WO1997046549A1 - Derives xanthene efficaces en tant qu'agents anti-neurodegeneratifs - Google Patents

Derives xanthene efficaces en tant qu'agents anti-neurodegeneratifs Download PDF

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WO1997046549A1
WO1997046549A1 PCT/EP1997/002885 EP9702885W WO9746549A1 WO 1997046549 A1 WO1997046549 A1 WO 1997046549A1 EP 9702885 W EP9702885 W EP 9702885W WO 9746549 A1 WO9746549 A1 WO 9746549A1
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alkylamino
alkyl
amino
alkoxy
xanthene
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PCT/EP1997/002885
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Silvio Roggo
Kaspar Zimmermann
Claudia Betschart
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Novartis Ag
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Priority to AU31723/97A priority Critical patent/AU3172397A/en
Publication of WO1997046549A1 publication Critical patent/WO1997046549A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C07D311/90—Xanthenes with hydrocarbon radicals, substituted by amino radicals, directly attached in position 9

Definitions

  • the invention relates to the use of xanthene derivatives of formula I
  • A signifies methylene, carbonyl or thiocarbonyl
  • R represents an amino group, either unsubstituted or mono- or di-substituted by monovalent aliphatic and or araliphatic radicals, or disubstituted by divalent aliphatic or araiiphatic radicals, and
  • R,, R 2 , R 3 and R 4 independently of one another, denote hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, and their pharmaceutically employable salts, as anti-neurodegenerative active ingredients for medicaments, or for the preparation thereof, as well as new compounds of formula I and their salts as such, processes for their production and pharmaceutical preparations containing them.
  • New compounds of formula I are for example those in which a) at least one of radicals Ri, R 2 , R 3 and R is different from hydrogen, if R signifies amino, chloroacetylamino, 2-diethylaminoethylamino or piperidino, or if R represents lower-alkylamino, di-lower-alkylamino, pyrrolidino, morpholino or 4-lower-alkyl- piperazino and A represents carbonyl; b) R, and R 3 are different from hydrogen, lower alkyl and halogen or R is different from optionally 4-lower-alkylated 4-amino- or 4-hydroxypiperidino, if R 2 and R 4 signify hydrogen and A is methylene; c) Ri is different from 2-methoxy, R 2 from 3-methoxy, R 3 from 7-methoxy or R 4 from 6-methoxy, if R is methylamino or acetylamino and A is methylene; d
  • Amino groups mono- or di-substituted by monovalent aliphatic or araliphatic radicals are for example lower alkylamino; phenyl-lower-alkylamino or phenyl-lower-alkyl-lower-alkylamino either unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and/or trifluoromethyl; hydroxy-lower-alkylamino, lower-alkoxy-lower-alkylamino, lower-alkanoyloxy- lower-alkylamino, lower-alkylamino-lower-alkylamino, di-lower-alkylamino-lower-alkylamino, lower-alkyieneamino-lower-alkylamino, lower-alkenylamino, hydroxy-lower-alkenylamino, lower-alkoxy-lower-alkenylamino, lower-alkanoyloxy-lower
  • Amino groups disubstituted by divalent aliphatic radicals are for example respectively 3- to 8-membered lower-alkylene-amino, lower-alkenyleneamino or lower-alkadienyleneamino; 3- or 4-aza-lower-alkyieneamino either unsubstituted or N-substituted by lower-alkyl, hydroxy- lower-alkyl, lower-alkoxy-lower-alkyl or lower-alkanoyl; 3- or 4-oxa-lower-alkyleneamino or optionally S-oxidised 3- or 4-thia-lower-alkyleneamino, such as in particular pyrrolidino, pyrrolino (2,5-dihydropyrrol-1-yl), pyrrolo (pyrrol- 1 -yl), piperidino, di-lower-alkylpiperidino, tetrahydropyridino, such as 1 ,2,5,6-tetrahydr
  • Amino groups substituted by divalent araliphatic radicals are for example phenyl-lower- alkyleneamino or N'-phenyl-lower-alkylaza-loweralkyleneamino radicals either unsubstituted or substituted in the phenyl moiety by lower-alkyl, lower-alkoxy, halogen and/or trifluoromethyl.
  • the lower radicals and compounds are understood to be for example those which have up to and including 7, preferably up to and including 4 carbon atoms (C-atoms).
  • Di(hydroxy-lower-alkyl)amino is for example N,N-di(hydroxy-C 2 -C 4 -alkyl)amino, such as N,N- di(2-hydroxyethyl)amino or N,N-di(3-hydroxypropyl)amino.
  • Di(lower-alkoxy-lower-alkenyl)amino is for example N,N-di(C ⁇ -C -alkoxy-C 2 -C4-alkenyl)- amino, such as N,N-di(4-methoxy-but-2-eny!amino.
  • Di(lower-alkoxy-lower-alkyl)amino is for example N,N-di(C ⁇ -C4-alkoxy-C ⁇ -C4-alkyl)amino, such as N t N-di(2-methoxyethyl)amino, N,N-di(2-ethoxyethyl)amino or N,N-di(3-methoxy- propyl)amino.
  • Di-lower-alkenylamino is for example N,N-di-C 2 -C 4 -alkenylamino, such as N,N-diallylamino or N-methallyl-N-allylamino.
  • Di-lower-alkylamino is for example N,N-di-C ⁇ -C 4 -a!kylamino, such as dimethylamino, diethyl- amino, ethyimethylamino, dipropylamino, methylpropylamino, ethylpropylamino, dibutyl- amino or butyimethylamino.
  • Di-lower-alkylamino-lower-alkenyl-lower-alkylamino is for example N-(di-C ⁇ -C 4 -alkylamino- C 2 -C -alkenyl)-N-C ⁇ -C4-alkylamino, such as N-(4-dimethylaminobut-2-enyl)-N-methylamino.
  • Di-lower-alkylamino-lower-alkenylamino is for example N-(di-CrC4-alkylamino-C 2 -C - alkenyl)amino, such as N-(4-dimethylaminobut-2-enyl)amino.
  • Di-lower-alkylamino-lower-alkinylamino is for example N-(di-C ⁇ -C4-alkylamino-C 2 -C4-alkinyl)- amino, such as N-(4-dimethylaminobut-2-inyl)amino.
  • Di-lower-aikylamino-lower-alkyl-lower-alkylamino is for example N-(di-C ⁇ -C4-alkylamino- C 2 -C -alkyl)-N-C ⁇ -C4-alkylamino, such as N-(2-dimethylaminoethyl)-N-methylamino, N-(2- dimethylaminoethyl)-N-ethylamino, N-(3-dimethylaminopropyl)-N-methylamino or N-(4- dimethylaminobutyl)-N-methylamino.
  • Di-lower-alkylamino-lower-alkylamino is for example N-(di-CrC4-alkylamino-C 2 -C4-alkyl)- amino, such as N-(2-dimethylaminoethyl)amino, N-(2-dimethylaminoethyl)amino, N-(3- dimethylaminopropyl)amino or N-(4-dimethylaminobutyl)amino.
  • Halogen is for example halogen with an atomic number of up to and including 35, such as chlorine or bromine.
  • Hydroxy-lower-alkenyl-lower-alkylamino is for example N-(hydroxy-C 2 -C4-alkenyl)-N-(C ⁇ -C 4 - alkylamino, such as N-(4-hydroxybut-2-enyl)-N-methylamino.
  • Hydroxy-lower-alkenylamino is for example hydroxy-C 2 -C 4 -alkenylamino, such as 4-hydroxy- but-2-enylamino.
  • Hydroxy-lower-alkinylamino is for example hydroxy-C 2 -C4-alkinytamino, such as 4-hydroxy- but-2-inylamino.
  • Hydroxy-lower-alkyl-lower-alkylamino is for example N-(hydroxy-C 2 -C 4 -e ⁇ lkyl)-N-C ⁇ -C 4 -alkyl- amino, such as N-(2-hydroxyethyl)-N-methylamino, N-(3-hydroxypropyl)-N-methylamino or N-(4-hyd roxybutyl)-N-m ethylami no.
  • Hydroxy-lower-alkylamino is for example hydroxy-C 2 -C4-alkylamino, such as 2-hydroxyethyl- amino, 3-hydroxypropylamino or 4-hydroxybutylamino.
  • N'-hydroxy-lower-alkylpiperazino is for example N'-(hydroxy-C -C -alkyl)piperazino, such as N'-(2-hydroxyethyl)piperazino or N'-(3-hydroxypropyl)piperazino.
  • N'-lower-alkanoylpiperazino is for example N'-d-Cralkanoylpiperazino, such as N'-acetyl- piperazino.
  • N'-lower-alkoxy-lower-alkylpiperazino is for example N'-(C ⁇ C4-alkoxy-C ⁇ -C4-alkyl)piperazino, such as N'-(2-methoxyethyl)piperazino or N'-(3-methoxypropyl)piperazino.
  • N'-lower-alkylpiperazino is for example N'-C ⁇ -C4-alkylpiperazino, such as N'-methyl- piperazino, N'-ethylpiperazino, N'-propylpiperazino or N'-butylpiperazino.
  • Lower alkoxy is for example Ci-Cralkoxy, preferably C ⁇ -C 5 -alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, secondary butyloxy, tertiary butyloxy, pentyloxy or a hexyloxy or heptyloxy group.
  • Ci-Cralkoxy preferably C ⁇ -C 5 -alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, secondary butyloxy, tertiary butyloxy, pentyloxy or a hexyloxy or heptyloxy group.
  • Lower-alkanoyloxy-lower-alkenyl-lower-alkylamino is for example N-(C ⁇ -C ⁇ -alkanoyloxy- C 2 -C -alkenyl)-N-(C ⁇ -C4-alkyl)-amino, such as N-(4-acetoxybut-2-enyl)-N-methylamino.
  • Lower-alkanoyloxy-lower-alkenylamino is for example N-(CrC ⁇ -alkanoyloxy-C 2 -C4-alkenyl)- amino, such as N-(4-acetoxybut-2-enyl)amino.
  • Lower-alkanoyloxy-lower-alkinyl-lower-alkylamino is for example N-(C ⁇ -C7-alkanoyloxy- C 2 -C4-alkinyl)-N-(C ⁇ -C4-alkyl)amino, such as N-(4-acetoxybut-2-inyl)-N-methylamino.
  • Lower-alkanoyioxy-lower-alkinylamino is for example N-(C ⁇ -Cralkanoyioxy-C 2 -C 4 -alkinyl)- amino, such as N-(4-acetoxybut-2-inyl)amino.
  • Lower-alkanoyloxy-lower-alkyl-lower-alkylamino is for example N-(C ⁇ -C ⁇ -alkanoyloxy-C 2 -C 4 - alkyl)-N-(C ⁇ -C 4 -alkyl)amino, such as N-(2-acetoxyethyl)-N-methylamino, N-(2-acetoxyethyl)- N-ethylamino, N-(3-acetoxypropyl)-N-methylamino or N-(4-acetoxybutyl)-N-methylamino.
  • Lower-alkanoyloxy-lower-alkylamino is for example N-(C ⁇ -C ⁇ -alkanoyloxy-C 2 -C4-alkyl)amino, such as N-(2-acetoxyethyl)amino, N-(3-acetoxypropyl)amino or N-(4-acetoxybutyl)amino.
  • Lower-alkenyl-lower-alkylamino is for example N-(C 2 -Cralkenyl)-N-(C 2 -C 7 -alkyl)-amino, especially N-(C 2 -C 4 -alkenyl)-N-(C ⁇ -C 4 -alkyl)-amino, such as N-vinyl-N-methylamino-N-allyl-N- methylamino, N-allyl-N-ethylamino, N-but-2-enyl-N-methylamino or N-but-3-enyl-N-methyl- amino.
  • Lower-alkenylamino is for example N-(C 2 -C ⁇ -alkenyl)amino, especially N-(C 2 -C 4 -alkenyl)- a ino, such as vinylamino, allylamino, but-2-enylamino or N-but-3-enylamino, especially allylamino.
  • Lower-alkinyl-lower-alkylamino is for example N-(C 2 -C4-alkinyl)-N-(C -C -alkyl)-amino, such as N-propargyl-N-methylamino, N-but-2-inyl-N-methyiamino or N-but-3-inyl-N-methylamino.
  • Lower-alkinylami ⁇ o is for example N-(C 2 -Cralkinyl)amino, especially N-(C 2 -C 4 -alkinyl)amino, such as propargylamino, but-2-i ⁇ ylamino or N-but-3-inylamino, especially propargylamino.
  • Lower-alkoxy is for example C ⁇ -C ⁇ -alkoxy, preferably C ⁇ -C -alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy, but may also be isobutyloxy, secondary butyl ⁇ oxy, tertiary butyloxy or a C 3 -C ⁇ -alkoxy group, such as a pentyloxy, hexyloxy or heptyloxy group.
  • C ⁇ -C ⁇ -alkoxy such as methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy, but may also be isobutyloxy, secondary butyl ⁇ oxy, tertiary butyloxy or a C 3 -C ⁇ -alkoxy group, such as a pentyloxy, hexyloxy or heptyloxy group.
  • Lower-alkoxy-lower-alkenyl-lower-alkylamino is for example N-(C ⁇ -C -alkoxy-C 2 -C4-alkenyl)- N-N-(C 1 -C4-alkyl)-amino, such as N-(4-methoxybut-2-enyl)-N-(methylamino, N-(4-methoxy- but-2-enyl)-N-ethylamino or N-(4-ethoxybut-2-enyl)-N-methylamino.
  • Lower-alkoxy-lower-alkenylamino is for example N-(C ⁇ -C 4 -alkoxy-C 2 -C4-alkenyJ)amino, such as N-(4-methoxybut-2-enyl)amino or N-(4-ethoxybut-2-enyl)amino.
  • Lower-alkoxy-lower-alkinyl-lower-alkylamino is for example N-(C ⁇ -C 4 -alkoxy-C 2 -C4-alkinyl)-N- (C ⁇ -C 4 -alkyl)amino, such as N-(4-methoxybut-2-inyl)-N-methylamino, N-(4-methoxybut-2- inyl)-N-ethylamino or N-(4-ethoxybut-2-inyl)-N-methylamino.
  • Lower-alkoxy-lower-alkinylamino is for example N-(C ⁇ -C 4 -alkoxy-C 2 -C 4 -alkiny1)amino, such as N-(4-methoxybut-2-inyl)amino, N-(4-ethoxybut-2-inyl)amino or N-(4-propyioxybut-2-inyl)- amino.
  • Lower-alkoxy-lower-alkylamino is for example C ⁇ -C4-alkoxy-C 2 -C -alkyiamino, such as 2- methoxyethylamino, 2-ethoxyethylamino, 2-propyloxyethylamino, 3-methoxypropylamino, 3-ethoxypropylamino, 4-methoxybutylamino, 2-isopropyloxyethylamino or 2-butyloxyethyl- amino.
  • Lower-alkoxy-lower-alkyl-lower-alkylamino is for example N-(C ⁇ -C 4 -alkoxy-C 2 -C4-alkyl)-N- (C ⁇ -C -alkyl)-amino, such as N-(2-methoxyethyl)-N-methylamino, N-(2-ethoxyethyl)-N- methylamino, N-(2-propyloxyethyl)-N-methylamino, N-(3-methoxypropyl)-N-methylamino, N- (3-ethoxypropyl)-N-methylamino or N-(4-methoxybutyl)-N-methylamino.
  • Lower alkyl is for example Ci-Cralkyl, preferably C ⁇ -C -alkyl, such as methyl, ethyl, propyl, isopropyl or butyl, but it may also be isobutyl, secondary butyl, tertiary butyl or a C 5 -C ⁇ -alkyl group, such as a pentyl, hexyl or heptyl group.
  • Ci-Cralkyl preferably C ⁇ -C -alkyl, such as methyl, ethyl, propyl, isopropyl or butyl, but it may also be isobutyl, secondary butyl, tertiary butyl or a C 5 -C ⁇ -alkyl group, such as a pentyl, hexyl or heptyl group.
  • Lower alkylamino is for example C ⁇ -C ⁇ -alkylamino, preferably C ⁇ -C 4 -alkytamino, such as methylamino, ethylamino, propylamino, isopropylamino or butylamino, but may also be isobutylamino, secondary butylamino, tertiary butylamino or a Cs-Cralkylamino group, such as a pentylamino, hexytamino or heptylamino group, and it is in particular methylamino or propylamino.
  • Lower-alkylamino-lower-alkylamino is for example N-(C 1 -C -alkylamino,-CrC4-alkyl)amino ⁇ such as N-(2-methylaminoethyl)amino, N-(1-methylaminoethyl)amino, N-(3-methylamino- propyl)amino, N-(4-methylaminobutyl)amino, N-(2-ethylaminoethyl)amino, N-(1 -ethylamino- ethyl)amino, N-(3-ethylaminopropyl)amino or N-(4-ethylaminobutyl)amino.
  • N-(C 1 -C -alkylamino,-CrC4-alkyl)amino ⁇ such as N-(2-methylaminoethyl)amino,
  • Lower-alkyleneamino-lower-alkylamino is for example 3- to 8-membered alkyleneamino-C 2 - C4-alkylamino, such as 2-pyrrolidinoethylamino, 2-piperidinoethylamino, 2-dimethyl- piperidinoethylamino, 2-hexamethyleneiminoethylamino, 3-pyrrolidinopropylamino, 3- piperidinopropylamino, 3-dimethylpiperidinopropylamino or 3-hexamethyleneiminopropyl- amino.
  • Phenyl-lower-alkyl-lower-alkylamino is for example N-(phenyl-C ⁇ -C 4 -alkyl)-N-(C r C4-alkyl)- amino, such as N-benzyl-N-methylamino, N-(2-phenylethyl)-N-methylam ⁇ no or N-(4-phenyl- butyl)-N-methylam ⁇ no.
  • Phenyl-iower-alkylamino is for example phenyl-CrC4-alkylam ⁇ no, such as benzylamino, 1- or 2-phenylethylam ⁇ no, 3-phenylpropylam ⁇ no or 4-phenylbutylam ⁇ no
  • Phenyl-lower-alkyl-lower-alkyleneamino is for example phenyl-CrC 4 -alkyl-py ol ⁇ d ⁇ no either unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and/or trifluoromethyl, such as 2- or 3-benzylpyrrolidino; phenyl-d-C alkylpipendino such as 2-, 3- or 4-benzyl- pipendino, furthermore phenyl-C ⁇ -C4-alkylhexahydroazep ⁇ no such as 2-, 3- or 4-benzyl- hexahydroazepmo, phenyl-C ⁇ -C -alkylazirid ⁇ no such as 2-benzylaz ⁇ nd ⁇ no or phenyl-C ⁇ -C 4 - alkylazetidino such as 2- or 3-benzylazet ⁇ d ⁇ no
  • N-phenyl-lower-alkylaza-lower-alkyleneamino is for example N'-phenyl-C 1 -C 4 -alkyl- imidazolidino either unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and/or trifluoromethyl, such as N'-benzyl ⁇ midazolid ⁇ no, phenyl-C ⁇ -C 4 -alkylp ⁇ peraz ⁇ no such as N'- benzyipiperazino, or phenyl-CrC4-alkylhexahydro-1 ,3-d ⁇ azep ⁇ no such as N'-benzyl- hexahydro-1 ,3-diazep ⁇ no, furthermore phenyl-C 1 -C 4 -alkyl-1 ,3-diazet ⁇ d ⁇ no such as N'-benzyl- 1 ,3-d ⁇ azet ⁇ d ⁇ no
  • Salts of compounds of formula I are for example the pharmaceutically employable acid addition salts thereof with appropnate mineral acids, such as hydrohalic acids, sulphu ⁇ c acid or phospho ⁇ c acid, e.g. hydrochlorides, hydrobromides, sulphates, hydrogen sulphates or phosphates, or salts with appropnate aliphatic or aromatic sulphonic acids or N-substituted sulphaminic acids, e.g methane sulphonates, benzene sulphonates, p- toluene sulphonates or N-cyclohexyl sulphaminates (cyclamates), similarly acid addition salts with pharmaceutically employable organic carboxylic acids, for example pharmaceutically employable acid addition salts with optionally hydroxylated lower alkanoic acids, e.g.
  • mineral acids such as hydrohalic acids, sulphu ⁇ c acid or phospho ⁇ c acid, e.g. hydrochlorides, hydrobro
  • acetic acid, propionic acid, pivaiic acid, glycolic acid, pyroacemic acid, lactic a ⁇ d or giuconic acid, optionally hydroxylated, ammated and/or oxo-substituted lower alkane- dicarboxyiic acids e.g. oxalic acid, malomc acid, succinic acid, glutamic a ⁇ d, aspartic acid, tarta ⁇ c acid or malic acid, optionally hydroxylated and or oxo-substituted lower-alkane- t ⁇ carboxy c acids, e.g.
  • cit ⁇ c acid or aconitic acid optionally hydroxylated and or oxo- substituted lower-alkene-dicarboxylic acids, e.g. fumaric acid, maleic acid or itaconic acid, optionally hydroxylated and/or oxo-substituted lower-alkine-dicarboxylic acids, e.g. acetylene-dicarboxytic acid, furthermore with aromatic, hetero-aromatic or araliphatic carboxylic acids, such as benzoic acid, salicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid or nicotinic acid.
  • the invention is based on the su ⁇ rising discovery that compounds of formula I, when administered to newly-born rats in an experimental setup according to Ansari et al., J. Neuroscience 13, 4042-4053 (1993) at doses of approximately 0.1 mg/kg s.c. and less, have a marked protective effect of the facial motor neurones from apoptotic cytolysis, and when administered to fully-developed rats in an experimental setup according to Golowitz and Paterson, Soc. Neurosc. Abstr.2Q_, 246, 113.2 (1994) at 0.275 mg/kg s.c. and less over 4 days, have a marked protective effect of hippocampal pyramidal cells from cytolysis by administering kainic acid.
  • compounds of formula I protect mesencephalic, dopaminergic neurones in culture at approximately 10-8 molar concentrations, from apoptotic cytolysis induced by MPP+.
  • the compounds of formula I and their pharmaceutically employable salts are consequently eminently suitable for the prophylactic or therapeutic treatment of neurodegenerative disorders, especially those in which apoptotic cytolysis plays a role, such as cerebral ischaemia, Alzheimer's disease, Huntington's and Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, types of glaucoma, retina degeneration, especially retinitis pigmentosa, as well as general or diabetic peripheral neuropathy.
  • the invention relates primarily to the use of compounds of formula I, wherein
  • A signifies methylene, carbonyl or thiocarbonyl
  • R represents amino, iower-alkylamino; phenyl-lower-alkylamino or phenyl-lower-alkyl-lower- alkylamino either unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and/or trifluoromethyl; hydroxy-lower-alkylamino, lower-alkoxy-lower-alkylamino, lower-alkanoyloxy- lower-alkylamino, lower-alkylamino-lower-alkylamino, di-lower-alkylamino-lower-alkylamino, lower-alkyleneamino-lower-alkylamino, lower-alkenylamino, hydroxy-lower-alkenylamino, lower-alkoxy-lower-alkenytamino, lower-alkanoyloxy-lower-alkenylamino, di-lower-alkyl- amino-lower-al
  • R L R 2 , R 3 and R 4 independently of one another, denote hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, and their pharmaceutically employable salts, as well as compounds of formula I as such, and their salts, as well as processes for the production thereof.
  • the invention relates primarily for example to the use of compounds of formula I, wherein A signifies methylene, carbonyl or thiocarbonyl,
  • R represents amino, lower-alkylamino; phenyl-lower-alkylamino or phenyl-lower-alkyl-lower- alkyl amino either unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and/or trifluoromethyl; hydroxy-lower-alkylamino, lower-alkoxy-lower-alkylamino, lower-alkanoyloxy- lower-alkylamino, lower-alkylamino-lower-alkylamino, di-lower-aikylamino-lower-alkylamino, lower-alkyleneamino-lower-alkylamino, lower-alkenylamino, hydroxy-lower-alkenylamino, lower-alkoxy-lower-alkenylamino, lower-alkanoyloxy-lower-alkenylamino, di-lower-alkyl- amino-lower-alkenylamin
  • Ri, R 2 , R 3 and R 4 independently of one another, denote hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, and their pharmaceutically employable salts, as well as compounds of formula I as such, and their salts, as well as processes for the production thereof.
  • the invention relates in particular to the use of compounds of formula I, wherein A signifies methylene or carbonyl,
  • R represents C ⁇ -C 4 -alkylamino, such as methylamino, ethylamino, propylamino or butyl ⁇ amino; phenyl-C ⁇ -C4-alkylamino either unsubstituted or substituted by C ⁇ -C 4 -alkyl such as methyl, C ⁇ -C 4 -alkoxy such as methoxy, halogen with an atomic number up to and including 35 such as chlorine or bromine, and or by trifluoromethyl; such as benzylamino or phenethylamino, phenyl-C ⁇ -C4-alkyI-CrC4-alkylamino either unsubstituted or substituted by C ⁇ -C 4 -alkyl such as methyl, C ⁇ -C 4 -alkoxy such as methoxy, halogen with an atomic number up to and including 35 such as chlorine or bromine, and/or by trifluoromethyl; such as N- benzyl-
  • the invention relates in particular for example to the use of compounds of formula I, wherein
  • A signifies methylene or carbonyl
  • R represents C ⁇ -C 4 -alkylamino, such as methylamino, ethylamino, propylamino or butyl ⁇ amino
  • phenyl-C ⁇ -C 4 -alkylamino either unsubstituted or substituted by C 1 -C 4 -alkyl such as methyl, d-C -alkoxy such as methoxy, halogen with an atomic number up to and including 35 such as chlorine or bromine, and/or by trifluoromethyl
  • benzylamino or phenethylamino, phenyl-d-C4-alkyl-C ⁇ -G 4 -alkylamino either unsubstituted or substituted by C ⁇ -C 4 -alkyl such as methyl, d-d-alkoxy such as methoxy, halogen with an atomic number up to and including 35 such as chlorine or bromine, and/or by triflu
  • the invention preferably relates on the one hand to compounds of formula I, wherein A signifies methylene or carbonyl,
  • R represents C 2 -C7-alkenylamino such as allylamino, methallylamino or but-2-enylamino, C 2 - C -alkinylamino such as propargylamino or but-2-inylamino, N-C 2 -Cralkenyl-N-C ⁇ -C 4 -alkyl- amino such as N-allyl-N-methylamino, N-allyl-N-ethylamino, N-methallyl-N-methylamino or N-but-2-enyl-N-methylamino, N-CrCralkinyl-N-d-d-alkylamino such as N-propargyl-N- methylamino, N-propargyl-N-ethylamino or N-but-2-inyl-N-methylamino; carbamoyl-Ci-d- alkylamino, such as carbamoylmethylamino,
  • the invention preferably relates on the other hand to compounds of formula I, wherein
  • A signifies methylene or carbonyl
  • R signifies pyrrolidino, pyrrolino (2,5-dihydropyrrol-1-yl), pyrrolo (pyrrol-1-yl), piperidino, tetrahydropyridino, such as 1 ,2,5,6-tetrahydropyridino or 1 ,2,3,4-tetrahydropyridino, mo ⁇ holino, piperazino, N'-d-d-alkylpiperazino, such as N'-methylpiperazino, or N'-
  • R L R 2 , R 3 and R 4 independently of one another, denote hydrogen, d-C -alkyl such as methyl, d-d-alkoxy such as methoxy, halogen with an atomic number up to and including
  • 35 such as chlorine or bromine and/or trifluoromethyl, and their salts, processes for their production and their use.
  • the invention relates primarily to compounds of formula I, wherein A is methylene,
  • R represents C 2 -C ⁇ -alkenylamino such as allylamino, methallylamino or but-2-enylamino, C 2 - Craikinylamino such as propargylamino or but-2-inylamino, N-C 2 -C ⁇ -alkenyl-N-d-C 4 -alkyl- amino such as N-allyl-N-methylamino, N-allyl-N-ethylamino, N-methallyl-N-methylamino or N-but-2-enyl-N-methytamino, N-CrCralkinyl-N-Ci-d-alkylamino such as N-propargyl-N- methylamino, N-propargyl-N-ethylamino or N-but-2-inyl-N-methylamino, or cyano-d-C 4 - alkyl-Ci-d-alkylamino, such
  • the invention most preferably relates to compounds of formula I, wherein
  • A is methylene
  • R represents C 2 -C ⁇ -alkenyiamino such as allylamino, methallylamino or but-2-enylamino, C 2 -
  • C -alkinytamino such as propargylamino or but-2-inylamino
  • N-Crd-alkenyl-N-Ci-d-alkyl- amino such as N-allyl-N-methylamino, N-allyl-N-ethylamino, N-methallyl-N-methylamino or
  • N-but-2-enyl-N-methylamino, or N-CrCralkinyl-N-d-d-alkylamino such as N-propargyl-N- methylamino, N-propargyl-N-ethylamino or N-but-2-inyl-N-methylamino and
  • Ri and R 3 independently of one another, signify hydrogen, Ci-d-alkyl, d-d-alkoxy, halogen or trifluoromethyl and
  • R 2 , R 4 signify hydrogen, and their salts.
  • the invention relates particularly to the compounds of formula I named in the examples, and the pharmaceutically employable salts thereof, and their use.
  • X signifies reactive, esterified hydroxy, or where A represents carbonyl or thio- carbonyl, it signifies free or etherified hydroxy
  • R 1t R 2 , R 3 and R 4 have the significances indicated
  • Y-R III
  • Y signifies optionally intermediately protected amino
  • R has the significance indicated
  • the optionally intermediately introduced amino protecting groups are cleaved, and, if desired, a compound which is obtainable according to this process is converted into another compound of formula I, an isomeric mixture which is obtainable according to this process is separated into its components and the desired isomer isolated and/or a salt which is obtainable according to this process is converted into the free compound or a free compound which is obtainable according to this process is converted into a salt.
  • Reactive, esterified hydroxy in the starting materials of formula II is for example hydroxy which is esterified with a hydrohalic acid or an organic sulphonic acid, such as halogen, e.g. chlorine, bromine or iodine, benzene-sulphonyioxy optionally substituted by lower alkyl, halogen and/or nitro, such as benzene-sulphonyioxy, p-bromobenzene-sulphonyloxy or p- toluene-sulphonyloxy, or optionally halogenated lower-alkane-sulphonyloxy such as methane-sulphonyloxy or trifluoromethane-sulphonyloxy.
  • Etherified hydroxy is for example lower alkoxy or a phenyl or phenyl-lower-alkyl group optionally substituted by lower alkyl, lower alkoxy, halogen and/or nitro.
  • reaction of compounds of formulae II and III is effected in conventional manner, for example in the presence of a basic condensation agent, such as a tertiary or sterically hindered binary organic nitrogen base, such as a tri-lower-alkylamine or sterically hindered di-iower-alkylamine, such as triethylamine or diisopropylamine, or a hetero-aromatic base such as pyridine or dimethylaminopyridine, starting from compounds of formula II, wherein X is hydroxy, advantageously in the presence of a water-binding agent, such as a carbo- diimide, for example N-dimethylaminopropyl-N'-ethyl-carbodiimide, preferably in an organic solvent such as a halogenated aliphatic hydrocarbon, e.g. dichloromethane, or toluene, and if necessary with cooling or heating, e.g. in a temperature range of ca. 0°C
  • the amino protecting groups which may be considered are those which are usual for the intermediate protection of primary amino groups, especially solvolytically cleavable amino protecting groups.
  • These are for example acyl groups derived from a carboxylic acid or a semi-ester of carbonic acid, such as optionally halogenated lower alkanoyl, for example lower alkanoyl such as formyl, acetyl or pivaioyl, polyhalogen-lower-alkanoyl such as trifluoroacetyl, lower-alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, isopropyl- oxycarbonyl, or tertiary-butyloxycarbonyl, or optionally substituted phenyl-lower-alkoxy- carbonyl such as benzyloxycarbonyl, furthermore silyl groups such as tri-lower-alkylsiiyl, e.g. trimethylsilyl.
  • Cleavage of these amino protecting groups is effected in conventional manner, for example by treatment with a solvolysis agent, such as with water in the presence of an acid, e.g. an aqueous mineral acid such as hydrohalic acid, or an alkali metal hydroxide such as caustic soda or caustic potash solution, especially for cleaving a tri-lower-alkoxycarbonyl, a sulphonic acid such as methanesulphonic acid in a halogenated hydrocarbon such as dichloromethane, or in particular for cleaving formyl, an appropriate silyl compound such as a tri-lower-alkylsiiyl halide, such as trimethylsilyl bromide, or a disilazane such as hexamethyldisilazane.
  • a solvolysis agent such as with water in the presence of an acid, e.g. an aqueous mineral acid such as hydrohalic acid, or an alkali metal hydro
  • the starting materials of formulae II and III are known or may be produced analogously to the method of forming known compounds of formulae II and III.
  • compounds of formula II, wherein A is methylene and X is trifluoromethane-sulphonyloxy are obtained for example by reacting the corresponding hydroxymethyl compound with trifluoromethanesulphonic acid anhydride in an ether, such as diethylether.
  • the hydroxy ⁇ methyl compound to be used for this may be obtained by means of conventional reduction of the corresponding carboxylic acid or a lower alkylester therof, for example by means of a reaction with a di-light metal hydride, such as lithium aluminium hydride.
  • R signifies unsubstituted amino and or R 5 signifies hydrogen
  • the amino group may be substituted in conventional manner by one or two identical or different monovalent aliphatic or araliphatic radicals or one divalent aliphatic radical.
  • R signifies amino which is substituted by a monovalent aliphatic or araliphatic radical
  • a further monovalent aliphatic or araliphatic radical may also be introduced.
  • carbonyl or thiocarbonyl may be reduced to methylene in conventional manner, for example by means of reduction with a di-light metal hydride, such as lithium aluminium hydride in tetrahydrofuran.
  • the salts obtained may be converted in a manner known perse into the free compounds, e.g. by treatment with a base, such as an alkali metal hydroxide, a metal carbonate or hydrogen carbonate, or another salt-forming base mentioned initially, or with an acid such as a mineral acid, e.g. hydrochloric acid, or another salt-forming acid mentioned initially.
  • a base such as an alkali metal hydroxide, a metal carbonate or hydrogen carbonate, or another salt-forming base mentioned initially
  • an acid such as a mineral acid, e.g. hydrochloric acid, or another salt-forming acid mentioned initially.
  • the salts obtained may be converted in a manner known perse into other salts, acid addition salts, e.g. by means of treatment with an appropriate metal salt, such as a sodium, barium or silver salt, or another acid in an appropriate solvent in which the inorganic salt being formed is insoluble and thus separates from the equilibrium of the reaction, and base salts, by releasing them from the free acid and forming the salt again.
  • an appropriate metal salt such as a sodium, barium or silver salt
  • the compounds of formula I may also be obtained in the form of hydrates, or may include the solvents used for crystallisation.
  • the free compounds and their salts are understood to also optionally refer to the corresponding salts and free compounds, as appropriate.
  • the diastereoisomeric mixtures and racemic mixtures may be separated in known manner into the pure diastereoisomers and racemates, for example by means of chromatography and/or fractional crystallisation.
  • racemates obtained may also be dissociated by known methods into the optical antipodes, for example by recrystallisation from an optically active solvent, with the assistance of micro-organisms or by reacting the diastereoisomeric mixture or racemate obtained with an optically active adjuvant compound, e.g. corresponding to the acidic, basic or functionally variable groups contained in compounds of formula I with an optically active acid, base or an optically active alcohol, into mixtures of diastereoisomeric salts or functional derivatives such as esters, separating them into the diastereoisomers, from which the respectively desired enantiomers may be released in the usual manner.
  • an optically active adjuvant compound e.g. corresponding to the acidic, basic or functionally variable groups contained in compounds of formula I with an optically active acid, base or an optically active alcohol
  • acids or alcohols that are suitable for this are for example optically active alkaloid bases, such as strychnine, cinchonine or brucine, or D- or L-(1-phenyl)ethylamine, 3-pipecoline, ephedrin, amphetamine and similar synthetically accessible bases, optically active carboxylic or sulphonic acids, such as quinic acid or D- or L-tartaric acid, D- or L-di-o-toluyl-tartaric acid, D- or L-malic acid, D- or L-mandelic acid, or D- or L-camphorsulphonic acid, or optically active alcohols, such as bomeol or D- or L-(1-phenyl)ethanol.
  • optically active alkaloid bases such as strychnine, cinchonine or brucine, or D- or L-(1-phenyl)ethylamine, 3-pipecoline, ephedrin, amphetamine and similar synthetically accessible bases
  • the invention also relates to those embodiments of the process according to which it is possible to start from a compound obtainable as an intermediate product at any stage of the process and to carry out the missing steps, or to use a starting material in salt form or in particular to form the same under the reaction conditions.
  • the invention relates to pharmaceutical preparations, which contain the compounds of formula I according to the invention or pharmaceutically employable salts thereof as active ingredients, as well as processes for the production thereof.
  • compositions according to the invention which contain the compound according to the invention or pharmaceutically employable salts thereof, are intended for enteral, such as oral, also rectal, and parenteral administration to warm-blooded animals, whereby the pharmacological active ingredient contained therein is on its own or together with a pharmaceutically employable carrier material.
  • the daily dosage of the active ingredient depends on the age and individual condition as well as on the method of application.
  • the new pharmaceutical preparations contain e.g. from ca. 10% to ca. 80%, preferably from ca. 20% to ca. 60%, of the active ingredient.
  • Pharmaceutical preparations according to the invention for enteral or parenteral administration are e.g. those in single dose form, such as dragees, tablets, capsules or suppositories, furthermore ampoules. These are produced in a manner known perse, e.g. by means of conventional mixing, granulating, dragee-forming, dissolving or lyophilisation processes.
  • pharmaceutical preparations for oral application may be obtained by combining the active ingredient with soiid carrier substances, optionally granulating the mixture obtained, and processing the mixture or granulate into tablets or dragee cores, if desired or if necessary after adding appropriate excipients.
  • Appropriate carriers are in particular fillers such as sugar, e.g. lactose, saccharose, mannitol or sorbitol, cellulose preparations and or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, furthermore binding agents such as starch paste using e.g. com, wheat, rice or potato starch, gelatin, tragacanth, methyl cellulose and/or polyvinyl- pyrrolidone, if desired, disintegrants such as the above-mentioned starches, furthermore carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate.
  • fillers such as sugar, e.g. lactose, saccharose, mannitol or sorbitol, cellulose preparations and or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, furthermore binding agents such as
  • Excipients are primarily mobile phases, mobile phase regulators and lubricants, e.g. silicic acid, talc, stearic acid or salts thereof such as magnesium or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with appropriate coatings that are resistant to gastric juices if required. Those used include inter alia concentrated sugar solutions which optionally contain gum arabic, talc, polyvinyl pyrroiidone, polyethylene glycol and/or titanium dioxide, or lacquer solutions in appropriate organic solvents or solvent mixtures, or to produce coatings that are resistant to gastric juices, solutions of appropriate cellulose preparations such as acetyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate. Dyes or pigments may be added to the tablets or dragee coatings, e.g. to identify or characterise different dosages of active ingredient.
  • compositions are hard two-piece gelatin capsules, as well as soft, closed capsules consisting of gelatin and a softener such as glycerol or sorbitol.
  • the hard capsules may contain the active ingredient in the form of a granulate, e.g. mixed with fillers such as lactose, binding agents such as starches, and/or lubricants such as talc or magnesium stearate, and optionally stabilizers.
  • the active ingredient is preferably dissolved or suspended in appropriate liquids such as fatty oils, paraffin oil or liquid polyethylene glycols, whereby stabilizers may similarly be added.
  • Suppositories may be considered e.g. as rectally applicable pharmaceutical preparations. These consist of a combination of the active ingredient with a suppository base.
  • Suitable suppository bases may be e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • rectal capsules of gelatin may also be used, which contain a combination of the active ingredient with a base substance.
  • the base substances may be e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.
  • aqueous solutions of an active ingredient in water-soluble form are primarily suitable, e.g. a water-soluble salt, also suspensions of the active ingredient, such as appropriate oily suspensions, whereby suitable lipophilic solvents or vehicles are used, such as fatty oils, sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, or aqueous suspensions which contain viscosity-increasing substances, e.g. sodium carboxymethyl cellulose, sorbitol and/or dextran, and optionally also stabilizers.
  • suitable lipophilic solvents or vehicles such as fatty oils, sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides
  • viscosity-increasing substances e.g. sodium carboxymethyl cellulose, sorbitol and/or dextran, and optionally also stabilizers.
  • the dosage of active substance depends on the species of warm-blooded animal, the age and the individual condition, as well as the method of application. Under normal circumstances, for a patient of about 75 kg weight, an approximately daily dose for oral application is from ca. 10 mg to ca. 500 mg.
  • temperatures are indicated in degrees celsius, and pressures in mbar.
  • Xanthene-9-carboxylic acid- mo ⁇ holinyl-amide is obtained as a crystalline product; M.p. 177-178°; 1 H-NMR (CDCI 3 , 300 MHz): 3.16 (d, br, 4H); 3.62 (s, br, 4H); 5.45 (s, 1 H); 7.02-7.31 (m, 8H).
  • a suspension of 0.7 g (2.37 mmols) of 1-(xanthene-9-carbony1)mo ⁇ holine in 50 ml of ether is added in drops at 15-20° to 0.4 g (10.5 mmols) of lithium aluminium hydride in 20 ml of ether, and stirred at room temperature for 1.5 hours.
  • the reaction mixture is mixed with ammonium sulphate solution whilst cooling with ice, taken up in ethyl acetate, and washed with water and saturated sodium chloride solution.
  • the organic phases are dried with sodium sulphate and concentrated on a rotary evaporator.
  • Xanthene-9-carboxylic acid propargylamide is isolated as a crystalline product; M.p. 238-239°; ⁇ -NMR (CDCI 3 , 300 MHz): 2.12 (dd, 1 H); 3.92 (dd, 2H); 4.92 (s, 1 H); 5.44 (s.br, 1 H); 7.10-7.45 (m, 8H).
  • Example 6 N-methyl-xanthene-9-carboxylic acid-propargylamide A solution of 1.2 g (5.3 mmols) of xanthene-9-carboxylic acid, 1.25 g (6.5 mmols) of N-(3- dimethylaminopropyl)-N'-ethyl-carbodiimide-hydrochloride, 0.798 g (6.5 mmols) of 4- dimethylaminopyridine, 0.55 ml (6.5 mmols) of N-methylpropargyiamine and 50 ml of dichloromethane is stirred for 20 hours at room temperature under argon, subsequently taken up in ethyl acetate, and the organic phases are washed with saturated NaHC0 3 solution, water and saturated sodium chloride solution, dried with sodium sulphate and concentrated on a rotary evaporator.
  • N-methyl-xanthene-9-carboxylic acid-propargylamide in 50 ml of ether are added in drops at 0°C to a suspension of 0.4 g (10.53 mmols) of lithium aluminium hydride in 20 ml of ether, and stirred for 1 hour.
  • the reaction is slowly hydrolysed with diluted ammonium suphate solution, the suspension taken up in ethyl acetate, the organic phases are washed with saturated sodium chloride solution, dried with sodium sulphate, and concentrated on a rotary evaporator.
  • N-methyl-N-(9-xanthylmethyl)-propargylamine is obtained by chromatography on silica gel and crystallisation from methanol;
  • N-methyl- xanthene-9-carboxylic acid-cyanomethylamide is isolated as a crystalline product; M.p. 166-167°; 'H-NMR (CDCI 3l 300 MHz): 2.81 (s, 3H); 4.30 (s, 2H); 5.52 (s, 1 H); 7.05- 7.35 (m, 8H).
  • Example 9 N-methyl-N-(xanthen-9-ylmethyl)-cyanomethylamine
  • a solution of 1.06 g (5 mmols) of 9-hydroxymethyl-xanthene, 2.1 ml (15 mmols) of triethyl- amine and 10 ml of ether is added in drops at -70°C, under argon, to a solution of 2.46 ml (15 mmols) of trifluorosulphonic acid anhydride in 50 ml of ether, and stirred for 15 minutes at this temperature. Subsequently, 3.5 g (50 mmols) of N-methylaminoacetonitrile are added in drops, and the solution heated to room temperature over 1.5 hours.
  • Example 10 1-(xanthen-9-ylmethyQpyrrolidinium hydrogen maleate 1.90 g (16.4 mmols) of maleic acid in 45 ml of methanol are added at room temperature to a solution of 4.34 g (16.4 mmols) of 1-(xanthen-9-ylmethyl)pyrrolidine (example 1) in 20 ml of methylene chloride and 25 ml of methanol. Afterwards, the product is concentrated on a rotary evaporator to a total volume of 30 ml, and left to crystallise over night.
  • Example 13 1 -(xanthene-9-carbony ⁇ -1.2.5.6-tetrahydro-pyridine
  • Example 14 1 -(xanthen-9-ylmethyl)-1.2.5.6-tetrahydro-pyridine-hydrochloride 0.7 g (2.53 mmols) of 1-(xanthene-9-carbonyl)-1 ,2,5,6-tetrahydro-pyridine in 50 ml of ether is slowly added in drops at 0°C to a suspension of 0.4 g (10.53 mmols) of LiAIH 4 in 20 ml of ether, and stirred for 6 hours.
  • Example 16 1 -(xanthen-9-ylmethy ⁇ -2.5-dihvdro-pyrrole and 1 -f xanthen-9-ylmethyD- pyrrole
  • 1 -(xanthen-9-ylcarbonyl)-2,5-dihydro-pyrrole is obtained as a by-product, and is isolated by chromatography on silica gel with ethyl acetate/hexane (9:1) as eluant; M.p. 86-88°; 1 H-NMR (CDCI 3 , 300 Mhz): 4.03 (d, 2H); 4.29 (t, 1 H); 6.08 (dd, 2H); 6.31 (dd, 2H); 6.85-7.32 (m, 8H).
  • Example 17 Tablets, each containing 50 mg of N-(xanthen-9-ylmethyl)-propargylamine, may be produced as follows:
  • composition 10,000 tablets
  • active ingredient 500.0 g lactose 500.0 g potato starch 352.0 g gelatin 8.0 g talc 60.0 g magnesium stearate 10.0 g siicon dioxide (highly disperse) 20.0 g ethanol q.s.
  • the active ingredient is mixed with the lactose and 292 g of potato starch, the mixture moistened with an ethanolic solution of the gelatin and granulated through a sieve. After drying, the remainder of the potato starch, the magnesium stearate, the talc and the silicon dioxide are mixed in, and the mixture is pressed into tablets each of 145.0 mg weight and 50.0 mg active ingredient content. If desired, they may be provided with partial notches for finer adjustment of the dosage.
  • Example 18 A sterile-filtered aqueous gelatin solution with 20% cyclodextrins as dissolving intermediary, each containing 3 mg of N-(xanthen-9-ylmethyl)-propargylamine as active ingredient, is mixed whilst heating, under aseptic conditions, with a sterile gelatin solution containing phenol as a preservative, such that 1.0 ml of solution has the following composition: active ingredient 3 mg gelatin 150.0 mg phenol 4.7 mg dist. water with 20% cyclodextrins as dissolving intermediary 1.0 ml
  • Example 19 To produce a sterile dry substance for injection, each containing 5 mg of N-(9-xanthylmethyl)-propargylamine, 5 mg of one of the compounds of formula I named in the preceding examples as the active ingredient are dissolved in 1 ml of an aqueous solution with 20 mg of mannitol and 20% cyclodextrins as dissolving intermediary. The solution is sterile-filtered and filled into a 2 ml ampoule under aseptic conditions, deep- frozen and lyophilized. Prior to usage, the lyophilzate is dissolved in 1 ml of distilled water or 1 ml of physiological sodium chloride solution. The solution is used intramuscularly or intravenously. This formulation may also be filled into double-chamber injection ampoules.
  • Example 20 For the production of 10,000 lacquer-coated tablets, each containing lOO mg of
  • active ingredient 1000 g com starch 680 g colloidal silicic acid 200 g magnesium stearate 20 g stearic acid 50 g sodium carboxymethyl starch 250 g water q.s.
  • a mixture of one of the compounds of formula I named in the preceding examples as active ingredient, 50 g of com starch and the colloidal silicic acid is worked into a moist mass with starch paste consisting of 250 g of com starch and 2.2 kg of demineralised water. This mass is forced through a sieve of 3 mm mesh size, and dried for 30 minutes at 45° in a fluidised bed drier. The dried granulate is pressed through a sieve of 1 mm mesh size, mixed with a previously-sieved mixture (1 mm sieve) of 330 g of com starch, the magnesium stearate, the stearic acid and the sodium carboxymethyl starch, and then pressed into slightly domed tablets.
  • Example 2 In addition, pharmaceutical preparations containing another compound according to one of examples 1 to 16 or
  • xanthene-9-carboxylic acid amide 1-(xanthene-9-carbonyl)-4-methyl-piperazine; 1-(xanthene-9-methyl)-4-methyl-piperazine;
  • 1-(xanthene-9-carbonyl)pyrrolidine alias xanthene-9-carboxylic acid pyrrolidide;
  • 1-(xanthene-9-carbonyl)piperidine alias xanthene-9-carboxylic acid piperidide;

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Abstract

L'invention concerne des dérivés xanthène de la formule (I) ainsi que des sels de ceux-ci, acceptables sur le plan pharmacologique. Dans cette formule, A représente méthylène, carbonyle ou thiocarbonyle, R représente un groupe amino, soit non substitué, soit mono ou disubstitué par des radicaux monovalents aliphatiques et/ou araliphatiques, ou disubstitué par des radicaux aliphatiques divalents, et R1, R2, R3 et R4 représentent, indépendamment l'un de l'autre, hydrogène, alkyle inférieur, alcoxy inférieur, halogène ou trifluorométhyle. On peut utiliser ces principes actifs anti-neurodégénératifs pour des médicaments. L'invention concerne également des nouveaux composés de la formule (I).
PCT/EP1997/002885 1996-06-05 1997-06-04 Derives xanthene efficaces en tant qu'agents anti-neurodegeneratifs WO1997046549A1 (fr)

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AU31723/97A AU3172397A (en) 1996-06-05 1997-06-04 Anti-neurodegeneratively effective xanthene derivatives

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CH143196 1996-06-05
CH1431/96 1996-06-05
CH1804/96 1996-07-18
CH180496 1996-07-18

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US6780897B1 (en) 1999-10-02 2004-08-24 Basf Coating Ag Solid substance mixture containing bonds that can be activated by actinic radiation and the use thereof
WO2005047401A2 (fr) 2003-11-17 2005-05-26 Basf Coatings Ag Dispersions aqueuses a viscosite intrinseque, leur procede de production, et leur utilisation
EP1897894A1 (fr) 2001-06-01 2008-03-12 BASF Coatings AG Suspensions de laque pulvérulente (pâtes pulvérulentes) et laque pulvérulente, leur procédé de fabrication et leur utilisation
DE102008054283A1 (de) 2008-11-03 2010-06-02 Basf Coatings Japan Ltd., Yokohama Farb- und/oder effektgebende Mehrschichtlackierungen mit pigmentfreien Lackierungen als Füller-Ersatz, ihre Herstellung und Verwendung
US8147923B2 (en) 2001-06-27 2012-04-03 Basf Coatings Gmbh Method for producing coatings from coating materials that can be cured by the action of heat or actinic radiation
DE102014007805A1 (de) 2014-05-27 2015-12-03 WindplusSonne GmbH Solarabsorber, Verfahren zu seiner Herstellung und seine Verwendung
US10556013B2 (en) 2017-06-20 2020-02-11 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US11084807B2 (en) 2016-08-18 2021-08-10 Vidac Pharama Ltd. Piperazine derivatives, pharmaceutical compositions and methods of use thereof
US11530184B2 (en) 2020-06-30 2022-12-20 Imbria Pharmaceuticals, Inc. Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
US11780811B2 (en) 2020-06-30 2023-10-10 Imbria Pharmaceuticals, Inc. Methods of synthesizing 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
US11883396B2 (en) 2021-05-03 2024-01-30 Imbria Pharmaceuticals, Inc. Methods of treating kidney conditions using modified forms of trimetazidine

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6780897B1 (en) 1999-10-02 2004-08-24 Basf Coating Ag Solid substance mixture containing bonds that can be activated by actinic radiation and the use thereof
EP1897894A1 (fr) 2001-06-01 2008-03-12 BASF Coatings AG Suspensions de laque pulvérulente (pâtes pulvérulentes) et laque pulvérulente, leur procédé de fabrication et leur utilisation
US7935746B2 (en) 2001-06-01 2011-05-03 Basf Coatings Ag Powder coating suspension, process for preparing the same and process for preparing powder coating material
US8147923B2 (en) 2001-06-27 2012-04-03 Basf Coatings Gmbh Method for producing coatings from coating materials that can be cured by the action of heat or actinic radiation
WO2005047401A2 (fr) 2003-11-17 2005-05-26 Basf Coatings Ag Dispersions aqueuses a viscosite intrinseque, leur procede de production, et leur utilisation
DE102008054283A1 (de) 2008-11-03 2010-06-02 Basf Coatings Japan Ltd., Yokohama Farb- und/oder effektgebende Mehrschichtlackierungen mit pigmentfreien Lackierungen als Füller-Ersatz, ihre Herstellung und Verwendung
DE102014007805A1 (de) 2014-05-27 2015-12-03 WindplusSonne GmbH Solarabsorber, Verfahren zu seiner Herstellung und seine Verwendung
US11084807B2 (en) 2016-08-18 2021-08-10 Vidac Pharama Ltd. Piperazine derivatives, pharmaceutical compositions and methods of use thereof
US10918728B2 (en) 2017-06-20 2021-02-16 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US10953102B2 (en) 2017-06-20 2021-03-23 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US10556013B2 (en) 2017-06-20 2020-02-11 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US11376330B2 (en) 2017-06-20 2022-07-05 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US11844840B2 (en) 2017-06-20 2023-12-19 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US11530184B2 (en) 2020-06-30 2022-12-20 Imbria Pharmaceuticals, Inc. Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
US11746090B2 (en) 2020-06-30 2023-09-05 Imbria Pharmaceuticals, Inc. Crystal forms of 2-[4-[(2,3,4- trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
US11780811B2 (en) 2020-06-30 2023-10-10 Imbria Pharmaceuticals, Inc. Methods of synthesizing 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
US11883396B2 (en) 2021-05-03 2024-01-30 Imbria Pharmaceuticals, Inc. Methods of treating kidney conditions using modified forms of trimetazidine

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