formulating components, e.g. solvents such as water for injection, water, alcohols (e.g. ethanol, ethylene glycol, propylene glycol, etc.), solubilizers such as ethanol, polyethylene glycol, propylene glycol, D-mannitol, cholesterol, triethanolamine, sodium carbonate, sodium citrate, benzyl benzoate, benzyl alcohol, etc.; nonionic surfactants (e.g.
  • polysorbate 80 HCO-50 (polyoxyethylene (50)-hydrogenated castor oil adduct), stearyltriethanolamine, sodium lauryl sulfate, lecithin, glycerin monostearate, etc.); suspending agents such as hydrophilic macromolecular substances, e.g.
  • polyvinyl alcohol polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxy ethylcellulose , hydroxyethylcellulose , hydroxypropylcellulose, etc.
  • isotonizing agents such as sodium chloride, glycerin, D-mannitol, etc.; buffers such as phosphate, acetate, carbonate, citrate, and other buffer solutions, local anesthetics (soothing agents) such as benzyl alcohol etc., glucose, amino acids, and others.
  • the above solid and liquid forms may be respectively supplemented with a preservative, solubilizer, emulsifier, dispersant, thickener, plasticizer, adsorbent, perfume, colorant, corrigent, sweetener, antiseptic, antioxidant, etc. in the per se known manner.
  • the above dosage forms can be manufactured using the routine techniques such as mixing, compounding, granulation, compression, coating, sterilization, emulsification, etc. according to their characteristics. Manufacture of each dosage form can be carried out with reference to the corresponding section of the General Rules of Preparation of the Pharmacopoeia of Japan, among other protocols.
  • Injectable dosage forms can be manufactured by dissolving, suspending or emulsifying compound [I] typically in a sterile aqueous or oily medium which is generally used in the preparation of an injection.
  • the oily medium includes sesame oil and soybean oil, among other oils.
  • the injection so prepared is dispensed in suitable ampules and provided for parenteral use.
  • Suppositories for rectal administration can be manufactured by the per se known technology, for example by incorporating compound [I] in an ordinary suppository base and molding the mixture. There is no particular restriction on the suppository base that can be used for purposes of the invention.
  • the water-soluble base includes polyethylene glycol (e.g. PEG-400, 1000, 1540, 4000, 6000, and mixtures thereof), glycerin, glycerogelatin, propylene glycol, sorbitol, mannitol, natural gums (e.g.
  • tragacanth gum acacia gum, karaya gum, island moss, guaiac gum, xanthane gum, locust bean gum, etc.
  • cellulose derivatives e.g. methylcellulose, carboxymethylcellulose, etc.
  • acrylic polymers e.g. polyacrylic acid, polymethacrylic acid, etc.
  • vinyl polymers e.g. polyvinylpyrrolidone, polyvinylmethylcellulose, carboxypolymethylene, etc.
  • synthetic polysaccharides e.g. polysucrose, polyglucose, polylactose, etc.
  • starch dextrin, pectin, sodium alginate, etc.
  • the oleagenous base includes fatty acid glycerides such as cacao batter, laurin fat, isocacao, Suppocire (Gatefosse, France), Witepsol, Dynamit Nobel, West Germany) and vegetable oils such as sesame oil, soybean oil, corn oil, cottonseed oil, olive oil, etc.
  • fatty acid glycerides such as cacao batter, laurin fat, isocacao, Suppocire (Gatefosse, France), Witepsol, Dynamit Nobel, West Germany
  • vegetable oils such as sesame oil, soybean oil, corn oil, cottonseed oil, olive oil, etc.
  • the emulsion base includes but is not limited to mixtures of cacao butter with cholesterol and glycerin, with lecithin and water, with lanette wax SX (predominantly composed of the sulfuric acid esters of cetyl alcohol and stearyl alcohol, with about 10% of phosphoric acid ester), with cetyl alcohol and sodium lauryl sulfate, or with glycerin monostearate and mixtures of fatty acid ono- glycerol ester, monolene (propylene glycol -mono- stearate), wood wax, white wax, stearyl alcohol, or cetyl alcohol with sodium laurate, Tween, etc.
  • lanette wax SX predominantly composed of the sulfuric acid esters of cetyl alcohol and stearyl alcohol, with about 10% of phosphoric acid ester
  • cetyl alcohol and sodium lauryl sulfate or with glycerin monostearate and mixtures of fatty acid ono- glyce
  • the ointment base includes purified lanolin, sodium lauryl sulfate, etc.
  • the preferred water- soluble base is polyethylene glycol
  • the preferred oleagenous base is the fatty acid mono-, di- or triglyceride, e.g. Witepsol or Miglyol (Dynamit Nobel, West Germany)
  • the preferred emulsion base is a mixture of cacao butter and lanette wax SX
  • the preferred ointment base is purified lanolin.
  • Those bases can be used singly or in admixture and in a suitable proportion.
  • the above composition may contain other physiologically active substances not undergoing untoward interactions with compound [I].
  • active substances are therapeutic drugs for pancreatitis such as FOY, Futhan, etc.; various antibiotics such as the first-generation to third- generation cephem drugs (e.g.
  • cephaloridine cephalothin, cefazolin, cephapirin, cephacetrile, ceftezole, cefa andole, cefotiam, cefoperazone, cefuroxime, cefotaxime, ceftizoxime, cefmenoxime, cefpiramide, ceftazidime, ceftriaxone, cefpimizole, cefuzona , cefozidi e, etc.), penicillins (e.g.
  • benzylpenicillin phenoxymethylpenicillin, phenethicillin, propicillin, methicillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, nafcillin, ampicillin, hetacillin, cyclacillin, amoxicillin, talampicillin, pivampicillin, bacampicillin, mezlocillin, lenampicillin, aspoxicillin, piperacillin, apalcillin, carbenicillin, sulbenicillin, carindacillin, carfecillin, ticarcillin, mecillinam, pivmecillinam, sultamicillin, etc.), aminoglycosides (e.g.
  • streptomycin fradiomycin, kanamycin, paromomycin, bekanamycin, lividomycin, ribostamycin, gentamicin, dibekacin, tobramycin, amikacin, sisomicin, micronomicin, netilmicin, astromicin, isepamicin, arbekacin, spectinomycin, etc.
  • monobactams e.g. aztreonam, carumonam, etc.
  • carbapenems e.g.
  • TNF tumor necrosis factor
  • the proportion of the present pyridinium derivatives in the composition of the present invention should be such that, after administration, its effective amount will be made available for expression of prophylactic or therapeutic efficacy in the above- mentioned diseases and varies with different dosage forms.
  • the present pyridinium derivatives should account for 0.05 to 100 weight %, preferably 1 to 50 weight %, and more preferably 5 to 20 weight %, based on the total weight of the dosage form.
  • the present pyridinium derivatives should account for 0.01 to 8 weight % or preferably 0.1 to 3 weight % in each ampule. Examples
  • 3-Anilinopropionitrile 3.0 kg, was suspended in a solution of 1.7 kg sodium hydroxide in 12 L water and the suspension was refluxed with stirring for 2 hours. After cooling to 30°C or below, this reaction mixture was adjusted to pH 4.5 with concentrated hydrochloric acid and extracted with 6 L of ethyl acetate. The aqueous layer was further adjusted to pH 2.6 with concentrated hydrochloric acid and re-extracted with 6 L of ethyl acetate. The organic layers were pooled and concentrated under reduced pressure at an external temperature of not higher than 50°C. The residue was dissolved in 4.5 L of toluene at an external temperature of 50 to 60°C.
  • the reaction was conducted at an internal temperature of 25°C for 2 hours, at the end of which time the reaction mixture was diluted with 12.5 L of water and allowed to stand.
  • the aqueous layer was extracted with 5.6 L of ethyl acetate and the organic layers were pooled and washed with 5.6 L of water.
  • the organic layer was concentrated under reduced pressure and the residue was dissolved in 8.9 L of toluene with heating at 50°C
  • the solution was cooled gradually to 5°C and the resulting precipitate was recovered by filtration.
  • This organic layer was washed with 1.9 L of lN-sodium hydroxide/water 4 times and then with 2.2 L of water. After further washing with 1.4 L of lN-hydrochloric acid and 2.2 L of water, the organic layer was concentrated under reduced pressure. The residue was dissolved in 8 L of toluene with heating at 60°C and the solution was cooled gradually to 4°C.
  • the organic layer was concentrated under reduced pressure and 9 L of ethanol and 100 g of activated carbon were sequentially added to the residue.
  • the mixture was stirred at 41 to 48°C for 20 minutes and the activated carbon were filtered off and the resulting liquid was washed with 1 L of ethanol .
  • the filtrate and washes were combined and cooled to a liquid temperature of 25°C. After 3 hours of aging, the crystals were collected by filtration, pressure- filtered using nitrogen gas, and washed with 2 L of ethanol.
  • the column was irrigated with 260 L of 1N- sodiu hydroxide/water and 130 L of pure water in the order mentioned. After confirming that the effluent was neutral, the column was further irrigated with 260 L of 2N-nitric acid/water and 430 L of pure water and the neutrality of the effluent was confirmed.
  • Example 4 Example 4
  • This chloroform solution was gradually added dropwise to 5 L of IPE and the mixture was stirred at room temperature for 1 hour.
  • the precipitate was collected by filtration, washed with 380 ml of IPE, and dried in vacuo at 50°C.
  • the resulting powders were dissolved in 2.6 L of 70% methanol/water and adsorbed on 2.6 L of an ion exchange resin IRA-410 (Cl " ) .
  • Elution was carried out with 70% methanol/water and the fractions containing the reaction product were pooled and concentrated under reduced pressure.
  • the residue was extracted with 1 L of chloroform twice and the organic layers were combined and concentrated to dryness under reduced pressure.
  • the active fractions were collected, and the fractions were concentrated under reduced pressure to 500 ml.
  • the concentrate was extracted with 800 ml of ethyl acetate.
  • organic layer was concentrated under reduced pressure, and to the concentrated residue was added 800 ml of acetone to dissolve.
  • the dissolution was mixed for one hour under ice-cooling, causing the emergence of crystals.
  • the crystals were recovered by filtration to obtain the titled crystals.
  • the concentrate was extracted with 500 ml of ethyl acetate.
  • the obtained organic layer was concentrated under reduced pressure, and to the concentrated residue was added 400 ml of 1,4-dioxane to dissolve.
  • the dissolution was mixed for one hour under ice-cooling, causing the emergence of crystals.
  • the crystals were recovered by filtration to obtain the titled crystals.
  • pyridinium derivatives can be produced on a commercial high-production scale and these pyridinium derivatives can be provided as very stable and homogeneous crystals by an expedient procedure, in high purity, and in good yield, the pyridinium derivatives showing very satisfactory antagonizing activity against septic shock due to PAF (platelet activating factor) antagonism and endotoxin- induced pancreatitis and of use as prophylactic and therapeutic agents for PAF-associated gastrointestinal diseases, PAF-associated circulatory disturbances (e.g. grave infectious diseases, postoperative endotoxin shock, etc.), hyperendothelinism (e.g.
  • the ethanol solvate of pyridinium derivative (I) that can be provided by the method of this invention is crystalline, purification to a very high degree of purity can be made feasible and the pyridinium derivative available on elimination of the solvent is very easy to handle because of its low hygroscopicity and high stability.
  • the present invention provides a neat solution to the problem of hygroscopicity, (because of its low water-solubility, the derivative normally presents a major problem in the conventional lyophylization from a dilute aqueous solution), and the problem of non-homo- geniety (this is a major problem when lyophilization is carried out in an oil-separated phase using a small quantity of water to overcome the hygroscopicity problem) .

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Abstract

Cristaux de dérivés de pyridinium ou cristaux de solvate de dérivés de pyridinium, lesdits dérivés de pyridinium étant un composé représenté par la formule: dans laquelle R1b représente un groupe alkyle ou un groupe aralkyle, R2b représente un atome d'hydrogène, un atome d'halogène, un groupe alkyle, un groupe alkoxy, un groupe hydroxyle, un groupe amino, un groupe nitro, un groupe carbamoyle, un groupe mercapto ou un groupe cyano, R3b représente (1) un atome d'hydrogène, (2) un groupe alkyle, (3) un groupe aryle pouvant être éventuellement substitué par alkyle, alkoxy, halogène, amino, hydroxy ou nitro, (4) un groupe aralkyle, mb est un entier de 0 à 3, chacun de R?4b et R5b¿ représente un atome d'hydrogène, un groupe alkyle ou un groupe aralkyle ou R?4b et R5b¿ peuvent être combinés afin de constituer un groupe hétérocyclique contenant azote avec l'atome d'azote contigu ou son groupe hétérocyclique condensé et Wυ représente un anion. Ce composé peut être préparé à une échelle de production commerciale et ces dérivés de pyridinium peuvent être préparés en tant que cristaux très stables et homogènes au moyen d'un procédé efficace, ce qui permet d'obtenir des dérivés de pyridinium extrêmement purs et en quantités satisfaisantes. Ces dérivés présentent une efficacité antagoniste contre le choc septique provoqué par le facteur d'activation des plaquettes (PAF) et contre la pancréatite provoquée par les endotoxines et peuvent être utilisés en tant qu'agents prophylactiques et thérapeutiques contre des maladies gastro-intestinales associées à PAF, contre des problèmes circulatoires associés à PAF, la pancréatite aiguë fulminante, les maladies infectieuses, la septicémie provenant de causes différentes des endotoxines, ainsi que contre leurs complications.
PCT/JP1997/002522 1996-07-25 1997-07-22 Derives cristallins de pyridinium en tant qu'antagonistes du facteur d'activation des plaquettes WO1998004547A1 (fr)

Priority Applications (1)

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AU34633/97A AU3463397A (en) 1996-07-25 1997-07-22 Crystalline pyridinium derivatives as paf-antagonists

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JP8/196686 1996-07-25
JP19668696 1996-07-25

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0301751A1 (fr) * 1987-07-31 1989-02-01 Takeda Chemical Industries, Ltd. Dérivés de pyridinium, leur préparation et leur utilisation
EP0369810A2 (fr) * 1988-11-18 1990-05-23 Takeda Chemical Industries, Ltd. Antagonistes de PAF comme agents anti-hyperendothélinémiques
EP0382380A1 (fr) * 1989-01-30 1990-08-16 Takeda Chemical Industries, Ltd. Nitrate de pyridinium, sa préparation et son utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0301751A1 (fr) * 1987-07-31 1989-02-01 Takeda Chemical Industries, Ltd. Dérivés de pyridinium, leur préparation et leur utilisation
EP0369810A2 (fr) * 1988-11-18 1990-05-23 Takeda Chemical Industries, Ltd. Antagonistes de PAF comme agents anti-hyperendothélinémiques
EP0382380A1 (fr) * 1989-01-30 1990-08-16 Takeda Chemical Industries, Ltd. Nitrate de pyridinium, sa préparation et son utilisation

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