WO1996002542A1 - Composes tricycliques, leur production et utilisation - Google Patents

Composes tricycliques, leur production et utilisation Download PDF

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Publication number
WO1996002542A1
WO1996002542A1 PCT/JP1995/001382 JP9501382W WO9602542A1 WO 1996002542 A1 WO1996002542 A1 WO 1996002542A1 JP 9501382 W JP9501382 W JP 9501382W WO 9602542 A1 WO9602542 A1 WO 9602542A1
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group
compound
mmol
optionally substituted
dihydro
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PCT/JP1995/001382
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English (en)
Inventor
Muneo Takatani
Yumiko Shibouta
Kiminori Tomimatsu
Tetsuji Kawamoto
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Takeda Chemical Industries, Ltd.
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Priority to EP95925104A priority Critical patent/EP0771319A1/fr
Priority to AU29358/95A priority patent/AU2935895A/en
Publication of WO1996002542A1 publication Critical patent/WO1996002542A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/16—Peri-condensed systems

Definitions

  • the present invention relates to a novel tricyclic compound, which is useful as a medicine having an excellent activity of inhibiting platelet-derived growth factor (PDGF), antihypertensive activity, ameliorating activity of renal diseases and lowering the cholesterol level, a process for producing the compound, and a pharmaceutical composition containing the compound.
  • PDGF platelet-derived growth factor
  • ischemic diseases in cerebral and cardiac vessels have been also increasing.
  • calcium channel blockers or angiotensin converting enzymes (ACE) inhibitors have been widely used in the clinical field and have served to decrease cerebrovascular disturbances due to hypertension.
  • ACE angiotensin converting enzymes
  • the mortality from ischemic heart diseases has not yet been decreased.
  • lowering blood pressure is not sufficient but improving lipid metabolism is necessary.
  • the degree of antihypertensive action is important; namely, it has been considered that, the agents which keep the elasticity of blood vessels are more preferable even if their antihypertensive action is milder than the agents which lower blood pressure markedly.
  • vascular hypertrophy For keeping the elasticity of blood vessels, it is necessary to positively improve vascular hypertrophy or fibrosis.
  • diseases causing vascular hypertrophy there are mentioned, for example, hypertension, diabetes, glomerulosclerosis (chronic renal failure) and arteriosclerosis.
  • Precutaneous transliminal coronary angioplasty (PTCA) is generally carried out in the case of coronary artery obstruction caused by platelet aggregation and accumulation. In this case, however, there is often observed that endothelium is injured to cause proliferation of vascular smooth muscle toward the inside of vessels and to lead to restoerosis.
  • PDGF platelet-derived growth factor
  • mRNA PDGF receptors
  • PDGF proliferates vascular smooth muscle cells or renal glomerular mesangial cells in vitro experiments (R. Ross et al., Cell, 46, 155/1986); J. Floege et al. , Clin. Exp. Immunol., 86, 334/1991) and in vivo experiments (A. Jawien et al., J. Clin. Invest., 89, 507/1992; Y. Isaka et al. , J. Clin. Invest., 92 2597/1993; J. Floege et al. , J. Clin. Invest., 92, 2952/1993).
  • cytokine TGF- ⁇ transforming growth factor ⁇
  • TGF- ⁇ transforming growth factor ⁇
  • Circumstances being such as above, the development of novel and safely administrable therapeutic agents has been desired, which inhibit the action of PDGF.
  • ring A is a nitrogen-containing heterocyclic ring, having two nitrogen atoms as the hetero-atoms, which is optionally substituted with oxo or thioxo; ring Q may optionally be substituted;
  • Y is an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted mercapts group, excluding methyl group as
  • R is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group, or a salt thereof, whose characteristic feature of the chemical structure lies in the tricyclic condensed heterocyclic ring of the formula:
  • ring A, ring Q and R are as defined above; B is an optionally substituted divalent hydrocarbon; X is a bond, an oxygen atom or a sulfur atom; R is a hydrogen atom or an optionally substituted hydrocarbon group or, R and B may form a ring together with the adjacent nitrogen atom; and
  • R is an electron-withdrawing group, or a salt thereof, whose characteristic feature of the chemical structure lies in the tricyclic condensed heterocyclic ring of the formula:
  • the compound (I' ) or (I) produced thus above or a salt thereof has, unexpectedly, excellent PDGF-inhibiting action (e.g. actions of inhibiting cell proliferation or vascular constriction) , antihypertensive action, action of ameliorating nephropathy and, further, action of lowering cholesterol level.
  • PDGF-inhibiting action e.g. actions of inhibiting cell proliferation or vascular constriction
  • antihypertensive action e.g. actions of inhibiting cell proliferation or vascular constriction
  • action of ameliorating nephropathy e.g., a lowering cholesterol level.
  • the present inventors have further developed studies to accomplish the present invention. More specifically, the present invention relates to
  • Y is a hydrocarbon group, a hydroxyl group or a mercapto group, each of which optionally has a substituent comprising an amino group which is substituted with at least one electron-withdrawing group,
  • B is an optionally substituted divalent hydrocarbon group
  • X is a bond, an oxygen atom or a sulfur atom
  • R is a hydrogen atom or an optionally substituted hydrocarbon group, or R and B may from a ring together with the adjacent nitrogen atom;
  • R * is an electron-withdrawing group
  • R 2 and R 3a may form a ring together with the adjacent nitrogen atom, or a salt thereof,
  • ring Q may optionally be substituted with 1 to 3 substituents selected from the group consisting of (i) halogen atom, (ii) a C ⁇ alkyl group, (iii) a C ⁇ _ 4 alkoxy group, (iv) a Cj., alkylthio group, (v) a hydroxyl group, (vi) a carboxyl group, (vii) a cyano group, (viii) a nitro group, (ix) a amino group, ( x) a mono- or di- C ⁇ alkyl amino group, (xi) a formyl group, (xii) a mercapto group, (xiii) a C ⁇ alkyl- carbonyl group, (xiv) a C__ alkoxy-carbonyl group, (xv) a sulfonyl group, (xvi) a C__ 4 alkyl sulfony
  • R 1 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aralkyl group, an optionally substituted aryl group, an alkoxy carbonyl group, an alkyl carbamoyl group or an alkanoyl group,
  • R 2 is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted alkenyl group
  • X is an oxygen atom or a sulfur atom, and the other symbols are of the same meanings as defined in (6) or a salt thereof,
  • (31) a process for producing the compound as described in (1) above, which comprises reacting a compound of the formula:
  • E 1 is a leaving group and the other symbol is defined in (1) above, or a salt thereof, (32) a compound of the formula: or
  • R a is a halogen atom, an optionally substituted hydrocarbon group or an acyl group, except for methyl group as Rla;
  • R lb is a halogen atom, an optionally substituted hydrocarbon group or an acyl group; and the other symbols are of the same meanings as defind above, or a salt thereof,
  • compositions which comprises the compound as described in (1) above (33) a composition which comprises the compound as described in (1) above, (34) a pharmaceutical composition which comprises the compound as described in (1) above, (35) a pharmaceutical composition for suppressing platelet-derived growth factor, which comprises the compound as described in (1) above, (36) a therapeutic composition for hypertension, which comprises the compound as described in (1) above, (37) a therapeutic composition for renal diseases, which comprises the compound as described in (1) above, and (38) a composition for lowering lipid level, which comprises the compound as described in (1) above.
  • nitrogen-containing heterocyclic ring used in the present specification means, for example, 5- to 10-membered ring containing, two nitrogen atoms as hetero-atoms. Among them, 5- or 6-membered ring is widely used. These ring may be saturated or unsaturated, and may contain 1 or 2 hetero atoms (e.g. sulfur atom, oxygen atom, nitrogen atom) . More specifically, for example, the following ones
  • nitrogen-containing heterocyclic rings may optionally be substituted with one or two of oxo or thioxo groups .
  • divalent hydrocarbon group used in the present specification means, for example, divalent chain-like hydrocarbon groups including C__ 15 alkylene groups (e.g. methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene, heptamethylene and octamethylene) , C 2 _ 16 alkenylene groups (e.g. vinylene, propenylene, 1-butenylene, 2-butenylene, 1-pentenylene, 2-pentenylene and 3-pentenylene) , C 2 _ 16 alkynylene groups (e.g.
  • C__ 15 alkylene groups e.g. methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene, heptamethylene and octamethylene
  • C 2 _ 16 alkenylene groups e.g. vinylene, propenylene, 1-butenylene, 2-butenylene, 1-pentenylene, 2-pentenylene and 3-
  • substituents which the said "divalent hydrocarbon group” optionally have mention is made of, for example, optionally substituted alkyl groups, optionally substituted aralkyl groups and optionally substituted aryl groups, and optionally substituted alkyl groups are preferable.
  • the said "phenylene group” may be substituted
  • substituents which the said "phenylene group” optionally have, mention is made of one to four selected from, for example, halogen atoms (e.g. fluorine, chlorine, bromine and iodine), C ⁇ _ 4 alkyl groups (e.g. methyl, ethyl, propyl, isopropyl and butyl), Ci., alkoxy groups (e.g. methoxy, ethoxy, propoxy and isopropoxy) , C__ alkylthio groups (e.g.
  • halogen atoms e.g. fluorine, chlorine, bromine and iodine
  • C ⁇ _ 4 alkyl groups e.g. methyl, ethyl, propyl, isopropyl and butyl
  • Ci. alkoxy groups (e.g. methoxy, ethoxy, propoxy and isopropoxy)
  • C__ alkylthio groups e.g.
  • halogen atom used in the present specification means, for example, fluorine, chlorine, bromine and iodine.
  • hydrocarbon group of the term “optionally substituted hydrocarbon group” used in the present specification means, for example, alkyl group, cycloalkyl group, alkenyl group, aralkyl group and aryl group. Examples of the substituents, which the said
  • hydrocarbon group optionally have, use is made of, the substituents which the said "alkyl group”, “cycloalkyl group”, alkenyl group”, “aralkyl group” and “aryl group” optionally have.
  • alkyl group use is made of, for example, “straight-chain or branched Ci.
  • l5 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, tridecyl, tetradecyl and pentadecyl.
  • cycloalkyl group use is made of, for example, "C 3 _ 8 cycloalkyl group” such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • substituents which the said
  • alkyl group and “cycloalkyl group” optionally have, include (i) nitro group, (ii) hydroxyl group, (iii) cyano group, (iv) carbamoyl group, (v) mono- or di- C ⁇ alkyl-carbamoyl groups (e.g. N-methylcarbamoyl, N- ethylcarbamoyl, N,N-dimethylcarbamoyl and N,N- diethylcarbamoyl) , (vi) carboxyl group, (vii) C l . il alkoxy-carbonyl groups (e.g.
  • acylamino groups e.g. acetylamino and propionylamino
  • mono- or di- C ⁇ e.g. methylamino, ethylamino, dimethylamino and diethylamino
  • _ alkylamino groups e.g. methylamino, ethylamino, dimethylamino and diethylamino
  • 4 to 6 membered cyclic amino groups e.g. 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino and 1-piperazinyl
  • C__ 3 acyl groups e.g.
  • the said "alkyl group” optionally have 1 to 5 of these substituents at any substituable positions.
  • Preferable examples of the said “alkyl group” include C__ 6 straight-chain or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • substituents which the said "C ⁇ alkyl groups” optionally have use is made of 1 to 3 of, for example, halogen atoms, C ⁇ alkoxyl group, hydroxyl group, Ci_ A alkoxy-carbonyl groups, carboxyl group, carbamoyyl group, mono- or di- Ci_ 4 alkylcarbamoyl groups and pyridylthio group.
  • alkenyl group examples include "C 2 _ 18 alkenyl groups” such as vinyl, allyl, isopropenyl, 3- butenyl, 3-octenyl and 9-octadecenyl.
  • substituents which the said "alkenyl groups” optionally have use is made of, for example, the same ones as the above-mentioned “alkyl group” optionally have.
  • substituents which the said "alkenyl group” include C 2 _ 6 alkenyl groups such as vinyl, allyl, 2- butenyl and 3-butenyl .
  • substituents which the said "C 2 _ 6 alkenyl groups” optionally have use is made of, for example, the same ones as the above-mentioned "C j . ⁇ alkyl group” optionally have.
  • C 7 _ 16 aralkyl groups which are specifically exemplified by phenyl- C,_ 6 alkyl groups such as benzyl, phenethyl, 3-phenylpropyl and 4-phenylbutyl, and naphthyl- Ci_ 6 alkyl group such as ( 1-naphthyl)methyl, 2-(l-naphthyl)ethyl and 2-(2-naphthyl)ethyl.
  • substituents which the said "aralkyl group” optionally have, include halogen atoms (e.g. fluorine, chlorine, bromine and iodine), C ⁇ alkyl groups (e.g. methyl, ethyl, propyl, isopropyl and butyl), C 2 _ 6 alkenyl groups (e.g. vinyl, allyl, 2- butenyl and 3-butenyl), C ⁇ acyl groups (e.g. formyl and acetyl), C ⁇ alkoxyl groups (e.g.
  • halogen atoms e.g. fluorine, chlorine, bromine and iodine
  • C ⁇ alkyl groups e.g. methyl, ethyl, propyl, isopropyl and butyl
  • C 2 _ 6 alkenyl groups e.g. vinyl, allyl, 2- butenyl and 3-butenyl
  • C ⁇ acyl groups e.g. for
  • aryl group use is made of, for example, aromatic monocyclic, dicyclic or tricyclic C 6 _ 4 aryl groups exemplified by phenyl, 1-naphthyl, 2- naphthyl, phenanthryl and anthryl.
  • substituents which the said "aryl group” optionally have use is made of, besides the substituents which the said "aralkyl group” may optionally have, oxo group.
  • the said "aryl group” may optionally have 1 to 4, preferably 1 or 2, of these substituents at any substitutable positions.
  • Examples of the aryl group having oxo group include benzoquinonyl, naphthoquinolyl and anthraquinonyl.
  • electrostatic-withdrawing group used in the present specification is exemplified by (i) -S0 2 R*, (ii) -CO-R 5 , (iii) -COOR 6 ,(iv) -CON(R 7 )R 8 , (v) a nitro group and (vi) a cyano group, preferably -S0 2 R*, -CO-R 5 - and -COOR , especially -S0 2 R is commonly used.
  • R* stands for an optionally substituted hydrocarbon group
  • R stands for a hydrogen atom or an optionally substituted hydrocarbon group
  • R stands for an optionally substituted hydrocarbon group
  • R 7 and R 8 independently stand for a hydrogen atom or an optionally substituted hydrocarbon group, or R 7 and R 8 form, combined with the adjacent nitrogen atom, an nitrogen atom-containing heterocyclic ring.
  • acyl group used in the present specification is exemplified by the acyl group derived from carboxylic acid, which is exemplified by alkoxycarbonyl group, alkylcarbonyl group and alkanoyl group.
  • alkoxycarbonyl group use is made of C:_ 6 alkoxycarbonyl groups including, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarb ⁇ nyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl and tert-pentyloxycarbonyl.
  • alkoxycarbonyl groups including, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarb ⁇ nyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl and tert-pentyloxycarbon
  • alkylcarbamoyl group use is made of mono-C. ⁇ -N-alkylcarbamoyl groups, for example, N- methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl and N-butylcarbamoyl, and di-Cj.s-NjN-dialkylcarbamoyl groups, for example, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N,N-dipropylcarbamoyl, N,N- dibutylcarbamoyl and N-ethyl-methylcarbamoyl, and 4- to 6-membered cyclic carbamoyl groups formed by combination of the dialkyl portions with each other (e.g. 1-azetidinylcarbonyl, morpholinocarbonyl, 1- pyrrolidinylcarbonyl,
  • the ring A stands for a nitrogen-containing heterocyclic ring having two nitrogen atoms containing the nitrogen atom at the head of the bridge in the condensed ring, which be further substituted with oxo or thioxo.
  • ring A Preferable examples of the ring A include 5- or 6- membered nirogen-containing heterocyclic ring optionally substituted with one or two oxo groups. Especially, the following ones are commonly employed.
  • the ring Q is optionally substituted.
  • substituents which the ring Q optionally have, include halogen atoms (e.g. fluorine, chlorine, bromine and iodine), C . ⁇ alkyl groups (e.g. methyl, ethyl, propyl, isopropyl and butyl), C . . ⁇ alkoxy groups (e.g. methoxy, ethoxy, propoxy and isopropoxy) , C ; _ 4 alkylthio groups (e.g.
  • halogen atoms e.g. fluorine, chlorine, bromine and iodine
  • C . ⁇ alkyl groups e.g. methyl, ethyl, propyl, isopropyl and butyl
  • C . . ⁇ alkoxy groups e.g. methoxy, ethoxy, propoxy and isopropoxy
  • C _ 4 alkylthio groups e.g.
  • alkylsulfonyl groups e.g. methylsulfonyl, ethylsulfonyl and propylsulfonyl
  • carbamoyl group and mono- or di- C ⁇ alkyl-carbamoyl groups (e.g. N-methylcarbamoyl, N- ethylcarbamoyl, N,N-dimethylcarbamoyl and N,N- diethylcarbamoyl) .
  • One to three of these substituents may be substituted on any substitutable position on the ring Q.
  • the ring Q is preferably unsubstituted.
  • R 1 stands for a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or acyl group.
  • R include a hydrogen atom, optionally substituted alkyl groups, optionally substituted alkenyl groups, optionally substituted aralkyl groups, optionally substituted aryl groups, alkoxy carbonyl groups, alkylcarbamoyl groups and alkanoyl groups; especially a hydrogen atom, Cj. , alkyl groups (e.g. methyl, ethyl, propyl, isopropyl and butyl) or phenyl group are commonly used, and, a hydrogen atom is employed most commonly.
  • alkyl groups e.g. methyl, ethyl, propyl, isopropyl and butyl
  • phenyl group are commonly used, and, a hydrogen atom is employed most commonly.
  • Y stands for an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted mercapto group, excluding methyl group as Y.
  • the optionally substituted hydrocarbon group shown by Y include those described in respect of the above-mentioned "optionally substituted hydrocarbon group", excluding unsubstituted methyl group.
  • substituents which the hydroxyl group or the mercapto group shown by Y optionally have, include optionally substituted hydrocarbon group, the groups comprising at least one nitrogen atom and/or the groups comprising at least one electron-withdrawing groups .
  • substituents which the hydroxyl group or the mercapto group shown by Y optionally have, include optionally substituted hydrocarbon group.
  • optionally substituted hydrocarbon group use is made of the same ones as the above-mentioned "optionally substituted hydrocarbon group”.
  • substituents which the hydrocarbon group, the hydroxyl group and the mercapto group shown by Y optionally have, include the groups comprising at least one nitrogen atom and/or the groups comprising at least one electron-withdrawing group, especially the groups comprising an amino group substituted with at least one electron-withdrawing group.
  • the group comprising at least one nitrogen atom use is made of, for example, alkylaminoalkyl groups aralkylaminoalkyl groups, arylaminoalkyl groups, alkylaminoaralkyl groups, aralkylaminoaralkyl groups, arylaminoaralkyl groups, alkylaminoaryl groups, aralkylaminoaryl groups, arylaminoaryl groups, aminoalkyl groups, aminoaralkyl group and aminoaryl groups.
  • the group comprising at least one electron- withdrawing group use is made of, for example, the hydrocarbon groups comprising at least one "electron- withdrawing group as mentioned above".
  • the group comprising an amino group which is substituted with at least one electron-withdrawing group use is made of, for example, the hydrocarbon groups comprising an amino group substituted with at least one "electron-withdrawing group as mentioned above” .
  • the most preferable examples of Y include the groups represented by the formula
  • B stands for an optionally substituted divalent hydrocarbon group. Specific examples of the group include those represented by (i)
  • n, o independently are integers of 0 to
  • R 9, R10, R11, R12, R13 and R14 independently stand for a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group or an optionally substituted aryl group, and, R 9 and R 10 ; R 11 and R 12 ;, R 13 and R 1 ; R 9 or R 10 and R 2 ; R 11 or R 12 and R 2 ; , or, R or R and R may respectively be combined to form rings, and R or R may be combined with R 13 or R 14 respectively to form rings, or (ii)
  • phenylene group may be substituted, and, p and q are independently an integer of 0 to 5.
  • optionally substituted alkyl, aralkyl or aryl group shown by R 9 to R 1 * include those described in respect of the above-mentioned "optionally substituted hydrocarbon groups" .
  • the rings formed by combination of R 9 and R10, R and R , and R and R are exemplified by C 3 _ 8 cycloalkyl groups including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the rings formed by combination of R 9 or R10 and R2; R11 or R12 and R2; or RIT or R and R are exemplified by azetidinyl, pyrrolidinyl or piperidino.
  • the rings formed by combination of R or R with R 13 or R 14 , respectively are exemplified by C 3 _ 8 cycloalkyl groups including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R to R 14 include a hydrogen atom or C__ 4 alkyl groups (e.g. methyl, ethyl, propyl and isopropyl), and, especially, a hydrogen atom or methyl group is commonly used.
  • B include C 2 _ 10 alkylene groups (e.g. ethylene, propylene, butylene, pentamethylene, hexamethylene, heptamethylene and octamethylene) , and, among them, especially C 3 _ 8 alkylene groups (e.g. ethylene, propylene, butylene, pentamethylene, hexamethylene and heptamethylene) are commonly employed.
  • C 2 _ 10 alkylene groups e.g. ethylene, propylene, butylene, pentamethylene, hexamethylene, heptamethylene and octamethylene
  • C 3 _ 8 alkylene groups e.g. ethylene, propylene, butylene, pentamethylene, hexamethylene and heptamethylene
  • X stands for a bond, an oxygen atom or a sulfur atom.
  • X is a bond.
  • R 2 stands for a hydrogen atom or an optionally substituted hydrocarbon group, and, R and B may optionally form a ring together with the adjacent nitrogen atom.
  • R include a hydrogen atom, optionally substituted alkyl groups or optionally substituted alkenyl groups, especially a hydrogen atom is commonly used.
  • R stands for an electron-withdrawing group, or R and R may form a ring together with the adjacent nitrogen atom.
  • the electron-withdrawing group include (i) -S0 2 R (R stands for an optionally substituted hydrocarbon group), (ii) -CO-R 5 (R 5 stands for a hydrogen atom or an optionally substituted hydrocarbon group), (iii) -COOR (R stands for an optionally substituted hydrocarbon group), (iv) -C0N(R 7 )R 8 (R 7 and R each stand for a hydrogen atom or an optionally substituted hydrocarbon group, or R 7 and R 8 may form a ring together with the adjacent nitrogen atom) , (v) a nitro group and (vi) a cyano group.
  • Examples of the electron-withdrawing group include -S0 2 R 4a , -CO-R 5a and -COOR 6a (R 4a , R 5a and R 6a each stand for an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aralkyl group or an optionally substituted aryl group), especially -S0 2 R 4a (R 4a stands for an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aralkyl group or an optionally substituted aryl group) is commonly used among others.
  • R include an optionally substituted alkyl group, especially a halogeno- C ⁇ alkyl group (e.g. chloromethyl, trifluoromethyl, 2,2,2- trifluoroethyl and 3,3,3-trifluoropropyl) .
  • a halogeno- C ⁇ alkyl group e.g. chloromethyl, trifluoromethyl, 2,2,2- trifluoroethyl and 3,3,3-trifluoropropyl
  • R include an optionally substituted alkyl group, especially a halogeno- C__ 6 alkyl group (e.g. chloromethyl, trifluoromethyl, 2,2,2- trifluoroethyl and 3,3,3-trifluoropropyl) .
  • a halogeno- C__ 6 alkyl group e.g. chloromethyl, trifluoromethyl, 2,2,2- trifluoroethyl and 3,3,3-trifluoropropyl
  • R include an optionally substituted alkyl group, especially a halogeno- C : _ 6 alkyl group (e.g. chloromethyl, trifluoromethyl, 2,2,2- trifluoroethyl and 3,3,3-trifluoropropyl) .
  • a halogeno- C : _ 6 alkyl group e.g. chloromethyl, trifluoromethyl, 2,2,2- trifluoroethyl and 3,3,3-trifluoropropyl
  • R 7 and R8 include a hydrogen atom or an optionally substituted alkyl group, especially a hydrogen atom or a halogeno- C j .. alkyl group (e.g. chloromethyl, trifluoromethyl, 2,2,2- trifluoroethyl and 3,3,3-trifluoropropyl) .
  • a hydrogen atom or an optionally substituted alkyl group especially a hydrogen atom or a halogeno- C j .. alkyl group (e.g. chloromethyl, trifluoromethyl, 2,2,2- trifluoroethyl and 3,3,3-trifluoropropyl) .
  • Examples of the ring, which R 2 and R 3 form together with the adjacent nitrogen atom, include pyrrolidine-2-one, piperidine-2-one, indoline-2-one, isoindoline-1-one, isoindoline-1,3-dione, oxazolidine- 2-one, oxazolidine-2,4-dione, thiazolidine-2-one, thiazolidine-2,4-dione and 1,2-benzisothiazole-3(2H)- one.
  • These rings optionally have substituents such as electron-withdrawing groups.
  • electron- withdrawing group use is made of, for example, the above-mentioned "electron-withdrawing groups”.
  • R stands for a hydrogen atom, an optionally substituted alkyl group or an optionally substituted alkenyl group, is preferable, and, especially those, wherein R stands for a hydrogen atom or a C alkyl group (e.g. methyl, ethyl, propyl, isopropyl and butyl), is commonly used;
  • R stands for a hydrogen atom or a C 1-6 alkyl group (e.g. methyl, ethyl, propyl, isopropyl and butyl), is preferable, and, especially those, wherein R stands for a hydrogen atom, is commonly used;
  • B stands for a C 2 _ 10 alkylene group (e.g. ethylene, propylene, butylene, pentamethylene, hexamethylene and octamethylene) , is preferable, and, especially those, wherein B stands for a C 3 _ 8 alkylene group (e.g. propylene, butylene, pentamethylene, hexamethylene and heptamethylene), are preferable;
  • R a stands for an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aralkyl group or an optionally substituted aryl group
  • R a stands for an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aralkyl group or an optionally substituted aryl group
  • R stands for a halogeno- C j .g alkyl group (e.g. chloromethyl, trifluoromethyl, 2,2,2- trifluoroethyl and 3,3,3-trifluoropropyl) , is preferable.
  • R stands for a halogeno- C j .g alkyl group (e.g. chloromethyl, trifluoromethyl, 2,2,2- trifluoroethyl and 3,3,3-trifluoropropyl) , is preferable.
  • salts of the compound (I') (hereinafter included the compound (I))
  • pharmaceutically acceptable salts and physiologically acceptable acid salts are exemplified by those with inorganic acids (e.g. hydrochloric acid, phosphoric acid, hydrobromic acid and sulfuric acid) or with organic acids (e.g. acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methansulfonic acid and benzenesulfonic acid) .
  • inorganic acids e.g. hydrochloric acid, phosphoric acid, hydrobromic acid and sulfuric acid
  • organic acids e.g. acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methansulfonic acid and
  • the compound (I') of the present invention may optionally form a salt with, for example, an inorganic base (e.g. an alkali metal or an alkaline earth metal such as sodium, potassium, calcium and magnesium, or ammonia) or an organic base (e.g. a tri- Cj_ 3 alkylamine such as triethylamine).
  • an inorganic base e.g. an alkali metal or an alkaline earth metal such as sodium, potassium, calcium and magnesium, or ammonia
  • an organic base e.g. a tri- Cj_ 3 alkylamine such as triethylamine
  • the compound (I') or a salt thereof have, in some instances, asymmetric carbons in the molecule.
  • sterioisomers of R-configuration and S- configurated isomers are present, each of them and a mixture of them are all included in the scope of the present invention.
  • the compound (I') or a salt thereof of the present invention can be synthesized by the following method.
  • E stands for a leaving group such as halogen (e.g. chlorine, bromine, iodine), methanesulfonyloxy and p-toluenesulfonyloxy; the other symbols are of the same meaning as defind above.
  • halogen e.g. chlorine, bromine, iodine
  • methanesulfonyloxy and p-toluenesulfonyloxy the other symbols are of the same meaning as defind above.
  • the compound (XII) include novel compounds represented by the formula
  • R la stands for a halogen atom, an optionally substituted hydrocarbon group or an acyl group, except for methyl group as R a ;
  • R stands for a halogen atom, an optionally substituted hydrocarbon group or an acyl group; and the other symbols are of the same meaning as defined above, or a salt thereof.
  • the compound (I') or a salt thereof of the present invention can be synthesized by, for example, a process for producing the compound (I') or a salt thereof which comprises reacting a compound of the formula
  • G stands for a halogen (e.g. chloro, bromo or iodo) or -OR ;
  • E stands for a leaving group such as halogen (e.g. chlorine, bromine or iodine), methanesulfonyloxy and p-toluenesulfonyloxy; and the other symbols are of the same meaning as defined above,
  • the compound (I) or a salt thereof can also be synthesized.
  • j denotes 0 or 1
  • J stands for a hydrogen atom or a protecting group (e.g. benzyloxycarbonyl, tert- butoxycarbonyl, trifluoroacetyl, trityl and benzyl)
  • R 15 stands for an optionally substituted alkyl group, and the other symbols are of the same meaning as defined above.
  • the synthesis can be carried out by the following methods . (1) A method of producing the compound (I) or a salt thereof by allowing a compound represented by the general formula
  • E 1 stands for a leaving group such as a halogen (e.g. chlorine, bromine and iodine), methanesulfonyloxy and p-toluenesulfonyloxy, and the other symbols are of the same meaning as defined above, or a salt thereof.
  • a halogen e.g. chlorine, bromine and iodine
  • methanesulfonyloxy and p-toluenesulfonyloxy and the other symbols are of the same meaning as defined above, or a salt thereof.
  • J stands for a hydrogen atom or a protecting group (e.g. benzyloxycarbonyl, tert- butoxycarbonyl, trifluoroacetyl, trityl and benzyl), and the other symbols are of the same meaning as defined above or a salt thereof to trichloroacetylation, then, upon necessity, deprotection of the protecting group J, and, further subjecting the resultant compound to ring-closure reaction.
  • a protecting group e.g. benzyloxycarbonyl, tert- butoxycarbonyl, trifluoroacetyl, trityl and benzyl
  • R 1 stands for a C X . alkyl group, and the other symbols are of the same meaning as defined above or a salt thereof to react with a compound represented by the general formula
  • G ,2 stands for a halogen (e.g. chlorine) or RCO-0-, and the other symbols are of the same meaning as defined above.
  • G stands for a halogen (e.g. chlorine) or R 6 C0 2 -0-, and the other symbols are of the same meaning as defined above.
  • J stands for a protecting group of an amino group, and the other symbols are of the same meaning as defined above.
  • a compound, which can form a salt may be used in the form of salt.
  • Examples of such a salt include those as described in the above-mentioned compound (I'). In the following description of the respective methods, of a salt of each compound may also be included.
  • reaction between the compound (XII) and the compound E -Y in the method of producing the compound (I') / °ne equivalent to a large excess amount (1 to 10 equivalents) of the compound E -Y is employed relative to the compound (XII).
  • a basic compound such as sodium hydroxide, potassium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine and 1,8-diazabicyclo[5,4,0]-7- undecene may be used in an amount of 1 to 10 equivalents.
  • the reaction temperature ranges from -20 to 200°C.
  • the solvents to be employed include water, lower alcohols (e.g.
  • reaction promotor sodium iodide may be added in an amount ranging from 1 equivalent to a large excess (1 to 10 equivalents).
  • the reaction time ranges usually from 10 minutes to 24 hours, preferably from 0.5 to 6 hours.
  • reaction temperature ranges from -30 to 100°C.
  • solvents to be employed include halogenated hydrocarbons (e.g.
  • the reaction time ranges usually from 10 minutes to 24 hours, preferably from 0.5 to 6 hours.
  • the reaction between the compound (VIII) and the compound of G -CO-R in the method B is conducted, for example, under conditions similar to those of the reaction between the compound (VIII) and the compound G 1 -S0 2 -R 4 in the method A.
  • the reaction between the compound (VIII) and the compound G -C00-R in the method C is conducted, for example, under conditions similar to those of the reaction between the compound (VIII) and the compound G 1 -S0 2 -R 4 in the method A.
  • the reaction between the compound (VIII) and the compound of G -CO-N(R )R in the method D is conducted, for example, under conditions similar to those of the reaction between the compound (VIII) and the compound G 1 -S0 2 -R 4 in the method A.
  • the compound R 2 -E ! is used in an amount ranging from one equivalent to a large excess (1 to 10 equivalents) relative to the compound (IX).
  • a basic compound such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium carbonate, triethylamine, diisopropylethylamine and l,8-diazabicyclo[5.4.0]-7- undecene may optionally be used in an amount of 1 to 10 equivalents.
  • the reaction temperature ranges from -20 to 200°C.
  • the solvent to be employed include water, lower alcohols (e.g. methanol, ethanol and propanol), ketones (e.g. acetone and methyl ethyl ketone), ethers (e.g. tetrahydrofuran) and aprotic polar solvents (e.g.
  • reaction time ranges usually from 10 minutes to 24 hours, preferably from 0.5 to 6 hours.
  • the reaction between the compound (X) and the compound (XI) in the method F is conducted, for example, under conditions similar to those of the reaction between the compound (IX) and the compound R 2 - E 1 in the method E.
  • the reaction between the compound (XII) and the compound (XIII) in the method G is conducted, for example, under conditions similar to those of the reaction between the compound (IX) and the compound R 2 - E 1 in the method E.
  • trichloroacetyl chloride or anhydrous trichloroacetate is used in an amount ranging from one equivalent to a large excess (1 to 10 equivalents) relative to the compound (XIV) .
  • 1 to 10 equivalents of an inorganic base e.g. potassium carbonate and sodium hydrogencarbonate
  • an organic base e.g. 4-N,N-dimethylaminopyridine, triethylamine, pyridine, dimethylaniline and 1,4- diazabicyclo[2.2.2 ]octane
  • the reaction temperature ranges from 0 to 100°C.
  • Examples of the solvent then employed include halogenated hydrocarbons (e.g. methylene chloride, chloroform and dichloroethane) , ethers (e.g. diethyl ether and tetrahydrofuran), esters (e.g. methyl acetate and ethyl acetate) and aprotic polar solvents (e.g. N,N-dimethylformamide, dimethyl sulfoxide and acetonitrile) .
  • the reaction time ranges usually from 10 minutes to 100 hours, preferably from 3 to 24 hours.
  • the above-mentioned deprotection reactions of the protective group of secondary amino group are all per s_e known reactions, which can be conducted in according to known conditions.
  • the benzyloxycarbonyl group or the benzyl group as the amino-protecting group can be removed by catalytic reduction (reaction temperatures ranging from room temperature to 100°C) in a solvent (e.g. alcohol, acetic acid, water, tetrahydrofuran and an appropriate mixture of them) in the presence of a catalyst (e.g. palladium carbon or platinum oxide) .
  • a catalyst e.g. palladium carbon or platinum oxide
  • trityl group or tert-butoxycarbonyl group it can be removed by the reaction in a solvent (e.g. water, alcohol, tetrahydrofuran and dioxane) in the presence of an acid (e.g.
  • a mineral acid such as hydrochloric acid, phosphoric acid and sulfuric acid or an organic acid such as toluenesulfonic acid, methansulfonic acid and acetic acid
  • a mineral acid such as hydrochloric acid, phosphoric acid and sulfuric acid or an organic acid such as toluenesulfonic acid, methansulfonic acid and acetic acid
  • tert-butoxycarbonyl group it can be removed by processing with, for example, iodotrimethylsilane in a solvent such as chloroform.
  • trifluoroacetyl group can be easily removed by treating with alkali (e.g. an aqueous solution of sodium hydroxide or sodium hydrogencarbonate) .
  • alkali e.g. an aqueous solution of sodium hydroxide or sodium hydrogencarbonate
  • the ring-closure reaction can be conducted concurrently with the reaction of removing the protecting group.
  • the ring- closure reaction can be conducted by using 1 to 10 equivalents of an inorganic base (e.g. potassium carbonate and sodium hydrogencarbonate) or an organic base (e.g. 4-N,N-dimethylaminopyridine, triethylamine, pyridine, dimethylaniline and 1,4- diazabicyclo[2.2.2]octane.
  • an inorganic base e.g. potassium carbonate and sodium hydrogencarbonate
  • an organic base e.g. 4-N,N-dimethylaminopyridine, triethylamine, pyridine, dimethylaniline and 1,4- diazabicyclo[2.2.2]octane.
  • the reaction temperatures ranges from 0 to 100°C.
  • the solvent then employed include halogenated hydrocarbons (e.g. methylene chloride, chloroform and dichloroethane) , ethers (e.g. diethyl ether and tetrahydrofuran), esters (e.g
  • reaction time ranges usually from 10 minutes to 24 hours, preferably from 10 minutes to 6 hours.
  • formalin is used in an amount of large excess (2 to 20 equivalents) relative to the compound (XV).
  • the reaction temperature ranges from -20 to 150°C.
  • the solvent then used include water, lower alcohols (e.g. methanol, ethanol, propanol and isopropanol) and lower fatty acids (e.g. acetic acid and propionic acid) .
  • the reaction time ranges usually from 10 minutes to 24 hours, preferably from 10 minutes to 3 hours .
  • the reaction between the compound (XVI) and the compound (XVII) in the method J is conducted, for example, under conditions similar to those of the reaction between the compound (VIII) and the compound G 1 -S0 2 -R in the method A.
  • the conversion of the compound (XIX) to the thiolacta in the method K can be conducted with, for example, one equivalent to a large excess (1 to 10 equivalents) of phosphorus pentachloride relative to the compound (XIX) .
  • the reaction temperature ranges from 0 to 200°C.
  • the solvent then employed include aromatic hydrocarbons (e.g. benzene, toluene and xylene) and pyridine.
  • the reaction time ranges usually from 30 minutes to 24 hours, preferably from 1 to 12 hours .
  • the reaction for removing the amino-protective group of the compound (XX) in the method L can be conducted, for example, under conditions similar to removing the amino-protecting group in the method H.
  • the compound (VIII) can be synthesized by, for example, the following methods.
  • reaction between the compound (X) and the compound (XXI) is conducted under conditions similar to those of the reaction between the compound (X) and the compound (XI) in the method F. ( ⁇ )
  • reaction between the compound (XII) and the compound (XXII) is conducted under conditions similar to those of the reaction between the compound (XII) and the compound (XIII) in the method G.
  • reaction for removing the amino-protective group is conducted under conditions similar to those of removing the protective group in the method H.
  • the compound (IX) can be synthesized by, for example, the following method.
  • S0 2 -R is conducted, for example, under conditions similar to those of the reaction between the compound (VIII) and in the method A.
  • the reaction between the compound (XXIII) and G 2 -CO-R 5 is conducted, for example, under conditions similar to those of the reaction between the compound (VIII) and G 2 -CO-R 5 in the method B.
  • the reaction between the compound (XXIII) and G 2 -CO-R 5 is conducted, for example, under conditions similar to those of the reaction between the compound (VIII) and G 2 -CO-R 5 in the method B.
  • (XXIII) and G 3 -COO-R 6 is conducted, for example, under conditions similar to those of the reaction between the compound (VIII) and G 3 -COO-R 6 in the method C.
  • the reaction between the compound (XXIII) and G 4 -CO-N(R 7 )R 8 is conducted, for example, under conditions similar to those of the reaction between the compound (VIII) and G 4 -CO-N(R 7 )R 8 in the method D.
  • the compound (X) can be synthesized by, for example, the following method.
  • the reaction between the compound (XII) and the compound (XXIV) is conducted, for example, under conditions similar to those of the reaction between the compound (XII) and the compound (XIII) in the method G.
  • the compound (XII) can be synthesized by, for example, the following method.
  • a base such as sodium hydride, potassium hydride or lithium diisopropyl amide relative to one equivalent of the compound (XXV) .
  • the reaction temperature ranges from -20 to 150°C.
  • the solvent then employed is exemplified by ethers (e.g. tetrahydrofuran and dioxane) and aprotic polar solvents (e.g. N,N- dimethylformamide and dimethyl sulfoxide) .
  • the reaction time ranges usually from 10 minutes to 6 hours, preferably from 0.5 to 3 hours.
  • the ring-closure reaction of the compound (XXVII) is conducted, for example, under conditions similar to those of the ring-closure reaction of the compound (XV) in the method I.
  • the reaction for removing the amino-protecting group is conducted, for example, under conditions similar to those of the reaction of removing the protective group in the method H.
  • the ring-closure reaction of the compound (XVI) can be conducted with, for example, one equivalent to a large excess amount (1 to 100 equivalents) of aqueous ammonia relative to one equivalent of the compound (XVI).
  • the reaction temperature ranges from 0 to 150°C.
  • the solvent then employed is exemplified by water, lower alcohols (e.g. methanol, ethanol, propanol and isopropanol) , halogenated hydrocarbons (e.g. methylene chloride, chloroform and dichloroethane) , ethers (e.g. tetrahydrofuran and dioxane), esters (e.g.
  • the reaction temperature ranges usually from 10 minutes to 24 hours, preferably from 3 to 12 hours.
  • the compound (XIV) can be synthesized by, for example, the following method, (i) When j is 1;
  • the reaction between the compound (XXXI) and the compound (XVII) is conducted, for example, under conditions similar to those of the reaction between the compound (X) and the compound (XI) in the method F.
  • the reaction for introducing the amino-protecting group is a p_g£ ⁇ 3. known reaction such as the above-mentioned deprotection of the amino group, which can be conducted according to known conditions. (ii) When j is 0 and J is a hydrogen atom;
  • E stands for, for example, a halogen (e.g. chlorine, bromine and iodine), and the other symbols are of the same meaning as defined above.
  • halogen e.g. chlorine, bromine and iodine
  • reaction between the compound (XXXII) and the compound (XVII) is conducted, for example, under conditions similar to those of the reaction between the compound (X) and the compound (XI) in the method F.
  • j is 0, and, J and R 2 are both a hydrogen atom;
  • the reaction between the compound (XXXII) and the compound (XXXIV) is conducted, for example, under conditions similar to those of the reaction between the compound (X) and the compound (XI) in the method F.
  • Introduction of R is conducted, for example, under conditions similar to those of the reaction between the compound (VIII) and G -S0 2 -R in the method A, those of the reaction between the compound (VIII) and G 2 -C0-R 5 in the method B, those for the reaction between the compound (VIII) and G -COO-R in the method C and those for the reaction between the compound (VIII) and G 4 -CO- N(R 7 )R 8 in the method D.
  • j is 1 and R is a hydrogen atom;
  • the reaction between the compound (XXXI) and the compound (XXXIV) and the introduction of R 3 are conducted under conditions similar to those of the reaction between the compound (XXXII) and the compound (XXXIV) and for the introduction of R described in (iii) above.
  • the reactions for introducing the amino-protecting group are all per _____ known ones as described above, for example, and they can be conducted according to the conditions of them.
  • the compound (XV) can be synthesized by, for example, the following methods, (i)
  • the reaction between the compound (XXXI) and the compound (XVII) is conducted, for example, under conditions similar to those of the reaction between the compound (X) and the compound (XI) in the method F.
  • R is a hydrogen atom
  • the reaction between the compound (XXXI) and the compound (XXXIV) is conducted, for example, under conditions similar to those of the reaction between the compound (X) and the compound (XI) in the method F.
  • Introduction of R is conducted, for example, under conditions similar to those of the reaction between the compound (VIII) and G -S0 2 -R in the method A, those of the reaction between the compound (VIII) and G z -C0 2 -R 5 in the method B, those of the reaction between the compound (VIII) and G -COO-R in the method C and those of the reaction between the compound (VIII) and G 4 -CO- N(R 7 )R 8 in the method D.
  • the compound (XVI) can be synthesized by, for example, the following method.
  • Trichloroacetylation of the compound (XXXVIII) is conducted, for example, under conditions similar to those of trichloroacetylation of the compound (XIV) in the method H.
  • the compound (XXIII) can be synthesized by the following methods.
  • the reaction between the compound (XII) and the compound (XL) is conducted, for example, under conditions similar to those of the reaction between the compound (XII) and the compound (XIII) in the method G.
  • the removal of phthalimido group, which is the amino- protecting group, can be conducted by the reaction with hydrazine hydrate in a solvent (e.g. methanol and ethanol) .
  • the reaction between the compound (XVI) and the compound (XXXIV) is conducted, for example, under conditions similar to those of the reaction between the compound (XVI) and the compound (XVII) in the method J.
  • the compound (XXV) can be synthesized by, for example, the following method.
  • the compound (XLII) is used in an amount ranging from one equivalent to a large excess (1 to 10 equivalents) relative to one equivalent of the compound (XLI).
  • the reaction temperature ranges from 0 to 200°C.
  • the solvent then employed include water, lower alcohols (e.g. methanol, ethanol and propanol), ethers (e.g. tetrahydrofuran, dimethoxyethane and dioxane), nitriles (e.g. acetonitrile and propionitrile) and aprotic polar solvents (e.g. N,N-dimethylformamide and dimethyl sulfoxide) .
  • reaction system may optionally be added, as the agent for removing acid 1 to 10 equivalents of an inorganic base such as potassium carbonate and sodium hydrogencarbonate, or an organic base such as triethylamine, pyridine and dimethylaniline.
  • an inorganic base such as potassium carbonate and sodium hydrogencarbonate
  • organic base such as triethylamine, pyridine and dimethylaniline.
  • the reaction time ranges usually from 10 minutes to 7 days, preferably from one hour to two days.
  • the compound (XXVII) can be synthesized by, for example, the following method.
  • the reactions for introducing primary amino group into the compound (XXXI) are all per se known ones, which can be conducted according to known reaction conditions. For example, hexamethylene tetramine in an amount of one equivalent to a large excess (1 to 10 equivalents) is used relative to one equivalent of the compound (XXXI).
  • the solvent for this reaction include water, lower alcohols (e.g. methanol, ethanol and propanol), ethers (e.g. tetrahydrofuran, dimethoxyethane and dioxane), nitriles (e.g. acetonitrile and propionitrile) and aprotic polar solvents (e.g.
  • the reaction temperature ranges from 0 to 200°C
  • the quaternary ammonium salt then formed can be hydrolyzed with an acid, such as hydrochloric acid (1 to 20 equivalents).
  • the reaction temperature ranges from 0 to 100°C.
  • the reaction time ranges usually from 10 minutes to 24 hours, preferably from 1 to 3 hours. Further, the reactions for introducing a protective group into primary amino group are all per se known ones, which can be conducted according to known reaction conditions.
  • the compound (XXXI) can be synthesized by, for example, the following method.
  • the reduction of the compound (XXXVIII) is conducted by using a reducing agent, for example, a metal hydride complex compound such as sodium borohydride, lithium borohydride and aluminum lithium hydride or borane complex compounds in an amount ranging from one equivalent to a large excess (1 to 10 equivalents) relative to one equivalent of the compound (XXXVIII).
  • a reducing agent for example, a metal hydride complex compound such as sodium borohydride, lithium borohydride and aluminum lithium hydride or borane complex compounds in an amount ranging from one equivalent to a large excess (1 to 10 equivalents) relative to one equivalent of the compound (XXXVIII).
  • the reaction temperature ranges from -20 to 100°C.
  • the solvent employed for this reaction include alcohols (e.g. methanol and ethanol) and ethers (e.g. ethyl alcohol, tetrahydrofuran and dioxane) .
  • the reaction time ranges usually from 10 minutes to 24 hours,
  • the conversion of hydroxyl group to E is conducted, when E 1 is halogen atom, by allowing 1 to 5 equivalents of a halogenating agent, for example, phosphorus halogenide such as phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride and phosphorus tribromide, a mixture of red phosphorus and halogen, or thionyl chloride to react with one equivalent of an alcohol compound.
  • a halogenating agent for example, phosphorus halogenide such as phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride and phosphorus tribromide, a mixture of red phosphorus and halogen, or thionyl chloride.
  • a halogenating agent for example, phosphorus halogenide such as phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride and phosphorus tribromide, a mixture
  • an inorganic base such as potassium carbonate and sodium hydrogencarbonate or an organic base such as 4-N,N-dimethylaminopyridine, triethylamine, pyridine, dimethyl aniline and 1,4-diazabicyclo[2.2.2]octane
  • the reaction temperature ranges from 0 to 100°C.
  • the solvent used in this case include halogenated hydrocarbons (e.g. methylene chloride, chloroform and dichloroethane), water, ethers (e.g. diethyl ether and tetrahydrofuran), esters (e.g.
  • reaction time ranges usually from 10 minutes to 100 hours, preferably from 3 to 24 hours.
  • the compound (XXXII) can be synthesized by, for example, the following method.
  • the reaction between the compound (XLIII) and the compound (XLIV) can be conducted under conditions similar to those of the reaction between the compound (XLI) and the compound (XLII) in the above-mentioned method of synthesizing the compound (XXV) .
  • the compound (XXXVIII) can be synthesized by, for example, the following method. *X!'»* a n0 ⁇ 2 _crCN ⁇ rrTU.lBnB»i B'-C0-CH 2 E 2 (XLIV) protest xxxviii )
  • the intermediate compounds for synthesizing the target compound (I' ) or a salt obtained by the above- mentioned methods can be isolated by the following conventional separation means, or reaction mixture per se may optionally be used, as the starting materials for the subsequent step without isolation.
  • the isolation and purification of the compound (I') from the reaction mixture is conducted according to conventional separation means (for example, extraction, concentration, filtration, recrystallization, column chromatography and thin-layer chromatography) .
  • conventional separation means for example, extraction, concentration, filtration, recrystallization, column chromatography and thin-layer chromatography.
  • the starting compounds and intermediate compounds when they has amino group, carboxyl group or hydroxyl group as the substituent, they may have a protective group generally used in the peptide chemistry.
  • the target compound can be obtained by removing the protective group upon necessity.
  • amino-protecting group examples include optionally substituted alkyl carbonyl (e.g. for yl, methyl carbonyl and ethyl carbonyl), phenyl carbonyl,
  • Ci. 6 alkyl-oxycarbonyl e.g. methoxycarbonyl and ethoxycarbonyl
  • phenyloxycarbonyl e.g. benzoxycarbonyl
  • C 7 _ 10 aralkyloxy-carbonyl e.g. benzyloxycarbonyl
  • substituents of them include halogen atoms (e.g. fluoro, chloro, bromo and iodo), C 6 alkyl-carbonyl
  • Examples of the carboxyl-protecting group include Ci.s alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, n- butyl and tert-butyl), phenyl, trityl and silyl.
  • substituents of them include halogen atoms (e.g. fluorine, chlorine, bromine and iodine), C 6 alkylcarbonyl (formyl, methylcarbonyl, ethylcarbonyl and butylcarbonyl) and nitro group, and the number of the substituents ranges from about 1 to 3.
  • hydroxyl-protecting group examples include for example, optionally substituted Ci_ 6 alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl and tert- butyl), phenyl, C 7 _ 10 aralkyl (e.g. benzyl), C x _ 6 alkylcarbonyl (e.g. formyl, methylcarbonyl and ethylcarbonyl), phenyloxycarbonyl, C 7 _ 10 aralkyloxy- carbonyl (e.g. benzyloxycarbonyl), pyranyl, furanyl and silyl.
  • Ci_ 6 alkyl e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl and tert- butyl
  • phenyl C 7 _ 10 aralkyl (e.g. benzyl)
  • halogen atoms e.g. fluoro, chloro, bromo and iodo
  • C__ 6 alkyl, phenyl, C 7 _ 10 aralkyl and nitro group were used.
  • the number of substituents ranges from about 1 to 4.
  • the protecting groups can be introduced and removed by per se known means or those analogous thereto (for example, I.F.W. McO ie et al . , PROTECTIVE GROUPS IN ORGANIC CHEMISTRY, Plenum Press). More specifically, those protecting groups are removed by, for example, acid, base, reduction, ultraviolet ray, hydrazine, phenylhydrazine, sodium N- methyldithiocarbamate, tetrabutyl ammonium fluoride or palladium acetate.
  • the compound (I' ) produced by the above-mentioned methods can be isolated and purified by a conventional separating means such as recrystallization, distillation and chromatography.
  • the compound (I') thus obtained When the compound (I') thus obtained is in the free form, it can be converted to a salt by per s_e known means or analogous means thereto (e.g. neutralization). 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') when it is an optically active compound, it can be resolved into d-isomer and 1-isomer by a conventional means for optical resolution.
  • the compound (I') and the pharmaceutically acceptable salt of the present invention have an excellent inhibiting activity of PDGF action, antihypertensive activity, ameliorating activity of renal diseases and activity of lowering lipid level, and are relatively less toxic. 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 therapeutic agents of, for used as hypertension, renal diseases (e.g. acute renal failure, diabetic nephropathy and nephritis), arteriosclerotic diseases, the other cardiovasular diseases, chronic rheumatoid arthritis, cancers and hyperlipemia.
  • renal diseases e.g. acute renal failure, diabetic nephropathy and nephritis
  • arteriosclerotic diseases the other
  • the compound (I') or a salt thereof can be administered as it is, it is usually administered in the form of preparation formulated by a conventional method using carriers or diluents for pharmaceutical preparations adequately selected from excipients (e.g. calcium carbonate, kaolin, sodium hydrogencarbonate, lactose, starch, crystalline cellulose, talc, fine granulated sugar and porous substance), binders (e.g. dextrin, gum, alcoholated starch, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and furfuran) , disintegrants (e.g.
  • excipients e.g. calcium carbonate, kaolin, sodium hydrogencarbonate, lactose, starch, crystalline cellulose, talc, fine granulated sugar and porous substance
  • binders e.g. dextrin, gum, alcoholated starch, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and furfuran
  • carboxymethyl cellulose calcium closcarmellose sodium, clospovidone, low-substituted hydroxypropyl cellulose and partial ⁇ - starch
  • lubricants e.g. magnesium stearate, calcium stearate, talc, starch and sodium benzoate
  • colorants e.g. tar pigment, caramel, iron sesquioxide, titanium oxide and riboflavins
  • flavoring agents e.g. sweeteners and perfume
  • stabilizers e.g. sodium sulfite
  • preservatives e.g. parabens and sorbic acid
  • the therapeutic agent of the present invention containing the above-mentioned pharmaceutical preparation contains the compound (I') or a salt thereof in a amount effective for the therapy and prophylaxis.
  • the content of the compound (I') or a salt thereof in the pharmaceutical preparation of the present invention ranges usually from 0.1 to 100 weight % relative to the whole weight of the pharmaceutical preparation.
  • the pharmaceutical preparation of the present invention 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 this invention is attained, and can be used in adequate ratios.
  • the said “medicinal components” use is made of, for example, diuretic, angiotensin II receptor antagonist, calcium blocker, ACE inhibitor, kimase inhibitor, HMG-CoA reductase inhibitor and squalene synthetase inhibitor.
  • Specific examples of the formulation include tablets (including sugar-coated tablets and film-coated tablets), pills, capsules, granules, powdery preparations, syrups, emulsions, suspensions, injections, inhalants and ointments. These formulations are prepared by a conventional method (e.g. the method described in the Japanese Pharmacopeia) .
  • tablets can be prepared by, for example, the following processes: 1) the pharmaceutical preparation as it is, or a homogeneous mixture of the pharmaceutical preparation 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; 2) the pharmaceutical preparation as it is, or a homogeneous mixture of the pharmaceutical preparation with an excipient, a binder, a disintegrant or any other suitable additive, is directly subjected to compression molding; or 3) the granules prepared in advance as they are, or a homogeneous mixture of the granules with a suitable additive, is subjected to compression molding.
  • a colorant or a flavoring agent may optionally be supplemented upon necessity.
  • this pharmaceutical preparation may optionally be coated with a coating agent.
  • Injectable preparations can be provided by dissolving, suspending or emulsifying a given amount of the pharmaceutical preparation in, when using an aqueous solvent, e.g. water for injection, physiological saline or Ringer's solution, and, when using a water-insoluble solvent, usually e.g. vegetable oil, or by filling a given amount of the pharmaceutical preparation into a vessel, followed by sealing the vessel.
  • an aqueous solvent e.g. water for injection, physiological saline or Ringer's solution
  • a water-insoluble solvent usually e.g. vegetable oil
  • the carriers for orally administrable preparations use is made of substances commonly employed in the field of pharmaceutical preparations, for example, starch, mannitol, crystalline cellulose and sodium carboxymethyl cellulose.
  • the carriers for injectable preparations use is made of, for example, distilled water, physiological saline solution, glucose solution and an agent of infusion. Besides, additives generally employed for pharmaceutical preparations can be adequately supplemented.
  • the pharmaceutical preparations of this invention are relatively less toxic and useful as medicinal preparations, which have PDGF-inhibiting activity, antihypertensive activity, ameliorating activity of renal diseases and lipid lowering activity. Therefore, the pharmaceutical preparations of this invention are useful as medicines for diseases due to these pharmacological actions.
  • the pharmaceutical preparations of this invention can thus be used as the therapy or prophylaxis of, among others, hypertension, acute renal failure, diabetic nephropathy, nephritis, arteriosclerosis, chronic rheumatoid arthritis, cancers and hyperlipemia.
  • the dose of the pharmaceutical preparations of this invention varies with administration routes, symptoms, the age and body weight of patients and it is preferable that a daily dose for treating hypertension, renal diseases or orterisderotic diseases of 0.01 to 300 mg/kg, preferably 0.2 to 50 mg/kg, more preferably 5 to 30 mg/kg for oral administration is given once or divided into several times.
  • the administration route may be either oral or non-oral.
  • Test Example 1 Inhibitory effects on the contraction due to PDGF Method: The thoracic aorta of stroke prone spontaneously hypertensive rats at ages ranging from 16 to 36 weeks were isolated, and strip (2 mm in width, 2 cm in length) were prepared from the aorta. Each strip was mounted in 10 ml of an organ bath, which was loaded at 2 g and allowed to stabilized for 2 to 3 hours. As the nutrient, a Krebs-Henseleit solution, bubbled with a mixture gas (95% 02, 5% C0 2 ), was used.
  • each strip was applied by 1.7 nM of PDGF-AB (Cosmobio Inc.) for contraction. Observation was continued until the contraction become maximum and stable (30 to 40 minutes after application of PDGF-AB). Then, the strips were washed, and, in about one hour later (after the tone of the vaso-contraction was recovered to the original level), 10 ⁇ l of the drug (DMSO solution) was added. Thirty minutes after drug, 1.7 nM of PDGF-AB was added again and subjected to observation until the contraction became maximum. The PDGF-AB-induced contraction was isometrically recorded on a polygraph (Nihon Denki San-ei) .
  • SHRs spontaneously hypertensive rats
  • A/G B-test (Wako) .
  • the blood pressure was measured by the tail cuff method.
  • Test animals showing more proteinuria than that of Sham group were selected. Based on the amount of the proteinuria and the blood pressure level, the animals were grouped so that, the average and distribution of urinary protein and blood pressure same in each group.
  • the drug was suspended in gumarabic/water or dissolved in water, and orally administered once a day for 6-8 weeks in a volume of 2 ml/kg. The administration was consecutively performed, and, at 2, 4, 6 and 8th weeks of treatment, urine was collected and blood pressure was measured.
  • the vehicle group was orally administered with only water at a dose of 2 ml/kg. The results are shown in Table 3.
  • the compound (I') or a salt thereof act to decrease LDL (low density lipid) and VLDL (very low density lipid) in blood, and are useful against cardivascular diseases, for example, arteriosclerosis.
  • the present invention provides a novel tricyclic compound and a salt thereof which have excellent PDGF- inhibiting activity, antihypertensive activity, activity of ameliorating renal diseases, and activity of lowering lipid level, and therefore, can be safely used as, therapeutic agents of, for example, hypertension, renal diseases (e.g. acute renal failure, renal diabetes and nephritis) , diseases due to arteriosclerosis, the other cardiovascular diseases, chronic articular rhematism, cancers and hyperlipemia.
  • renal diseases e.g. acute renal failure, renal diabetes and nephritis
  • diseases due to arteriosclerosis the other cardiovascular diseases, chronic articular rhematism, cancers and hyperlipemia.
  • the reaction mixture was poured into 300 ml of ice-water, and the mixture was blended sufficiently, to which was then added 12N HCl until the pH of the solution reached 2. This solution was stirred for two hours at room temperature, which was then neutralized with a 6N aqueous solution of sodium hydroxide, followed by distilling off the solvent completely under reduced pressure. To the residue was added 300 ml of methanol. The mixture was blended sufficiently, and insolubles were filtered off, followed by distilling off the solvent under reduced pressure to leave 5.71 g of a crude product (88%, white solid substance). The crude product was used in the subsequent reaction without purification.
  • the organic layer was washed with 100 ml of a 1.ON aqueous solution of sodium thiosulfate, then with 100 ml of a saturated aqueous saline solution.
  • the organic layer was dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure.
  • the reaction mixture was poured into ice-water, which was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, which was extracted with 150 ml of chloroform.
  • the organic layer was washed with 250 ml of a saturated aqueous saline solution, which was dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure.
  • Example 9 4 ,5-Dihydro-2-methyl-4-[ -(trifluoromethanesulfonamido) butan-1-yl]-3H-1,4, 8b-triazaacenaphthylen-3- one.hydrochloride i) Synthesis of 2-methyl-5-[N-tert-butoxycarbonyl-N- [4-(trifluoromethanesulfonamido)butan-l- yl]aminomethyl]imidazo[1,2-a]pyridine To a solution of 2.41 g (6.61 mmol) of 2-methyl-5- [N-[4-(trifluoromethanesulfonamido)butan-1- yl]aminomethyl]imidazo[1,2-a]pyridine in 15 ml of ethanol was added dropwise, for 5 minutes, 1.44 g (6.61 mmol of di-tert-butyl dicarbonate.
  • reaction mixture was stirred for one hour at room temperature, then the solvent was distilled off under reduced pressure.
  • reaction mixture was poured into ice-water, which was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with 100 ml of chloroform.
  • the organic layer was washed with 200 ml of a saturated aqueous saline solution, which was dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure.
  • Example 12 5-Dihydro-4-[3-(trifluoromethanesulfonamido)propan-1- yl]-3H-1,4,8b-triazaacenaphthylene-3,5- dione-hydrochloride i) Synthesis of 4,5-dihydro-4-[3-(trifluoromethane ⁇ sulfonamido)propan-1-yl]-3H-1,4,8b-triazaacenaphthyl- ene-3,5-dione
  • reaction mixture was washed with water, and dried over anhydrous magnesium sulfate.
  • Example 36 1,2-Dihydro-3-methyl-1-[4-(propan-1- ylsulfonamido)butan-1-yl]-1,4,7b- triazaeyelopent[cd]inden-2-one-hydrochloride i) Synthesis of l,2-dihydro-3-methyl-l-[4-(propan-l- ylsulfonamido)butan-1-yl]-1,4,7b- triazacyclopent[cd]inden-2-one To a solution of 1.22 g (5.0 mmol) of l-[4-(amino) butan-1-yl]-1,2-dihydro-3-methyl-1,4,7b- triazacyclopent[cd]inden-2-one and 1.1 ml (7.9 mmol) of triethylamine in 40 ml of methylene chloride was added, while stirring under ice-cooling, 0.73 ml (6.5 mmol) of propan-1-
  • Example 56 5-Dihydro-4-( -trifluoroacetamidobutan-1-yl)-3H- 1,4,8b-triazaacenaphthylene-3-one•hydrochloride i) 5-[N-tert-butoxycarbonyl-N-(4-trifluoroacetamido butan-1-yl)aminomethyl]imidazo[1,2-a]pyridine
  • the solvent was distilled off under reduced pressure, and the residue was dissolved in 100 ml of purified water. To this solution was added 2N sodium hydroxide to adjust the pH to 8, and extracted with 100 ml of dichloromethane. The organic layer was washed with 100 ml of a saturated aqueous saline solution, dried over magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silica gel column chromatography to afford 2250 mg of the desired compound (83.2%, a pale yellow liquid).
  • the reaction mixture was cooled to room temperature to cause formation of triethylamine hydrochloride, which was filtered off.
  • the filtrate was concentrated under reduced pressure, and the concentrate was extracted with 150 ml of chloroform.
  • the organic layer was washed with 150 ml of a saturated aqueous saline solution.
  • the organic layer was dried over magnesium sulfate.
  • the solvent was distilled off under reduced pressure.
  • Example 67 1-[1-(tert-Butoxycarbonyl)piperidin-4-ylmethyl]-1,2- dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one
  • 187 mg (4.68 mmol) of 60 % sodium hydride (dispersion in oil) was stirred for 20 minutes at the same temperature.

Abstract

L'invention se rapporte à un composé tricyclique de la formule (I') dans laquelle le noyau A est un noyau hétérocyclique contenant de l'azote, et possédant deux atomes d'azote comme hétéro-atomes, et qui est éventuellement substitué par oxo ou thio; le noyau Q peut être éventuellement substitué; Y est un groupe hdyrocarbure éventuellement substitué, un groupe hdyroxyle éventuellement substitué ou un groupe mercapto éventuellement substitué, à l'exclusion d'un groupe méthyle; R1 est un atome d'hydrogène, un atome d'halogène, un groupe hydrocarbure éventuellement substituté ou un groupe acyle, ou un sel de celui-ci. Ce composé présente d'excellentes activités inhibant PDGF (facteur de croissance plaquettaire), des activités anti-hypertensives, des activités apportant une amélioration aux maladies rénales et des activités favorisant la réduction du taux lipidique.
PCT/JP1995/001382 1994-07-15 1995-07-12 Composes tricycliques, leur production et utilisation WO1996002542A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0826686A2 (fr) * 1996-09-02 1998-03-04 Takeda Chemical Industries, Ltd. Composés tricycliques, leur préparation et utilisation
WO1998029136A1 (fr) * 1996-12-27 1998-07-09 Takeda Chemical Industries, Ltd. Compose tricyclique stabilise
WO1998047901A1 (fr) * 1997-04-18 1998-10-29 Takeda Chemical Industries, Ltd. Procede de production de composes tricycliques et de leurs intermediaires
US5958942A (en) * 1994-07-15 1999-09-28 Takeda Chemical Industries, Ltd. Tricyclic nitrogen ring compounds, their production and use
WO2004011429A1 (fr) * 2002-07-26 2004-02-05 Nihon Nohyaku Co., Ltd. Nouveaux derives d'haloalkylsulfonanilide, herbicides et utilisation de ceux-ci
JP2004107323A (ja) * 2002-07-26 2004-04-08 Nippon Nohyaku Co Ltd 新規なハロアルキルスルホンアニリド誘導体及び除草剤並びにその使用方法
US8362030B2 (en) 2008-03-14 2013-01-29 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.R.L. Tricyclic derivatives as inhibitors of poly(ADP-ribose) polymerase (PARP)
US9309238B2 (en) 2009-11-05 2016-04-12 University Of Notre Dame Du Lac Imidazo [1,2-a]pyridine compounds, synthesis thereof, and methods of using same
US10919888B2 (en) 2015-09-17 2021-02-16 University Of Notre Dame Du Lac Benzyl amine-containing heterocyclic compounds and compositions useful against mycobacterial infection

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW202216714A (zh) * 2020-10-26 2022-05-01 大陸商上海青煜醫藥科技有限公司 含氮稠雜環類化合物及其製備方法和應用

Citations (1)

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EP0418071A2 (fr) * 1989-09-15 1991-03-20 Pfizer Inc. N-aryl et N-hétéroarylamide et dérivés d'urée comme inhibiteurs d'acyl coenzyme A: cholestérol acyl transférase

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GB2235925B (en) * 1989-09-12 1992-09-30 Sericol Group Ltd Photocurable compositions

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0418071A2 (fr) * 1989-09-15 1991-03-20 Pfizer Inc. N-aryl et N-hétéroarylamide et dérivés d'urée comme inhibiteurs d'acyl coenzyme A: cholestérol acyl transférase

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5958942A (en) * 1994-07-15 1999-09-28 Takeda Chemical Industries, Ltd. Tricyclic nitrogen ring compounds, their production and use
EP0826686A2 (fr) * 1996-09-02 1998-03-04 Takeda Chemical Industries, Ltd. Composés tricycliques, leur préparation et utilisation
EP0826686A3 (fr) * 1996-09-02 1998-05-06 Takeda Chemical Industries, Ltd. Composés tricycliques, leur préparation et utilisation
WO1998029136A1 (fr) * 1996-12-27 1998-07-09 Takeda Chemical Industries, Ltd. Compose tricyclique stabilise
WO1998047901A1 (fr) * 1997-04-18 1998-10-29 Takeda Chemical Industries, Ltd. Procede de production de composes tricycliques et de leurs intermediaires
JP2004107323A (ja) * 2002-07-26 2004-04-08 Nippon Nohyaku Co Ltd 新規なハロアルキルスルホンアニリド誘導体及び除草剤並びにその使用方法
WO2004011429A1 (fr) * 2002-07-26 2004-02-05 Nihon Nohyaku Co., Ltd. Nouveaux derives d'haloalkylsulfonanilide, herbicides et utilisation de ceux-ci
US8362030B2 (en) 2008-03-14 2013-01-29 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.R.L. Tricyclic derivatives as inhibitors of poly(ADP-ribose) polymerase (PARP)
US9309238B2 (en) 2009-11-05 2016-04-12 University Of Notre Dame Du Lac Imidazo [1,2-a]pyridine compounds, synthesis thereof, and methods of using same
US9908876B2 (en) 2009-11-05 2018-03-06 University Of Notre Dame Du Lac Imidazo [1,2-a]pyridine compounds, synthesis thereof, and methods of using same
US10913737B2 (en) 2009-11-05 2021-02-09 University Of Notre Dame Du Lac Imidazo [1,2-a]pyridine compounds, synthesis thereof, and methods of using same
US10919888B2 (en) 2015-09-17 2021-02-16 University Of Notre Dame Du Lac Benzyl amine-containing heterocyclic compounds and compositions useful against mycobacterial infection
US11820767B2 (en) 2015-09-17 2023-11-21 University Of Notre Dame Du Lac Benzyl amine-containing heterocyclic compounds and compositions useful against mycobacterial infection

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AU2935895A (en) 1996-02-16

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