WO1998047901A1 - Procede de production de composes tricycliques et de leurs intermediaires - Google Patents

Procede de production de composes tricycliques et de leurs intermediaires Download PDF

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Publication number
WO1998047901A1
WO1998047901A1 PCT/JP1998/001752 JP9801752W WO9847901A1 WO 1998047901 A1 WO1998047901 A1 WO 1998047901A1 JP 9801752 W JP9801752 W JP 9801752W WO 9847901 A1 WO9847901 A1 WO 9847901A1
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group
ring
alkyl
substituted
halogen
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PCT/JP1998/001752
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English (en)
Inventor
Tomomi Ikemoto
Mitsuhiro Wakimasu
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Takeda Chemical Industries, Ltd.
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Priority to AU68527/98A priority Critical patent/AU6852798A/en
Publication of WO1998047901A1 publication Critical patent/WO1998047901A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom

Definitions

  • the present invention relates to a process for producing tricyclic compounds having excellent activity in, for example, inhibiting platelet-derived growth factor (PDGF), ameliorating the activity of renal diseases, lowering cholesterol levels, and their useful intermediates .
  • PDGF platelet-derived growth factor
  • PCT international published application No. WO 96/02542 discloses a process for producing tricyclic compounds which are useful as medicines , having an excellent activity in, for example, inhibiting platelet-derived growth factor (PDGF), antihypertensive activity, ameliorating activity of renal diseases, and lowering cholesterol levels.
  • PDGF platelet-derived growth factor
  • the present invention relates to (1) a process for producing a compound of the formula
  • ring A may be substituted
  • ring B may have one oxo group
  • R 1 is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group
  • X is an optionally substituted divalent hydrocarbon group
  • ring Y is an optionally substituted nitrogen-containing 5- or 6-membered heterocyclic ring and R is an optionally substituted hydrocarbon group, or a salt thereof, which comprises reacting a compound of the formula (II):
  • ring A may be substituted with 1 to 3 groups selected from halogen , C 1 . 6 alkyl, alkoxy, alkoxy, C ⁇ alkylthio, halogeno-C j .g alkylthio, hydroxy, carboxy, cyano, nitro, amino, mono- or alkylamino, formyl, mercapto, C 1 _ 6 alkyl-carbonyl, C x _ ⁇ alkoxy-carbonyl, sulfo, C- L.J alkylsulfonyl , carbamoyl and mono- or alkyl-carbamoyl , ring B is a ring of the formula:
  • X is (l)a C x _ 15 alkylene group, a C 2 . 16 alkenylene group or a C 2 _ 16 alkynylene group, which may be substituted with 1 to 5 groups selected from C 1 _ 6 alkyl and phenyl, (2)a phenylene group which may be substituted with 1 to 4 groups selected from halogen, C 1 _ 6 alkyl, C ⁇ _ 6 alkoxy, C ⁇ alkylthio, hydroxy, carboxy, cyano, nitro, amino, mono- or alkylamino, formyl, mercapto, C ⁇ alkyl-carbonyl, C ⁇ .
  • ring Y is a piperidine, a pyrrolidine or a pyridine which may be substituted with 1 to 3 groups selected from halogen, alkyl, C x _ 6 alkoxy, halogeno- C 1 _ 6 alkoxy, alkylthio, alkylthio , hydroxy, carboxy, cyano, nitro, amino, mono- or alkylamino, formyl, mercapto, alkyl-carbonyl alkoxy-carbonyl, sulfo, alkylsulfonyl, carbamoyl and mono- or di-C ⁇ g alkyl-carbamoyl, R is a C x .
  • alkyl group 15 alkyl group, a C 3 . 8 cycloalkyl group, a C 2 _ 18 alkenyl group, a C 7 . 16 aralkyl group or a C 6 . 14 aryl group, which may be substituted with 1 to 5 groups selected from nitro, hydroxy, cyano, carbamoyl, mono- or alkyl-carbamoyl, carboxy, C 1-6 alkoxy-carbonyl, sulfo, halogen, C x _ 6 alkoxy, phenoxy, halogeno-phenoxy, C ⁇ alkylthio, mercapto, phenylthio, pyridylthio, C ⁇ alkylsulfinyl, alkylsulfonyl, amino, C 1 _ 6 acylamino , mono- or lkylamino, 4- to 6-membered cyclic amino, C 1 .
  • acyl benzoyl, 5- or 6-membered monocyclic heteroaromatic ring containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, bicyclic heteroaromatic ring which is formed by condensing 5- or 6-membered heteroaromatic ring containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom with benzene ring, and a C 7 _ 16 aralkyl group or a C 6 .
  • R 1 is ( 1 )a hydrogen atom, ( 2 )a halogen atom, (3)anacyl group derived from carboxylic acid or (4)a C ⁇ alkyl group, a C 3 . 8 cycloalkyl group, a C 2 .
  • alkenyl group a C 7 _ 16 aralkyl group or a C 6 _ 14 aryl group, which may be substituted with 1 to 5 groups selected from nitro, hydroxy, cyano, carbamoyl, mono- or alkyl, carboxy, CAg lkoxy-carbonyl, sulfo, halogen, lkoxy, phenoxy, halogeno-phenoxy alkylthio, mercapto, phenylthio, pyridylthio, alkylsulfinyl, acylamino, mono- or alkylamino, 4- to 6-membered cyclic amino, C 1 .
  • acyl benzoyl, 5- or 6-membered monocyclic heteroaromatic ring containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, bicyclic heteroaromatic ring which is formed by condensing 5- or 6-membered heteroaromatic ring containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom with benzene ring, or a C 7 . 16 aralkyl group or a C 6 _ 14 aryl group which may be substituted with C ⁇ _ 6 alkyl, halogeno-Ci.g alkyl or oxo, and
  • Z is a halogen atom, a C ⁇ ,, alkylsulfonyloxy group or a C 6 . 10 arylsulfonyloxy group.
  • R is a hydrogen atom or a alkyl group
  • X is a alkylene group
  • ring Y is a piperidine and R is a halogeno-C ⁇ alkyl group
  • R 1 is (l)a hydrogen atom, (2)a C 1 _ 10 alkyl group or a C 6 _ 14 aryl group which may be substituted with halogen, hydroxy, carboxy, nitro or amino, (3)a alkoxy-carbonyl group or (4)a C 1 .
  • Z is a halogen atom, a C ⁇ ,, alkylsulfonyloxy group or a C ⁇ _ 10 arylsulfonyloxy group
  • X is a alkylene group which may be substituted with halogen, hydroxy, C ⁇ alkyl or C 6 _ 14 aryl
  • ring Y is a nitrogen-containing 6- membered heterocyclic ring
  • R is a C ⁇ _ 15 alkyl group, a C 3 _ 8 cycloalkyl group, a C 2 remedy 10 alkenyl group, a C 6 . 14 aryl group or a C 7 .
  • 16 aralkyl group which may be substituted with (i)halogen, (ii)cyano, ( iii)hydroxy, ( ⁇ v ) C 1 _ 6 alkyl which may be substituted with halogen, (v) C 1 , 6 alkoxy which may be substituted with halogen, (vi)C 6 . 14 aryl, (vii) carboxy which may be esterified or (viii)5- or 6-membered heterocyclic group,
  • ring A may be substituted with halogen or C 2 . 4 alkyl
  • ring B is a ring of the formula:
  • R 1 is a hydrogen atom, a alkyl group or a C 6 . 14 aryl group
  • X is a alkylene group which may be substituted with halogen, hydroxy or C : _ 4 alkyl
  • ring Y is a nitrogen- containing 6-membered heterocyclic ring
  • R is a C ⁇ .10 alkyl group which may be substituted with halogen, hydroxy or carboxy which may be esterified
  • R 1 is a hydrogen atom
  • ring Y is a nitrogen-containing 6-membered heterocyclic ring and R is a alkyl group
  • R 1 is a hydrogen atom
  • Z is a chlorine atom
  • X is an ethylene group
  • ring Y is a piperidine and R is a trifluoromethyl group
  • 16 alkynylene group which may be substituted with 1 to 5 groups selected from alkyl and phenyl, (2)a phenylene group which may be substituted with 1 to 4 groups selected from halogen, alkyl, alkoxy, alkylthio, hydroxy, carboxy, cyano, nitro, amino, mono- or alkylamino, formyl, mercapto, alkoxy-carbonyl, sulfo, alkylsulfonyl , carbamoyl and mono- or alkyl-carbamoyl, or (3)a divalent group formed by combining these groups, ring Y is a piperidine, a pyrrolidine or a pyridine which may be substituted with 1 to 3 groups selected from halogen, alkyl, alkyl, alkoxy, alkoxy, C 1 .
  • alkylthio alkylthio, alkylthio, hydroxy, carboxy, cyano, nitro, amino, mono- or di-C 1 _ 6 alkylamino, formyl, mercapto, alkoxy-carbonyl, sulfo, alkylsulfonyl, carbamoyl and mono- or alkyl-carbamoyl,
  • R is a C j ⁇ s alkyl group, a C 3 _ 8 cycloalkyl group, a C 2 . 18 alkenyl group, a C 7 . 16 aralkyl group or a C 6 _ 14 aryl group, which may be substituted with 1 to 5 groups selected from nitro, hydroxy, cyano, carbamoyl, mono- or alkyl, carboxy, alkoxy, phenoxy, halogeno-phenoxy, alkylthio, mercapto, phenylthio, pyridylthio, C 1 _ 6 alkylsulfinyl, C 1 _ 6 alkylsulfonyl, amino, acylamino, mono- or alkylamino, 4- to 6-membered cyclic amino, C 1-7 acyl, benzoyl, 5- or 6-membered monocyclic heteroaromatic ring containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom
  • Z is a halogen atom, a C x _ 4 alkylsulfonyloxy group or a C 6 . 10 arylsulfonyloxy group,
  • ring A may be substituted.
  • Example substituents of ring A include (1) halogen(e.g. fluorine, chlorine, bromine and iodine), (2)C X _ 6 alkyl (e.g. methyl, ethyl, propyl, isopropyl and butyl), ( 3)halogeno-C x _ 6 alkyl such as alkyl which is substituted with 1 to 5 halogens ( e. g. trifluoromethyl and trichloroethyl) , (4) ⁇ . 6 alkoxy(e.g.
  • alkylsulfonyl e.g. methylsulfonyl, ethylsulfonyl and propylsulfonyl
  • the ring A may be substituted with these same or different 1 to 3 substituents at substitutable positions.
  • ring B may have one oxo group.
  • ring B include a nitrogen-containing 5- or 6-membered heterocyclic ring such as rings of the formula :
  • X is an optionally divalent hydrocarbon group.
  • Examples of the divalent hydrocarbon group of an optionally divalent hydrocarbon group represented by X include linear divalent hydrocarbon group such as C 1 . 15 alkylene group (e.g. methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene , heptamethylene and octamethylene) , C 2 . 16 alkenylene group(e.g. vinylene, propenylene, 1-butenylene, 2- butenylene, 1-pentenylene, 2-pentenylene and 3- pentenylene) , C 2 . 16 alkynylene group(e.g.
  • Preferable examples are C ⁇ alkylene groups (e.g. methylene , ethylene, propylene, butylene, pentamethylene, hexamethylene, heptamethylene and octamethylene), more preferably C x _ 6 alkylene groups (e.g. methylene, ethylene and propylene) .
  • the said linear divalent hydrocarbon group may have same or different 1 to 5 substituents selected from C 1 _ 6 alkyl(e.g. methyl, ethyl, propyl, isopropyl and butyl) and phenyl at substitutable positions.
  • substituents which the said phenylene group may have at substituable positions include same or different 1 to 4 substituents selected from, ( l)halogen(e.g. fluorine, chlorine, bromine and iodine) , ( 2 ) C 1 _ 6 alkyl (e.g. methyl, ethyl, propyl, isopropyl and butyl), (3)0 ⁇ alkoxy(e.g. methoxy, ethoxy, propoxy, isopropoxy and butoxy) , ⁇ ) C 1 _ 6 alkylthio (e.g.
  • ring Y is an optionally substituted nitrogen-containing 5- or 6- membered heterocyclic ring.
  • the said nitrogen-containing 5- or 6-membered heterocyclic ring may be saturated or unsaturated.
  • Examples of the said nitrogen-containing 5- or 6-membered heterocyclic ring include a piperidine, a pyrrolidine or a pyridine. Practically, examples of the group of the formula :
  • R is an optionally substituted hydrocarbon group.
  • the hydrocarbon group of the optionally substituted hydrocarbon group represented by R include an alkyl group , a cycloalkyl grou , an alkenyl group, an aralkyl group and an aryl group.
  • Examples of the said alkyl group include C 1 . 15 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, tridecyl, tetradecyl and pentadecyl .
  • Preferable examples are C 1 . 6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • Examples of the said cycloalkyl group include C 3 _ 8 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • alkenyl group examples include C 2 _ 18 alkenyl groups such as vinyl, allyl, isopropenyl, 3-butenyl, 3- octenyl and 9-octadecenyl.
  • Preferable examples are C 2.6 alkenyl groups such as vinyl, allyl, 2-butenyl and 3- butenyl.
  • Examples of the said aralkyl group include C 7 . 16 aralkyl groups, practically, alkyl group such as benzyl, phenethyl, 3-phenylpropyl and 4-phenylbutyl, and alkyl group such as ( 1-naphtyl)methyl and 2- ( 1-naphtyl) ethyl.
  • alkyl groups such as benzyl .
  • aryl group examples include monocyclic, bicyclic or tricyclic aromatic C 6 . 14 aryl groups such as phenyl, 1-naphtyl, 2-naphtyl, phenanthryl and anthryl. Preferable examples are C 6 _ 10 aryl group such as phenyl.
  • substituents which the said hydrocarbon group may have include (l)nitro, (2)hydroxy, (3)cyano, ( 4 ) carbamoyl , (5)mono- or alkyl (e.g. N-methylcarbamoyl, N-ethylcarbamoyl, N,N- dimethylcarbamoyl and N,N-diethylcarbamoyl) , (6)carboxy, ( 7 ) C X _ 6 alkoxy-carbonyl(e. g.methoxycarbonyl, ethoxycarbonyl , propoxycarbonyl and isopropoxycarbonyl) , (8)sulfo, ( 9 )halogen(e.g.
  • acetylamino and propionylamino ) , (21)mono- or alkylamino (e.g. methylamino , ethylamino , dimethylamino and diethylamino), (22) cyclic amino (e.g. 4- to 6-membered cyclic amino such as 1-azethydinyl, 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino and 1-piperadinyl) , (23)0 ⁇ 7 acyl(e.g. formyl and C ⁇ alkyl-carbonyl such as acetyl), ( 24)benzoyl and (25)heterocyclic group(e.g.
  • 5- or 6-membered monocyclic heteroaromatic group containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom and bicyclic heteroaromatic group which is formed by condensing 5- or 6-membered cyclic heteroaromatic ring containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom with benzene ring such as 2- or 3-thienyl, 2- or 3-furyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5- isothiazolyl, 2-, 4- or 5-oxazolyl, 1,2,3- or 1,2,4- triazolyl, 1H- or 2H-tetrazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidyl, 3- or 4-pyridazinyl, quinolyl, isoquinolyl and indolyl) .
  • substituents which the said aralkyl group or aryl group may have include, in addition to these substituents, groups selected from alkyl(e.g. methyl, ethyl, propyl, isopropyl and butyl), alkyl such as C ⁇ _ 6 alkyl which is substituted with 1 to 5 halogens (e.g. alkyl group such as C 1 .
  • the said hydrocarbon group may have these 1 to 5 substituents at substituable positions.
  • R 1 is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group.
  • halogen atoms represented by R 1 include fluorine, chlorine, bromine and iodine.
  • Examples of the hydrocarbon group of the optionally substituted hydrocarbon group represented by R 1 include the same ones as the above-mentioned hydrocarbon group represented by R, and examples of the substituents include the same ones as the above-mentioned substituents which the hydrocarbon group may have.
  • Examples of the acyl group represented by R 1 include acyl groups derived from carboxylic acid such as alkoxycarbonyl group, alkylcarbamoyl group and alkanoyl group .
  • alkoxycarbonyl group examples include alkoxy-carbonyl groups such as methoxycarbonyl , ethoxycarbonyl , propoxycarbonyl , isopropoxycarbonyl, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl , isopentyloxycarbonyl , neopentyloxycarbonyl and tert-pentyloxycarbonyl.
  • alkylcarbamoyl group examples include mono-C 1 _ 6 -N-alkyl-carbamoyl groups such as N- methylcarbamoyl , N-ethylcarbamoyl, N-propylcarbamoyl and N-butylcarbamoyl, groups such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N- dipropylcarbamoyl , N,N-dibutylcarbamoyl and N-ethyl-N- methylcarbamoyl and 4- to 6-membered cyclic carbamoyl groups combined with dialkyl(e.g. 1-azethydinylcarbonyl, morpholinocarbonyl , 1-pyrrolidinylcarbonyl, 1- piperidinylcarbonyl and 1-piperadinylcarbonyl) .
  • dialkyl e.
  • alkanoyl group examples include C ⁇ alkanoyl groups such as formyl, C 1 _ 9 alkyl-carbonyl group(e.g. acetyl, propionyl, butyryl, isobutyryl, valelyl, isovalelyl, pivaloyl and hexanoyl) .
  • Z is a leaving group.
  • Examples of leaving groups represented by Z include (l)a halogen atom such as fluorine, chlorine, bromine and iodine, (2)a alkanoyloxy group such as acetoxy and propionyloxy, (3)a C 7 _ arylcarbonyloxy group such as benzoyloxy, (4)a C x _ 4 alkylsulfonyloxy group such as methanesulfonyloxy and ethanesulfonyloxy and (5)a C 6 . 14 arylsulfonyloxy group such as benzenesulfonyloxy and p- toluenesulfonyloxy.
  • Ring A is preferably unsubstituted or substituted with halogen, alkylthio, C x _ 4 alkoxy, hydroxy, carboxy, nitro or amino. Ring A is more preferably unsubstituted or substituted with halogen or alkyl. The most preferable example of ring A is unsubstituted pyridine ring.
  • ring B Preferable examples of ring B include the ring of the formula :
  • R 1 include (l)a hydrogen atom, (2)a C ⁇ o alkyl group or a C 6 _ 14 aryl group which may be substituted with halogen, hydroxy, carboxy, nitro or amino, (3)a alkoxy-carbonyl group and (4)a C 1 _ 6 alkanoyl group, and R 1 is more preferably a hydrogen atom, a alkyl group or a C 6 _ 14 aryl group.
  • the most preferable example of R 1 is a hydrogen atom.
  • Preferable examples of Z include a halogen atom, a C ⁇ alkylsulfonyloxy group and a C 6 . 10 arylsulfonyloxy grou .
  • the most preferable example of Z is a chlorine .
  • Preferable examples of X include a C x _ alkylene group which may be substituted with halogen, hydroxy, C ⁇ _. alkyl or C 6 . 14 aryl, and more preferable examples are alkylene groups which may be substituted with halogen, hydroxy or C ⁇ alkyl.
  • the most preferable example is an ethylene group.
  • Preferable examples of ring Y include nitrogen- containing 6-membered heterocyclic rings and a piperidine is most preferable.
  • R include a C ⁇ _ 15 alkyl group, a C 3 - 8 cycloalkyl group, a C 2 . 10 alkenyl group, a C 6 . 14 aryl group and a C 7 _ 16 aralkyl group which may be substituted with (i)halogen, (ii) cyano, (iii)hydroxy, ( ⁇ v ) C ⁇ . 6 alkyl, alkyl which may be substituted with halogen, alkoxy group which may be substituted with halogen, (vii)C 6 _ 14 aryl. (viii) carboxy which may be esterified or (ix)5- or 6- membered heterocyclic ring.
  • R are C 1 . 10 alkyl groups which may be substituted with halogen, hydroxy or carboxyl which may be esterified.
  • An especially preferable example of R is a alkyl group.
  • the most preferable example of R is a trifluoromethyl group.
  • preferable examples of compounds of the formula ( I ) or a salt thereof include compounds wherein ring A is unsubstituted, ring B is a ring of the formula:
  • R 1 is a hydrogen atom or a alkyl group
  • X is a alkylene group
  • ring Y is a piperidine group
  • R is a alkyl group
  • the compound ( I ) obtained by the process of the present invention may form salts, preferably physiologically acceptable acid addition salts .
  • the salts of the compound in the present invention are inorganic acid salts (e.g. hydrochloric acid salt, phosphoric acid salt, hydrobromic acid salt and sulfuric acid salt ) , organic acid salts (e.g. acetic acid salt, formic acid salt, propionic acid salt, fumaric acid salt, maleic acid salt, succinic acid salt, tartaric acid salt, citric acid salt, malic acid salt, oxalic acid salt, benzoic acid salt, methanesulfonic acid salt and benzenesulfonic acid salt) .
  • inorganic acid salts e.g. hydrochloric acid salt, phosphoric acid salt, hydrobromic acid salt and sulfuric acid salt
  • organic acid salts e.g. acetic acid salt, formic acid salt, propionic acid salt, fumaric acid salt, maleic acid salt, succin
  • salts of the compound (I) include inorganic base salts (e.g. an alkali metal salt or an alkaline earth metal salt such as sodium salt, potassium salt, calcium salt and magnesium salt, aluminum salt and ammonium salt) or organic base salts (e.g. trimethylamine salt and triethylamine salt).
  • the compound (I) may be hydrate or non-hydrate.
  • the compound ( I ) or a salt thereof has , in some instances, asymmetric carbons in the molecule and when two kinds of stereoisomers of R-configuration and S- configurated isomers are present, each of them and mixture of them are all included in the scope of the present invention.
  • the compound (II) or a salt thereof In the reaction between the compound (II) or a salt thereof and the compound (III) or a salt thereof, one equivalent to a large excess amount (1 to 10 equivalents) of the compound (III) are employed relative to the compound ( II ) .
  • the solvents to be employed include water, lower alcohols (e.g. methanol, ethanol and propanol) , ketones(e.g. acetone and methylethylketone) , ethers (e.g. tetrahydrofuran) and aprotic polar solvents (e. g. N,N- dimethylformamide , acetonitrile and dimethylsulfoxide) .
  • This reaction is employed efficiently under basic conditions.
  • Examples of the base include basic compounds such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium carbonate, triethylamine, diisopropylethylamine and 1 , 8-diazabicyclo[ 5.4.0 ] -7- undecene.
  • the base is preferably used in an amount of 1 to 10 equivalents.
  • sodium iodide as a reaction-promoting agent may be added in an amount ranging from one equivalent to a large excess (1 to 10 equivalents).
  • the reaction temperature ranges from about -20 to 200°C .
  • the reaction time ranges usually from about 10 minutes to 24 hours, preferably from about 0.5 to 6 hours.
  • the compound (I) in the above-mentioned reaction when the compound (I) in the above-mentioned reaction is obtained in the free form, it can be converted to a salt by per se known means or analogous means thereto (e.g. neutralization), and conversely, when the compound (I) is obtained in the form of a salt, it can be converted to the free form or any other salt by per se known means or analogous means thereto.
  • the compound ( I ) thus obtained can be isolated and purified by a conventional separating means such as washing , concentration, extraction of solvents, filtration, crystallization, recrystallization, distillation, chromatography) .
  • the compound ( I ) or a salt thereof is , for example , a diastereoisomer , conformer or etc.
  • it can be isolated by a conventional separating or purifying means.
  • compound (I) or a salt thereof is a racemic compound, it can be resolved into d-isomer and 1-isomer by a conventional means for optical resolution.
  • the starting material compounds (II) and (III) to be used in the process of the present invention can be produced by the following methods .
  • the compound (II) used in the process of the present invention can be produced by the methods disclosed in Journal of Heterocyclic Chemistry, Vol.9, page 81 (1972) and Japanese unexamined published application No. H8( 1996) -81467 (corresponding to PCT international published application No. WO 96/02542).
  • a sulfonylating reagent containing an optionally substituted hydrocarbon group is reacted with the compound (IV).
  • Examples of the optionally substituted hydrocarbon group which the sulfonylating reagent contains include the same ones as the above-mentioned optionally substituted hydrocarbon group represented by R.
  • the said sulfonylating reagent examples include trifluoromethanesulfonylating reagent (e.g. trifluoromethanesulfonic acid anhydride, trifluoromethanesulfonylchloride and N- phenyltrifluoromethanesulfonimide) , alkylsulfonylating reagent (e.g. methanesulfonylchloride ) , aromaticsulfonylating reagent (e.g. benzenesulfonylchloride and p-toluenesulfonylchloride ) .
  • the said sulfonylating reagent is used in an amount of one equivalent to large excess, preferably about 1 to 5 equivalents .
  • solvents to be employed in the reaction include halogenated hydrocarbon( e. g. methylene chloride, chloroform and dichloroethane) , ethers (e.g. diethylether and tetrahydrofuran) , esters (e.g. methyl acetate and ethyl acetate), aprotic polar solvents (e.g. acetonitrile, acetone and dimethylsulfoxide) and aromatics(e.g. benzene and toluene) .
  • bases may be employed.
  • the bases to be employed include inorganic base(e.g. potassium carbonate and sodium carbonate), organic base (e.g.
  • the reaction temperature ranges from about -80 to 100°C , preferably about -30 to 50°C .
  • the reaction time ranges usually from about 1 minutes to 24 hours, preferably from about 1 minutes to 10 hours.
  • the compound (II), compound (III) and compound (IV) may form salts and examples of salts include the same ones of the above-mentioned salt of the compound (I).
  • the compound ( I ) or a salt thereof obtained by the process of the present invention has an excellent inhibiting activity of PDGF action, ameliorating activity of renal diseases and activity of lowering lipid level, and are low in toxicity. Therefore, these compounds or their salts can be safely used in mammals (e.g. mouse , rat , hamster , rabbit, cat, dog, cow, horse, sheep, monkey and human ) , as agents for preventing or treating renal diseases [e.g. acute renal failure, diabetic nephropathy, nephritis (e.g.
  • chronic or acute glomerulonephritis such as mesangial proliferative glomerulonephritis, endocapillary proliferative glomerulonephritis , membranoproliferative glomerulonephritis type I, II, III, crescentic glomerulonephritis and diffuse sclerosing glomerulonephritis], arteriocslerotic diseases, restenosis after PTCA(percutaneous transluminal coronary angioplasty) , chronic rheumatoid arthritis, cancers and hyperlipidemia .
  • PTCA percutaneous transluminal coronary angioplasty
  • compositions formulated by a conventional method using carriers for pharmaceutical compositions adequately selected from excipients (e.g. calcium carbonate, kaolin, sodium hydrogencarbonate, lactose, corn starch, crystalline cellulose, talc, fine granulated sugar and porous substance), binders (e.g. dextrin, gum, -starch, gelatin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and furran) , thickener(e. g. natural rubbers and cellulose derivatives ) , disintegrants (e. g.
  • excipients e.g. calcium carbonate, kaolin, sodium hydrogencarbonate, lactose, corn starch, crystalline cellulose, talc, fine granulated sugar and porous substance
  • binders e.g. dextrin, gum, -starch, gelatin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and furran
  • thickener e. g. natural rubbers
  • carboxymethyl cellulose calcium closcarmellose sodium, clospovidone, low-substituted hydroxypropyl cellulose and partial ⁇ - starch
  • solvents e. g. water for injection, physiological saline, ringels solution, alcohol, propylene glycol, sesame oil and corn oil
  • dispersing agent e.g. Tween 80, HCO 60, carboxymethyl cellulose and sodium alginate
  • suspending agents e.g. sodium lauryl sulfate and benzalkonium chloride
  • dissolution acids e.g.
  • the pharmaceutical composition in the present invention which may contain the above-mentioned carriers for pharmaceutical compositions contains the compound (I) or a salt thereof in pharmaceutically effective amounts.
  • the content of the a salt thereof in the pharmaceutical composition ranges usually from 0.1 to 100 weight % relative to the whole weight of the pharmaceutical composition.
  • the pharmaceutical composition may contain, as active components, medicinal components other than the compound (I) or a salt thereof. These medicinal components are not specifically restricted so long as the object of the medicines is attained, and can be used in adequate ratios. Examples of the said medicinal components include diuretic, angiotensin II receptor antagonist, calcium blocker, angiotensin converting enzyme (ACE) inhibitor, Chymase inhibitor, antiphlogistic, hydroxymethylglutaryl-
  • ACE angiotensin converting enzyme
  • formulations include tablets (including sugar-coated tablets and film-coated tablets) , pills, capsules, granules, powdery preparations , syrups, emulsions, suspensions, injections, inhalants and ointments .
  • tablets including sugar-coated tablets and film-coated tablets
  • pills including sugar-coated tablets and film-coated tablets
  • granules powdery preparations
  • syrups emulsions
  • suspensions emulsions
  • injections inhalants and ointments
  • the compound ( I ) or a salt thereof as it is , or a homogeneous mixture of them with an excipient, a binder, a disintegrant or any other suitable additive, is granulated by an adequate means, to which is added, for example, a lubricant, and the whole mixture is subjected to compression molding.
  • this pharmaceutical composition may be coated with a coating agent for purpose of, for example, masking the taste, insuring dissolution in the intestinal fluid or sustaining release.
  • Injections can be prepared by dissolving, suspending or emulsifying a given amount of the compound (I) or a salt thereof in, for example, water for injection, to which is added, if necessary, for example, stabilizers, dissolution aids, suspending agents, buffers and preservations or by filling a given amount of the compound (I) or a salt thereof into a vessel for injections.
  • Capsules can be prepared by, for example, filling granules, granules coated with a coating agent or a homogenous mixture of the compound (I) or a salt thereof with pharmaceutical carriers such as excipients, into a capsule.
  • the pharmaceutical compositions thus obtained have PDGF-inhibiting activity, ameliorating activity of renal diseases and lipid lowering activity and are low in toxicity . Therefore, the pharmaceutical compositions are useful as medicines for preventing or treating diseases due to these pharmacological activities .
  • the pharmaceutical composition according to the invention can be used to prevent or treat hypertension, acute renal failure, diabetic nephropathy, nephritis (e.g. proliferative glomerulonephritis such as mesangial proliferative glomerulonephritis, diffuse sclerosing glomerulonephritis), arteriosclerosis, restenosis after PTCA, chronic rheumatoid arthritis, cancers and hyperlipemia .
  • diabetic nephropathy e.g. proliferative glomerulonephritis such as mesangial proliferative glomerulonephritis, diffuse sclerosing glomerulonephritis
  • arteriosclerosis e.g
  • the dose of the pharmaceutical composition varies with administration routes , symptoms , the age and body weight of patients.
  • the dose of the compound (I) or a salt thereof as effective components, for oral administration to adult patient of diabetic nephropathy is about 0.05 to 50mg/kg, preferably about 0.1 to 30 mg/kg per day which is given once or divided into several times per day (for example 1 to 3 times).
  • the administration route is not intended to be restricted by various situations and may be either oral or non-oral. Examples of the non-oral administration route include intravenously, intramuscularly, subcutaneously, intranasally, intrarectally, intravaginally and intraperitoneally.
  • the reaction mixture was ice-cooled and the formed crystals were collected by filtration.
  • the crystals were washed with 20% water containing methanol( 50ml) and dried to provide 10.8g of 1 , 2-dihydro-l- [2- (trifluoromethanesulfonylpiperidin- 4- yl ) ethan- 1 -yl ] - 1 , 4 , 7b-triazacyclopent [ cd] inden-2- one(yield 81%) .
  • tricyclic compounds having excellent pharmacological activities can be obtained having few steps , high yield and without the use of expensive materials.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Procédé de production de composés tricycliques qui sont utiles comme agents de traitement des néphropathies et de l'artériosclérose. Ledit procédé ne comporte que peu d'étapes et utilise des substances peu onéreuses. Le composé utilisé est un composé de formule (III) dans laquelle Z est un groupe labile, X est un groupe hydrocarbure divalent éventuellement substitué, l'anneau Y est un noyau hétérocyclique à 5 ou 6 éléments, contenant de l'azote et éventuellement substitué, et R est un groupe hydrocarbure divalent éventuellement substitué, ou un sel dudit composé.
PCT/JP1998/001752 1997-04-18 1998-04-16 Procede de production de composes tricycliques et de leurs intermediaires WO1998047901A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU68527/98A AU6852798A (en) 1997-04-18 1998-04-16 Process for producing tricyclic compounds and their intermediates

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/101254 1997-04-18
JP10125497 1997-04-18

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Publication Number Publication Date
WO1998047901A1 true WO1998047901A1 (fr) 1998-10-29

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WO (1) WO1998047901A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022089406A1 (fr) * 2020-10-26 2022-05-05 上海青煜医药科技有限公司 Composé hétérocyclique condensé contenant de l'azote, son procédé de préparation et son utilisation

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WO1991010647A1 (fr) * 1990-01-06 1991-07-25 Pfizer Limited Antagonistes de recepteurs muscariniques
WO1996002542A1 (fr) * 1994-07-15 1996-02-01 Takeda Chemical Industries, Ltd. Composes tricycliques, leur production et utilisation
DE4438083A1 (de) * 1994-10-25 1996-05-02 Thomae Gmbh Dr K Basisch substituierte Acylpyrrolidine und Acylpiperidine, deren Salze, diese Verbindungen enthaltende Arzneimittel und deren Verwendung sowie Verfahren zu ihrer Herstellung
EP0826686A2 (fr) * 1996-09-02 1998-03-04 Takeda Chemical Industries, Ltd. Composés tricycliques, leur préparation et utilisation

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WO1991010647A1 (fr) * 1990-01-06 1991-07-25 Pfizer Limited Antagonistes de recepteurs muscariniques
WO1996002542A1 (fr) * 1994-07-15 1996-02-01 Takeda Chemical Industries, Ltd. Composes tricycliques, leur production et utilisation
DE4438083A1 (de) * 1994-10-25 1996-05-02 Thomae Gmbh Dr K Basisch substituierte Acylpyrrolidine und Acylpiperidine, deren Salze, diese Verbindungen enthaltende Arzneimittel und deren Verwendung sowie Verfahren zu ihrer Herstellung
EP0826686A2 (fr) * 1996-09-02 1998-03-04 Takeda Chemical Industries, Ltd. Composés tricycliques, leur préparation et utilisation

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022089406A1 (fr) * 2020-10-26 2022-05-05 上海青煜医药科技有限公司 Composé hétérocyclique condensé contenant de l'azote, son procédé de préparation et son utilisation

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