CA2036586A1 - Oxazolidinones - Google Patents
OxazolidinonesInfo
- Publication number
- CA2036586A1 CA2036586A1 CA002036586A CA2036586A CA2036586A1 CA 2036586 A1 CA2036586 A1 CA 2036586A1 CA 002036586 A CA002036586 A CA 002036586A CA 2036586 A CA2036586 A CA 2036586A CA 2036586 A1 CA2036586 A1 CA 2036586A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- oxazolidin
- ethyl
- piperidino
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Psychiatry (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Abstract Novel oxazolidinones of the formula I
Description
- 2~3~
~ Merck Patent Gesellschaft mit beschr~nkter Haftung 6100 D a r m ~ t a d t Oxazolidinones The invention relates to new oxazolidinoneq of the formula I
~ CnH2n NR
R -N~o in which R is ( 2)~R ~ (C~2) R2 ~R2 OH
/~ /~ ': ' \~ CZ , ' ' 2 N' `NH
CO-R , or ~ C~_ NR
2 ii3 0 or S, Rl and R2 ar~ each phenyl radicals which are unsubstitu-t~d or mono- or di ubstituted by alkyl, alkoxy, alkylthi:o,~alkylsuIfinyl or alkyl~ulfonyl each 15~ ha~ing: 1-4 C ~atoms, alkanoyloxy and/or alkanoyl~mino each having 1-6 C atoms, F, Cl, Br, ON and/or CP3 or are mono- or binuclear h~teroaryl radicals containing 1-4 heteroatoms, m:;~ i8 0~ or }, and 20; ~ n~ is~2: or~3:,~
and~also~3alts~thereof.
; The~o;b~ect of;the inv2ntion was to find novel compounds whioh can ~e~used for preparing medicaments.
It has~been found that the:substances mentioned 2 ~ 3 ~
have valuable pharmacological properties in combination with a high tolerance. ~hus, they have, for example, a preferably calming (for example sedating, tranquillizing, neuroleptic and/or antidepressant) effect on the central -nervouq system. Specifically, the compounds have a calming effect on the behaviour of mice (for methodics compare Irwin, Psychopharmacologia 13 (1968), 222-257), inhibit the apomorphin-induced climbing behaviour in mice (for methodology compare Costall and others, European J.
Pharmacol. 50 (1968), 39-50) or induce contra-lateral rotation behaviour in Hemiparkinson rats (detectable by the method of Ungerstedt and others, Brain Res. 24 (1970), 485-493) without the occurrence of any ~ignifi-cant cataleptic side effects (for methodic~ compare Dolini-Stola, Pharmakopsychiat. 6 (1973), 189-197).
Furthermore, the substances inhibit the binding of tritium-labelled dopamine agonists and dopamine antago-nists to striatal receptors (detectable by the method of Schwarcz and others, J. Neurochemi try 34 (1980), 772-778, and Creese and other8, European J. ~harmacol. 46 (1977), 377-381). In addition, the compound~ inhibit the tongue-~aw reflex in the anaesthetized rat (detectable in analogy with the method~ of Barnett and others, European J. Pharmacol. 21 (1973), 178-182 and of Ilhan and other~, European J. Pharmacol. 33 (1975), 61-64). Furthermore, analgesic and hypotensive action~ are observed; thus, in ; csthetQrized alert, 8pontaneou81y hypertonic rat~ (strainSHR/NIH-M0/lCHB-EMD; for the method compare Weeks and ; Jones, Proc.Soc.Exptl.Biol.Med. 104 (1960), 646-648), the ~ art-rial~ blood pressur- ~ea~ured directly is lowered after the intraga8tric application of the compounds.
Compounds of the formula I and their phy~iologi-cally safe acid additian salts can therefor6 be used as active substances ~for medicament8 and also as inter~
~medlat-s ~for~ preparlng other activ- sub~tance~ of ; medicaments.
The invention relates to oxazolidinones of the formula I and their salt~
The inv-ntion~ further relates to a process for ` `
:, . : . . -.. - ... . , , . ........... , . . , ~ .
.: .... : : - : , . : . .. . .. : . -: . .
2 ~ ~3 preparing oxazolidinones of the formula I and also of salt~ thereof, characterized in that a compound of the formula II
Ox-CnH2n-Xl II
5in which OX i8 the radical R -N~
xl is X or NH2~
X i~ Cl, Br, I, OH or a reactive fuhctionally modified OH group and 10 Rl and n have the meani.ngs given, i~ reacted with a compound of the formula III
in which X2 and X3 are identical or different and, if Xl i~ NH2, are each X, otherwi~ togeth~r they are NH and R - has the me~ning given, and/or that a compound which oth~rwi~e correspond~ to the .
formula I but contalns, in~tead of one or more hydrogen atom~, one or more r~ducible groups and/or on~ or more additional C-C and/sr C-N bonds is treated with a reduc- :~
ing agent :~ ~ and/or that in order to prep~re a compound of the forI~la I Ln which R is ~ (C~2)mR or ~ , a compound of the formula IV C~2) R2 , 2 5: ox-CnH2r,-E~5 . ::
~, in which ~ ,; .
~ .
E ~ 4 ~ ~3~ 3 il R5 is -N ~ (CH2)mR2 or -N ~ -E
one radical E is X, CN or NH2, E (cH2)mR2 ~.
the other radical E is H and Ox, RZ, X and n have the meanings given is treated with an agent which eliminateY HE, or that a compound of the formula V
Rl-NH-CH2-CHOH-CnH2,,"-NR V
in which R, R1 and n have the meaning~ given are reacted with a reactive derivative of c~rbonic acid and/or that, if desired, in a compound of the foxmula I an O-alkyl group is cleaved to give an OH group and/or a compound of the formula I is con~erted by reduction to another compound of the ~ormula I, and/or that a base of the formula I is converted to one of its ~alt~ by treatment lS with an acid.
Compound~ of the fonmula I include the foilowing compounds (in which x repre~ent 2-, 3- or 4-position, y represent~ 2-, 3-, 4-, 5- or 6-po~ition and z repre~ents .
6-, ?- or 8-pos1tion):
~ Merck Patent Gesellschaft mit beschr~nkter Haftung 6100 D a r m ~ t a d t Oxazolidinones The invention relates to new oxazolidinoneq of the formula I
~ CnH2n NR
R -N~o in which R is ( 2)~R ~ (C~2) R2 ~R2 OH
/~ /~ ': ' \~ CZ , ' ' 2 N' `NH
CO-R , or ~ C~_ NR
2 ii3 0 or S, Rl and R2 ar~ each phenyl radicals which are unsubstitu-t~d or mono- or di ubstituted by alkyl, alkoxy, alkylthi:o,~alkylsuIfinyl or alkyl~ulfonyl each 15~ ha~ing: 1-4 C ~atoms, alkanoyloxy and/or alkanoyl~mino each having 1-6 C atoms, F, Cl, Br, ON and/or CP3 or are mono- or binuclear h~teroaryl radicals containing 1-4 heteroatoms, m:;~ i8 0~ or }, and 20; ~ n~ is~2: or~3:,~
and~also~3alts~thereof.
; The~o;b~ect of;the inv2ntion was to find novel compounds whioh can ~e~used for preparing medicaments.
It has~been found that the:substances mentioned 2 ~ 3 ~
have valuable pharmacological properties in combination with a high tolerance. ~hus, they have, for example, a preferably calming (for example sedating, tranquillizing, neuroleptic and/or antidepressant) effect on the central -nervouq system. Specifically, the compounds have a calming effect on the behaviour of mice (for methodics compare Irwin, Psychopharmacologia 13 (1968), 222-257), inhibit the apomorphin-induced climbing behaviour in mice (for methodology compare Costall and others, European J.
Pharmacol. 50 (1968), 39-50) or induce contra-lateral rotation behaviour in Hemiparkinson rats (detectable by the method of Ungerstedt and others, Brain Res. 24 (1970), 485-493) without the occurrence of any ~ignifi-cant cataleptic side effects (for methodic~ compare Dolini-Stola, Pharmakopsychiat. 6 (1973), 189-197).
Furthermore, the substances inhibit the binding of tritium-labelled dopamine agonists and dopamine antago-nists to striatal receptors (detectable by the method of Schwarcz and others, J. Neurochemi try 34 (1980), 772-778, and Creese and other8, European J. ~harmacol. 46 (1977), 377-381). In addition, the compound~ inhibit the tongue-~aw reflex in the anaesthetized rat (detectable in analogy with the method~ of Barnett and others, European J. Pharmacol. 21 (1973), 178-182 and of Ilhan and other~, European J. Pharmacol. 33 (1975), 61-64). Furthermore, analgesic and hypotensive action~ are observed; thus, in ; csthetQrized alert, 8pontaneou81y hypertonic rat~ (strainSHR/NIH-M0/lCHB-EMD; for the method compare Weeks and ; Jones, Proc.Soc.Exptl.Biol.Med. 104 (1960), 646-648), the ~ art-rial~ blood pressur- ~ea~ured directly is lowered after the intraga8tric application of the compounds.
Compounds of the formula I and their phy~iologi-cally safe acid additian salts can therefor6 be used as active substances ~for medicament8 and also as inter~
~medlat-s ~for~ preparlng other activ- sub~tance~ of ; medicaments.
The invention relates to oxazolidinones of the formula I and their salt~
The inv-ntion~ further relates to a process for ` `
:, . : . . -.. - ... . , , . ........... , . . , ~ .
.: .... : : - : , . : . .. . .. : . -: . .
2 ~ ~3 preparing oxazolidinones of the formula I and also of salt~ thereof, characterized in that a compound of the formula II
Ox-CnH2n-Xl II
5in which OX i8 the radical R -N~
xl is X or NH2~
X i~ Cl, Br, I, OH or a reactive fuhctionally modified OH group and 10 Rl and n have the meani.ngs given, i~ reacted with a compound of the formula III
in which X2 and X3 are identical or different and, if Xl i~ NH2, are each X, otherwi~ togeth~r they are NH and R - has the me~ning given, and/or that a compound which oth~rwi~e correspond~ to the .
formula I but contalns, in~tead of one or more hydrogen atom~, one or more r~ducible groups and/or on~ or more additional C-C and/sr C-N bonds is treated with a reduc- :~
ing agent :~ ~ and/or that in order to prep~re a compound of the forI~la I Ln which R is ~ (C~2)mR or ~ , a compound of the formula IV C~2) R2 , 2 5: ox-CnH2r,-E~5 . ::
~, in which ~ ,; .
~ .
E ~ 4 ~ ~3~ 3 il R5 is -N ~ (CH2)mR2 or -N ~ -E
one radical E is X, CN or NH2, E (cH2)mR2 ~.
the other radical E is H and Ox, RZ, X and n have the meanings given is treated with an agent which eliminateY HE, or that a compound of the formula V
Rl-NH-CH2-CHOH-CnH2,,"-NR V
in which R, R1 and n have the meaning~ given are reacted with a reactive derivative of c~rbonic acid and/or that, if desired, in a compound of the foxmula I an O-alkyl group is cleaved to give an OH group and/or a compound of the formula I is con~erted by reduction to another compound of the ~ormula I, and/or that a base of the formula I is converted to one of its ~alt~ by treatment lS with an acid.
Compound~ of the fonmula I include the foilowing compounds (in which x repre~ent 2-, 3- or 4-position, y represent~ 2-, 3-, 4-, 5- or 6-po~ition and z repre~ents .
6-, ?- or 8-pos1tion):
3-R1-5-(x-R2~CN2)m-piperidinoethyl or -propyl)-oxazolidin-2-one~ (Ia), 3-R1-5-(y-R2~CH2)~-l,2,3,6-tetrahydropyridinoethyl or propyl)-o~azolidin-2ones (Ib), 3-R1-5-(x-R2-x-hydroxy-piperidinoethyl or -propyl)-oxazo-lidin-2-ones (Ic), : 3-R1-5-(x-R2-CO-piperidinoethyl or -propyl)-oxazolidin-2- . .
ones:(Id)~
3-R1-5-tx-(2-oxobenzimidazolin-l-yl)-piperidinoethyl or -propyl]-ox~zolidin-2-ones (Ie), 3-R1-S-[x-(2-thioxobenzimidazolin-l-yl)-piperidinoethyl or -propyl]-oxazolidin-2-ones ~If), R2-4-oxo-z-(3-Rl-oxazolid~n-2-on-5-yl-ethylor-propyl)-; l,3,z-triaza~piro[4,5]-decane~ (Ig).
Preference i3 given to compounds of the formula Ic.
Formula Ia with x - 2 (Iaa);
~ . : ' . .
.: . - : : . , Fonnula Ia with x = 3 ( Iab);
Fonnula la with x = 4 ( Iac );
Formula Ib with y = 2 ( I~a );
Formula Ib with y = 3 ( Ibb);
Formula Ib with y ~ 4 ~ Ibc );
Formula Ib with y - S ( Ibd);
Formula Ib with y - 6 (Ibe);
Fonnula IC with x ~ 2 ( Ica );
Formula IC with x - 3 ( Icb);
Formula Ic with x - 4 ~ Icc );
Formula Id wLth x 8 2 (Ida);.
Formula Id with x ~ 3 (Idb);
Formula Id with x - 4 (Idc);
For~ul~ Ie with x ~ 2 (Ie~);
lS For~ula I~ ~ith x - 3 (Ieb); .
Formul~ Ie with x - 4 ( Ie~ );
Formul~ If with x - 2 (Ifa);
Formula If with x - 3 (Ifb);
Pormul~ If with x - 4 (Ifc);
Formul~ Ig with 2 ' 6 (Iga);
Formula Ig with z ~ 7 (~gb);
Formula Ig with z - a ~Ige).
Preference i~ gi~en to compounds of the formula Ice, furth~rmor- thoso of th for~ulae Ia~, Iab, Iac, Ibe, Ica, Icb, ~de, Ioe, If~ and I~e.
In th radie~l~ R1and R2, ~lkyl i~ preferably m~thyl, furthor~or~ o ethyl, n-propyl, i~opropyl, n-butyl, i~obutyl, ~ee.butyl or t~rt.-butyl. Alkoxy i~
preforably ~othoxy, furthermore al~o ethoxy, n-propoxy i~opropoxy, n-~utoxyt i-obutoxy, ~ee.-butoxy or tert.-butoxy.
: Th0 x~dle~ and R2 are pro~erably unsubstitu-~ed or monosub~titut~d phenyl. ~f Rl or R2 are ~ub~titu-ted ph~nyl ~roup~, they ean, how~er, al~o b~ disub~titu-ted, it being possibLo for th~ ~ub~tLtuonts to b~ identi- -cal or difforent. Proferred sub~tituente on the phenyl group~ ~re me~hyl, methoxy, F, Cl or CF3; furthormore, prefer~bl~ su~stitu~nt~ are ethyl, ethoxy, Br and/or OH.
In dotail, Rl and ~3 are pr-ferably ph~nyl, o-, m- or ' ' ~" ' ' ' ' ' ' ' . : ': -' ' ` '" ''~' ' "` '. '' .',, ' , '",. "'' ~' .'` ' - 6 - 2~
p-tolyl, o-, m- or p-methoxyphenyl, o-, m- or p-fluoro-phenyl, o-, m- or p-chlorophenyl, o-, m- or p-trifluoro-methylphenyl, furthermore o-, m- or p-ethylphenyl, o-, m-or p-ethoxyphenyl, o-, m- or p-bromophenyl, o-, m- or p-hydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dLmethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dihydroxyphenyl, 2-methyl-4-chlorophenyl.
The radical~ Rl and R2 can also be mono- or binuclear heteroaryl radLcals containing 1-4 heteroatom~, which contain preferably 5 or 6 ring members in each ring. Pre~erably, the heteroatom~ are 0, S and/or N. In detail, heteroaryl radicals are preferably 2- or 3-furyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, furthermore 1-, 2-or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or S-oxazolyl, 3-, 4- or 5-isoxazo-lyl, 2-, 4- or 5-thia~olyl, 3-, 4- or 5-isothiazolyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadia-zol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 2,1,5-thiadiazol-3- or -4-yl, 2-, 3-, 4-, 5- or 6-2H-thLopyranyl, 2-, 3- or 4-4H-thio-pyranyl, 3- or 4-pyridaziny}, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 30 ~ 5-, 6- or 7- benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzo-xazolyl, 3-, 4-, 5-, 6- or 7-benzi~oxazolyl, 2-,4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benziso-thiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, S:-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or `:35 : 8-iRoquinolinyl, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 2-, 4~ 5-, 6-, 7- or 8-quinazolinyl, 2-, 5-or 6-quinoxa-- linyl.
The radical R~ iY very particularly preferably p-metho~yphenyl or p-fluorophenyl, the radical R2 is - 7 - ~ ~ 3 ~
phenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, m-trifluoromethylphenyl or 2-thienyl.
z is preferably o. The parameter m is preferably o, so that the group R2(CH2)m- preferably adopts the meaning R2. If m is 1, the group R2CHz is preferably benzyl, 2-, 3- or in particular 4-methoxyben~yl, 2-, 3-or in particular 4-chlorobenzyl.
The parameter n i~ preferably 2. The group CnH2n i9 preferably -(CH2)n-, i.e. in detail it is preferably -CH2CH2- or -CH2CH2CH2-, but also -CH(CH3~-, -CH(CH3)CH2--CH2CH(CH3)- or -C(CH3)2.
Accordingly, the invention relates in particular to those compounds of the formula I or Ia to Igc in which at least one of th~ radical~ mentioned ha~ one of the abovem~ntio~ed meaning~, in particular of the abovemen-tioned preferred meaning~. Some preferred groups of compounds corxespond to the abovementioned formulae, in .!'.'~.. ' ' which the radicals and parameters which have not been mentioned individually have the meaning given under formulae I and Ia to Igc, but in which (a) Rl i8 phenyl, tolyl, methoxyphenyl, fluoro-phenyl, chlorophenyl, hydroxyph~nyl, trifluoromethylphenyl or dimethoxyphenyl;
25 (b) R1 i~ phenyl, o-, m- or p-tolyl, m- or p-methoxyphenyl, p-fluorophenyl, p-chloro-phenyl, m- or p-hydroxyphenyl, m-tri-fluoromethylphenylor3,4-dimothoxyphenyl;
(c) Rl is p-methoxyphenyl or p-fluorophenyl;
30 (d) R2 is phenyl, tolyl, methoxyphenyl, fluoro-phenyl, chlorophenyl, trifluorom~thyl-phenyl or thienyl e) R2 ia phenyl, o- m- or p-tolyl, p-methoxy-phenyl, p-fluorophenyl, p-chlorophenyl, m-trifluoromethylphenyl or 2-thienyl;
(f) R2 is phenyl, p-methoxyphenyl~ p-chlorophenyl or 2-thienyl;
~g) Rl is phenyl, o-, m- or p-tolyl, m- or p-methoxyph~nyl, p-fluorophenyl, ~
~: ... ..
' ~
2~33~5~
ones:(Id)~
3-R1-5-tx-(2-oxobenzimidazolin-l-yl)-piperidinoethyl or -propyl]-ox~zolidin-2-ones (Ie), 3-R1-S-[x-(2-thioxobenzimidazolin-l-yl)-piperidinoethyl or -propyl]-oxazolidin-2-ones ~If), R2-4-oxo-z-(3-Rl-oxazolid~n-2-on-5-yl-ethylor-propyl)-; l,3,z-triaza~piro[4,5]-decane~ (Ig).
Preference i3 given to compounds of the formula Ic.
Formula Ia with x - 2 (Iaa);
~ . : ' . .
.: . - : : . , Fonnula Ia with x = 3 ( Iab);
Fonnula la with x = 4 ( Iac );
Formula Ib with y = 2 ( I~a );
Formula Ib with y = 3 ( Ibb);
Formula Ib with y ~ 4 ~ Ibc );
Formula Ib with y - S ( Ibd);
Formula Ib with y - 6 (Ibe);
Fonnula IC with x ~ 2 ( Ica );
Formula IC with x - 3 ( Icb);
Formula Ic with x - 4 ~ Icc );
Formula Id wLth x 8 2 (Ida);.
Formula Id with x ~ 3 (Idb);
Formula Id with x - 4 (Idc);
For~ul~ Ie with x ~ 2 (Ie~);
lS For~ula I~ ~ith x - 3 (Ieb); .
Formul~ Ie with x - 4 ( Ie~ );
Formul~ If with x - 2 (Ifa);
Formula If with x - 3 (Ifb);
Pormul~ If with x - 4 (Ifc);
Formul~ Ig with 2 ' 6 (Iga);
Formula Ig with z ~ 7 (~gb);
Formula Ig with z - a ~Ige).
Preference i~ gi~en to compounds of the formula Ice, furth~rmor- thoso of th for~ulae Ia~, Iab, Iac, Ibe, Ica, Icb, ~de, Ioe, If~ and I~e.
In th radie~l~ R1and R2, ~lkyl i~ preferably m~thyl, furthor~or~ o ethyl, n-propyl, i~opropyl, n-butyl, i~obutyl, ~ee.butyl or t~rt.-butyl. Alkoxy i~
preforably ~othoxy, furthermore al~o ethoxy, n-propoxy i~opropoxy, n-~utoxyt i-obutoxy, ~ee.-butoxy or tert.-butoxy.
: Th0 x~dle~ and R2 are pro~erably unsubstitu-~ed or monosub~titut~d phenyl. ~f Rl or R2 are ~ub~titu-ted ph~nyl ~roup~, they ean, how~er, al~o b~ disub~titu-ted, it being possibLo for th~ ~ub~tLtuonts to b~ identi- -cal or difforent. Proferred sub~tituente on the phenyl group~ ~re me~hyl, methoxy, F, Cl or CF3; furthormore, prefer~bl~ su~stitu~nt~ are ethyl, ethoxy, Br and/or OH.
In dotail, Rl and ~3 are pr-ferably ph~nyl, o-, m- or ' ' ~" ' ' ' ' ' ' ' . : ': -' ' ` '" ''~' ' "` '. '' .',, ' , '",. "'' ~' .'` ' - 6 - 2~
p-tolyl, o-, m- or p-methoxyphenyl, o-, m- or p-fluoro-phenyl, o-, m- or p-chlorophenyl, o-, m- or p-trifluoro-methylphenyl, furthermore o-, m- or p-ethylphenyl, o-, m-or p-ethoxyphenyl, o-, m- or p-bromophenyl, o-, m- or p-hydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dLmethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dihydroxyphenyl, 2-methyl-4-chlorophenyl.
The radical~ Rl and R2 can also be mono- or binuclear heteroaryl radLcals containing 1-4 heteroatom~, which contain preferably 5 or 6 ring members in each ring. Pre~erably, the heteroatom~ are 0, S and/or N. In detail, heteroaryl radicals are preferably 2- or 3-furyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, furthermore 1-, 2-or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or S-oxazolyl, 3-, 4- or 5-isoxazo-lyl, 2-, 4- or 5-thia~olyl, 3-, 4- or 5-isothiazolyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadia-zol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 2,1,5-thiadiazol-3- or -4-yl, 2-, 3-, 4-, 5- or 6-2H-thLopyranyl, 2-, 3- or 4-4H-thio-pyranyl, 3- or 4-pyridaziny}, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 30 ~ 5-, 6- or 7- benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzo-xazolyl, 3-, 4-, 5-, 6- or 7-benzi~oxazolyl, 2-,4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benziso-thiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, S:-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or `:35 : 8-iRoquinolinyl, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 2-, 4~ 5-, 6-, 7- or 8-quinazolinyl, 2-, 5-or 6-quinoxa-- linyl.
The radical R~ iY very particularly preferably p-metho~yphenyl or p-fluorophenyl, the radical R2 is - 7 - ~ ~ 3 ~
phenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, m-trifluoromethylphenyl or 2-thienyl.
z is preferably o. The parameter m is preferably o, so that the group R2(CH2)m- preferably adopts the meaning R2. If m is 1, the group R2CHz is preferably benzyl, 2-, 3- or in particular 4-methoxyben~yl, 2-, 3-or in particular 4-chlorobenzyl.
The parameter n i~ preferably 2. The group CnH2n i9 preferably -(CH2)n-, i.e. in detail it is preferably -CH2CH2- or -CH2CH2CH2-, but also -CH(CH3~-, -CH(CH3)CH2--CH2CH(CH3)- or -C(CH3)2.
Accordingly, the invention relates in particular to those compounds of the formula I or Ia to Igc in which at least one of th~ radical~ mentioned ha~ one of the abovem~ntio~ed meaning~, in particular of the abovemen-tioned preferred meaning~. Some preferred groups of compounds corxespond to the abovementioned formulae, in .!'.'~.. ' ' which the radicals and parameters which have not been mentioned individually have the meaning given under formulae I and Ia to Igc, but in which (a) Rl i8 phenyl, tolyl, methoxyphenyl, fluoro-phenyl, chlorophenyl, hydroxyph~nyl, trifluoromethylphenyl or dimethoxyphenyl;
25 (b) R1 i~ phenyl, o-, m- or p-tolyl, m- or p-methoxyphenyl, p-fluorophenyl, p-chloro-phenyl, m- or p-hydroxyphenyl, m-tri-fluoromethylphenylor3,4-dimothoxyphenyl;
(c) Rl is p-methoxyphenyl or p-fluorophenyl;
30 (d) R2 is phenyl, tolyl, methoxyphenyl, fluoro-phenyl, chlorophenyl, trifluorom~thyl-phenyl or thienyl e) R2 ia phenyl, o- m- or p-tolyl, p-methoxy-phenyl, p-fluorophenyl, p-chlorophenyl, m-trifluoromethylphenyl or 2-thienyl;
(f) R2 is phenyl, p-methoxyphenyl~ p-chlorophenyl or 2-thienyl;
~g) Rl is phenyl, o-, m- or p-tolyl, m- or p-methoxyph~nyl, p-fluorophenyl, ~
~: ... ..
' ~
2~33~5~
p-chlorophenyl, m- or p-hydroxyphenyl, m-trifluoromethylphenyl or 3,4-dime~hoxy-phenyl and R2 iS phen~l, o-, m- or p-tolyl, p-methoxy-phenyl, p-fluorophenyl, p-chlorophenyl, m-trifluoromsthylphenyl or 2-thienyl;
(h) Rl i~ p-m~thoxyphanyl and R2 is phenyl, p-methoxyphenyl, p~chlorophenyl or 2-thi~nyl.
In detail, all compounds of th~ abovementioned formulae in which RL and/or R2 h~ve the abovem~ntioned preferred m~aning~ ar~ pre~erred, tho group -C~H~-furthermore being -CH2C~2- and/or, if appropriat0, the parameter m being 0.
A8 for the preparation of the compound~ of th~
formula I, it i~ carried ou~ by m~thod~ kncwn p~s 9~, ~uch aJ ar~ d~cribed in the lit-ratur~ (for exampl~ in ths ~tandard work~ ~uch a8 ~oub n-N~yl, N0thoden dar Organi~ch n Ch~mi~ thod~ Of Organlc Chqmi~try), Gaorg- :
20ThiQm -VerlagO Stuttgart; Organic RQ~ct~on-, John Niley ~ Son~, Inc., N0w York), undQr~ro~ction conditions such as are known ~nd ~u~tabl- for tho re~CtionJ ~ nt~oned.
~: ~or th ~- r-~ction~ v~iatlonD known p~r 8- whlch ~r~
not m-ntlon d h r~ in d tail can alJo b~ u~Qd. -: 25~h~ Jtarting mat~ri~l~ for tho proc~J clalmQd can, if de~ired, al~o b~ for~d in ~itu, such that they ~: ar- not iJol~t-d from the~rQa~tion M~xtura but imme~ia-toly r~act~d ~urth~to g~vo th compound~ of the formul~
30 ~Xl in th colmpound~ of the form~la II i~ prefer-ably X; accordingly, X2 and X3 in th~ compound o~' the .-.
formula III are tog~th~r praferably NH. Th~ r~dical X is profarably Cl: or Br; :but: it can al90 ~e ~, OX or a re~ctiv~ ~ tion~lly~odi~ied~OH group , in p~rt~cular :3S~ lXyl~ulfonyloxy~hl~n~ 1-6 C atomqfor exa~plo mothane-ulfonyloxy) or~ryl~ulfonyloxy h~ving 6-10 C atoms ~f'or ox~pl-~b-nzen~ul~onyloxy, p-tolu~n ~ulfonyloxy, 1- or 2-naphthalone-~ulfonyloxy)~
cord~n~gly,:th- co~pound~ of th ~or~ula I can 2 ~
_ 9 _ be obtained in particular by reaction of compounds of the formulae Ox-CnH2~-Cl, Ox-CnH2n-Br or ox-cnH2n-oso2cH3 with compounds of the formula III, in which x2 and X3 together represent an NH group (designated below as IIIa).
Some of the compounds of the formulae II and III
are known; the unknown compounds of the formulae II and III can easily be prepared analogously to the known compounds. Primary alcohols of the formula Ox-CnH&-OH can be obtained, for example, by reductlon of the correspond-ing carboxylic acids or ~heir ester~. Treatment with thionyl chloride, hydrogen bromide, phosphoru tribromide or similar halogen compounds gives the corresponding halides of the formula Ox-CnH2n-Hal. The corresponding sulfonyloxy compounds are obtainable from the alcohols Ox-CnH2n-OH by reaction with the corresponding sulfonyl chlorides. The iodine compounds of the formula Ox-CnH2n-I
are obtainable, for example, by the action of potassium iodide on the corresponding p-toluene3ulfonic e~ters. The amines of the formula Ox-CnH2n-NH2 can be prepared, for example, from the halides with pota~ium phthalimide or by reduction of the corresponding nitrile~. -The compounds of the formula IIIa are in part known (compare German Offenlegungsschrift 2,060,816) and can be obtained, for example, by reaction of 2-, 3- or 4-piperidone with organometallic compounds of the formula M-(CH2)mR2 (in which M i~ an Li atom or MgHal), ~ubsequent hydrolysis to give the corre~ponding 2-[R2(CH2)m]-2-hydroxy-,3-[R2(CH2)m3-3-hydroxy-or4-tR2(CH2)m]-4-hydroxy-piperidines and, if desired, subsequent dehydràtion to 3~0 ~ glv-~ 2-, 3- or ~ 4-:~R2(CH2)m~-2,3- or -3,4-dehydro-piperidines and hydrogenation to give 2-, 3- or 4-[R2(CH2)m]-piperidines Compounds of the formula III (X2 .
and X3 are each X) can be prepared, for example, by reduetion of appropriate diesters to gi~e diols of the ~ formula~HO-R-OH ~(III, X2~ = X3 = OH) and, if desired, sub~equent~reaction with SOC12 or PBr3.
The reaction of compounds II and III is carried out by methods such as~are known from the literature for the alkylation of amines. The components can be fused .~
f~3~
with one another in the absence of a qolvent, if necessary in a sealed tube or in an autoclave. However, it is also possible to react the compounds in the pre-sence of an inert solvent. Examples of suitable solvents are hydrocarbons such as benzene, toluene, xylene;
ketones such as acetone, butanone; alcohols ~uch as methanol, ethanol, isopropanol, n-butanol; ethers such as tetrahydrofuran (THF) or dioxane; amide~ such as dLme-thylformamide ~DMF) or N-methylpyrrolidone; nitriles such as acetonitrile; where appropriate even mixtureq of these solvents with one anothex or mixtures with water. It can be advantageous to add an acid-binding agent, for example an alkali metal hydroxide or alkaline earth metal hy-droxide, an alkali metal carbonate or bicarbonate, or alkaline earth metal carbonate or bicarbonate or another salt of a weak acid of the alkali metals or alkaline earth metals, preferably of potassium, sodium or calcium, or to add an organic base such as triethylamine, dime-thylaniline, pyridine or quinoline or an excess of the amine component Ox-CnH~-NH2 or of the compound of the formula IIIa. Depending on the conditions used, the reaction temperature is between approx. 0 and 150, usually between 20 and 130.
Furthermore, it is pos~ible to obtain a compound of the~formula I by treating a precursor which instead of hydrogen atoms contains one or more reducible group(s) and/or one or more additional C-C and/or C-N bond(s) with a reducing agent, preferably at temperatures between -80 and +250-~in the~pres-nce of at least one inert solvent.
30 ~ Reducible groups~(replaceable by hydrogen) are, in~ particular, oxygen in a carbonyl group, hydroxyl, arylsulfonyloxy (for example p-toluenesulfonyloxy), N-benzenesulfonyl, N-benzyl or 0-benzyl.
In~general,~t i~possible to convert compounds - 35~ ; which;have onIy~Qne or those which have two or more of thesè groups or additional bonds~next to each other to a compound of the~formula I by reduction. Preferably, this done~by cataLytic hydrogenation, by naqcent hydrogen or by certain complex metal hydride~ such a~ NaBH~.
2 ~ ~ 6 ~ 3 ~ ~ ~
One group of preferred starting material for the ~-reduction corresponds to the formula VI
Ox-cnH2n-N ~ Ane VI
( CH2 )mR2 in which S Ox, RZ, m and n have the meanings mentioned and Ane i8 an anion of a strong acid, preferably Cle or Bre. Compounds of the formula VI can be prepared, for example, by reaction of a compound of the formula II with a 2-, 3- or 4-[R2(CH2)m]-pyridine under the conditions given above for the reaction of II and III.
Suitable catalyst~ for the catalytic hydrogena-tion axe for example noble metal, nickel and cobalt ' catalysts. The noble metal catalysts can be present on '~
support material~ (for example platinum or palladium on charcoal, palladium on calcium carbonate or strontium carbonate)~ a~ oxide catalysts (for example platinum ~ -oxide)l or as finely divided metal catalysts. Nickel and cobalt cataIyst~ are preferably u~ed aa Raney metals, '' ;'~
nickel is also used on kieselguhr or pumice as support 20material. The hydrogenation can be carried out at room ~
~- ~ temperature~and atmospheric pressure or even at elevated ~;
temperature and/or elevated pressure. Preferably, the reaction i carried out~at pressures between l~and 100 ;atmospheres~ and at temperature- between -80 and ~150, 2~5~primarily~between~room~te ~ rature and +100. The reac-tion~is;preferably c~rried~out in an acidic, neutral or '~
b~sic~ range~a in~th ~ s`~e~ of ~a solvent uch as water,~methanol,~ ethanol,~isopropanol, n-butanol, ethyl acetàt~ dioxans~r~acetic~acid or THF; mixtures of these 30~;solvents with one~another can also be used.
If~nasc-nt~ hydrogen L-~ used;~ as the reducing ' ~ nt,~ it can~be;~generated,~'for~example, by treating ls~with~we ~acids~or~with~bases. Thus, for example a~mixture~of zinc with~alXali~meeal hydroxide solution or ;35~of iron~with~ acetic~ acid~'can be used. rhe use of ~odium r~an-othér~alksli~metal ~Ln~an alcohol such as ~ethanol, ' ' iBopropBnol~ butanol, amyl~or isoamyl alcohol or phenol j ' ~$~J
is also suitable. Furthermore, an aluminium-nickel alloy in an alkaline-aqueous solution, with or without ethanol, can be used. Even amalgamated sodium or aluminium in an aqueous-alcoholic or aqueous solution are suitable for generating nascent hydrogen. The reaction can al~o be carried out in a heterogeneous phase, in which case an aqueouq and a benzene or toluene phase is preferably used .
Reducing agents which can al o be used are complex metal hydrides such a~ NasH4, diisobutylaluminium hydride or NaAl(OCH2CH20CH3)2H2 and also diborane, if desired, with ~he addition of catalysts such as BF3, AlC13 or LiBr. Suitable solvents are, in particular, ethers such as diethyl ether, di n-butyl ether, THF, dioxane, diglyme or 1,2-dimethoxyethane and also hydrocarbons such as benzene. Suitable ~olvents for a reduction with NaBH4 are primarily alcohols such as methanol or ethanol, furthermore water and also aqueous alcohols. Using these method~, the reduction i~ preferably carried out at temperatures between -80 and +150, in particular between about 0 and about 100.
Catalytic hydrogenation of compounds of the formula VI usually gives the corresponding piperidine derivative~. If, in contrast, the compounds of the formula VI are reduced with NaBH4, the main products are the corresponding 1,2,3,6-tetrahydropyridine derivatives.
Furth~rmore, compounds of the formula I in which NR is a 3- or 4-tR2(CH2)m]-l,2,3,6-tetrahydropyridyl group are obtained by eliminating HE from compounds of the formula IV, which leads to the for~ation of a double bond. According to the definition of E, the compounds eliminated can be, for example, hydrogen halide, water (dehydration), a carboxylic acid or a different acid, ammonia or HCN. The 3tartlng materials of the formula IV
are obtainable, for example, by reaction of II ~Xl = X) with a compound of the formula HR5, in which R5 has the meaning given.
If one of the radical~ E is Hal, this substituent can easily be eliminated under basic reaction conditions.
:
. .
.: .. ... , .... .. . . . ... . ~. ,. ~ ,- . . . . .
13 2 Q 3 ~
.
Bases which can be used are: alkali metal hydroxides, alkali -metal carbonates, alcoholates such as, for ex-ample, potas~ium tert.-butylate, amines, such as, for example, dimethylaniline, pyridine, collidine or quino-line; the solvents which are used are, for example, benzene, toluene, cyclohexane, THF or tert.-butanol. The amines which are used as bases can also be used in excess as a solvent. If one of the r~dicals E i~ an OH group, acids such as acetic acid, hydrochloric acid or mixtures lQ of the two are preferably used as the water-elLminating agent. ~he addition of a solvent (for example water or ethanoL) can be advantageous. The elimination of acyl-, alkylsulfonyl and alkoxysulfonyloxy or amino radicals can be carried out under the same conditions. Elimination of sulfo radicals, for example of mesylatec or tosylates, can be carried out under mild conditions by boiling in DMF or dimethyl su~foxide with alkali metal carbonates, for example Li2C03, or with potassium acetate. Ammonia can be eliminated simply by heating the ~altc of the cor-responding amino compounds ~in particular of the 4-amino derivatives).
In a similar manner, HCN can be eliminated from compound~ of the formula IV ~a group B = CN) by heating.
Elimination of HE from IV occurs in general at tempera-tures between 0 and about 250, preferably between 50 and ~00 . , ' .
Compounds of the formula I are al~o obtainable by reaction of amino alcohols of the formula V with reactive derivative~ of carbonic acid. Suitable examples of those are~pr-ferably dialkyl carbonate~ such a~ dimethyl or diethyl carbonate, esters of chloroformic acid ~uch as methyl or ethyl chloroformate,~N,N~-carbonyldiimidazole or phosgene. The reactLon is preferably achieved in the ~, presence of an inert ~olvent, preferably of a halogenated 35~ ~hydrocarbon ~uch as~chloroform, of a hydrocarbon ~uch as toluene or of an amide such as DMF at temperatures between about 20 and~200, preferably between 100 and 150. The carbonic acid derivative is preferably used in excess.
- 14 - 2~e3~e~
Furthermore, a compound of the formula I can, if desired, be converted by methods known per ~e to another compound of the formula I.
Thus ethers (0-alkyl derivatives) can be cleaved, giving the corresponding hydroxy derivatives. For ex-ample, the ethers can be cleaved by treatment with the dimethyl sulfide-boron tribromide comple~, for example in toluene, 1,2-dichloroethane, THF or dLmethyl sulfoxide, by fusion with pyridinium or anilinium hydrohalides, preferably pyridinium hydrochloride, at about 150-250, with HBr/acetic acid or with Al trihalides in chlorinated hydrocarbons such a~ 1,2-dichloroethane.
The compounds of the formula I can have one or more asymmetric centre~. Accordingly, they can be ob-tained during their preparation in the form of racematesor, if optically active ~tarting materials are used, also in optically active forms. If the compounds have two or more asymmetric centres, they are in general formed during the synthe~is as mixture~ of racemates, from which the individual racemates, for example by recrystal-lisation from inert solvents ~ can be isolatad in pure form. The racemates obtained can, if desired, be separated mechanically or chemically into their optical antipodes by methods known per se. Preferably, dia~tereomers are formed from the racemates by reaction with an optically active resolving agent. Example~ of suitabla re~olvlng agents are optically active acids, such ~ the D and L ~0rm8 of tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, camphorsulfonic acids, mandelic acid, malic acid or lactic acid. The different forms of diastereomer~ can be separated in a manner known per ~e, for example by fractional cry~tal- -lisation, and the optically active compound~ of the formula I can be liberated from the diastereomers in a manner known per se.
Aft~r a ba~e of the formula I has been obtained, it can be converted with an acid to the corresponding acid addition salt. Acids suitable for this reac~ion are preferably tho~e which give physiologically 3afe salts.
. . .
: : - : . ~ . . .. . : .
:. - - . , . . . . . . . . .
c3 ~ r~
~ e,l Thus, inorganic acids can be used, for example ~ulfuric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such a~ orthophospho-ric acids, nitric acid, sulfamic acid, furthermore organic acid~, aromatic or heterocyclic mono- or poly-basic carbo~ylic, sulfonic or ~ulfuric acids such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, citric acid, gluconic acid, ascorbic acid, nicoti-nic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethane~ulfonic acid, benzenesulfonic a~id, p-toluene~ulfonic acid, naphthalene-mono- and -disulfonic acids, and laurylsul-furic acid. Acid addition salts which are not physiologi-cally ~afe (for example picrate3) can be suitable for theisolation and purification of ba~es of the formula I.
The free bases of the formula I can, if desired, be liberated from th2ir salt~ by treatment with strong bases such a~ sodium hydroxide or potas~ium hydroxide and sodium carbonate or potassium carbonate.
The invention further relates to ths use of compounds of the formula I and their physiologically ~afe salts for preparing pharmaceutical preparations, in paxticular by non-chemical methods. For this purpo~e, they can be brought into a ~uitable dosage form together with at lea~t one carrier or auxiliary and, if desired, in combination with one or more further acti~e substance(s).
The invention further relates to agents, in particular pharmsceutical preparations, containing at lea~t one compound of the formula I and/or one of its phy~iologically s~fe ~alts. These preparations can be used as medicament~ in human and veterinary medicine.
Example~ of carrlsr materials are organic or inorganic substances which are suitable for the enteral (for example oral), parenteral or topical application and do not react with the novel compounds~ for e~ample water, vegetable oils, benzyl alcohol3, polyethylen~ glycols, gelatin, carbohydrates such a~ lactose or starch, ,.
2"~
magnesium ~tearate, tal~, and paraffin jelly. Suitable dosage forms for enteral application are, in particular, tablets, coated pills, capsules, syrup , juices, drops or suppositorie~, for parenteral application 801ution8, preferably oily or aqueous ~olutions, furthermore suspen-sions, emulsions or implants, and for topical application ointment~, creams or powders. The novel compounds can also be freeze-dried, and the freeze-dried compounds obtained can be used~ for example, for preparing injec-tion preparations.
The prepa-ations mentioned can be sterilized and/or contain au~iliaries such as lubricants, preserva-tives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorant~, flavours and/or aromas. If desl-red, they can also contain one or more further active substance~, for example one or more vitamins.
The compounds of the formula I and their physio-logically safe salts can be used for the therapautic treatment of the human or anLmal body and for fighting diseases, in particular ~chizophrenia and psychoreactive disturbances and psychopathie~, depres~ions, severe chronic pains and di~ea~es which are accompanied by high blood pressure. The compounds can further be used for the treatment of extrapyramidal di~turbances.
The 3ub~tance~ according to the invention are usu~lly given by analogy with known, commercially avail-able product~ (thioridAzine, haloperidol), preferably in dosage amounts ~etween about O.2 and 500 mg, in par-ticular between 0.2 and 5~ mg per dosage unit. The dailydosage i~ prefsrably between about 0.003 and 10 mg/kg of body weight.
The ~p~cific dose amount for each individual patient depends, however, on a wide variety of factors, for example on the activity of thQ specific compound used, on age, body weight, general state of health, sex, on tha food, on thc date and route of application, on the rate of excretion, ~edicament combination and seriousne-~of disease ln question for which the therapy is intended.
~ : .
Preference is given to oral application.
In the following examples, ~conventional workup~
means: if necesqary, water is added, the product i8 extracted with dichloromethane, and ~eparated off, the organic phase is dried over sodium sulfate, filtered, evaporated, and the residue is purified by chromatography over silica gel and/or by crystallization. Temperatures are given in C.
Example 1 4.10 g of 5-(2-methanesulfonyloxyethyl)-3-p-methoxyphenyl-oxazolidin-2-one [m.p. 61-64; obtainable by reaction of 3,4-epoxy-1-butanol with N-benzyl-p-methoxyaniline to give 1-(N-benzyl-p-methoxy-anilino)-butane-2,4-diol (resin), hydrogenolysis to give l-p-methoxyanilinobutane-2,4-diol (resin), reaction with diethyl carbonate to give 5-(2-hydroxyethyl)-3-p-methoxy-phenyl-oxazolidin-2-one (m.p. 77-78) and reaction with CH3S02Cl] is boiled together with 3.03 g of 4-p-chloro-phenyl-4-hydroxypiperidine, 2.16 g of potas~ium iodide and 1.8 g of pota~sium carbonate in 100 ml of acetoni-trile for 16 hours, the mixture i8 cooled and worked up in a conventional manner to give 3-p-methoxyphenyl-5-[2-(4-p-chlorophenyl-4-hydroxy-piperidino)-ethyl]-oxazoli-din-2-one, m.p. 95-97.
The following example~ are obtained analogously fromthecorrespondingS-(2-hydroxyethyl)-3-R1-oxazolidin-2-ones:
5-(2-hydro~yethyl)-3-p-fluorophenyl-oxazolidin-2-one ` 5-(2-hydroxyethyl)-3-p-chlorcphenyl-oxazolidin-2-one 5-(2-hydroxyethyl)-3-m-trifluoromethylphenyl-oxazolidin-2-one 5-(2-hydroxyethyl)-3-(3,4-dimethoxyphenyl)-oxazolidin-2-one via the corresponding 5-(2-m~thanesulfonyloxyethyl)-, 5-(2-chloroethyl)- or 5-(2-bromoethyl)-3-R1-oxazolidin-2-ones of the formula II, for example:
~5-(2-chloroethyl)-3-p-methoxyphenyl-oxazolidin-2-one 5-(2-methanesulfonyloxyethyl)-3-p-fluorophenyl-oxazoli-~' .. ..... . ..... . .
. . .: ,- . . .- , . ~ . .
18 - ~ G Y f ~ s din-2-one 5-(2-methanesulfonyloxyethyl)-3-p-chlorophenyl-o~azoli-din-2-one 5-(2-methanesulfonyloxyethyl-3-m-trifluoromethylphenyl-oxazolidin-2-one 5-(2-methanesulfonyloxyethyl)-3-(3,4-dimethoxyphenyl)-oxazolidin-2-one with the corresponding piperidine derivatives of the formula III (in which X2 and X3 together are NH):
3-phenyl-5-[2-(4-phenyl-piperidino)-ethyl]-oxazolidin-2-.
one 3-phenyl-5-[2-(2-benzyl-piperidino)-ethyl]-oxazolidin-2 one 3-m-tolyl-5-[2-(2-benzyl-piperidino)-ethyl]-oxazolidin-2-one 3-o-methoxyphenyl-5-[2 (2-benzyl-piperidino)-ethyl]-ox~zolidin-2-one -3-m-methoxyphenyl-5- r 2-(2-benzyl-piperidino)-ethyl]-oxazolidin-2-one 3-p-methoxyphenyl-5-t2-(2-benzyl-piperidino)-ethyl]
oxazolidin-2-one 3-p-fluorophQnyl-5-~2-(2-benzyl-piperidino)-ethyl]-oxazolidin-2-one 3-p-chl~orophenyl-5-[2-(2-benzyl-piperidino)-ethyl]
oxs~olidin-2-on~
3-m-trifluoromethylphenyl-s-[2-(2-benzyl-piperidino) ethyl]-oxaæolidin-2-one 3-(3,4-dimethoxyphenyl)-5-[2-(2-~enzyl-piperidino)- .
ethyl]-oxazolidin-2-one 3-phenyl-5-~2-(3-benzyl-piperidino)-ethyl]-oxazolidin-2-one 3-m-tolyl-5-[~-(3-benzyl-piperidino~-ethyl]-oxazolidin-2-one 3-o-methoxyphenyl-5-[2-(3-benzyl-piperidino)-ethyl]-;~ : 35 oxazolidin-2-one 3-m-methoxyphenyl-5-[2-t3-benzyl-piperidino)-ethyl]-.~ ~
~ 19~ 2~3~
oxazolidin-2-one -3-p-methoxyphenyl-5-[2-(3-benzyl-piperidino)-ethyl]
oxazolidin-2-one 3-p-fluorophenyl-5-[2-(3-benzyl-piperidino)-ethyl]-oxazolidin-2-one 3-p-chlorophenyl-5-[2-(3-benzyl-piperidino)-ethyl]-oxazolidin-2-one .
3-m-trifluoromethylphenyl-5-[2-(3-benzyl-piperidino)-ethyl]-oxazolidin-2-one 3-(3,4-dimethoxyphenyl)-5-12-(3-benzyl-piperidino)- .
ethyl]-oxazolidin-2-one 3-phenyl-5-[2-(4-benzyl-piperidino)-ethyl]-oxazolidin-2-one 3-m-tolyl-s-[2-(4-benzyl-piperidino)-ethyl]-oxazolidin 2-one 3-o-methoxyphenyl-5-[2-(4 benzyl-piperidino)-ethyl]- : .
: oxazolidin-2-one : 3-m methoxyphenyl-5-[2-(4-benzyl-piperidino)-ethyl]-oxazolidin-2-one 3-p-methoxyphenyl-5-[2-~4-benzyl-piperidino)-ethyl]- .. .
~ oxazolidin-2-one ~
:~ 3-p-fluoropheny}-5-t2-(4-benzyl-piperidino)-ethyl]- :
oxazolidin-2-one ~ 3~-p-chloroph-nyl-5-[2-~4-benzyl-piperidino)-ethyl] : : :: 25 oxazolidin-2-one 3-m-trifluoromethylphenyl-5-~2-~4-benzyl-piperidino) ethyl]-oxazol~Ldln-2-one 3-~(3~,~4-dimethox~yphenyl)-5-~2-(4-benzyl-piperidino)-ethy}]-oxazolidin-2-one 30 ~ 3-ph-nyl-5-[2-~4-hydroxy-4-phenyl-piperidino)-ethyl]-oxazolidin-2-one~
3-m-tolyl-5~-~2-:(4-hydroxy-4-phenyl-piperidino)-ethyl]-oxazolidin-2-one ~
3-o-methoxyphenyl-5-~2-~4-h~ydroxy-4-phenyl-piperidino)-35~ ; ethyl]-oxazolidin-2-one 2~3~ f~
3-m-methoxyphenyl-5-[2-(4-hydroxy-4-phenyl-piperidino~
ethyl]-oxazolidin 2-one 3-p-methoxyphenyl-5-~2-t4-hydroxy-4-phenyl-piperidino)-ethyl]-oxazolidin-2-one, m.p. 145-147 3-p-fluorophenyl~5-[2-(4-hydroxy-4-phenyl-piperidino)-ethyl]-oxazolidin-2-one 3-p-chlorophenyl-5-[2-(4-hydroxy-4-phenyl-piperidino)-ethyl]-oxazolidin-2-one 3-m-trifluoromethylphenyl-5-[2-t4-hydroxy-4-phenyl-piperidino)-ethyl]-oxazolidin-2-one 3-(3,4-dLmethoxyphenyl)-5-[2-(4-hydroxy-4-phenyl-piperi-dino)-ethyl]-oxazolidin-2-one 3-phenyl-5-[2-(4-hydroxy-4-p-methoxyphenyl-piperidino)- .
ethyl]-oxazolidin-2-one 3-m-tolyl-S-[2-(4-hydroxy-4-p-methoxyphenyl-piperidino)-ethyl]-oxazolidin-2-one 3-o-methoxyphenyl-s-[2-(4-hydroxy-4-p-methoxyphen piperidino)-ethyl]-oxazolidin-2-one 3-m-methoxyphenyl-5-[2-~4-hydroxy-4-p-methoxyphenyl-pLperidino)-ethyl]-oxazolidin-2-one 3-p-methoxyphenyl-5-~2-(4-hydroxy-4-p-methoxyphenyl-piperidino)-ethyl]-oxazolidin-2-one 3-p-fluorophenyl-5-[2-(4-hydroxy-4-p-methoxyphenyl-piperidino)-ethyl]-oxazolid~n-2-one : 25 3-p-chlorophenyl-5-~2-(4-hydroxy-4-p-methoxyphenyl-piperidino)-ethyl]-oxazolidin-2-one :
: 3-~-trifluoromethylphenyl-5-t2-(4-hydroxy-4-p-methoxy-:: phenyl-piperidino)-ethyl]-oxazolidin-2-one 3-(3,4-dimethoxyphenyl)-5-[2-(4-hydroxy-4-p-methoxy-: 30 : phenyl-piperidino)-ethyl]-oxazolidin-2-one 3-phe~nyl-s-t2-:(~4-hydroxy-4-p-fluorophenyl-piperidino)- ~;-,.
: ethyl]-oxazolidin-2-one 3-m-tolyl-5-:[2-(~4-hydroxy-4-p-fluorophenyl-piperidino)-ethyl]-oxazolidin-2-o~e ~ :
35~: ~3-o-m-thoxyphenyI-5-[2:-(4-hydroxy-4-p-fluorophenyl-piperidino)-ethyl]:-oxazolidin-2_one .:
3-m-methoxyphenyl-5-[2-(4-hydroxy-4-p-fluorophenyl-piperidino)-ethyl]-oxazolidin-2-one 3-p-methoxyphenyl-5-[2-(4-hydroxy-4-p-fluorophenyl- , piperidino)-ethyl]-oxazolidin-2-one 3-p-fluorophenyl-5-[2-t4-hydroxy-4-p-fluorophenyl-piper-idino)-ethyl]-oxazolidin-2-one 3-p-chlorophenyl-5-[2-(4-hydroxy-4-p-fluorophenyl-piperi-dino)-ethyl]-oxazolidin-2-one :
3-m-trifluoromethylphenyl-5-[2-(4-hydroxy-4-p-fluoro-phenyl-piperidino)-ethyl]-oxazolidin-2-one 3-(3,4-dimethoxyphenyl)-5-[2-(4-hydroxy-4-p-fluorophenyl-piperidino)-ethyl]-oxazolidin-2-one -3-phenyl-5-t2-(4-hydroxy-4-p-chlorophenyl-piperidino)-ethyl]-oxazolidin-2-one 3-m-tolyl-5-[2-(4-hydroxy-4-p-chlorophenyl-piperidino)- .
ethyl]-oxazolidin-2-one 3-o-methoxyphenyl-5-[2-(4-hydroxy-4-p-chlorophenyl-piperidino-)-ethyl]-oxazolidin-2-one 3-m-methoxyphenyl-5-~2-(4-hydroxy-4-p-chlorophenyl-piperidino)-ethyl]-oxazolidin-2-one 3-p-fluorophenyl-5-[2-(4-hydroxy-4-p-chlorophenyl-piper-idino)-ethyl]-oxazolidin-2-one 3-p-chlorophenyl-5-[2-(4-hydroxy-4-p-chlorophenyl-piper-idino)-ethyl]-oxazolidin-2-one 3-m-trifluoromethylphenyl-5-[2-(4-hydroxy-4-p-chloro-henyl-piperidino)-ethyl]-oxazolidin-2-one 3-(3,4-d:imethoxyphenyl)-5-[2-(4-hydroxy-4-p-chlorophenyl- :
pLperldino)-ethyl]-oxazolidin-2-one : 3-phenyl-5-[2-(4-hydroxy-4-m-trifluoromethylphenyl-; 30 ~ ~piperidino)-ethyl]~-oxazolidin-2-one 3-m-tolyl-5-~2-(4-hydroxy-4-m-trifluoromethylphen piperidino)-ethyl]-oxazolidin-2-one 3-o-methoxyphenyl-5-[2-(4-hydroxy-4-m-trifluoromethyl-;phenyl-piperidino)-ethyl]-oxazolidin-2-one 3-m methoxyphenyl-5-[2-(4-hydroxy-4-m-trifluoromethyl-ph~nyl-piperidino)-ethyl]-oxazolidin-2-one - 2 ~
3-p-methoxyphen~l-5-[2-(4-hydroxy-4-m-trifluorometh phenyl-piperidino)-ethyl]-oxazolidin-2-one 3-p-fluorophenyl-5-[2-(4-hydroxy-4-m-trifluoromethyl-phenyl-piperidino)-ethyl]-oxazolidin-2-one 3-p-chlorophenyl-5-[2-(4-hydroxy-4-m-trifluorometh phenyl-piperidino)-ethyl]-oxazolidin-2-one 3-m-trifluoromethylphenyl-5-[2-(4-hydroxy-4~m-trifluoro-methylphenyl-piperidino)-ethyl]-oxazolidin-2-one 3-(3,4-dimethoxyphenyl)-5-~2-(4-hydroxy-4-m-trifluoro-methylphenyl-piperidino)-ethyl]-oxazolidin-2-one 3-phenyl-5-[2-(4-benzyl-4-hydroxy-piperidino)-ethyl]-oxazolidin-2-one 3-phenyl-5-12-(4-hydroxy-4-(2-thienyl)-piperidino-ethyl]~
oxazolidin-2-one, m.p. 132-134-3-phenyl-s-[2-(4-benzoyl-piperidino)-ethyl]-oxazolidin 2-one 3-m-tolyl-5-[2-(4-benzoyl-piperidino)-ethyl]-oxazolidin-2-one 3-o-methoxyphenyl-5-~2-(4-benzoyl-piperidino)-ethyl]-oxazolidin-2-one 3-m-methoxyphenyl-s-~2-(4-benzoyl-piperidino)-ethyl]
; oxazolidin-2-one 3-p-methoxyphenyl-S-~2-(4-benzoyl-piperidino)-ethyl]-;oxazolidin-2-one 25 ~ 3-p-fluorophenyl-5-~2-~4-benzoyl-piperidino)-ethyl]- ~ -oxazolidin-2~-one 3~-p-chlorophenyl-5-~2-(4-benzoyl-piperidino)-ethyl]
oxazolidin-2-one 3-m-trifluoromethylphenyl-5-r2-(4-benzoyI-piperidino) ~ ethylJ-oxazolidin-2-oné
3-~3~4-dimethoxyphenyl)-s-~2-(4-benzoyl-piperidino) ethyl]-oxazolidin-2-one 3-phenyl-5`-c2-(4-(2-oxobenzimid zol-l-yl)-piperidino)-e ~ l]-oxazolidin-2-one ; ~ -35~ 3-~-tolyl-5-t2-(4-(~2-oxobenzimidazolin-1-yl)-piperidino)-: ethyl]-oxazolidin-2-orle o-~ thoxyphenyl-s- [ 2 - ( 4 - ~ 2 -oxobenz imidazolin- l-yl ) pLperidino)-ethyl]-oxazolidln-2-one ;~
:.
3-m-m~thoxyphenyl-5-[2-(4-(2-oxobenzimidazolin-l-yl)-pipQridino)-e~hyl]-oxazolidin-2-one -3-p-methoxyphenyl-5-[2-(4-(2-oxobenzimidazolin-1-yl)-piperidino)-ethyl]-oxazolidin-2-one m.p. 184-186 3-p-fluorophenyl-5-[2-(4-(2-oxobenzimidazolin-1-yl)-piperidino)-~thyl]-oxazolidin-2-one 3-p-chlorophenyl-5-[2-(4-(2-oxobenzimidazolin-1-yl)-piperidino)-ethyl]-oxazolidin-2-one 3-m-trifluoromethylphenyl-s-[2^(4-(2-oxobenzimidazelin 1-yl)-piperidino)-ethyl]-oxazolidin-2-one 3-(3,4-dimethoxyphenyl)-5-[2-(4-(2-oxobenzLmidazolin-l-yl)-piperidino)-ethyl]-oxazolidin-2-one 4-phenyl-5-~2-(4-(2-thioxobenzimidazolin-1-yl)-piperi-dino)-ethyl]-oxazolidin-2-one 3-m-tolyl-5-[2-(4-(2-thioxobenzimid~zolin-1-yl)-piperi-dino)-ethyl]-ox~zolidin-2-one 3-o-methoxyphenyl-5-~2-(4-(2-thioxob~nzimidazolin-1-yl)-piperidino)-ethyl~-oxazolidin-2-one 3-m-methoxyphenyl-s-t2-(4-(2-thioxobenzimid~zolin-l-yl) piperidino)-ethyl]-oxasolidin-2-on 3-p-meth~xyphenyl-5-t2-(4-(2-thioxobensimidazolin-1-yl)-piperidino)-othyll-ox~zolidin-2-one ,,~
3-p-fluoroph-nyl-5-t2-(4-(2-thioxobenzimida201in-l-yl)-,piperidino)-ethyll-oxazolidin-2-one 3-p-chloroph-nyl-5-[2-(4-(2-thioxobenzimid~zolin-1-yl)-iper~dino)-ethyll-ox~zolidin-2-on-3-m-trifluorom thylph~nyl-S-t2-(4-(2-thioxobenzimidazo-n-l-yl)-piperidino)-ethyl]-oxazolidin-2-on~
3-(3,4-dlmethoxyphenyl)-5-t2-(4-(2-thioxobonzimidazolin-30 ~ 1-yl)-piperidino)-ethyl]-oxazolidin-2-one phenyl~-4-oxo-8-t2-(3-phenyl-oxazolidin-2-on-5-yl)-athyl]-1,3,8-tr~aza~pirot4,5]decane henyl-4-oxo-8-t2-(3-m-tolyl-oxazolidin-2-on-s-yl) ethyl]~-1,3,8-triaza~pirot4,5]decano l-phenyl-4-oxo-8-~2-(3-o-methoxyphenyl-oxazolidin-2-on 5-yl)--thyl]-1,3,8-tri~za~pirot4,5]decane henyl-4-oxo-8-t2-(3-m-m thoxyph nyl-ox~zoIidin-2-on-~ ~ -2 ~ '.3 5-yl)-et~yl]-1,3,8-triazaspiro~4,5]decane l-phenyl-4-oxo-8-[2-(3-p-methoxyphenyl-oxazolidin-2-on-s-yl)-ethyl]-l~3~8-triazaspiro~4~5]decane 1-ph~nyl-4-oxo-8 t2-(3-p-fluorophenyl-oxazolidin-2-on-5-yl~-Qthyl]-1,3,8-triazaspirot4,5]decane.
l-phenyl-4-oxo-8-[2-(3-p-chlorophenyl-oxazolidin-2-on-5 yl)-ethyl]-1,3,8-triazaspiro[4,5]decane l-ph~nyl-4-oxo-8-~2-(3-m-trifluorom~thylph~nyl-oxazoli din-2-on-5-yl)-sthy~ 3l8-triazaspirot~5~decane 1-ph~nyl-4-oxo-a-~2-(3-~3,4_dimethoxyphenyl)-oxazolidin-2-on-5-yl)-ethyl]-l~3~-triazaspiro~4t5]decane.
Example 2 Analogou~ly to ~xa~ple 1, th~ following ar~
obtained u~ing 5-(3-methane~ulfonyloxypropyl)-3-p-meth-oxyphenyl-oxazolidin-2-one t~.p. 75-76-; obtain~ble from 4-ponton-1-ol via4-po~t~n-1-olbenzoat~, 4,5-~po~yp~ntan-l-olbonzo~t~, S-p-methoxy~nilino-pentane-1,4-diol 1-b-nzo~ta, 5-(3-~enzoyloxypropyl)-3-Q-~thoxyphen oxa201idi~-2-ono ~nd 5-(3-hydroxypropyl)-3-p-~ethoxy-ph-nyl-oxazolidin 2-on (~.p. 78-79-)]5 ~.
3-p-~othoxyphonyl-5-t3-l4-p-chloroph~nyl-4-hydroxy-piperidino)-propyl~-ox~201idin-2-one~ m.p. 1~2-145-3-p-~ethoxyph nyl-S-t3-(~-phenyl-4-hydroxy-p~peridino)-propyl]-o~zolidln-2-on ;:
3-p-~ethoxypho~yl-5-t3-(4-p-~Rt~oxyphenyl-4-hydr pip~ridino)-propyl]-ox~zolidin-2-ono 3-p-~othoxyph-nyl-S-t3-t4-p-fluorophenyl-4-hydroxy-pipN~idino)-propyl]-oxazolidi~-2-onQ : ~:
3-p-mQtho~yph~nyl-S-t3-~4-m-trifluoro~ethylph~nyl-4-hydroxy-plporidino)-propyll-oxazolidin-2-one 3-p-~ethoxyphonyl-5-[3-(4-(2-th~enyl)-4-hydro~y-piper idino) -propyl~-oxazolidin-2-one, ~.p. 148-150-.
: Exa~pl- 3 Analogou~ly to Exa~ple 1, (S)-3-p-mathoxyphanyl-5-12-~4-p-chloroph~nyI-4-hydroxy-piperidino)-~thyll~ .
sxazolidin-2-on~ i~ obtained from (S)-S-(2-mathano-sulfonyloxy~thyl)-3-p-~ thoxypharlyl-oxa2c~1idin-2-on~
~: , .
.: ~. , ... . ,.~., , . . . ..... , . , . , . . . --: . .
2 ~
~obtainable from (S)-3,4-epoxy-1-butanol].
Example 4 A mixture of 2.06 g of 5-(2-amino~thyl~-3-phenyl-oxazolidin-2-one [obtainable by reaction of 5-(2-chloro-ethyl)-3-phenyl-oxazolidin-2-one with potas~ium phthali-~id~, followed by hydrolysi~l ~nd 2.15 g of 1,5-d$chloro-3-phenyl-2-pentene in 40 ml of aceton~ and 40 ml of water i~ boiled for 24 hour~ and worked up a~ u~ual. 3-phenyl-5-t2-~4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)-ethyl]-oxazolidin-2-one is obtained.
E~ple 51 g of Na~H, in 20 ~1 of water is added, with ~tirring, to a ~olution of 4.55 g of 1-t2-~3-p-methoxy-phanyl-oxazolidin-2-on-5-yl)-ethyl]-4-phenyl-pyridinium bromide (obta$nab1e from 3-p-methoxyphQnyl-5-~2-bromo-ethyl)-oxazolidin-2-one and 4-phenylpyridine) in 50 ~1 of 1 N NaOH, and th~mixtur ~ th n ~tirred at 60- for 3 hour~.. A convontional workup give- 3-p-m thoxyphenyl-5-t2-(4-ph~nyl-1,2,3,6-tetra-hydro-1-pyrityl)-ethyl]-oxa2elidin-2-en .
Exampl~ 6 1 g of 3-p-methoxyphenyl-5-t2-(4-hy~ro~y-4-ph nyl-plp ~idino)-othyl~-o~ol~din-2-on i- heatedwith 10 ml of 1 N hydrochloric ~cid to 100- for 2 hour~; the m~xtur i~ work d up in a con~ ntion~l.m~nner to ~ive ~-p-m-thoxyph-nyl-5- E 2-(4-phonyl-1,2,3,6-t-tr~hydro-1-pyridyl)-ethyl]-oxazolidin-2-one.
~x~ple 7 A mi~tura o 3.7 g of 4-hyd~o~y-1-~3-hydroxy-4-p- ~tho~ranilino-butyl)-4-ph nyl-pip ridine (obtain~ble 30 :~ ~by ~eactlon o~ p-lm~thoxyanilin~ with ethyl 3,4-epoxybuty ~ -rata~to~give ethyl 3-hydroxy-4-p-metho~yanilino-butyrat~, ..
;reduct~on~ with LiAlH~ to: givo 4-p-methoxyanilino-1,3-;propan~dioi, d*h ~ ation to the epoxid~ and re~ction wit~
4-hyd~oxy~4-ph~nyl-p~posldino)~ 1.5 g of diethyl car-:3S~ :bon~t-~ ~nd: 50~1 of DXr i~:h~at~d at 120- for 4 hour~. -Evaporation a~d c:onv~nt~on~l worXup giv~ 3-p-methoxy-henyl-s-t~-(4-hydroxy-4-ph-nyl-pip-rldino)-~th oxazolidin-2-on~.
~ ~ :
`', . ' ' , :
'.. : `: .`: : , .... ' .. : ,, ' `: , . , .
2$~
Example 8 A mixture o~ 10 g of 3-p-methoxyphenyl-5-[2-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)-ethyl~-oxazolidin-2-one and 10 g of pyridinium hydrochloride i~ stirred at s 160 for 3 hours. Conventional workup give~ 3-p-hydroxy-phenyl-5-~2-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl) -ethyl]-oxazolidin-2-one, Example 9 A ~uspen~ion of 3.8 ~ of 3-p-methoxyphenyl-5-[2- ~ - -(4-benzyl-piperidino)-ethyl~-oxazolidin-2-one in 50 ml of 1, 2-diChloroQth~ne i8 ~dded dropwise to a boiling ~olu-tion of 15.6 g of dimethyl sulfide/boron tribromide complex in S0 ml of 1,2-dichloroethane; the mixture is boiled for another 30 minutes and worked up in a conven-tional manner to give 3-p-hydroxyphenyl-5-~2-(4-ben p~peridLno)-ethyl~-oxazolidin-2-one.
The following example~ denl with pharmaceutlcal prepar_tion~ which contain amine~ of the formula I or their acid Addition aAltJ t Ex~mple As Tabl-t~
A mixture of 1 kg of 3-p-methoxyphenyl-5-t2-(4- !~
hydroxy-4-p-chlorophenyl-piperidino)-ethyl~-oxazolidin-2-one, 4 kg of lactoJe, 1.2 kg of potato ~tarch, 0.2 kg of talc and 0.1 kg of magnesiu~ ~tear~te i~ compres~ed into ta~let- in a con~entional manner and in ~uch a way that ach tabIet contaln- 10 mg of active sub~tance.
Ex~ple ~s ~ Coatod tablet~
An~logou~ly ~o ~xample ~, tablets are pre~ed and -~
th n~ coated ~ ~A a ~ conventional ~nn~r with a coating ~ con~l~tlng of ucro~e,~potato starch, talc, tragacanth and colorant.
t~ ~ Exampl- Cs~ ; Cap~ul~-2~kg of 3-p-methoxyphenyl-5-t2-(4-hydroxy-4-henyl-piperidino)-~thyll-oxazolidin-2-ono are poured in 35~ a conventlonal m~nner~into h-rd yel-tin cap~ule~ ~o that each cap~ule contain~ 20 mg of active sub~t~nce.
Example Ds~ ~ AmpouleJ
A ~olut~on of 1 kg of 3-p-mothoxyphonyl-5-t2-(4-benzyl-pip-ridino)-ethyl~-ox~zolid~n-2-on h~drochloride . ~ ..
-- 2 ~
in 60 1 of twice-distilled water is filtered under sterile conditions, filled into ampoules, freeze-dried under sterile conditions and sealed under sterile condi-tions. Each ampoule contains 10 mg of active ubstance.
Analogously tablets, coated tablets, capsules and ampoules are obtainable which contain one or more of the remaining active substances of the formula I and/or their -~
physiologically safe acid addition salts.
~ .
~ -: ~
~ ; ~
(h) Rl i~ p-m~thoxyphanyl and R2 is phenyl, p-methoxyphenyl, p~chlorophenyl or 2-thi~nyl.
In detail, all compounds of th~ abovementioned formulae in which RL and/or R2 h~ve the abovem~ntioned preferred m~aning~ ar~ pre~erred, tho group -C~H~-furthermore being -CH2C~2- and/or, if appropriat0, the parameter m being 0.
A8 for the preparation of the compound~ of th~
formula I, it i~ carried ou~ by m~thod~ kncwn p~s 9~, ~uch aJ ar~ d~cribed in the lit-ratur~ (for exampl~ in ths ~tandard work~ ~uch a8 ~oub n-N~yl, N0thoden dar Organi~ch n Ch~mi~ thod~ Of Organlc Chqmi~try), Gaorg- :
20ThiQm -VerlagO Stuttgart; Organic RQ~ct~on-, John Niley ~ Son~, Inc., N0w York), undQr~ro~ction conditions such as are known ~nd ~u~tabl- for tho re~CtionJ ~ nt~oned.
~: ~or th ~- r-~ction~ v~iatlonD known p~r 8- whlch ~r~
not m-ntlon d h r~ in d tail can alJo b~ u~Qd. -: 25~h~ Jtarting mat~ri~l~ for tho proc~J clalmQd can, if de~ired, al~o b~ for~d in ~itu, such that they ~: ar- not iJol~t-d from the~rQa~tion M~xtura but imme~ia-toly r~act~d ~urth~to g~vo th compound~ of the formul~
30 ~Xl in th colmpound~ of the form~la II i~ prefer-ably X; accordingly, X2 and X3 in th~ compound o~' the .-.
formula III are tog~th~r praferably NH. Th~ r~dical X is profarably Cl: or Br; :but: it can al90 ~e ~, OX or a re~ctiv~ ~ tion~lly~odi~ied~OH group , in p~rt~cular :3S~ lXyl~ulfonyloxy~hl~n~ 1-6 C atomqfor exa~plo mothane-ulfonyloxy) or~ryl~ulfonyloxy h~ving 6-10 C atoms ~f'or ox~pl-~b-nzen~ul~onyloxy, p-tolu~n ~ulfonyloxy, 1- or 2-naphthalone-~ulfonyloxy)~
cord~n~gly,:th- co~pound~ of th ~or~ula I can 2 ~
_ 9 _ be obtained in particular by reaction of compounds of the formulae Ox-CnH2~-Cl, Ox-CnH2n-Br or ox-cnH2n-oso2cH3 with compounds of the formula III, in which x2 and X3 together represent an NH group (designated below as IIIa).
Some of the compounds of the formulae II and III
are known; the unknown compounds of the formulae II and III can easily be prepared analogously to the known compounds. Primary alcohols of the formula Ox-CnH&-OH can be obtained, for example, by reductlon of the correspond-ing carboxylic acids or ~heir ester~. Treatment with thionyl chloride, hydrogen bromide, phosphoru tribromide or similar halogen compounds gives the corresponding halides of the formula Ox-CnH2n-Hal. The corresponding sulfonyloxy compounds are obtainable from the alcohols Ox-CnH2n-OH by reaction with the corresponding sulfonyl chlorides. The iodine compounds of the formula Ox-CnH2n-I
are obtainable, for example, by the action of potassium iodide on the corresponding p-toluene3ulfonic e~ters. The amines of the formula Ox-CnH2n-NH2 can be prepared, for example, from the halides with pota~ium phthalimide or by reduction of the corresponding nitrile~. -The compounds of the formula IIIa are in part known (compare German Offenlegungsschrift 2,060,816) and can be obtained, for example, by reaction of 2-, 3- or 4-piperidone with organometallic compounds of the formula M-(CH2)mR2 (in which M i~ an Li atom or MgHal), ~ubsequent hydrolysis to give the corre~ponding 2-[R2(CH2)m]-2-hydroxy-,3-[R2(CH2)m3-3-hydroxy-or4-tR2(CH2)m]-4-hydroxy-piperidines and, if desired, subsequent dehydràtion to 3~0 ~ glv-~ 2-, 3- or ~ 4-:~R2(CH2)m~-2,3- or -3,4-dehydro-piperidines and hydrogenation to give 2-, 3- or 4-[R2(CH2)m]-piperidines Compounds of the formula III (X2 .
and X3 are each X) can be prepared, for example, by reduetion of appropriate diesters to gi~e diols of the ~ formula~HO-R-OH ~(III, X2~ = X3 = OH) and, if desired, sub~equent~reaction with SOC12 or PBr3.
The reaction of compounds II and III is carried out by methods such as~are known from the literature for the alkylation of amines. The components can be fused .~
f~3~
with one another in the absence of a qolvent, if necessary in a sealed tube or in an autoclave. However, it is also possible to react the compounds in the pre-sence of an inert solvent. Examples of suitable solvents are hydrocarbons such as benzene, toluene, xylene;
ketones such as acetone, butanone; alcohols ~uch as methanol, ethanol, isopropanol, n-butanol; ethers such as tetrahydrofuran (THF) or dioxane; amide~ such as dLme-thylformamide ~DMF) or N-methylpyrrolidone; nitriles such as acetonitrile; where appropriate even mixtureq of these solvents with one anothex or mixtures with water. It can be advantageous to add an acid-binding agent, for example an alkali metal hydroxide or alkaline earth metal hy-droxide, an alkali metal carbonate or bicarbonate, or alkaline earth metal carbonate or bicarbonate or another salt of a weak acid of the alkali metals or alkaline earth metals, preferably of potassium, sodium or calcium, or to add an organic base such as triethylamine, dime-thylaniline, pyridine or quinoline or an excess of the amine component Ox-CnH~-NH2 or of the compound of the formula IIIa. Depending on the conditions used, the reaction temperature is between approx. 0 and 150, usually between 20 and 130.
Furthermore, it is pos~ible to obtain a compound of the~formula I by treating a precursor which instead of hydrogen atoms contains one or more reducible group(s) and/or one or more additional C-C and/or C-N bond(s) with a reducing agent, preferably at temperatures between -80 and +250-~in the~pres-nce of at least one inert solvent.
30 ~ Reducible groups~(replaceable by hydrogen) are, in~ particular, oxygen in a carbonyl group, hydroxyl, arylsulfonyloxy (for example p-toluenesulfonyloxy), N-benzenesulfonyl, N-benzyl or 0-benzyl.
In~general,~t i~possible to convert compounds - 35~ ; which;have onIy~Qne or those which have two or more of thesè groups or additional bonds~next to each other to a compound of the~formula I by reduction. Preferably, this done~by cataLytic hydrogenation, by naqcent hydrogen or by certain complex metal hydride~ such a~ NaBH~.
2 ~ ~ 6 ~ 3 ~ ~ ~
One group of preferred starting material for the ~-reduction corresponds to the formula VI
Ox-cnH2n-N ~ Ane VI
( CH2 )mR2 in which S Ox, RZ, m and n have the meanings mentioned and Ane i8 an anion of a strong acid, preferably Cle or Bre. Compounds of the formula VI can be prepared, for example, by reaction of a compound of the formula II with a 2-, 3- or 4-[R2(CH2)m]-pyridine under the conditions given above for the reaction of II and III.
Suitable catalyst~ for the catalytic hydrogena-tion axe for example noble metal, nickel and cobalt ' catalysts. The noble metal catalysts can be present on '~
support material~ (for example platinum or palladium on charcoal, palladium on calcium carbonate or strontium carbonate)~ a~ oxide catalysts (for example platinum ~ -oxide)l or as finely divided metal catalysts. Nickel and cobalt cataIyst~ are preferably u~ed aa Raney metals, '' ;'~
nickel is also used on kieselguhr or pumice as support 20material. The hydrogenation can be carried out at room ~
~- ~ temperature~and atmospheric pressure or even at elevated ~;
temperature and/or elevated pressure. Preferably, the reaction i carried out~at pressures between l~and 100 ;atmospheres~ and at temperature- between -80 and ~150, 2~5~primarily~between~room~te ~ rature and +100. The reac-tion~is;preferably c~rried~out in an acidic, neutral or '~
b~sic~ range~a in~th ~ s`~e~ of ~a solvent uch as water,~methanol,~ ethanol,~isopropanol, n-butanol, ethyl acetàt~ dioxans~r~acetic~acid or THF; mixtures of these 30~;solvents with one~another can also be used.
If~nasc-nt~ hydrogen L-~ used;~ as the reducing ' ~ nt,~ it can~be;~generated,~'for~example, by treating ls~with~we ~acids~or~with~bases. Thus, for example a~mixture~of zinc with~alXali~meeal hydroxide solution or ;35~of iron~with~ acetic~ acid~'can be used. rhe use of ~odium r~an-othér~alksli~metal ~Ln~an alcohol such as ~ethanol, ' ' iBopropBnol~ butanol, amyl~or isoamyl alcohol or phenol j ' ~$~J
is also suitable. Furthermore, an aluminium-nickel alloy in an alkaline-aqueous solution, with or without ethanol, can be used. Even amalgamated sodium or aluminium in an aqueous-alcoholic or aqueous solution are suitable for generating nascent hydrogen. The reaction can al~o be carried out in a heterogeneous phase, in which case an aqueouq and a benzene or toluene phase is preferably used .
Reducing agents which can al o be used are complex metal hydrides such a~ NasH4, diisobutylaluminium hydride or NaAl(OCH2CH20CH3)2H2 and also diborane, if desired, with ~he addition of catalysts such as BF3, AlC13 or LiBr. Suitable solvents are, in particular, ethers such as diethyl ether, di n-butyl ether, THF, dioxane, diglyme or 1,2-dimethoxyethane and also hydrocarbons such as benzene. Suitable ~olvents for a reduction with NaBH4 are primarily alcohols such as methanol or ethanol, furthermore water and also aqueous alcohols. Using these method~, the reduction i~ preferably carried out at temperatures between -80 and +150, in particular between about 0 and about 100.
Catalytic hydrogenation of compounds of the formula VI usually gives the corresponding piperidine derivative~. If, in contrast, the compounds of the formula VI are reduced with NaBH4, the main products are the corresponding 1,2,3,6-tetrahydropyridine derivatives.
Furth~rmore, compounds of the formula I in which NR is a 3- or 4-tR2(CH2)m]-l,2,3,6-tetrahydropyridyl group are obtained by eliminating HE from compounds of the formula IV, which leads to the for~ation of a double bond. According to the definition of E, the compounds eliminated can be, for example, hydrogen halide, water (dehydration), a carboxylic acid or a different acid, ammonia or HCN. The 3tartlng materials of the formula IV
are obtainable, for example, by reaction of II ~Xl = X) with a compound of the formula HR5, in which R5 has the meaning given.
If one of the radical~ E is Hal, this substituent can easily be eliminated under basic reaction conditions.
:
. .
.: .. ... , .... .. . . . ... . ~. ,. ~ ,- . . . . .
13 2 Q 3 ~
.
Bases which can be used are: alkali metal hydroxides, alkali -metal carbonates, alcoholates such as, for ex-ample, potas~ium tert.-butylate, amines, such as, for example, dimethylaniline, pyridine, collidine or quino-line; the solvents which are used are, for example, benzene, toluene, cyclohexane, THF or tert.-butanol. The amines which are used as bases can also be used in excess as a solvent. If one of the r~dicals E i~ an OH group, acids such as acetic acid, hydrochloric acid or mixtures lQ of the two are preferably used as the water-elLminating agent. ~he addition of a solvent (for example water or ethanoL) can be advantageous. The elimination of acyl-, alkylsulfonyl and alkoxysulfonyloxy or amino radicals can be carried out under the same conditions. Elimination of sulfo radicals, for example of mesylatec or tosylates, can be carried out under mild conditions by boiling in DMF or dimethyl su~foxide with alkali metal carbonates, for example Li2C03, or with potassium acetate. Ammonia can be eliminated simply by heating the ~altc of the cor-responding amino compounds ~in particular of the 4-amino derivatives).
In a similar manner, HCN can be eliminated from compound~ of the formula IV ~a group B = CN) by heating.
Elimination of HE from IV occurs in general at tempera-tures between 0 and about 250, preferably between 50 and ~00 . , ' .
Compounds of the formula I are al~o obtainable by reaction of amino alcohols of the formula V with reactive derivative~ of carbonic acid. Suitable examples of those are~pr-ferably dialkyl carbonate~ such a~ dimethyl or diethyl carbonate, esters of chloroformic acid ~uch as methyl or ethyl chloroformate,~N,N~-carbonyldiimidazole or phosgene. The reactLon is preferably achieved in the ~, presence of an inert ~olvent, preferably of a halogenated 35~ ~hydrocarbon ~uch as~chloroform, of a hydrocarbon ~uch as toluene or of an amide such as DMF at temperatures between about 20 and~200, preferably between 100 and 150. The carbonic acid derivative is preferably used in excess.
- 14 - 2~e3~e~
Furthermore, a compound of the formula I can, if desired, be converted by methods known per ~e to another compound of the formula I.
Thus ethers (0-alkyl derivatives) can be cleaved, giving the corresponding hydroxy derivatives. For ex-ample, the ethers can be cleaved by treatment with the dimethyl sulfide-boron tribromide comple~, for example in toluene, 1,2-dichloroethane, THF or dLmethyl sulfoxide, by fusion with pyridinium or anilinium hydrohalides, preferably pyridinium hydrochloride, at about 150-250, with HBr/acetic acid or with Al trihalides in chlorinated hydrocarbons such a~ 1,2-dichloroethane.
The compounds of the formula I can have one or more asymmetric centre~. Accordingly, they can be ob-tained during their preparation in the form of racematesor, if optically active ~tarting materials are used, also in optically active forms. If the compounds have two or more asymmetric centres, they are in general formed during the synthe~is as mixture~ of racemates, from which the individual racemates, for example by recrystal-lisation from inert solvents ~ can be isolatad in pure form. The racemates obtained can, if desired, be separated mechanically or chemically into their optical antipodes by methods known per se. Preferably, dia~tereomers are formed from the racemates by reaction with an optically active resolving agent. Example~ of suitabla re~olvlng agents are optically active acids, such ~ the D and L ~0rm8 of tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, camphorsulfonic acids, mandelic acid, malic acid or lactic acid. The different forms of diastereomer~ can be separated in a manner known per ~e, for example by fractional cry~tal- -lisation, and the optically active compound~ of the formula I can be liberated from the diastereomers in a manner known per se.
Aft~r a ba~e of the formula I has been obtained, it can be converted with an acid to the corresponding acid addition salt. Acids suitable for this reac~ion are preferably tho~e which give physiologically 3afe salts.
. . .
: : - : . ~ . . .. . : .
:. - - . , . . . . . . . . .
c3 ~ r~
~ e,l Thus, inorganic acids can be used, for example ~ulfuric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such a~ orthophospho-ric acids, nitric acid, sulfamic acid, furthermore organic acid~, aromatic or heterocyclic mono- or poly-basic carbo~ylic, sulfonic or ~ulfuric acids such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, citric acid, gluconic acid, ascorbic acid, nicoti-nic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethane~ulfonic acid, benzenesulfonic a~id, p-toluene~ulfonic acid, naphthalene-mono- and -disulfonic acids, and laurylsul-furic acid. Acid addition salts which are not physiologi-cally ~afe (for example picrate3) can be suitable for theisolation and purification of ba~es of the formula I.
The free bases of the formula I can, if desired, be liberated from th2ir salt~ by treatment with strong bases such a~ sodium hydroxide or potas~ium hydroxide and sodium carbonate or potassium carbonate.
The invention further relates to ths use of compounds of the formula I and their physiologically ~afe salts for preparing pharmaceutical preparations, in paxticular by non-chemical methods. For this purpo~e, they can be brought into a ~uitable dosage form together with at lea~t one carrier or auxiliary and, if desired, in combination with one or more further acti~e substance(s).
The invention further relates to agents, in particular pharmsceutical preparations, containing at lea~t one compound of the formula I and/or one of its phy~iologically s~fe ~alts. These preparations can be used as medicament~ in human and veterinary medicine.
Example~ of carrlsr materials are organic or inorganic substances which are suitable for the enteral (for example oral), parenteral or topical application and do not react with the novel compounds~ for e~ample water, vegetable oils, benzyl alcohol3, polyethylen~ glycols, gelatin, carbohydrates such a~ lactose or starch, ,.
2"~
magnesium ~tearate, tal~, and paraffin jelly. Suitable dosage forms for enteral application are, in particular, tablets, coated pills, capsules, syrup , juices, drops or suppositorie~, for parenteral application 801ution8, preferably oily or aqueous ~olutions, furthermore suspen-sions, emulsions or implants, and for topical application ointment~, creams or powders. The novel compounds can also be freeze-dried, and the freeze-dried compounds obtained can be used~ for example, for preparing injec-tion preparations.
The prepa-ations mentioned can be sterilized and/or contain au~iliaries such as lubricants, preserva-tives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorant~, flavours and/or aromas. If desl-red, they can also contain one or more further active substance~, for example one or more vitamins.
The compounds of the formula I and their physio-logically safe salts can be used for the therapautic treatment of the human or anLmal body and for fighting diseases, in particular ~chizophrenia and psychoreactive disturbances and psychopathie~, depres~ions, severe chronic pains and di~ea~es which are accompanied by high blood pressure. The compounds can further be used for the treatment of extrapyramidal di~turbances.
The 3ub~tance~ according to the invention are usu~lly given by analogy with known, commercially avail-able product~ (thioridAzine, haloperidol), preferably in dosage amounts ~etween about O.2 and 500 mg, in par-ticular between 0.2 and 5~ mg per dosage unit. The dailydosage i~ prefsrably between about 0.003 and 10 mg/kg of body weight.
The ~p~cific dose amount for each individual patient depends, however, on a wide variety of factors, for example on the activity of thQ specific compound used, on age, body weight, general state of health, sex, on tha food, on thc date and route of application, on the rate of excretion, ~edicament combination and seriousne-~of disease ln question for which the therapy is intended.
~ : .
Preference is given to oral application.
In the following examples, ~conventional workup~
means: if necesqary, water is added, the product i8 extracted with dichloromethane, and ~eparated off, the organic phase is dried over sodium sulfate, filtered, evaporated, and the residue is purified by chromatography over silica gel and/or by crystallization. Temperatures are given in C.
Example 1 4.10 g of 5-(2-methanesulfonyloxyethyl)-3-p-methoxyphenyl-oxazolidin-2-one [m.p. 61-64; obtainable by reaction of 3,4-epoxy-1-butanol with N-benzyl-p-methoxyaniline to give 1-(N-benzyl-p-methoxy-anilino)-butane-2,4-diol (resin), hydrogenolysis to give l-p-methoxyanilinobutane-2,4-diol (resin), reaction with diethyl carbonate to give 5-(2-hydroxyethyl)-3-p-methoxy-phenyl-oxazolidin-2-one (m.p. 77-78) and reaction with CH3S02Cl] is boiled together with 3.03 g of 4-p-chloro-phenyl-4-hydroxypiperidine, 2.16 g of potas~ium iodide and 1.8 g of pota~sium carbonate in 100 ml of acetoni-trile for 16 hours, the mixture i8 cooled and worked up in a conventional manner to give 3-p-methoxyphenyl-5-[2-(4-p-chlorophenyl-4-hydroxy-piperidino)-ethyl]-oxazoli-din-2-one, m.p. 95-97.
The following example~ are obtained analogously fromthecorrespondingS-(2-hydroxyethyl)-3-R1-oxazolidin-2-ones:
5-(2-hydro~yethyl)-3-p-fluorophenyl-oxazolidin-2-one ` 5-(2-hydroxyethyl)-3-p-chlorcphenyl-oxazolidin-2-one 5-(2-hydroxyethyl)-3-m-trifluoromethylphenyl-oxazolidin-2-one 5-(2-hydroxyethyl)-3-(3,4-dimethoxyphenyl)-oxazolidin-2-one via the corresponding 5-(2-m~thanesulfonyloxyethyl)-, 5-(2-chloroethyl)- or 5-(2-bromoethyl)-3-R1-oxazolidin-2-ones of the formula II, for example:
~5-(2-chloroethyl)-3-p-methoxyphenyl-oxazolidin-2-one 5-(2-methanesulfonyloxyethyl)-3-p-fluorophenyl-oxazoli-~' .. ..... . ..... . .
. . .: ,- . . .- , . ~ . .
18 - ~ G Y f ~ s din-2-one 5-(2-methanesulfonyloxyethyl)-3-p-chlorophenyl-o~azoli-din-2-one 5-(2-methanesulfonyloxyethyl-3-m-trifluoromethylphenyl-oxazolidin-2-one 5-(2-methanesulfonyloxyethyl)-3-(3,4-dimethoxyphenyl)-oxazolidin-2-one with the corresponding piperidine derivatives of the formula III (in which X2 and X3 together are NH):
3-phenyl-5-[2-(4-phenyl-piperidino)-ethyl]-oxazolidin-2-.
one 3-phenyl-5-[2-(2-benzyl-piperidino)-ethyl]-oxazolidin-2 one 3-m-tolyl-5-[2-(2-benzyl-piperidino)-ethyl]-oxazolidin-2-one 3-o-methoxyphenyl-5-[2 (2-benzyl-piperidino)-ethyl]-ox~zolidin-2-one -3-m-methoxyphenyl-5- r 2-(2-benzyl-piperidino)-ethyl]-oxazolidin-2-one 3-p-methoxyphenyl-5-t2-(2-benzyl-piperidino)-ethyl]
oxazolidin-2-one 3-p-fluorophQnyl-5-~2-(2-benzyl-piperidino)-ethyl]-oxazolidin-2-one 3-p-chl~orophenyl-5-[2-(2-benzyl-piperidino)-ethyl]
oxs~olidin-2-on~
3-m-trifluoromethylphenyl-s-[2-(2-benzyl-piperidino) ethyl]-oxaæolidin-2-one 3-(3,4-dimethoxyphenyl)-5-[2-(2-~enzyl-piperidino)- .
ethyl]-oxazolidin-2-one 3-phenyl-5-~2-(3-benzyl-piperidino)-ethyl]-oxazolidin-2-one 3-m-tolyl-5-[~-(3-benzyl-piperidino~-ethyl]-oxazolidin-2-one 3-o-methoxyphenyl-5-[2-(3-benzyl-piperidino)-ethyl]-;~ : 35 oxazolidin-2-one 3-m-methoxyphenyl-5-[2-t3-benzyl-piperidino)-ethyl]-.~ ~
~ 19~ 2~3~
oxazolidin-2-one -3-p-methoxyphenyl-5-[2-(3-benzyl-piperidino)-ethyl]
oxazolidin-2-one 3-p-fluorophenyl-5-[2-(3-benzyl-piperidino)-ethyl]-oxazolidin-2-one 3-p-chlorophenyl-5-[2-(3-benzyl-piperidino)-ethyl]-oxazolidin-2-one .
3-m-trifluoromethylphenyl-5-[2-(3-benzyl-piperidino)-ethyl]-oxazolidin-2-one 3-(3,4-dimethoxyphenyl)-5-12-(3-benzyl-piperidino)- .
ethyl]-oxazolidin-2-one 3-phenyl-5-[2-(4-benzyl-piperidino)-ethyl]-oxazolidin-2-one 3-m-tolyl-s-[2-(4-benzyl-piperidino)-ethyl]-oxazolidin 2-one 3-o-methoxyphenyl-5-[2-(4 benzyl-piperidino)-ethyl]- : .
: oxazolidin-2-one : 3-m methoxyphenyl-5-[2-(4-benzyl-piperidino)-ethyl]-oxazolidin-2-one 3-p-methoxyphenyl-5-[2-~4-benzyl-piperidino)-ethyl]- .. .
~ oxazolidin-2-one ~
:~ 3-p-fluoropheny}-5-t2-(4-benzyl-piperidino)-ethyl]- :
oxazolidin-2-one ~ 3~-p-chloroph-nyl-5-[2-~4-benzyl-piperidino)-ethyl] : : :: 25 oxazolidin-2-one 3-m-trifluoromethylphenyl-5-~2-~4-benzyl-piperidino) ethyl]-oxazol~Ldln-2-one 3-~(3~,~4-dimethox~yphenyl)-5-~2-(4-benzyl-piperidino)-ethy}]-oxazolidin-2-one 30 ~ 3-ph-nyl-5-[2-~4-hydroxy-4-phenyl-piperidino)-ethyl]-oxazolidin-2-one~
3-m-tolyl-5~-~2-:(4-hydroxy-4-phenyl-piperidino)-ethyl]-oxazolidin-2-one ~
3-o-methoxyphenyl-5-~2-~4-h~ydroxy-4-phenyl-piperidino)-35~ ; ethyl]-oxazolidin-2-one 2~3~ f~
3-m-methoxyphenyl-5-[2-(4-hydroxy-4-phenyl-piperidino~
ethyl]-oxazolidin 2-one 3-p-methoxyphenyl-5-~2-t4-hydroxy-4-phenyl-piperidino)-ethyl]-oxazolidin-2-one, m.p. 145-147 3-p-fluorophenyl~5-[2-(4-hydroxy-4-phenyl-piperidino)-ethyl]-oxazolidin-2-one 3-p-chlorophenyl-5-[2-(4-hydroxy-4-phenyl-piperidino)-ethyl]-oxazolidin-2-one 3-m-trifluoromethylphenyl-5-[2-t4-hydroxy-4-phenyl-piperidino)-ethyl]-oxazolidin-2-one 3-(3,4-dLmethoxyphenyl)-5-[2-(4-hydroxy-4-phenyl-piperi-dino)-ethyl]-oxazolidin-2-one 3-phenyl-5-[2-(4-hydroxy-4-p-methoxyphenyl-piperidino)- .
ethyl]-oxazolidin-2-one 3-m-tolyl-S-[2-(4-hydroxy-4-p-methoxyphenyl-piperidino)-ethyl]-oxazolidin-2-one 3-o-methoxyphenyl-s-[2-(4-hydroxy-4-p-methoxyphen piperidino)-ethyl]-oxazolidin-2-one 3-m-methoxyphenyl-5-[2-~4-hydroxy-4-p-methoxyphenyl-pLperidino)-ethyl]-oxazolidin-2-one 3-p-methoxyphenyl-5-~2-(4-hydroxy-4-p-methoxyphenyl-piperidino)-ethyl]-oxazolidin-2-one 3-p-fluorophenyl-5-[2-(4-hydroxy-4-p-methoxyphenyl-piperidino)-ethyl]-oxazolid~n-2-one : 25 3-p-chlorophenyl-5-~2-(4-hydroxy-4-p-methoxyphenyl-piperidino)-ethyl]-oxazolidin-2-one :
: 3-~-trifluoromethylphenyl-5-t2-(4-hydroxy-4-p-methoxy-:: phenyl-piperidino)-ethyl]-oxazolidin-2-one 3-(3,4-dimethoxyphenyl)-5-[2-(4-hydroxy-4-p-methoxy-: 30 : phenyl-piperidino)-ethyl]-oxazolidin-2-one 3-phe~nyl-s-t2-:(~4-hydroxy-4-p-fluorophenyl-piperidino)- ~;-,.
: ethyl]-oxazolidin-2-one 3-m-tolyl-5-:[2-(~4-hydroxy-4-p-fluorophenyl-piperidino)-ethyl]-oxazolidin-2-o~e ~ :
35~: ~3-o-m-thoxyphenyI-5-[2:-(4-hydroxy-4-p-fluorophenyl-piperidino)-ethyl]:-oxazolidin-2_one .:
3-m-methoxyphenyl-5-[2-(4-hydroxy-4-p-fluorophenyl-piperidino)-ethyl]-oxazolidin-2-one 3-p-methoxyphenyl-5-[2-(4-hydroxy-4-p-fluorophenyl- , piperidino)-ethyl]-oxazolidin-2-one 3-p-fluorophenyl-5-[2-t4-hydroxy-4-p-fluorophenyl-piper-idino)-ethyl]-oxazolidin-2-one 3-p-chlorophenyl-5-[2-(4-hydroxy-4-p-fluorophenyl-piperi-dino)-ethyl]-oxazolidin-2-one :
3-m-trifluoromethylphenyl-5-[2-(4-hydroxy-4-p-fluoro-phenyl-piperidino)-ethyl]-oxazolidin-2-one 3-(3,4-dimethoxyphenyl)-5-[2-(4-hydroxy-4-p-fluorophenyl-piperidino)-ethyl]-oxazolidin-2-one -3-phenyl-5-t2-(4-hydroxy-4-p-chlorophenyl-piperidino)-ethyl]-oxazolidin-2-one 3-m-tolyl-5-[2-(4-hydroxy-4-p-chlorophenyl-piperidino)- .
ethyl]-oxazolidin-2-one 3-o-methoxyphenyl-5-[2-(4-hydroxy-4-p-chlorophenyl-piperidino-)-ethyl]-oxazolidin-2-one 3-m-methoxyphenyl-5-~2-(4-hydroxy-4-p-chlorophenyl-piperidino)-ethyl]-oxazolidin-2-one 3-p-fluorophenyl-5-[2-(4-hydroxy-4-p-chlorophenyl-piper-idino)-ethyl]-oxazolidin-2-one 3-p-chlorophenyl-5-[2-(4-hydroxy-4-p-chlorophenyl-piper-idino)-ethyl]-oxazolidin-2-one 3-m-trifluoromethylphenyl-5-[2-(4-hydroxy-4-p-chloro-henyl-piperidino)-ethyl]-oxazolidin-2-one 3-(3,4-d:imethoxyphenyl)-5-[2-(4-hydroxy-4-p-chlorophenyl- :
pLperldino)-ethyl]-oxazolidin-2-one : 3-phenyl-5-[2-(4-hydroxy-4-m-trifluoromethylphenyl-; 30 ~ ~piperidino)-ethyl]~-oxazolidin-2-one 3-m-tolyl-5-~2-(4-hydroxy-4-m-trifluoromethylphen piperidino)-ethyl]-oxazolidin-2-one 3-o-methoxyphenyl-5-[2-(4-hydroxy-4-m-trifluoromethyl-;phenyl-piperidino)-ethyl]-oxazolidin-2-one 3-m methoxyphenyl-5-[2-(4-hydroxy-4-m-trifluoromethyl-ph~nyl-piperidino)-ethyl]-oxazolidin-2-one - 2 ~
3-p-methoxyphen~l-5-[2-(4-hydroxy-4-m-trifluorometh phenyl-piperidino)-ethyl]-oxazolidin-2-one 3-p-fluorophenyl-5-[2-(4-hydroxy-4-m-trifluoromethyl-phenyl-piperidino)-ethyl]-oxazolidin-2-one 3-p-chlorophenyl-5-[2-(4-hydroxy-4-m-trifluorometh phenyl-piperidino)-ethyl]-oxazolidin-2-one 3-m-trifluoromethylphenyl-5-[2-(4-hydroxy-4~m-trifluoro-methylphenyl-piperidino)-ethyl]-oxazolidin-2-one 3-(3,4-dimethoxyphenyl)-5-~2-(4-hydroxy-4-m-trifluoro-methylphenyl-piperidino)-ethyl]-oxazolidin-2-one 3-phenyl-5-[2-(4-benzyl-4-hydroxy-piperidino)-ethyl]-oxazolidin-2-one 3-phenyl-5-12-(4-hydroxy-4-(2-thienyl)-piperidino-ethyl]~
oxazolidin-2-one, m.p. 132-134-3-phenyl-s-[2-(4-benzoyl-piperidino)-ethyl]-oxazolidin 2-one 3-m-tolyl-5-[2-(4-benzoyl-piperidino)-ethyl]-oxazolidin-2-one 3-o-methoxyphenyl-5-~2-(4-benzoyl-piperidino)-ethyl]-oxazolidin-2-one 3-m-methoxyphenyl-s-~2-(4-benzoyl-piperidino)-ethyl]
; oxazolidin-2-one 3-p-methoxyphenyl-S-~2-(4-benzoyl-piperidino)-ethyl]-;oxazolidin-2-one 25 ~ 3-p-fluorophenyl-5-~2-~4-benzoyl-piperidino)-ethyl]- ~ -oxazolidin-2~-one 3~-p-chlorophenyl-5-~2-(4-benzoyl-piperidino)-ethyl]
oxazolidin-2-one 3-m-trifluoromethylphenyl-5-r2-(4-benzoyI-piperidino) ~ ethylJ-oxazolidin-2-oné
3-~3~4-dimethoxyphenyl)-s-~2-(4-benzoyl-piperidino) ethyl]-oxazolidin-2-one 3-phenyl-5`-c2-(4-(2-oxobenzimid zol-l-yl)-piperidino)-e ~ l]-oxazolidin-2-one ; ~ -35~ 3-~-tolyl-5-t2-(4-(~2-oxobenzimidazolin-1-yl)-piperidino)-: ethyl]-oxazolidin-2-orle o-~ thoxyphenyl-s- [ 2 - ( 4 - ~ 2 -oxobenz imidazolin- l-yl ) pLperidino)-ethyl]-oxazolidln-2-one ;~
:.
3-m-m~thoxyphenyl-5-[2-(4-(2-oxobenzimidazolin-l-yl)-pipQridino)-e~hyl]-oxazolidin-2-one -3-p-methoxyphenyl-5-[2-(4-(2-oxobenzimidazolin-1-yl)-piperidino)-ethyl]-oxazolidin-2-one m.p. 184-186 3-p-fluorophenyl-5-[2-(4-(2-oxobenzimidazolin-1-yl)-piperidino)-~thyl]-oxazolidin-2-one 3-p-chlorophenyl-5-[2-(4-(2-oxobenzimidazolin-1-yl)-piperidino)-ethyl]-oxazolidin-2-one 3-m-trifluoromethylphenyl-s-[2^(4-(2-oxobenzimidazelin 1-yl)-piperidino)-ethyl]-oxazolidin-2-one 3-(3,4-dimethoxyphenyl)-5-[2-(4-(2-oxobenzLmidazolin-l-yl)-piperidino)-ethyl]-oxazolidin-2-one 4-phenyl-5-~2-(4-(2-thioxobenzimidazolin-1-yl)-piperi-dino)-ethyl]-oxazolidin-2-one 3-m-tolyl-5-[2-(4-(2-thioxobenzimid~zolin-1-yl)-piperi-dino)-ethyl]-ox~zolidin-2-one 3-o-methoxyphenyl-5-~2-(4-(2-thioxob~nzimidazolin-1-yl)-piperidino)-ethyl~-oxazolidin-2-one 3-m-methoxyphenyl-s-t2-(4-(2-thioxobenzimid~zolin-l-yl) piperidino)-ethyl]-oxasolidin-2-on 3-p-meth~xyphenyl-5-t2-(4-(2-thioxobensimidazolin-1-yl)-piperidino)-othyll-ox~zolidin-2-one ,,~
3-p-fluoroph-nyl-5-t2-(4-(2-thioxobenzimida201in-l-yl)-,piperidino)-ethyll-oxazolidin-2-one 3-p-chloroph-nyl-5-[2-(4-(2-thioxobenzimid~zolin-1-yl)-iper~dino)-ethyll-ox~zolidin-2-on-3-m-trifluorom thylph~nyl-S-t2-(4-(2-thioxobenzimidazo-n-l-yl)-piperidino)-ethyl]-oxazolidin-2-on~
3-(3,4-dlmethoxyphenyl)-5-t2-(4-(2-thioxobonzimidazolin-30 ~ 1-yl)-piperidino)-ethyl]-oxazolidin-2-one phenyl~-4-oxo-8-t2-(3-phenyl-oxazolidin-2-on-5-yl)-athyl]-1,3,8-tr~aza~pirot4,5]decane henyl-4-oxo-8-t2-(3-m-tolyl-oxazolidin-2-on-s-yl) ethyl]~-1,3,8-triaza~pirot4,5]decano l-phenyl-4-oxo-8-~2-(3-o-methoxyphenyl-oxazolidin-2-on 5-yl)--thyl]-1,3,8-tri~za~pirot4,5]decane henyl-4-oxo-8-t2-(3-m-m thoxyph nyl-ox~zoIidin-2-on-~ ~ -2 ~ '.3 5-yl)-et~yl]-1,3,8-triazaspiro~4,5]decane l-phenyl-4-oxo-8-[2-(3-p-methoxyphenyl-oxazolidin-2-on-s-yl)-ethyl]-l~3~8-triazaspiro~4~5]decane 1-ph~nyl-4-oxo-8 t2-(3-p-fluorophenyl-oxazolidin-2-on-5-yl~-Qthyl]-1,3,8-triazaspirot4,5]decane.
l-phenyl-4-oxo-8-[2-(3-p-chlorophenyl-oxazolidin-2-on-5 yl)-ethyl]-1,3,8-triazaspiro[4,5]decane l-ph~nyl-4-oxo-8-~2-(3-m-trifluorom~thylph~nyl-oxazoli din-2-on-5-yl)-sthy~ 3l8-triazaspirot~5~decane 1-ph~nyl-4-oxo-a-~2-(3-~3,4_dimethoxyphenyl)-oxazolidin-2-on-5-yl)-ethyl]-l~3~-triazaspiro~4t5]decane.
Example 2 Analogou~ly to ~xa~ple 1, th~ following ar~
obtained u~ing 5-(3-methane~ulfonyloxypropyl)-3-p-meth-oxyphenyl-oxazolidin-2-one t~.p. 75-76-; obtain~ble from 4-ponton-1-ol via4-po~t~n-1-olbenzoat~, 4,5-~po~yp~ntan-l-olbonzo~t~, S-p-methoxy~nilino-pentane-1,4-diol 1-b-nzo~ta, 5-(3-~enzoyloxypropyl)-3-Q-~thoxyphen oxa201idi~-2-ono ~nd 5-(3-hydroxypropyl)-3-p-~ethoxy-ph-nyl-oxazolidin 2-on (~.p. 78-79-)]5 ~.
3-p-~othoxyphonyl-5-t3-l4-p-chloroph~nyl-4-hydroxy-piperidino)-propyl~-ox~201idin-2-one~ m.p. 1~2-145-3-p-~ethoxyph nyl-S-t3-(~-phenyl-4-hydroxy-p~peridino)-propyl]-o~zolidln-2-on ;:
3-p-~ethoxypho~yl-5-t3-(4-p-~Rt~oxyphenyl-4-hydr pip~ridino)-propyl]-ox~zolidin-2-ono 3-p-~othoxyph-nyl-S-t3-t4-p-fluorophenyl-4-hydroxy-pipN~idino)-propyl]-oxazolidi~-2-onQ : ~:
3-p-mQtho~yph~nyl-S-t3-~4-m-trifluoro~ethylph~nyl-4-hydroxy-plporidino)-propyll-oxazolidin-2-one 3-p-~ethoxyphonyl-5-[3-(4-(2-th~enyl)-4-hydro~y-piper idino) -propyl~-oxazolidin-2-one, ~.p. 148-150-.
: Exa~pl- 3 Analogou~ly to Exa~ple 1, (S)-3-p-mathoxyphanyl-5-12-~4-p-chloroph~nyI-4-hydroxy-piperidino)-~thyll~ .
sxazolidin-2-on~ i~ obtained from (S)-S-(2-mathano-sulfonyloxy~thyl)-3-p-~ thoxypharlyl-oxa2c~1idin-2-on~
~: , .
.: ~. , ... . ,.~., , . . . ..... , . , . , . . . --: . .
2 ~
~obtainable from (S)-3,4-epoxy-1-butanol].
Example 4 A mixture of 2.06 g of 5-(2-amino~thyl~-3-phenyl-oxazolidin-2-one [obtainable by reaction of 5-(2-chloro-ethyl)-3-phenyl-oxazolidin-2-one with potas~ium phthali-~id~, followed by hydrolysi~l ~nd 2.15 g of 1,5-d$chloro-3-phenyl-2-pentene in 40 ml of aceton~ and 40 ml of water i~ boiled for 24 hour~ and worked up a~ u~ual. 3-phenyl-5-t2-~4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)-ethyl]-oxazolidin-2-one is obtained.
E~ple 51 g of Na~H, in 20 ~1 of water is added, with ~tirring, to a ~olution of 4.55 g of 1-t2-~3-p-methoxy-phanyl-oxazolidin-2-on-5-yl)-ethyl]-4-phenyl-pyridinium bromide (obta$nab1e from 3-p-methoxyphQnyl-5-~2-bromo-ethyl)-oxazolidin-2-one and 4-phenylpyridine) in 50 ~1 of 1 N NaOH, and th~mixtur ~ th n ~tirred at 60- for 3 hour~.. A convontional workup give- 3-p-m thoxyphenyl-5-t2-(4-ph~nyl-1,2,3,6-tetra-hydro-1-pyrityl)-ethyl]-oxa2elidin-2-en .
Exampl~ 6 1 g of 3-p-methoxyphenyl-5-t2-(4-hy~ro~y-4-ph nyl-plp ~idino)-othyl~-o~ol~din-2-on i- heatedwith 10 ml of 1 N hydrochloric ~cid to 100- for 2 hour~; the m~xtur i~ work d up in a con~ ntion~l.m~nner to ~ive ~-p-m-thoxyph-nyl-5- E 2-(4-phonyl-1,2,3,6-t-tr~hydro-1-pyridyl)-ethyl]-oxazolidin-2-one.
~x~ple 7 A mi~tura o 3.7 g of 4-hyd~o~y-1-~3-hydroxy-4-p- ~tho~ranilino-butyl)-4-ph nyl-pip ridine (obtain~ble 30 :~ ~by ~eactlon o~ p-lm~thoxyanilin~ with ethyl 3,4-epoxybuty ~ -rata~to~give ethyl 3-hydroxy-4-p-metho~yanilino-butyrat~, ..
;reduct~on~ with LiAlH~ to: givo 4-p-methoxyanilino-1,3-;propan~dioi, d*h ~ ation to the epoxid~ and re~ction wit~
4-hyd~oxy~4-ph~nyl-p~posldino)~ 1.5 g of diethyl car-:3S~ :bon~t-~ ~nd: 50~1 of DXr i~:h~at~d at 120- for 4 hour~. -Evaporation a~d c:onv~nt~on~l worXup giv~ 3-p-methoxy-henyl-s-t~-(4-hydroxy-4-ph-nyl-pip-rldino)-~th oxazolidin-2-on~.
~ ~ :
`', . ' ' , :
'.. : `: .`: : , .... ' .. : ,, ' `: , . , .
2$~
Example 8 A mixture o~ 10 g of 3-p-methoxyphenyl-5-[2-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)-ethyl~-oxazolidin-2-one and 10 g of pyridinium hydrochloride i~ stirred at s 160 for 3 hours. Conventional workup give~ 3-p-hydroxy-phenyl-5-~2-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl) -ethyl]-oxazolidin-2-one, Example 9 A ~uspen~ion of 3.8 ~ of 3-p-methoxyphenyl-5-[2- ~ - -(4-benzyl-piperidino)-ethyl~-oxazolidin-2-one in 50 ml of 1, 2-diChloroQth~ne i8 ~dded dropwise to a boiling ~olu-tion of 15.6 g of dimethyl sulfide/boron tribromide complex in S0 ml of 1,2-dichloroethane; the mixture is boiled for another 30 minutes and worked up in a conven-tional manner to give 3-p-hydroxyphenyl-5-~2-(4-ben p~peridLno)-ethyl~-oxazolidin-2-one.
The following example~ denl with pharmaceutlcal prepar_tion~ which contain amine~ of the formula I or their acid Addition aAltJ t Ex~mple As Tabl-t~
A mixture of 1 kg of 3-p-methoxyphenyl-5-t2-(4- !~
hydroxy-4-p-chlorophenyl-piperidino)-ethyl~-oxazolidin-2-one, 4 kg of lactoJe, 1.2 kg of potato ~tarch, 0.2 kg of talc and 0.1 kg of magnesiu~ ~tear~te i~ compres~ed into ta~let- in a con~entional manner and in ~uch a way that ach tabIet contaln- 10 mg of active sub~tance.
Ex~ple ~s ~ Coatod tablet~
An~logou~ly ~o ~xample ~, tablets are pre~ed and -~
th n~ coated ~ ~A a ~ conventional ~nn~r with a coating ~ con~l~tlng of ucro~e,~potato starch, talc, tragacanth and colorant.
t~ ~ Exampl- Cs~ ; Cap~ul~-2~kg of 3-p-methoxyphenyl-5-t2-(4-hydroxy-4-henyl-piperidino)-~thyll-oxazolidin-2-ono are poured in 35~ a conventlonal m~nner~into h-rd yel-tin cap~ule~ ~o that each cap~ule contain~ 20 mg of active sub~t~nce.
Example Ds~ ~ AmpouleJ
A ~olut~on of 1 kg of 3-p-mothoxyphonyl-5-t2-(4-benzyl-pip-ridino)-ethyl~-ox~zolid~n-2-on h~drochloride . ~ ..
-- 2 ~
in 60 1 of twice-distilled water is filtered under sterile conditions, filled into ampoules, freeze-dried under sterile conditions and sealed under sterile condi-tions. Each ampoule contains 10 mg of active ubstance.
Analogously tablets, coated tablets, capsules and ampoules are obtainable which contain one or more of the remaining active substances of the formula I and/or their -~
physiologically safe acid addition salts.
~ .
~ -: ~
~ ; ~
Claims (8)
1. Oxazolidinones of the formula I
I
in which R is , , , , Z is O or S, R1 and R2 are each phenyl radicals which are unsubstitu-ted or mono- or disubstituted by alkyl, alkoxy, alkylthio, alXylsulfinyl or alkylsulfonyl each having 1-4 C atoms, alkanoyloxy and/or alkanoylamino each having 1-6 C atoms, F, Cl, Br, OH and/or CF3 or are mono- or binucl0ar heteroaryl radicals containing 1-4 heteroatoms m is 0 or 1,:and n is 2 or 3,:
and also salts thereof.
I
in which R is , , , , Z is O or S, R1 and R2 are each phenyl radicals which are unsubstitu-ted or mono- or disubstituted by alkyl, alkoxy, alkylthio, alXylsulfinyl or alkylsulfonyl each having 1-4 C atoms, alkanoyloxy and/or alkanoylamino each having 1-6 C atoms, F, Cl, Br, OH and/or CF3 or are mono- or binucl0ar heteroaryl radicals containing 1-4 heteroatoms m is 0 or 1,:and n is 2 or 3,:
and also salts thereof.
2. a) 3-p-methoxyphenyl-5-[2-(4-hydroxy-4-phenyl-piperidino:)-ethyl]-oxazolidin-2-one;
b) 3-p-methoxyphenyl-5-[2-(4-hydroxy-4-p-methoxy-phenyl-piperidino)-ethyl]-oxazolidin-2-one;
c) 3-p-methoxyphenyl-5-[2-(4-hydroxy-4-p-chloro-phenyl-piperidino)-ethyl]-oxazolidin-2-one;
d) 3-p-methoxyphenyl-5-[2-(4-hydroxy-4-(2-thienyl)-piperidino)-ethyl]-oxazolidin-2-one.
b) 3-p-methoxyphenyl-5-[2-(4-hydroxy-4-p-methoxy-phenyl-piperidino)-ethyl]-oxazolidin-2-one;
c) 3-p-methoxyphenyl-5-[2-(4-hydroxy-4-p-chloro-phenyl-piperidino)-ethyl]-oxazolidin-2-one;
d) 3-p-methoxyphenyl-5-[2-(4-hydroxy-4-(2-thienyl)-piperidino)-ethyl]-oxazolidin-2-one.
3. Process for preparing oxazolidinones of the formula I and also of salts thereof, characterized in that a compound of the formula II
Ox-CnH2n-X1 II
in which Ox is the radical , X1 is X or NH2, X is Cl, Br, I, OH or a reactive functionally modified OH group and R1 and n have the meanings given, is reacted with a compound of the formula III
in which X2 and X3 are identical or different and, if X1 is NH2, are each X, otherwise together they are NH and R has the meaning given, and/or that a compound which otherwise corresponds to the formula I but contains, instead of one or more hydrogen atoms, one of more reducible groups and/or one or more additional C-C and/or C-N bonds is treated with a reduc-ing agent and/or that in order to prepare a compound of the formula I in which R is or , a compound of the formula IV
Ox-CnH2n-R5 in which R5 is or one radical E is X, CN or NH2, the other radical E is H and Ox, R2, X and n have the meanings given is treated with an agent which eliminates HE, or that a compound of the formula V
R1-NH-CH2-CHOH-CnH2n,-NR V
in which R, R1 and n have the meanings given are reacted with a reactive derivative of carbonic acid and/or that, if desired, in a compound of the formula I an O-alkyl group is cleaved to give an OH group and/or a compound of the formula I is converted by reduction to another compound of the formula I, and/or that a base of the formula I is converted to one of its salts by treatment with an acid.
Ox-CnH2n-X1 II
in which Ox is the radical , X1 is X or NH2, X is Cl, Br, I, OH or a reactive functionally modified OH group and R1 and n have the meanings given, is reacted with a compound of the formula III
in which X2 and X3 are identical or different and, if X1 is NH2, are each X, otherwise together they are NH and R has the meaning given, and/or that a compound which otherwise corresponds to the formula I but contains, instead of one or more hydrogen atoms, one of more reducible groups and/or one or more additional C-C and/or C-N bonds is treated with a reduc-ing agent and/or that in order to prepare a compound of the formula I in which R is or , a compound of the formula IV
Ox-CnH2n-R5 in which R5 is or one radical E is X, CN or NH2, the other radical E is H and Ox, R2, X and n have the meanings given is treated with an agent which eliminates HE, or that a compound of the formula V
R1-NH-CH2-CHOH-CnH2n,-NR V
in which R, R1 and n have the meanings given are reacted with a reactive derivative of carbonic acid and/or that, if desired, in a compound of the formula I an O-alkyl group is cleaved to give an OH group and/or a compound of the formula I is converted by reduction to another compound of the formula I, and/or that a base of the formula I is converted to one of its salts by treatment with an acid.
4. Process for preparing pharmaceutical prepara-tions, characterized in that a compound of the formula I
and/or one of its physiologically safe salts is brought into a suitable dosage form together with at least one solid, liquid or semi-liquid carrier or auxiliary.
and/or one of its physiologically safe salts is brought into a suitable dosage form together with at least one solid, liquid or semi-liquid carrier or auxiliary.
5. Pharmaceutical preparation, characterized in that it contains at least one compound of the formula I and/or one of its physiologically safe salts.
6. Compounds of the formula I and/or their physiolo-gically safe salts for controlling diseases.
7. Use of compounds of the formula I and/or their physiologically safe salts for controlling diseases.
8. Use of compounds of the formula I and/or their physiologically safe salts for preparing medicaments.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4005371.7 | 1990-02-21 | ||
| DE4005371A DE4005371A1 (en) | 1990-02-21 | 1990-02-21 | New N-(hetero)aryl-substd. 2-piperidino:ethyl oxazolidinone derivs. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2036586A1 true CA2036586A1 (en) | 1991-08-22 |
Family
ID=6400608
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002036586A Abandoned CA2036586A1 (en) | 1990-02-21 | 1991-02-19 | Oxazolidinones |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0443197A3 (en) |
| JP (1) | JPH051061A (en) |
| KR (1) | KR910021400A (en) |
| AU (1) | AU7126591A (en) |
| CA (1) | CA2036586A1 (en) |
| DE (1) | DE4005371A1 (en) |
| HU (1) | HU910583D0 (en) |
| IE (1) | IE910583A1 (en) |
| PT (1) | PT96804A (en) |
| ZA (1) | ZA911262B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5627197A (en) * | 1995-02-15 | 1997-05-06 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Adhesion receptor antagonists |
| US5714502A (en) * | 1995-08-25 | 1998-02-03 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Piperidinylmethyloxazolidinones |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL174222B1 (en) * | 1993-01-27 | 1998-06-30 | Inst Farmaceutyczny | Pharmaceutical agent |
| DK0623615T3 (en) * | 1993-05-01 | 1999-12-13 | Merck Patent Gmbh | Adhesion receptor antagonists |
| DE4324393A1 (en) * | 1993-07-21 | 1995-01-26 | Merck Patent Gmbh | 4-aryloxy and 4-arylthiopiperidine derivatives |
| DE4332384A1 (en) * | 1993-09-23 | 1995-03-30 | Merck Patent Gmbh | Adhesion receptor antagonists III |
| DE4439846A1 (en) * | 1994-11-08 | 1996-05-09 | Merck Patent Gmbh | Adhesion receptor antagonists |
| DE19707628A1 (en) * | 1997-02-26 | 1998-08-27 | Merck Patent Gmbh | Oxazolidinones |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4082755A (en) * | 1977-02-14 | 1978-04-04 | Janssen Pharmaceutica N.V. | 1-[(Diarylmethyl)aminoalkyl]piperidimes |
| DE3723797A1 (en) * | 1987-07-18 | 1989-01-26 | Merck Patent Gmbh | OXAZOLIDINONE |
-
1990
- 1990-02-21 DE DE4005371A patent/DE4005371A1/en not_active Withdrawn
- 1990-12-24 EP EP19900125408 patent/EP0443197A3/en not_active Withdrawn
-
1991
- 1991-02-18 PT PT96804A patent/PT96804A/en not_active Application Discontinuation
- 1991-02-19 CA CA002036586A patent/CA2036586A1/en not_active Abandoned
- 1991-02-20 ZA ZA911262A patent/ZA911262B/en unknown
- 1991-02-20 IE IE058391A patent/IE910583A1/en unknown
- 1991-02-21 AU AU71265/91A patent/AU7126591A/en not_active Abandoned
- 1991-02-21 HU HU91583A patent/HU910583D0/en unknown
- 1991-02-21 KR KR1019910002799A patent/KR910021400A/en not_active Withdrawn
- 1991-02-21 JP JP3111245A patent/JPH051061A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5627197A (en) * | 1995-02-15 | 1997-05-06 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Adhesion receptor antagonists |
| US5714502A (en) * | 1995-08-25 | 1998-02-03 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Piperidinylmethyloxazolidinones |
Also Published As
| Publication number | Publication date |
|---|---|
| KR910021400A (en) | 1991-12-20 |
| EP0443197A2 (en) | 1991-08-28 |
| EP0443197A3 (en) | 1992-02-26 |
| DE4005371A1 (en) | 1991-08-22 |
| PT96804A (en) | 1991-10-31 |
| JPH051061A (en) | 1993-01-08 |
| HU910583D0 (en) | 1991-09-30 |
| AU7126591A (en) | 1991-08-22 |
| IE910583A1 (en) | 1991-08-28 |
| ZA911262B (en) | 1991-11-27 |
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