CA2133939A1 - 1,2-dihydro-2-oxo-pyridines - Google Patents
1,2-dihydro-2-oxo-pyridinesInfo
- Publication number
- CA2133939A1 CA2133939A1 CA002133939A CA2133939A CA2133939A1 CA 2133939 A1 CA2133939 A1 CA 2133939A1 CA 002133939 A CA002133939 A CA 002133939A CA 2133939 A CA2133939 A CA 2133939A CA 2133939 A1 CA2133939 A1 CA 2133939A1
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- formula
- dihydro
- oxo
- compound
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
- C07D413/10—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 aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
- C07D419/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D419/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Ophthalmology & Optometry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
Abstract of the Disclosure Novel 1,2-dihydro-2-oxopyridines of the formula I
I
wherein R is
I
wherein R is
Description
~`:
2~33939 - ~
J~ :~ ~erck Patffnt Go~ollochaft ~:
- ~it boochran~t~r ~aftung 6~271 D a r ~ ~ t a d t 1.2-Dlhydro-2-o~pyr$dlnes 5Th~ lnv~nt~on r~lat~s to nov~l 1,2-dlhydro-2-oxo-pyrldine~ of th- for~ula Is R-CH
wher~ln R $8 ~ CH2NR3R~
Rl ~
10 R~ , A, C2-C6-al~onyl or C2-Cc-alkynyl, R2 1~- 802N~ - CooR5, - 802NI~ - CoR5, - 802N~- 802RS, -8O2N~-CoNR5RC, -C(N~2).N0~, ~,S-dlhydro-5-oxo-1,2,~-oxadlazol-3-yl, ~,5-dlhydro-5-thloxo-1,2,4-oxadlazol-3-yl, 2-oxo-38-1,2,3,5-oxathladlazol-4-yl, Z,2-dloxo-3~-1,2,3,5-oxathladlazol-~-yl, 2,3-dlhydro-3-oxo-1,2,~-oxadlazol-5-yl, a, 5-dlhydro-2,5-dloxo-1~-lmldazol-~-yl, ~,5-dlhydro- ~;
5-oxo-1~-1,2,~-trlazol-3-yl, ~,5-dlhydro-5-thloxo-1~-1,2,4-trlazol-3-yl, 2,3-dl- .
hydro-2-oxo-1,3,4-thladlazol-5-yl or ~,5-dlhydro-5-oxo-1,2,~-thladlazol-3-yl, R3 1~ ~, A, C3-C8-cycloalkyl-C~2n- or Ar~Cn~2n~ ' ` - ~ ~ `
25 R~ 1~ A-CO-, Ar'-CO-, Ar'-C.~2~-CO-, R9-gO2-or Ar'-8O2-, .
, '~'"~
RS and R6 are oach ~, a Cl-C6-al~yl group, wheroln on~ C~2 group can aleo bo roplaood by O or 8 or an additional C-C double bond ean bo containod and whleh can add$tlonally bo sub~titutod by O~, oR7, Ar, ~t2, NR7a8, NR7-CooR~, N~7-COO-Ct~2t-Ar, NR7-COO-Ct~12t-Hot and/or CooR7, or aro C3-C8-cycloalkyl, Ar or ~-t, R7 and R~ aro oaeh A, C2-C6-alkonyl, C2-C6-alkynyl, C3-C~-cycloalkyl-C~2~- or Cl-C6-alkyl, whoroln ono C~2 group 1~ roplacod by O or 8, R9 i~ Cl-C6-al~yl, whoroin ono or more atom~ can al~o bo replacod by F, 15 A i~ Cl-C6-alkyl, Ar and Ar' ar- o-eh an un~ub~titutod phonyl group or a phonyl group monosub~titutod or disub-8tltutod by R~, O~, OR9, COOR, COOA, CN?, N02, NE~, N~A, N(A)~, N~COR9, N~COOA, N~8O2R9, ~al and/or lH-tetrazol-5-yl, a?-t 1~ a fivo- or ~ix-momborod hotoroaromatie radleal hav~ng 1 to 3 N, O and/or 8 atomJ, ~hieh oan al~o bo fusod wlth a b-nz n- or pyrldln- rlng, 25 ~al 1~ P, Cl, ~r or I, i~ 0, 1, 2, 3 or ~, and n ar- oaeh 1, 2 or 3 and t 1~ 1, 2, 3 or nd their salt~
8~1ar eompound- ar- known from ~uropean patent applieatlon A2-0530702 Th- ob~-et of tho invention was to find nov l eompound~ w~th valuabl- prop-rt$o~, o~poclally eompound~
~hleh ean bo u~-d for the pr-paratlon of drug~
It ha~ bo-n found that tho compounds of tho formula I and tholr ~alt- po~os~ vory valuabl- pharmaeo-logleal prop-rtl-- eoupl-d wlth a good tolerane- In partleular, th-y ~xhiblt antagoni~tie prop-rtio~ toward~
~ngloton-ln II and e~ thorefor- bo used a~
~ 2133939 pharmacoutlcal actlve lngredienta for the prophylaxis ~ and/or therapy of coronary, cardiovascular and vascular dlsorders, ln particular for the treatm~nt of aDglotensln II-dependent hyportenolon, aldo~teron~sm, card~ac lnsuf-f$clency and increaeed lntraocular preesure, and of dlsorders of tho central nervou~ eystem, al~o of hyper-trophy and hyperplasia of the blood vessole and of the heart, angina pectorle, cardlac $nfarct, stro~o, re-steno~es after angloplasty or by-pass oporatlons, of lechaemlc per~pheral clrculatory dl~ordera, artorlo-sclerosl-, glauc~m~s, macular degenerat~on, hypor-urica~mla, ~dnoy functlon dlsorders, o.g. ~ldney fall-ures, dlabotlc nephropathy, diabetlc retinopathy, psor$-asls, of ga~trolntestlnal dlsorder~, bladdar dlsorders, lS pulmonary oedema, chronlc bronchlti~, anglotonsln II-modlatod dlsorder~ ln femalo roproduct~ve organ~, porcep-tlvo dlsordor~, e.g. domentla, amne~a, memory functlon disordoro, anxioty stato~, depre~slon, opllepsy, Par~lnson's Dlseaoe and/or bul~a.
The~- ff~ct~ can bo determined by conventional ln vltro or ln rlvo methods such as, for examplo, thoso descrlbod ln ~8 Patent ~ 880 804, US Patont 5 036 0~8 and Internatlonal Patent Appllcatlon 91/14367 and al~o by A.T. Chlu ot al., ~. Phar~acol. Exp. Therap. 250, 867-874 (1989), and by P.C. Wong ot al., lbld. ~, 719-725 (199Os ln vlvo, on rate).
Tho lnvont~on relat-~ to th- compoundb of the formula I and tholr salts and to a proce~e for tho preparation of theso compound~ and thelr salt~, charac~
torlzod ln that (a) a compound of the formula II
E-CH2- ~ -X-whereln E le Cl, Br, I, a froe 0~ group or an 0~ group whlch has be~n functlonally modlflod to acqulro 2133939 ::
" ~
reactlvlty, and R2 1~ a~ de~lned in Clalm 1, 1~ roacted with a compound of tho formula III
~-R III
wherein R 1~ ~ def~nod ln Claim 1, or (b) a compound of th- formul~ I 18 froed from one of it~
functlonal derivatlv-~ by troatment with a ~ol~oly~lng or hydrog~noly~ing agont, (c) to preparo a compound of the formula I whereln R2 ie -C(NH2).NOH, a compound whlch corro~ponds to formula I but 1~ replacod by tho radlcal R2 ln whlch a C~
group, 1~ reactod wlth hydroxyl ~ine or (d) to propar- a compound of tho formula I whorein R2 1 -802NH-COOR5, -802N~-COR5, -So2N~-So2R5 or -S02N~-CoNR5RC, ~ compound which correspond- to the formula I but ln whlch th- radlcal R2 ~ replaced by n -SO~N~2 group, 1D roact-d wlth a compound of th-for~ul~ ~-CooR5, ~-CoR5, ~-802R5, Æ-CoNR5RC or ~ 3 o-C-NR5 and/or ln that on- or r- radlcal~ R ~nd/or R2 $n a compound of tho formul~ I ~r- conv-rt-d to one or mor-differ~nt radlcal~ R and/or R2, and/or a bas- or acld of th- for Nla I $~ converted to on~ of $ts salt~
Abov- and bolow, unles~ oxpreeely lnd$catod otherwl~-, th- radical~ or parametor~ R, Rl to R9, A, Ar, Ar', ~t, Hal, ~, m, n, t and ~, ar- as def$n-d ln formula~ I ~nd II
In th- abov- formulae, A h~ 6, preferably 1, 2, 3 or ~ C atomJ A $~ proforably mothyl, or els- othyl, propyl, i~opropyl, butyl, $~obutyl, so~-butyl or tert-butyl, or 180 pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-di~ethylpropyl, l-othylpropyl, hoxyl, 1-, 2-, 3- or ~-~ thylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-d~^thylbutyl, 1- or 2-othylbutyl, l-ethyl-l-methyl-propyl, l-othyl-2-~ thylpropyl or 1,1,2- or 1,2,2-trl-methylpropyl Al~enyl 1~ preferably ~inyl, prop-l-enyl, prop-2-onyl or but-1-~nyl, or 1~ pent-l-enyl or hox-;-enyl Al~ynyl i8 preferably thynyl, prop-1-ynyl or prop-2-ynyl, or 818~ but-l-ynyl, pent-1-ynyl or hex-l-ynyl If ~everal radical~ A, al~enyl or al~ynyl arepresent ln a compound of tho formula I, they can be ldentlcal to or dlfferent from one another ~al i~ proferably P, Cl or Br, or OlBe T-R lo a radlcal derivod from 1,2-dlhydro-2-oxo-pyrldln-, r- pr~cl~oly 1,2-dlhydro-2-oxo-3-(R3~N-methyl)-6-Rl-pyrldin-1-yl Ar and Ar' are each, lndependently of each other, preferably un~ub~tltuted or further, a~ lnd~cated, no~ubstituted phenyl~ in dotall pr-ferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylph~nyl, o-, m- or p-trifluoromethylphenyl, o-, m- or p-m thoxyphenyl, o-, ~-or p--thoxyph~yl, o, m- or p-difluoro-~ethoxyphenyl, o-, m- or p-trlfluoro-m~thoxyph-nyl, o-, _- or p-carboxy-phenyl, o-, ~- or p-~ethoxycarbonylphenyl, o-, m-or p-ethoxycarbonylphenyl, o-, ~- or p-cyanophenyl, o-, ~- or p-nltroph nyl, o-, m- or p-~m~noph nyl, o-, m- or p-m thylaminoph-nyl, o~ or p-dimethyl~m~nophenyl, o-, m- or p-trifluoroac-tum~dophonyl, o-, ~- or p-m thoxy-carbonylamino, o-, ~- or p--thoxycarbonyl~m1no, o-, ~- or p-~-thyl~ulfon midoph nyl, o-, m- or p-trifluoromothyl-~ulfonamidoph-nyl, o-, ~- or p-fluorophenyl, o-, ~- or p-chlorophenyl, o-, ~- or p-bro phenyl, o-, m- or p-~
t-trazol-5-yl)ph~nyl, furthermore preferably 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-dim~thoxyphonyl ~et 1~ preferably furan-2- or -3-yl, thi-n-2- or -3-yl, pyrrol-l-, -2- or -3-yl, imidazol-l-, -2-, -~- or -5-yl, pyrazol-l-, -3-, -4- or -5-yl, oxazol-2-, -4- or -5-yl, i~oxazol-3-, -~- or -5-yl, thiazol-2-, -~- or -5-yl, i~othlazol-3-, -4- or -5-yl, pyridin-2-, -3- or -4-yl or pyrimidin-2-, -4-, -5- or -6-yl, or l~e preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-tr$azol-l-, -3- or -5-yl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or . .
J~ :~ ~erck Patffnt Go~ollochaft ~:
- ~it boochran~t~r ~aftung 6~271 D a r ~ ~ t a d t 1.2-Dlhydro-2-o~pyr$dlnes 5Th~ lnv~nt~on r~lat~s to nov~l 1,2-dlhydro-2-oxo-pyrldine~ of th- for~ula Is R-CH
wher~ln R $8 ~ CH2NR3R~
Rl ~
10 R~ , A, C2-C6-al~onyl or C2-Cc-alkynyl, R2 1~- 802N~ - CooR5, - 802NI~ - CoR5, - 802N~- 802RS, -8O2N~-CoNR5RC, -C(N~2).N0~, ~,S-dlhydro-5-oxo-1,2,~-oxadlazol-3-yl, ~,5-dlhydro-5-thloxo-1,2,4-oxadlazol-3-yl, 2-oxo-38-1,2,3,5-oxathladlazol-4-yl, Z,2-dloxo-3~-1,2,3,5-oxathladlazol-~-yl, 2,3-dlhydro-3-oxo-1,2,~-oxadlazol-5-yl, a, 5-dlhydro-2,5-dloxo-1~-lmldazol-~-yl, ~,5-dlhydro- ~;
5-oxo-1~-1,2,~-trlazol-3-yl, ~,5-dlhydro-5-thloxo-1~-1,2,4-trlazol-3-yl, 2,3-dl- .
hydro-2-oxo-1,3,4-thladlazol-5-yl or ~,5-dlhydro-5-oxo-1,2,~-thladlazol-3-yl, R3 1~ ~, A, C3-C8-cycloalkyl-C~2n- or Ar~Cn~2n~ ' ` - ~ ~ `
25 R~ 1~ A-CO-, Ar'-CO-, Ar'-C.~2~-CO-, R9-gO2-or Ar'-8O2-, .
, '~'"~
RS and R6 are oach ~, a Cl-C6-al~yl group, wheroln on~ C~2 group can aleo bo roplaood by O or 8 or an additional C-C double bond ean bo containod and whleh can add$tlonally bo sub~titutod by O~, oR7, Ar, ~t2, NR7a8, NR7-CooR~, N~7-COO-Ct~2t-Ar, NR7-COO-Ct~12t-Hot and/or CooR7, or aro C3-C8-cycloalkyl, Ar or ~-t, R7 and R~ aro oaeh A, C2-C6-alkonyl, C2-C6-alkynyl, C3-C~-cycloalkyl-C~2~- or Cl-C6-alkyl, whoroln ono C~2 group 1~ roplacod by O or 8, R9 i~ Cl-C6-al~yl, whoroin ono or more atom~ can al~o bo replacod by F, 15 A i~ Cl-C6-alkyl, Ar and Ar' ar- o-eh an un~ub~titutod phonyl group or a phonyl group monosub~titutod or disub-8tltutod by R~, O~, OR9, COOR, COOA, CN?, N02, NE~, N~A, N(A)~, N~COR9, N~COOA, N~8O2R9, ~al and/or lH-tetrazol-5-yl, a?-t 1~ a fivo- or ~ix-momborod hotoroaromatie radleal hav~ng 1 to 3 N, O and/or 8 atomJ, ~hieh oan al~o bo fusod wlth a b-nz n- or pyrldln- rlng, 25 ~al 1~ P, Cl, ~r or I, i~ 0, 1, 2, 3 or ~, and n ar- oaeh 1, 2 or 3 and t 1~ 1, 2, 3 or nd their salt~
8~1ar eompound- ar- known from ~uropean patent applieatlon A2-0530702 Th- ob~-et of tho invention was to find nov l eompound~ w~th valuabl- prop-rt$o~, o~poclally eompound~
~hleh ean bo u~-d for the pr-paratlon of drug~
It ha~ bo-n found that tho compounds of tho formula I and tholr ~alt- po~os~ vory valuabl- pharmaeo-logleal prop-rtl-- eoupl-d wlth a good tolerane- In partleular, th-y ~xhiblt antagoni~tie prop-rtio~ toward~
~ngloton-ln II and e~ thorefor- bo used a~
~ 2133939 pharmacoutlcal actlve lngredienta for the prophylaxis ~ and/or therapy of coronary, cardiovascular and vascular dlsorders, ln particular for the treatm~nt of aDglotensln II-dependent hyportenolon, aldo~teron~sm, card~ac lnsuf-f$clency and increaeed lntraocular preesure, and of dlsorders of tho central nervou~ eystem, al~o of hyper-trophy and hyperplasia of the blood vessole and of the heart, angina pectorle, cardlac $nfarct, stro~o, re-steno~es after angloplasty or by-pass oporatlons, of lechaemlc per~pheral clrculatory dl~ordera, artorlo-sclerosl-, glauc~m~s, macular degenerat~on, hypor-urica~mla, ~dnoy functlon dlsorders, o.g. ~ldney fall-ures, dlabotlc nephropathy, diabetlc retinopathy, psor$-asls, of ga~trolntestlnal dlsorder~, bladdar dlsorders, lS pulmonary oedema, chronlc bronchlti~, anglotonsln II-modlatod dlsorder~ ln femalo roproduct~ve organ~, porcep-tlvo dlsordor~, e.g. domentla, amne~a, memory functlon disordoro, anxioty stato~, depre~slon, opllepsy, Par~lnson's Dlseaoe and/or bul~a.
The~- ff~ct~ can bo determined by conventional ln vltro or ln rlvo methods such as, for examplo, thoso descrlbod ln ~8 Patent ~ 880 804, US Patont 5 036 0~8 and Internatlonal Patent Appllcatlon 91/14367 and al~o by A.T. Chlu ot al., ~. Phar~acol. Exp. Therap. 250, 867-874 (1989), and by P.C. Wong ot al., lbld. ~, 719-725 (199Os ln vlvo, on rate).
Tho lnvont~on relat-~ to th- compoundb of the formula I and tholr salts and to a proce~e for tho preparation of theso compound~ and thelr salt~, charac~
torlzod ln that (a) a compound of the formula II
E-CH2- ~ -X-whereln E le Cl, Br, I, a froe 0~ group or an 0~ group whlch has be~n functlonally modlflod to acqulro 2133939 ::
" ~
reactlvlty, and R2 1~ a~ de~lned in Clalm 1, 1~ roacted with a compound of tho formula III
~-R III
wherein R 1~ ~ def~nod ln Claim 1, or (b) a compound of th- formul~ I 18 froed from one of it~
functlonal derivatlv-~ by troatment with a ~ol~oly~lng or hydrog~noly~ing agont, (c) to preparo a compound of the formula I whereln R2 ie -C(NH2).NOH, a compound whlch corro~ponds to formula I but 1~ replacod by tho radlcal R2 ln whlch a C~
group, 1~ reactod wlth hydroxyl ~ine or (d) to propar- a compound of tho formula I whorein R2 1 -802NH-COOR5, -802N~-COR5, -So2N~-So2R5 or -S02N~-CoNR5RC, ~ compound which correspond- to the formula I but ln whlch th- radlcal R2 ~ replaced by n -SO~N~2 group, 1D roact-d wlth a compound of th-for~ul~ ~-CooR5, ~-CoR5, ~-802R5, Æ-CoNR5RC or ~ 3 o-C-NR5 and/or ln that on- or r- radlcal~ R ~nd/or R2 $n a compound of tho formul~ I ~r- conv-rt-d to one or mor-differ~nt radlcal~ R and/or R2, and/or a bas- or acld of th- for Nla I $~ converted to on~ of $ts salt~
Abov- and bolow, unles~ oxpreeely lnd$catod otherwl~-, th- radical~ or parametor~ R, Rl to R9, A, Ar, Ar', ~t, Hal, ~, m, n, t and ~, ar- as def$n-d ln formula~ I ~nd II
In th- abov- formulae, A h~ 6, preferably 1, 2, 3 or ~ C atomJ A $~ proforably mothyl, or els- othyl, propyl, i~opropyl, butyl, $~obutyl, so~-butyl or tert-butyl, or 180 pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-di~ethylpropyl, l-othylpropyl, hoxyl, 1-, 2-, 3- or ~-~ thylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-d~^thylbutyl, 1- or 2-othylbutyl, l-ethyl-l-methyl-propyl, l-othyl-2-~ thylpropyl or 1,1,2- or 1,2,2-trl-methylpropyl Al~enyl 1~ preferably ~inyl, prop-l-enyl, prop-2-onyl or but-1-~nyl, or 1~ pent-l-enyl or hox-;-enyl Al~ynyl i8 preferably thynyl, prop-1-ynyl or prop-2-ynyl, or 818~ but-l-ynyl, pent-1-ynyl or hex-l-ynyl If ~everal radical~ A, al~enyl or al~ynyl arepresent ln a compound of tho formula I, they can be ldentlcal to or dlfferent from one another ~al i~ proferably P, Cl or Br, or OlBe T-R lo a radlcal derivod from 1,2-dlhydro-2-oxo-pyrldln-, r- pr~cl~oly 1,2-dlhydro-2-oxo-3-(R3~N-methyl)-6-Rl-pyrldin-1-yl Ar and Ar' are each, lndependently of each other, preferably un~ub~tltuted or further, a~ lnd~cated, no~ubstituted phenyl~ in dotall pr-ferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylph~nyl, o-, m- or p-trifluoromethylphenyl, o-, m- or p-m thoxyphenyl, o-, ~-or p--thoxyph~yl, o, m- or p-difluoro-~ethoxyphenyl, o-, m- or p-trlfluoro-m~thoxyph-nyl, o-, _- or p-carboxy-phenyl, o-, ~- or p-~ethoxycarbonylphenyl, o-, m-or p-ethoxycarbonylphenyl, o-, ~- or p-cyanophenyl, o-, ~- or p-nltroph nyl, o-, m- or p-~m~noph nyl, o-, m- or p-m thylaminoph-nyl, o~ or p-dimethyl~m~nophenyl, o-, m- or p-trifluoroac-tum~dophonyl, o-, ~- or p-m thoxy-carbonylamino, o-, ~- or p--thoxycarbonyl~m1no, o-, ~- or p-~-thyl~ulfon midoph nyl, o-, m- or p-trifluoromothyl-~ulfonamidoph-nyl, o-, ~- or p-fluorophenyl, o-, ~- or p-chlorophenyl, o-, ~- or p-bro phenyl, o-, m- or p-~
t-trazol-5-yl)ph~nyl, furthermore preferably 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-dim~thoxyphonyl ~et 1~ preferably furan-2- or -3-yl, thi-n-2- or -3-yl, pyrrol-l-, -2- or -3-yl, imidazol-l-, -2-, -~- or -5-yl, pyrazol-l-, -3-, -4- or -5-yl, oxazol-2-, -4- or -5-yl, i~oxazol-3-, -~- or -5-yl, thiazol-2-, -~- or -5-yl, i~othlazol-3-, -4- or -5-yl, pyridin-2-, -3- or -4-yl or pyrimidin-2-, -4-, -5- or -6-yl, or l~e preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-tr$azol-l-, -3- or -5-yl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or . .
-5-yl, 1,2,4-th$adlazol-3- or -4-yl, 2,1,5-thladlazol-3-or -4-yl, pyr~dazin-3- or -4-yl, pyrazinyl, benzo-f~ran-2-, -3-, -4-, -5-, -6- or -7-yl, benzothlen-2-, -3-, -4-, -5-, -6- or -7-yl, lndol-l-, -2-, -3-, -4-, -5-, -6- or -7-yl, ~olndol-l-, -2-, -3-, -4-, -5-, -6-or -7-yl, b~nzlmldazol-l-, -2-, -4- or -5-yl, benzo-pyrazol-l-, -3-, -4-, -5-, -6- or -7-yl, bonzoxazol-2-, -~, -5-, -6- or -7-yl, bonz~eoxazol-3-, -~-, -5-, -6- or -7-yl, benzothlazol-2-, -~-, -5-, -6- or -7-yl, bonzl~othlazol-2-, -~-, -5-, -6- or -7-yl, benz-2,1,3-oxad~azol-~-, -5-, -6- or -7-yl, qulnol-2-, -3-, -4-, -5-, -6-, -7- or -8-yl, isoqulnol-l-, -3-, -4-, -5-, -6-, -7- or -8-yl, cinnolln-3-, -~-, -5-, -6-, -7- or -8-yl, qylnazolln-2-, -~-, -5-, -6-, -7- or -8-yl, l~-lmidazo-[~,5-blpyrldln-1-, -2-, -S-, -6- or -7-yl, 3~-l~ldazol~,5-blpyrldln-2-, -3-, -5-, -6- or -7-yl, 1 l~ldazol~,5-clpyrldln-1-, -2-, -~-, -6- or -7-yl or 3 ~dazol~,5-clpyrldln-2-, -3-, -~-, -6- or -7-yl The group- -C~2~-, -C~2,-~ ~Cn~2n~ a~d -Ct~2t-are proferably stralght-chaln and are thu~ preferably -(C~2)~-~ -(C~2)~-/ ~(CH2)n~ and -(C~2)t-, ln p-rtlcular _C~2-, al-o -C~2C82-~ -(C~2)3-, -lC~2)~ C~2)s- or -(C~2)6-, but also, for oxamplo, -C~(C~3)-, -C~2-C~(C~3)-or -C(C~3)2- Tho param t-r ~ can proferably al~o be 0, ~o that th- group -C~2~- lo abcent The radlcal Rl 1~ proforably atralght-chaln and 1~ pr-ferably A, ln partlcular othyl, propyl or butyl, al~o mothyl, per~tyl or hexyl, furthermoro ln partlcular al~onyl proferably havlng 3-6 C ato~J, ln partlcular allyl or l-propenyl, also l-butonyl, l-pontonyl or l-hexenyl5 al~ynyl proforably having 3-6 C atoms, ln p~rtlcular propargyl or l-propynyl, al~o l-butynyl, l-pentynyl or l-hoxy~yl Th- radical R2 1~ preforably -So~N~-CooR5, ln partlcular -S02N~-COOA; -802NH-Co-R5, ln partlcular -S02NH-COAr ~uch a~ -802N~-COC6~5 t -S02N~-CONRSR6, ln partlcular -802N~-CO-N~Ar ~ucb a~ -S02NH-CO-NHC6~S or -S02N~-C0-NHC~2~0t2 ~uch a~ -802N~-C0-NHC~2-(2-pyrldyl) Th- radlcal R2 1- furth~r prof~rably ~,5-dlhydro-5-oxo-~' ` . ` "; . ; ~ ' :
. -, 1,2,4-oxadlazol-3-yl, or further preferably ~,5-dl~ydro-5-thloxo-1,2,4-oxadlazol-3-yl, 2-oxo-3H-1,2,3,5-oxathl-~dlaæol-4-yl, 2,2-dloxo-3H-1,2,3,5-oxathladlazol-4-yl or 4,5-dlhydro-5-oxo-1,2,4-thlad~azol-3-yl S Ths radlcal R3 lo proferably ~ A, in partlcular methyl, further othyl, propyl, isopropyl, hutyl or l~obutyl;, cyclopropylmothyl ?
Th- radlcal R~ 18 pr-forably R9-S02-Tho radlcal R5 1~ preforably A, ln partlcular methyl, ethyl, propyl or butyls Ar, ln part~cular phsnyl;
~et-al~yl, 1~ partlcular 2-, 3- or 4-pyrldylmothyl; or cycloal~yl, ln partlcular cyclopropyl Th- radical R6 1~ prof-rably ~, or further A
Th- radlcal~ R7 and R~ aro preferably oach A
Tho radlcal R9 1- pr-forably A, ln partlcular methyl, furth-r othyl, propyl, lsopropyl, butyl or l~obutyl `
Tho paramot~r ~ 1~ prof-rably 0 or 1 Tho para-~etor m 1~ prof-rably 1 or 2 Tho parameter~ n and t are 20 pref-rably 1, or furthor pr-f-rably 2, 3 or ~ -Th- compo~nd~ of th- for~ula I can po~ ono or moro chlral c-ntr-- ~nd can t~ r-for- exi~t ln dlff-r-nt formJ (optlcally activ- or optlcally lnactlv ) Pormula I lncludo~ all th-~- formu Accordlngly th- lnv-ntlon r-lat-s sp-cl-lly to tho~- compound- of tho for~ul- I ln ~hlch at lea~t ono of sald radlcal~ has on- of th- pr-f-rr-d meaning~ lndlcated abo~- Somo pr-forrod group- of compound~ can be ~-~
~pr-ssod by th- follo~lng partlal formNla- Ia to Ic, whlch correspond to formNla I and whereln th radlcals ~ot de~crlbed r- precls-ly aro a~ doflnod ln for~ula I, excopt thats ln Ia Rl 1~ A;
~n Ib R2 1~ ~,5-dlhydro-5-oxo-1,2,~-oxadiazol-3-ylt in Ic Rl 1~ A and R2 1~ ~,S-dlhydro-5-oxo-1,2,~-oxa-dlazol-3-yl Th- followlng ar- also prof-rrod oo~pound~ of th- formula- Id and Iad to Icd, wh~ch corrospond to tho co~pound~ of th- formulao I and Ia to Ic, except that in addltlon R3 1~ A or cyclopropylmethyl;
compound~ of the formulae I-, Ia~ to Ido and Iade to Icde, whlch corro~pond to formulae I, Ia to Id and Iad to Icd, except that ln addltlon R~ 1~ A-SO2-~h- oompounds of the formula I and also the etartlng materlal~ for thelr preparation are mcreover prspared by msthod~ ~nown per -, 0uch a~ those de~cribod ln th- llterature (for exampl- ln the ~tandard wor~ e ~oubon-Woyl, Methoden der organl~chen Chemi- (Methodc of Organlc Ch d ~try), Georg-Thl~ -V~rlag, Stuttgart, but especlally ln Buropoan patent appllcatlon A2-0 ~30 709 and U8 patont ~ 880 804), under condltlonc whlch are ~nown and suitabl~ for eald reactlon~, it al~o being posclble to ma~- u~- of varlant- ~fiown per ~e, whloh are not montloned ln greater detall h~ro If de~lred, th- ~tart~g material~ can also be form d ln ~ltu, ~o that th-y are not l~olated from the reactlon mlxture but ~medlately roacted furth-r to g~-th- compound~ of th- for~ula I
(a) Th- compound~ of the formula I can b~
obtaln-d by reactlng compound~ of the formula II wlth co pound~ of the formwla III
In th- compound~ of th- formula II, ~ lc as pref-rably Cl, Br, I or an 0~ group whlch ha~ been functlonally modlflod to acguir-r-actlvlty, uch a- al~ylsulfonylo~y having 1-6 C atom~ (preferably methylsul-fonyloxy) or arylsulfonyloxy havlng 6-lO
C atom~ (pr-ferAbly ph-nyl- or p-tolyl-sulfonyloxy).
Th- reactlon of II wlth III 1- con-venlently carrled out by flrct convertlng III to a salt by tr-atment with a ba~-, for exampl- wlth ~n al~all metal alcoholate` ~uch a~ C~30Na or pota~-lu~
t-rt-butylat- ln an alcohol cuch ac methanol or tert-butanol, or wlth an al~all m tal carbonate cuch a~ ~2CO3, or ~ .
g ~lth an al~all motal hydrldo ~uch ae Na~, or wlth ~n al~all motal alcoholato ln dlmethylformamfdo (DM~), and thon roactlng sald salt wlth II In au lnort solvont, for oxa~plo an amldo euch a~
DNF, N-methylpyrrolldono or dimothylacet-amldo, or a sulfoxlds such a~ d~methyl ~ulfoxldo (DMSO), convonlontly at tem-porature- of between -20 and 100 , pro-forably of betwaen 10 nd 30 Otb~r sult blo baso~ aro al~all metal hydrogen oarbonatoo ~uch a~ Na~C03 or ~HC03 ~-~
~b) It 1~ furthermoro po~lblo to froo a compound of the formula I fro~ ono of lts lS functional dorlvatlves by solvolyei~ (for oxampl- hydrolysi~) or hydrogonoly~is ;~
Thu~ carboxyllc aclde of th- forrula I ;
whlch conta~n (at loaet) ono COO~ group ~ ~ i can b- obtalnod by tho saponlflcatlon of `
corro~pondlng al~yl stor~, for oxampl~
wlth NaOH or ~0~ in aquooue ~olutlon, with or wlthout tho addlt$on of n inort ~
organlc ~olvont ~ueh a~ othanol, ~-thanol, T~F or dloxan-, at t _ oraturo~
of b~two-n O and 100', or by th~
hydrogonoly~l~ of corroqpondlng b nzyl -~
o~tor~, for xamplo on Pd-on-charcoal at proe~uro~ of botwoon 1 and 200 bar and at ~ -t-~p-raturo~ of botwoon O and 100 , ln on- of th- ln-rt solvent~ lndicatod It 1- al~o po~slblo to cleavo wlth al~all a eo~pound whleh ha~ tho formula I but in ~hleh th- radleal R2 i~ replacod by S~
trlchloro~othyl-1,2,4-oxadlazol-3-yl group (whleh ean bo obtained by r-actlng a earboxa~ido oximo of tho for ula I, R2 . -C(N~2).NO~, with trichloroacotle ~-anhydrldo), for ~xamplo wlth NaO~ ln ~at-r/dlox no at 0-10 , tho corroepondlng , r ~
' '' -- 10 -eompound I, R2 . 4,5-dthydro-5-oxo-1,2,4-oxad~azol-3-yl, bolng obtained (c) Roaction of a nltr~lo which correeponde to formula I but instead of the radical R2 contain~ a CN group, with hydroxylam~ne ylolds th- eorre~po~ding carboxamlde oxlmo I, R2 . -C(NH2)~N~ Thle reactlon le convenlontly carrlod out ln an lnert solvent such as THF at temporatures b-t~een 20 and 100 (d) Co~pound~ of th- formula I wherein R2 le -802N~-CooR5, -So2N~-CoR5, -S02NH-S02R5 or -So2N~-CoNR5R6 ean bo obta~ned by n-acylation of eompounde whleh correepond to th- formula I but ln whieh th- radical R2 1~ roplaced by an -S02N~2 group Sultabl- aeylatlng agent~ aro, for exampl-, co~pound~ of the formula- ~-cooa5, for e~amplo mothyl ehloroformat-and ethyl chloroformate; E-CoR5, for exampl- ae-tyl ehlorido, eyelopropano-earbonyl ehlorld- or b~nzoyl ahlorld-; ~-802R5, for xampl- methan-sulfo~yl ehlorld-, p-tolu nosulfonyl ehlorld-s ~-C0-NRSR~, for oxamplo dlphonylcarba~oyl ehlorld-; 0-C-NRs, for oxa~pl- phonyl leocyanato Normally, th- reaetlon le performed ~n tho pro~once of a ba~o, proforably of a tort~ary a~ln-, for oxample trlothylumin-, pyrid~n- or 4-dimethyl-amlnopyrldlnQ, convenlontly at tempor-atur-~ b-tw en 0 and 100 An exe-e~ of th- amin- e n al~o b- ueod ae a eolver,t Th- reaet~on with ~soeyanates of the formula 0-C.NR5 to glve th~ correopond~ng sulfonylur-as 1- pref-rably perforred at tomp~ratur-r botwe-n 50 and 100 , an r~e-~ of th l~oey-nat- ~-1ng u~-d ~ -~.
solv nt Somo of tho etarting materiale, eopoeially tho~c of the formula II, are ~nown If they are not ~nown, they ean be prepared by ~nown methode analogouely to ~nown eub~tances .
It ~ 8 aloo poeeibl- to eonvert one eompound of the formula I to another compound of tho formula I by converting on~ or moro of the radiealo R a~d/or R2 to oth-r radleals a and/or R2, for exa~ple by roaeting a eompound of th- formul- I(R3 . ~) with a compound of tho formula ~-R3 (ln which R3 le different from ~) or by reducing nitro groupe to amino groupo (for examplo by hydrogonation on Raney nie~-l or Pd-on-ehareoal in an inert oolvent eueh ae mothanol or ethanol), and/or funetlonally dlfying free amlno and/or hydroxyl groupe, and/or fre-lng funetlonally modifiod amlno and~or hydroxyl groupo by colvolyele or hydrogonolyoi-, and/or hydroly~lng nitrll- groupe to C008 group~, and/or eet-rlfylng a carboxylle aeld group, for examplo by reaetion with an aleohol of th- formula A-0~ and/or eonv-rting a earbamidoxim group to a ~,5-dihydro-5-oxo-1,2,~-oxadlazol-3-yl group by roaetlor~ (a) with 1,1'-earbonyldlimidazol- or an al~yl chlorofor~ato, (b) to a ~,5-dihydro-5-oxo-1,2,~-thladlasol-3-yl group u~lng 1,1'-thiocarbonyldiimldazol-, ~c) to a 2-oxo-3~-1,2,3,5-oxathiadiazol-~-yl group usi~g SOC12 or (d) to a 2,2-dioxo-3~-1,2,3,5-oxathladlazol-~-yl group uelng S02Cl2, and/or eonvorting an S02N~-COOR5 group to an -~02N~-CO-NR5RC group by amidation wlth a compound of th formul~
Compou~ds of tho formula I (R3 . H) ean thue b-al~ylatod by r~actlon ~lth eompoundo of th~ for~ul~ ~-R3 (~horoln R3 le diff-rent fro~ ~) Th~ roaetlon le profor-ably carrl~d out ln an lnert solv~nt, for oxa~pl- an aeld a id eueh ao DM~, N-methylpyrrolidon-, 1,3-dim thyl-2-oxohexahydropyrimldin- or hox~mothylphoephora~ldo, an aleohol ueh a~ m thanol or t-rt-butanol, an eth-r eueh ae T%P or ~ halog nat-d hydroearbon sueh ae dlehloro-methano or mixturoe thoreof ae eolv~nto and/or lu tho ~ $ ~ ~
~ r ' '~
~ 2133939 pre~ence of ~n al~ali motal alcoholate ~uch a~ sodium methylat~ or potaeei~m tort-butylate, ~ al~all motal hydrldo euch a~ sodiu~ hydrido or pota~lum hydrldo, an al~all metal carbo~ato ~uch as eodlum carbonato or S potae~um carbonate, àn al~all metal blcarbonato ~uch as ~od~um blcarbonate or potaeeium blcarbonate or a tertlary amin~ such a~ triethyla~i~e or ethyldii~opropylamine at temporaturo~ botwoon about -30 and 200, proferably betwoen 20 and 60 Further~oro, freo ~mino groupe can bo acylated ln con~ontlonal manner wlth an acld chlorld- or anhydr~do, or al~ylatod wlth an un~ub~tituted or cub~tltuted al~yl halido, convonlontly ln an lnort ~olvent ~uch as ~ethyl-eDe chlorlde or TEP, and/or in the prosonco of a ba~o ~uch ac triethylamtne or pyrid~ne, at temperature~ of betwoon -60 and ~30 If deelrod, a functlonally modlfiod amlno and/or hydroxyl group ln a co~pound of tho formula I can be frood by solvolyele or hydrogenolyele uelng conventlonal methode Thu~, for examplo, a compound of th- fo ula I
contalnlng an N~COR9 or COOA group can ~o conv-rtod to thc ¢orreepondtng compound of th- formula I containl~g an N9~ or ~OCC group instead COOA groupa can b- ~apontfled for oxa~pl- wlth ~aO~ or ~O~ ln wator, water/TEF or wator/dloxan-, at tomporatur-~ of botween 0 and 100 Th- abovemontionod eonv-relon8 of a earbamidoxt~o group (I, ~2 . -C(NE~).NO~) to varlous abov~mentloned hotoroeycllc radieal~ 1~ proforably earri~d out in th-pre~enco of an inert ~olvont, for example of an othor cuch a~ T~, of a hydroearbon ~ueh a~ toluon~, of an ~do ~ueh a~ DMF, of a halogenated hydrocarbon ~ueh a~
dlchloromothan- or of a ba~- ~ueh a~ pyridin- or of m$xt~so of two of thoso ~olv~nt~ at temporaturoa botwoon O and 100 A ba~o of tho formula I ean be conv0rtod with an aeid to th~ corrosponding aeld addition salt, for oxample by reactlon of oguivalont amount~ of tho ba~o and of tho ae$d ln an inort aolvont oueh aD othanol and eub~oguent ovaporation Po~siblo aeld~ for thi~ roaction aro ':
. ~
eepeclally thoso ~hlch yl~ld physlologically acceptabl~
- ealte ~hu~ lt 18 poseibl- to ue~ lnorganlc aclde, for example sulfuric acld, nltric acid, hydrohalic aclde euch as hydrochloric acld or hydrobromic acld, phoephorlc aclde euch ae orthophoephoric acld, and eulfamlc acld, ae woll ao organlc aclds, espoclally allphatic, allcyclic, arallphatlc, aromatlc or hetorocycllc monobaeic or polybaelc carboxylic, sulfonic or eulfurlc acld-, for oxamplo for~lc acid, acotic acid, prop~onic acld, plvalic acid, diothylac-tlc acid, malonlc ac~d, euc¢lnlc acld, pimellc acld, fumar~c acld, mal-lc acld, lactic acid, tartaric acld, mallc acid, citric acid, gluconlc acld, aecorbic acld, nlcotinic acid, ieonlcotinlc acld, mothano- or othan--eulfonic acid, ethanedleulfonlc acld, 2-hydroxy~than~eulfonlc acld, b-nzeneeulfonlo acld, p-toluon-sulfonlc acld, naphthal-no- noeulfonlc and -dlsulfonlc acid~ and lauryleulfuric acld 8alt~ wlth phy~lologlcally unacc-ptabl- acld~, for xampl- plcrat~, oan b- ue-d for l~olatlng and/or purlfylng th~ compound of tho for~ula I
On tho oth-r hand, compound~ of th- formula I
contalnlng C00~ or, for xa~pl-, 1,2,~-oxadiazol- group~
can b- oonv-rted wlth ba~ for xa~pl- eodlu~ or pota~lu~ hydroxid- or carbonat-) to th- oorro~ponding m tal ~alt~ p-cially al~ali m tal or al~alln arth m~tal ~alt~, or to th- oorr-~pondlng ammonlu~ ealt~ Th potaselu~ ealto of th- 1,2,~-oxadlazolo dorlvatlve~ ar-partloularly preforred Th- nov-l compound~ of the for~ula I and th-ir phyelologioally acooptabl- calts oan b- ueot for th manufaoturo of pha-mAo-utical preparation~ by incorporatlon lnto a ~ultablo doeag- fon~ tog~th r wlth at leaet ono exolplont or ad~unot and, lf deelr-d, together wlth on- or ~oro othor aotlvo lngredlent~ Th r-eultlng formulation~ ca~ bo ueod a~ drugs ln human or ~otorlnary ~odioin- Poe~lbl- oxoipient~ ar- organic or lnorganlc ~ub~tanc-~ whlch ar- ~ultabl- for onter-l (for examplo oral or root-l) or parentoral ~lnlstratlon or for ad~lnl-tratlon ln tho form of an inhalation epray, . ,~., and whlch do not roact wlth tho novol cQ~pound~ ple-belng wator, vegetablo oll-, be~zyl alcohols, polyothylone glycol~, glycorol trlacotato and other fatty acld glycorldo~, golatin, ~oya leclthln, carbohydrate~
~uch a~ lactoso or atarch, magne~lum ~tearat~, talc and celluloso Tablets, coatod tabloto, cap~ulee, syrupo, ~uices or drop~, ln partlcular, aro ueed for oral admlnlotratlons ~pocl-l lacquorod tablet- and cap~ulos wlth coatlng~ or sh-ll~ rooletant to ga~trlc ~ulce- ar~
of lntor~t ~uppo~ltorlo~ ar- used for rectal adblnl~-tratlon and ~olutlon-, proforably olly or aqueou~ aolu-tlon~, a~ woll a~ ~u~pon~lon~ uls~onc or lmplant~, ar-u~ed for paronteral adm~nl~trat$on For admlnlotratlon as lnhalatlon ~pray~, lt ~ po~lblo to uso opray~ contaln-lng tho actlv~ ingr-dlent olth-r d~s~olved or su~pended ln a propollant ga- ~lxtur- It 1~ con~onlont hor- to u~e tho actlv- lngr-dl-nt ln lcronl~od for~, lt bolng po~lbl- for ono or ~or- addltlonal phyclologlcally compatlbl- ~olvont-, for oxa pl- othanol, to bo pro~ont Inhalatlon ~olutlon~ c~u bo admlnlatorod wlth th- ald of conventlonal lnhalor~ Tho nov-l compounds can bo lyo-phllla-d nd th- r--ultlng lyophlllrat-- u~od for oxa~pl-for th- nuf-ctur- of ln~-ctabl- proparatlon~ Th lndlcat-d for~ul-tlon- c~n b- ~t-rllleod and/or can contaln ad~unet~ ~uch a- pr---rv tlvoc, ~tablll~or~
nd/or ~ ttlng ago~t-, ooulclfl-ra, a~lta for l~flu~ncing th- o-~otle pr-a-ur-, buff-r ubat ncoa and eolouro a~d/or flavourlnga If doalrod, th-y ean al80 coutaln ono or moro oth-r actlv- lngrodlont-, for oxamplo ono or ~oro vltamlna, dlur-tlea or antlphloglatlea Th- aub~tanc-a aecordlng to tho lnvention ar-normally admln~atorod nalogoualy to oth~r known, coomorclally avallablo pr-paratlon~, for exumpl- cap-toprll or nalaprll, but ln p rtlcular nalogoualy to th~
compounda d-acrlb-d ln ~ patent ~ 880 80~, pr-forably lu dos-a of bot~oon about 1 ~g and 1 g, o~p~c~ally of botwoon 50 nd 500 m~ por aoaag- unlt Th~ dally do~o 1 prof-rably b-t~-on bout 0 1 and 50 mg/~g, ~p-clally botwoon 1 and 10 ~g/~g of body ~$ght ~ow v~r, th-2133933 : ~:
~ 15 -partlcular dose for each ~ndividu~l patient deponds on a very wide variety of factor~, for example on the eficacy of tho partlcular compound u~ed, age, body weight, genoral ~tate of health, sox, diot, time and mode of adminietration, rat- of excretlon, drug co~bination and soverity of th- particular disea~e to which the therapy ie applied Oral administration ~ preferred Above and below, all temporatures aro givon in C ~n the following examples, ~conventional wor~ing-up~
mean~ Water i8 add-d if noc-soary, the p~ is ad~usted to between 2 and 10 if necessary, depending on the con~titution of th- end product, extraction 1~ carried out with ethyl ac-tate or ~ethylen- chlorlde and the organic phase i8 ~eparat-d off, dried ovor sodium ~ulfate, evaporated and purifi~d by chromatography on eillca g-l and/or by cry~talllzation FAB ~ molecul-r ion pea~ (M~ ~ 1) obtain-d ~a~ pectroecoplcally by the ~fa~t ato~ bombardment~ mothod Exampl- 1 A olutlon of 2 72 g of 1,2-dihydro-2-oxo-3-N-m thyl-N-~ethyl~ulfonylamino~ thyl-6-butylpyrldln- (PAB
273~ obtalnable by r-actlon of 1,2-dlhydro-2-oxo-6-butylpyrldln--3-carboxald-hyd- wlth ~ethylam~n-/E~ to glve 1,2-dlhydro-2-oxo-3-~ethylaminomethyl-6-butyl-pyrldln- and ~ub~-gu-nt roactlon wlth methan-~ulfonyl chlorld-) ln 30 ~1 of DMP 1~ treated wlth 1 12 g of t-rt-butoxld- and th- mixtur- 1- stlrred at 20 for 1 hour A eolutlon of 3 31 g of ~-bromomethyl-2'-~,5-dlhydro-5-oxo-1,2,~-oxodlazol-3-yl)blphenyl (obtalnable by reactlon of 4-methyl-2'-cyanobiphenyl with hydroxylamin- to glv- ~-~ethyl-2'-(am~nooxtminomethyl)-blph-nyl, reaotlon wlth ethyl chloroformat- to glve ~-~othyl-2'-(~,5-dlhydro-5-oxo-1,2,~-oxadlazol-3-yl)-blphenyl and brom$nat$on) ln 35 ml of DM~ lo then added dropw~s- at 0 wlth ~tirrlng The m~xture lo otirr~d at 20 for 16 hour- and evaporat-d, and the re~ldu~
wor~ed up ln th- cu-tomary m~nn-r and 1,2-dihydro-1-(2~-(~,5-dlhydro-S-oxo-1,2,~-oxad~azol-3-yl)biphenyl-~-.r~ 2133939 ylmethyl)-2-oxo-3-N-methyl-N-methylsulfonyl~nomethyl-6-butylpyridino ~Ix~), m p 207 i8 obtained ~ salt, Rf 0 27 on silica gol (ethyl acetate) ExamDl- 2 S 1 5 ml of 1 N NaO~ are added dropwlee w$th lce cooling to a ~olutlon of 1 g of 1,2-dihydro-1-(2'-(5-trichloromethyl-1,2,~-oxadiazol-3-yl)biphenyl-4-yl-methyl)-2-oxo-3-N-~ethyl-N-methylsulfonylaminomethyl-6-butylpyrid~n- (obtalnable from 3-(4'-bromomethyl-2-bi-ph-nylyl)-5-trichloromethyl-1,2,~-oxadiazole (~P-A2-520423, ~xamplo 22 c) and 1,2-dihydro-2-oxo-3-N-methyl-N-methylsulfonylaminomethyl-6-butylpyrldine analogously to Bxampl- 1) in a mixtur~ of 8 ml of dioxane and 2 ml of water, and the d xture ~8 stlrred for 30 min w~th lce-coollng, wor~-d up ln the customary manner (dllute hydrochlor~c ac$d/othyl acetate) and ~Ix~ i~
obtaln-d, m p 207 ExamDle 3 (a) A ~olution 7 1 g of hydroxylammonium chloride ln 30 ml of DMSO 1~ tr-ated wlth 14 4 ml of tri-thylamln- ln 40 ml of T~F Th- solut~on 1~ filt-red, and th- flltrat-i~ vaporat-d and tr-at-d with 4 63 g of 1,2-dihydro-1-(2'-oyanoblph-nyl-~-ylmothyl)-2-oxo-3-N-methyl-N-m thyl-~ulfonylaminom thyl-6-butylpyrldln- (Rf 0 35 (p-troleum ther/othyl acetat- ~ 6); obtalnabl- by reaction of 1,2-dihydro-2-oxo-3-N-methyl-N-methylsulfonylaminomethyl-6-butylpyrldin- with ~'-bromom thyl-2-cyanobiphenyl) and a furth-r 3 5 ~1 of tri-thylamine The solution ia stirr-d for 16 hour- at 75 It 18 cooled, poured into water, and the proolpltat-d 1,2-dihydro-1-(2'-( d noox~nomethyl)-biphenyl-~-ylmethyl)-2-oxo-3-N-methyl-N-methyl~ulfonyl-aminomothyl-6-butylpyridine (~A ) is filtered off and drl-d (b) A suspension of ~ 96 g of A (crude) in 32 ml of ~EF ie treat-d with 2 ~ g of l,l'-carbonyldilmldazolo and h-atod wlth ~tlrrlng for 7 hour~ Ths mi~ture 18 e~apor-atod and wor~ed up ln th- cu~tomary (ethyl acetate/dilute ~ ~133939 H2S0~, and ~Ix~ i~ obtained m.p. 207.
Analogou~ly to a~, fro~ tho 1,2-dlhydro-1-(2'-cyanobiphenyl-4-ylmsthyl)-2-oxo-3-N-R3-N-mothyleulfonyl-aminomethyl-6-butylpyridino~ below (obtainable by S reaction of 1,2-dihydro-2-oxo-6-butylpyridine-3-carbox-aldehydo with amine~ of the formula R3-NH2/H2 to give 1,2-dlhydro-2-oxo-3-N-R3-aminomethyl-6-butylpyridines, reac-tion with methane~ulfonyl chloride/pyridino to give 1,2-dihydro-2-oxo-3-N-R3-N-~ethyl~ulfonylamlnomethyl-6-butyl-pyridino- and reaction with ~'-bromomethyl-2-cyano-biphenyl):
-3-N-ethyl--3-N-propyl--3-N-i~opropyl--3-N-butyl--3-N-i~obutyl--3-N-cyclopropylmothyl-wlth hydroxyla~monium chloride/trlethylam~ne th- 1,2-dihydro-1-(2'-(aminooxim~no~thyl)blphenyl-4-ylmethyl)-2-oxo-3-N-R3-N-methyl-ulfonylaminomethyl-6-butylpyridlne~
below aro obtain-d: -~
-3-N-othyl--3-N-propyl--3-N-l~opropyl--3-N-butyl--3-N-i-obutyl--3-N-cyclopropylmethyl-and from tho~o analogou~ly to b) wlth 1,1'-carbonyldi-imldazolothol,2-dihydro-1-(2'-(4,5-dlhydro-S-oxo-1,2,4- ;
oxadiazol-3-yl)biphenyl-4-ylmethyl)-2-oxo-3-N-R3-N-meth- -~
yl~ulfonylamlnomethyl-6-butylpyridines below: -~ ~--3-N-othyl--3-N-propyl--3-N-isopropyl--3-N-butyl- ~ ---3-N-isobutyl--3-N-cyclopropylmothyl.
. 2133939 - le-Exampl~ ~
(a) 550 ~g of ethyl chloroformato ar~ added to a 801u-tion of 527 ~g of 1,2-dlhydro-1-(2'-amino~ulfo~yl-biphenyl-4-yl~ethyl)-2-oxo-3-N-mothyl-N-methyl-~ulfonylamlnomothyl-6-butylpyrldine(~B~;obtainabls by roaction of 1,2-dihydro-2-oxo-3~N-msthyl-N-methylsulfonylaminomethyl-6-butylpyr~d~no with N-tort-butyl-4~-bromomethylblphenyl-2-sulfonamide to g~e 1,2-d~hydro-1-(2'-N-tert-butylaminosulfonyl-biphenyl-~-ylmethyl)-2-oxo-3-N-mothyl-N-methyl-sulfonylAm~nomethyl-6-butylpyrid~ne and remo~al of tho t-rt-butyl group using CF3COO~/anl~ole) and 360 ~ of 4-d~methylaminopyr~dine in 12 ml of pyridine, the mixture 1B stirred for 48 hours at 20, 8 ml of methanol are addod and it i~ wor~ed up in th- customary manner 1,2-D~hydro-1-(2'-(N-etho~cycarbonyl~m~no~ulfonyl)blphonyl-4-ylmethyl)-2-oxo-3-N-thyl-N-m-thyl~ulfonylaoino~et~yl-6-butyl-pyridin- 1B obtained 1,2-Dihydro-1-(2'-(N-buto~ycarbonylamino-~ulfonyl)blph nyl-4-ylm-thyl)-2-oxo-3-N-mothyl-N-methyl-~ulfonylaminomethyl-6-butylpyridin~ 1~ obtalnsd analo-gously from ~ and butyl chlorofor~ate The 1,2-dlhydro-1-(2'-R2-biphenyl-4-ylmethyl)-2-oxo-3-N-m~thyl-N-methyl~ulfonylaminomethyl-6-butyl-pyridlne~ b-low ar- obtalned analogou~ly using acetyl chloride, propionyl chlorld~, butyryl chlorlde, cyclo-propylcarbonyl chlorld~, cyclopropylacotyl chlorld-, cyclopsntylcarbonyl chlorid-, bsnzoyl chlorids, p-meth-oxybsnzoyl chlorid-, p-chlorobonzoyl chlorld~ or 2-thlenylcarbonyl chloride inst-ad of ethyl chloroformat--3-(2'-(acetylaminosulfonyl)blphenyl-4-ylm~thyl)--3-(2'-(propionylaminosulfonyl)biphenyl-4-ylmethyl)--3-(2'-(butyrylaminosulfonyl)blphenyl-4-ylmet~yl)--3-(2'-(cyclopropylcarbonylaminosulfonyl)blphenyl-4-ylmothyl)--3-(2'-(cyclopropylacetyl~nosulfo~yl)blphsnyl-~-ylmethyl)-f~
.~.;,~............................ g -3-(2'-(cyclopentylcarbonylam~nosulfonyl)biphenyl-4-ylmethyl)--3-(2'-(benzoylaminosulfonyl)b$phenyl-4-ylmethyl)--3-(2'-(p-methoxybenzoylaminosulfonyl)blphenyl-4-ylmethyl)--3-(2'-(p-chlorobenzoylamlnosulfonyl)biphenyl-4-ylmethyl)--3-(2'-(2-thienylcarbonylaminosulfonyl)b~phenyl-4-ylmethyl)-. ~-10 (b) A solution of 598 mg of the ethoxycarbonyl ~ A'' compound obtalned a~ in (a) and 108 mg of 2-aminomethyl-pyridine ln 30 ml of tolue~e i~ heated for 2 hours, cooled and wor~ied up in th- customary manner. 1,2-Di-hydro-1-(2~-N-(N-2-pyridylmethylcarbamoyl)amlnosulfonyl-biphenyl-4-ylmethyl)-2-oxo-3-N-methyl-N-methylsulfonyl-aminomethyl-6-butylpyridine 18 obtained.
Example 5 A mlxture of 527 mg of ~B~ and 7 ml of phenyl lsocyanate i~ heated for 4 hour~ at 80. It i8 cooled, the exces~ phenyl isocyanato 18 di~tilled off and 1,2-dihydro-1-(2'-N-(N-phenylcarbaooyl)ami~osulfonylbiphenyl-4-ylmethyl)-2-oxo-3-N-methyl-N-m~thylsulfonyl-amino-methyl-6-butylpyrldine is obtained aft~r chromatographic puriflcation.
xample 6 496 mg of A- are suspended under argon ln 7 ml of pyridlne and treated dropwise at 0 wlth ~tlrrlng with a ~olution of 0.09 ml of ~OC12 in 3.5 ml of CH2C12. The mixture ~ 8 stirred for a further 2 hours at 0, poured into 500 ml of water and wor~ed up ln tho customary manner, and 1,2-dlhydro-1-(2'-(2-oxo-3~-1,2,3,5-oxathia-diazol-4-yl)biphenyl-4-ylmethyl)-2-oxo-3-N-m-thyl-N-mothylsulfonylaminomethyl-6-butylpyrldine is obtalned.
Bxample 7 1,2-Dlhydro-1-(2'-(2,2-dioxo-3~-1,2,3,5-oxa-thiadiazol-4-yl)biphe~yl-~-ylmothyl)-2-oxo-3-N-methyl-N-~ ~r .
methylsulfonylami~omethyl-6-butyl-pyr$dine i8 obtained analogou~ly to Example 6 from A- and S02C12.
.. . '.
Example 8 A mixture of 496 ~g of A-, 10 ~1 of TaP and S 180 mg of l,l'-thiocarbonyldlimidazole i8 st$rred for 30 min at 20 and evaporated. The re~idue i~ dissolved in ethyl ac~tate, washed with dilute hydrochlor$c acid and then with water, dried and evaporated agaln. The resldue ;~
thu~ obtalned i~ d~s~olved in a m$~tur~ of 60 ml of chloroform and 12 ml of methanol. 3.5 g of silica gel are added to thi~ solutlon, th~ mlxture 1~ stirred for 48 hours at 20, filtered and ovaporated and the residue ~e purified by chromatography on ~$1$ca gel. 1,2-Dihydro-l-(2'-(4,5-dihydro-5-oxo-1,2,4-thlad$azol-3-yl)blphenyl-4-ylmethyl)-2-oxo-3-N-methyl-N-metbylsulfonylamln~m^thyl-6-butylpyr$dine i~ obta$ned.
' ' : ~ . :-Example 9 4.96 g of A- are d$scolved in 50 ml of dichloro-mothane, 1.15 g of tr$etbylamine and 1.15 g of acetic anbydride ar- add-d and th- mlxtur- is stirred for 2 hours at 20. It ic evaporat-d and the res$due $e wor~ed up in the cu~tomary manner (ethyl acetat-/water;
washing with NaHC03 solution) and th- result$ng crude acetyl derivativ- ia d$ssolved ln 30 ~1 of DMP. 4 g of CS2 are added f$rct, then, ln the cour~e of 10 m~nutee, NaH (60 %, ln o$1; 1.4 g) and th~ mixture $8 stirred for 2 hours at 20. After cuotomary wor~ng up (pH 3, lce water), 1,2-dihydro-1-(2'-(4,5-dlhydro-5-thloxo-1,2,4-oxad$azol-3-yl)b$phenyl-4-ylmethyl)-2-oxo-3-N-metbyl-N-methyleulfonylamlnomethyl-6-butylpyrld$ne 18 obta$ned.
~, 21 2133939 E~ample 10 a) Analogously to E~arnple 3a), 1,2-dihydro 1-(2'-(a nino-oximino-methyl)-biphenylyl4-methyl)-2- o~o-3-N-methyl-N-methylsulfonyl-aminomethyl-~
propyl-pyridineisobtainedfrom 1,2-dihydro-1~2'-cyano-biphenylyl4- ~ ~ -methyl)-2-oxo-3-N-methyl-N-methylsulfonyl-aminomethyl-~propyl-pyridine (obtainable by reaction of 1,2-dihydr~2-oxo-3-N-methyl-N-methylsulfonyl-aminornethyl-~propyl-pyridine with 4'-bromomethyl-2-cyano-biphenyl) with hydro~ylammoniumchoride/triethylamine.
b) Analogously to E-~ample 3b), 1,2-dihydr~1-(2'-(4,5-dihydro-5-oxo-1,2,4-o~adiazol-3-yl)-biphenylyl-4-methyl)-2-oxo-3-N-methyl-N-methylsulfonyl-aminomethyl-~propyl-pyridine is obtained from the compound prepared according to a) with 1,1 carbonyldiimidazole.
Analogously to there are obtained from the following 1,2-dihydro-1-(2'-cyano-biphenylyl4-methyl)-2-o~o-3-N-R3-N-methylsulfonyl-amjnomethyl- .
~propyl-pyridines (obtainable by reaction of 1,2-dihydro-2-o~lo~propyl-pyridine-3 carbo~caldehyde with amines of formula R3-NH2/H2 to 1,2-dihydro-2-o~o-3-N-R3-aminomethyl-~propyl-pyridines, conversion with methanesulfonyl chloride/pyridine to 1,2 dihydro 2-oxo-3-N-R3-N-methyl-sulfonyl-aminomethyl~propyl-pyridines and reaction with 4'-bromomethyl-2-cyano-biphenyl):
-3-N~yl--3-N-propyl--3-N-isopropyl--3-N-butyl--3-N-isobutyl--3-N-cyclapropylmethyl-wi~ hydrw~ylarnmonjum chloride/triethylamine the following 1,2-dihydro-1-(2'-an~ino-o~imino-methyl)-biphenylyl~-methyl~2-o~o-3-N-R3-N-methylsulfonyl-aminomethyl-~propyl-pyridines:
~ , .
"` -22- 2133939 ... -. ~.
-3-N-ethyl- .; .. :.
-3-N-propyl--3-N-isopropyl- , -3-N-butyl--3-N-isobutyl -3-N-cyclopropylmethyl-,. . ;.
and from these, in analogy to b), with l,1'4arbonyldiimidazole the following 1,2-dihydr~1-(2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenylyl-4-methyl)-2-oxo-3-N-R3-N-methylsulfonyl-aminomethyl-~propyl-pyridines~
-3-N-ethyl--3-N-propyl- ~: ::
-3-N-isopropyl--3-N-butyl--3-N-isobutyl--3-N-cyclopropylmethyl-, oil.
Th- followlng axampl-- rol~t~ to pharmac-utlc~
for~ul~tlon~ contalnlng actlv lngredl-nt~ of th- formula ;~
I or tholr ~lt~
ExamDl- A Ta~l-tc and coat d tabl-t~
Tabl~t~ of tho follo~lng co~po~lt~on aro produc-d .:
.
,~ .
by compr-aaion in conventional mannor and, whero rogulr-d, are provlded with a conventional eucrose-baaed coating Activo lngredient of tho formula I100 mg 5 Microcry~talline celluloae 278 8 mg Lactoao 110 mg ~alze atarch 11 mg Magnoaium atearat- 5 mg Finely divlded eilicon dloxido0 2 mg ~xamplo ~ ~ard golatin cap~ulea Convent$onal two-part hard gelatin cap~ules are each filled with Actlvo lngrediont of tho formula I100 mg ~actoao 150 mg 15 Celluloao 50 mg Magnealum atearat- 6 mg Exampl- Cs Soft gelatin cap~uloa Conv-ntional aoft gelatin capaule~ aro filled with a mixturo of 50 mg of actlve ~ngrediont and 250 mg of ollvo oll ln oach ca~e Exampl- D~ Ampoul-a A ~olutlon of 200 g of actlvo lngredlent in 2 ~g of propano-1,2-diol 1~ mado up to 10 1 with ~at-r and flllod into a~pouloa ~o that oach ampoulo containa 20 mg of activo lngrodient ~xampl- ~ Aquooua au-penaion for oral adminiatration An aquooua au~pension of the activo ingrodient iB
propared i~ conventional manner Tho unit doao (5 d ) containa 100 mg of active lngr-dlent, 100 mg of Na carboxymothylcolluloao, 5 mg of Na benzoato and 100 mg of sorbitol ., '~ . '
. -, 1,2,4-oxadlazol-3-yl, or further preferably ~,5-dl~ydro-5-thloxo-1,2,4-oxadlazol-3-yl, 2-oxo-3H-1,2,3,5-oxathl-~dlaæol-4-yl, 2,2-dloxo-3H-1,2,3,5-oxathladlazol-4-yl or 4,5-dlhydro-5-oxo-1,2,4-thlad~azol-3-yl S Ths radlcal R3 lo proferably ~ A, in partlcular methyl, further othyl, propyl, isopropyl, hutyl or l~obutyl;, cyclopropylmothyl ?
Th- radlcal R~ 18 pr-forably R9-S02-Tho radlcal R5 1~ preforably A, ln partlcular methyl, ethyl, propyl or butyls Ar, ln part~cular phsnyl;
~et-al~yl, 1~ partlcular 2-, 3- or 4-pyrldylmothyl; or cycloal~yl, ln partlcular cyclopropyl Th- radical R6 1~ prof-rably ~, or further A
Th- radlcal~ R7 and R~ aro preferably oach A
Tho radlcal R9 1- pr-forably A, ln partlcular methyl, furth-r othyl, propyl, lsopropyl, butyl or l~obutyl `
Tho paramot~r ~ 1~ prof-rably 0 or 1 Tho para-~etor m 1~ prof-rably 1 or 2 Tho parameter~ n and t are 20 pref-rably 1, or furthor pr-f-rably 2, 3 or ~ -Th- compo~nd~ of th- for~ula I can po~ ono or moro chlral c-ntr-- ~nd can t~ r-for- exi~t ln dlff-r-nt formJ (optlcally activ- or optlcally lnactlv ) Pormula I lncludo~ all th-~- formu Accordlngly th- lnv-ntlon r-lat-s sp-cl-lly to tho~- compound- of tho for~ul- I ln ~hlch at lea~t ono of sald radlcal~ has on- of th- pr-f-rr-d meaning~ lndlcated abo~- Somo pr-forrod group- of compound~ can be ~-~
~pr-ssod by th- follo~lng partlal formNla- Ia to Ic, whlch correspond to formNla I and whereln th radlcals ~ot de~crlbed r- precls-ly aro a~ doflnod ln for~ula I, excopt thats ln Ia Rl 1~ A;
~n Ib R2 1~ ~,5-dlhydro-5-oxo-1,2,~-oxadiazol-3-ylt in Ic Rl 1~ A and R2 1~ ~,S-dlhydro-5-oxo-1,2,~-oxa-dlazol-3-yl Th- followlng ar- also prof-rrod oo~pound~ of th- formula- Id and Iad to Icd, wh~ch corrospond to tho co~pound~ of th- formulao I and Ia to Ic, except that in addltlon R3 1~ A or cyclopropylmethyl;
compound~ of the formulae I-, Ia~ to Ido and Iade to Icde, whlch corro~pond to formulae I, Ia to Id and Iad to Icd, except that ln addltlon R~ 1~ A-SO2-~h- oompounds of the formula I and also the etartlng materlal~ for thelr preparation are mcreover prspared by msthod~ ~nown per -, 0uch a~ those de~cribod ln th- llterature (for exampl- ln the ~tandard wor~ e ~oubon-Woyl, Methoden der organl~chen Chemi- (Methodc of Organlc Ch d ~try), Georg-Thl~ -V~rlag, Stuttgart, but especlally ln Buropoan patent appllcatlon A2-0 ~30 709 and U8 patont ~ 880 804), under condltlonc whlch are ~nown and suitabl~ for eald reactlon~, it al~o being posclble to ma~- u~- of varlant- ~fiown per ~e, whloh are not montloned ln greater detall h~ro If de~lred, th- ~tart~g material~ can also be form d ln ~ltu, ~o that th-y are not l~olated from the reactlon mlxture but ~medlately roacted furth-r to g~-th- compound~ of th- for~ula I
(a) Th- compound~ of the formula I can b~
obtaln-d by reactlng compound~ of the formula II wlth co pound~ of the formwla III
In th- compound~ of th- formula II, ~ lc as pref-rably Cl, Br, I or an 0~ group whlch ha~ been functlonally modlflod to acguir-r-actlvlty, uch a- al~ylsulfonylo~y having 1-6 C atom~ (preferably methylsul-fonyloxy) or arylsulfonyloxy havlng 6-lO
C atom~ (pr-ferAbly ph-nyl- or p-tolyl-sulfonyloxy).
Th- reactlon of II wlth III 1- con-venlently carrled out by flrct convertlng III to a salt by tr-atment with a ba~-, for exampl- wlth ~n al~all metal alcoholate` ~uch a~ C~30Na or pota~-lu~
t-rt-butylat- ln an alcohol cuch ac methanol or tert-butanol, or wlth an al~all m tal carbonate cuch a~ ~2CO3, or ~ .
g ~lth an al~all motal hydrldo ~uch ae Na~, or wlth ~n al~all motal alcoholato ln dlmethylformamfdo (DM~), and thon roactlng sald salt wlth II In au lnort solvont, for oxa~plo an amldo euch a~
DNF, N-methylpyrrolldono or dimothylacet-amldo, or a sulfoxlds such a~ d~methyl ~ulfoxldo (DMSO), convonlontly at tem-porature- of between -20 and 100 , pro-forably of betwaen 10 nd 30 Otb~r sult blo baso~ aro al~all metal hydrogen oarbonatoo ~uch a~ Na~C03 or ~HC03 ~-~
~b) It 1~ furthermoro po~lblo to froo a compound of the formula I fro~ ono of lts lS functional dorlvatlves by solvolyei~ (for oxampl- hydrolysi~) or hydrogonoly~is ;~
Thu~ carboxyllc aclde of th- forrula I ;
whlch conta~n (at loaet) ono COO~ group ~ ~ i can b- obtalnod by tho saponlflcatlon of `
corro~pondlng al~yl stor~, for oxampl~
wlth NaOH or ~0~ in aquooue ~olutlon, with or wlthout tho addlt$on of n inort ~
organlc ~olvont ~ueh a~ othanol, ~-thanol, T~F or dloxan-, at t _ oraturo~
of b~two-n O and 100', or by th~
hydrogonoly~l~ of corroqpondlng b nzyl -~
o~tor~, for xamplo on Pd-on-charcoal at proe~uro~ of botwoon 1 and 200 bar and at ~ -t-~p-raturo~ of botwoon O and 100 , ln on- of th- ln-rt solvent~ lndicatod It 1- al~o po~slblo to cleavo wlth al~all a eo~pound whleh ha~ tho formula I but in ~hleh th- radleal R2 i~ replacod by S~
trlchloro~othyl-1,2,4-oxadlazol-3-yl group (whleh ean bo obtained by r-actlng a earboxa~ido oximo of tho for ula I, R2 . -C(N~2).NO~, with trichloroacotle ~-anhydrldo), for ~xamplo wlth NaO~ ln ~at-r/dlox no at 0-10 , tho corroepondlng , r ~
' '' -- 10 -eompound I, R2 . 4,5-dthydro-5-oxo-1,2,4-oxad~azol-3-yl, bolng obtained (c) Roaction of a nltr~lo which correeponde to formula I but instead of the radical R2 contain~ a CN group, with hydroxylam~ne ylolds th- eorre~po~ding carboxamlde oxlmo I, R2 . -C(NH2)~N~ Thle reactlon le convenlontly carrlod out ln an lnert solvent such as THF at temporatures b-t~een 20 and 100 (d) Co~pound~ of th- formula I wherein R2 le -802N~-CooR5, -So2N~-CoR5, -S02NH-S02R5 or -So2N~-CoNR5R6 ean bo obta~ned by n-acylation of eompounde whleh correepond to th- formula I but ln whieh th- radical R2 1~ roplaced by an -S02N~2 group Sultabl- aeylatlng agent~ aro, for exampl-, co~pound~ of the formula- ~-cooa5, for e~amplo mothyl ehloroformat-and ethyl chloroformate; E-CoR5, for exampl- ae-tyl ehlorido, eyelopropano-earbonyl ehlorld- or b~nzoyl ahlorld-; ~-802R5, for xampl- methan-sulfo~yl ehlorld-, p-tolu nosulfonyl ehlorld-s ~-C0-NRSR~, for oxamplo dlphonylcarba~oyl ehlorld-; 0-C-NRs, for oxa~pl- phonyl leocyanato Normally, th- reaetlon le performed ~n tho pro~once of a ba~o, proforably of a tort~ary a~ln-, for oxample trlothylumin-, pyrid~n- or 4-dimethyl-amlnopyrldlnQ, convenlontly at tempor-atur-~ b-tw en 0 and 100 An exe-e~ of th- amin- e n al~o b- ueod ae a eolver,t Th- reaet~on with ~soeyanates of the formula 0-C.NR5 to glve th~ correopond~ng sulfonylur-as 1- pref-rably perforred at tomp~ratur-r botwe-n 50 and 100 , an r~e-~ of th l~oey-nat- ~-1ng u~-d ~ -~.
solv nt Somo of tho etarting materiale, eopoeially tho~c of the formula II, are ~nown If they are not ~nown, they ean be prepared by ~nown methode analogouely to ~nown eub~tances .
It ~ 8 aloo poeeibl- to eonvert one eompound of the formula I to another compound of tho formula I by converting on~ or moro of the radiealo R a~d/or R2 to oth-r radleals a and/or R2, for exa~ple by roaeting a eompound of th- formul- I(R3 . ~) with a compound of tho formula ~-R3 (ln which R3 le different from ~) or by reducing nitro groupe to amino groupo (for examplo by hydrogonation on Raney nie~-l or Pd-on-ehareoal in an inert oolvent eueh ae mothanol or ethanol), and/or funetlonally dlfying free amlno and/or hydroxyl groupe, and/or fre-lng funetlonally modifiod amlno and~or hydroxyl groupo by colvolyele or hydrogonolyoi-, and/or hydroly~lng nitrll- groupe to C008 group~, and/or eet-rlfylng a carboxylle aeld group, for examplo by reaetion with an aleohol of th- formula A-0~ and/or eonv-rting a earbamidoxim group to a ~,5-dihydro-5-oxo-1,2,~-oxadlazol-3-yl group by roaetlor~ (a) with 1,1'-earbonyldlimidazol- or an al~yl chlorofor~ato, (b) to a ~,5-dihydro-5-oxo-1,2,~-thladlasol-3-yl group u~lng 1,1'-thiocarbonyldiimldazol-, ~c) to a 2-oxo-3~-1,2,3,5-oxathiadiazol-~-yl group usi~g SOC12 or (d) to a 2,2-dioxo-3~-1,2,3,5-oxathladlazol-~-yl group uelng S02Cl2, and/or eonvorting an S02N~-COOR5 group to an -~02N~-CO-NR5RC group by amidation wlth a compound of th formul~
Compou~ds of tho formula I (R3 . H) ean thue b-al~ylatod by r~actlon ~lth eompoundo of th~ for~ul~ ~-R3 (~horoln R3 le diff-rent fro~ ~) Th~ roaetlon le profor-ably carrl~d out ln an lnert solv~nt, for oxa~pl- an aeld a id eueh ao DM~, N-methylpyrrolidon-, 1,3-dim thyl-2-oxohexahydropyrimldin- or hox~mothylphoephora~ldo, an aleohol ueh a~ m thanol or t-rt-butanol, an eth-r eueh ae T%P or ~ halog nat-d hydroearbon sueh ae dlehloro-methano or mixturoe thoreof ae eolv~nto and/or lu tho ~ $ ~ ~
~ r ' '~
~ 2133939 pre~ence of ~n al~ali motal alcoholate ~uch a~ sodium methylat~ or potaeei~m tort-butylate, ~ al~all motal hydrldo euch a~ sodiu~ hydrido or pota~lum hydrldo, an al~all metal carbo~ato ~uch as eodlum carbonato or S potae~um carbonate, àn al~all metal blcarbonato ~uch as ~od~um blcarbonate or potaeeium blcarbonate or a tertlary amin~ such a~ triethyla~i~e or ethyldii~opropylamine at temporaturo~ botwoon about -30 and 200, proferably betwoen 20 and 60 Further~oro, freo ~mino groupe can bo acylated ln con~ontlonal manner wlth an acld chlorld- or anhydr~do, or al~ylatod wlth an un~ub~tituted or cub~tltuted al~yl halido, convonlontly ln an lnort ~olvent ~uch as ~ethyl-eDe chlorlde or TEP, and/or in the prosonco of a ba~o ~uch ac triethylamtne or pyrid~ne, at temperature~ of betwoon -60 and ~30 If deelrod, a functlonally modlfiod amlno and/or hydroxyl group ln a co~pound of tho formula I can be frood by solvolyele or hydrogenolyele uelng conventlonal methode Thu~, for examplo, a compound of th- fo ula I
contalnlng an N~COR9 or COOA group can ~o conv-rtod to thc ¢orreepondtng compound of th- formula I containl~g an N9~ or ~OCC group instead COOA groupa can b- ~apontfled for oxa~pl- wlth ~aO~ or ~O~ ln wator, water/TEF or wator/dloxan-, at tomporatur-~ of botween 0 and 100 Th- abovemontionod eonv-relon8 of a earbamidoxt~o group (I, ~2 . -C(NE~).NO~) to varlous abov~mentloned hotoroeycllc radieal~ 1~ proforably earri~d out in th-pre~enco of an inert ~olvont, for example of an othor cuch a~ T~, of a hydroearbon ~ueh a~ toluon~, of an ~do ~ueh a~ DMF, of a halogenated hydrocarbon ~ueh a~
dlchloromothan- or of a ba~- ~ueh a~ pyridin- or of m$xt~so of two of thoso ~olv~nt~ at temporaturoa botwoon O and 100 A ba~o of tho formula I ean be conv0rtod with an aeid to th~ corrosponding aeld addition salt, for oxample by reactlon of oguivalont amount~ of tho ba~o and of tho ae$d ln an inort aolvont oueh aD othanol and eub~oguent ovaporation Po~siblo aeld~ for thi~ roaction aro ':
. ~
eepeclally thoso ~hlch yl~ld physlologically acceptabl~
- ealte ~hu~ lt 18 poseibl- to ue~ lnorganlc aclde, for example sulfuric acld, nltric acid, hydrohalic aclde euch as hydrochloric acld or hydrobromic acld, phoephorlc aclde euch ae orthophoephoric acld, and eulfamlc acld, ae woll ao organlc aclds, espoclally allphatic, allcyclic, arallphatlc, aromatlc or hetorocycllc monobaeic or polybaelc carboxylic, sulfonic or eulfurlc acld-, for oxamplo for~lc acid, acotic acid, prop~onic acld, plvalic acid, diothylac-tlc acid, malonlc ac~d, euc¢lnlc acld, pimellc acld, fumar~c acld, mal-lc acld, lactic acid, tartaric acld, mallc acid, citric acid, gluconlc acld, aecorbic acld, nlcotinic acid, ieonlcotinlc acld, mothano- or othan--eulfonic acid, ethanedleulfonlc acld, 2-hydroxy~than~eulfonlc acld, b-nzeneeulfonlo acld, p-toluon-sulfonlc acld, naphthal-no- noeulfonlc and -dlsulfonlc acid~ and lauryleulfuric acld 8alt~ wlth phy~lologlcally unacc-ptabl- acld~, for xampl- plcrat~, oan b- ue-d for l~olatlng and/or purlfylng th~ compound of tho for~ula I
On tho oth-r hand, compound~ of th- formula I
contalnlng C00~ or, for xa~pl-, 1,2,~-oxadiazol- group~
can b- oonv-rted wlth ba~ for xa~pl- eodlu~ or pota~lu~ hydroxid- or carbonat-) to th- oorro~ponding m tal ~alt~ p-cially al~ali m tal or al~alln arth m~tal ~alt~, or to th- oorr-~pondlng ammonlu~ ealt~ Th potaselu~ ealto of th- 1,2,~-oxadlazolo dorlvatlve~ ar-partloularly preforred Th- nov-l compound~ of the for~ula I and th-ir phyelologioally acooptabl- calts oan b- ueot for th manufaoturo of pha-mAo-utical preparation~ by incorporatlon lnto a ~ultablo doeag- fon~ tog~th r wlth at leaet ono exolplont or ad~unot and, lf deelr-d, together wlth on- or ~oro othor aotlvo lngredlent~ Th r-eultlng formulation~ ca~ bo ueod a~ drugs ln human or ~otorlnary ~odioin- Poe~lbl- oxoipient~ ar- organic or lnorganlc ~ub~tanc-~ whlch ar- ~ultabl- for onter-l (for examplo oral or root-l) or parentoral ~lnlstratlon or for ad~lnl-tratlon ln tho form of an inhalation epray, . ,~., and whlch do not roact wlth tho novol cQ~pound~ ple-belng wator, vegetablo oll-, be~zyl alcohols, polyothylone glycol~, glycorol trlacotato and other fatty acld glycorldo~, golatin, ~oya leclthln, carbohydrate~
~uch a~ lactoso or atarch, magne~lum ~tearat~, talc and celluloso Tablets, coatod tabloto, cap~ulee, syrupo, ~uices or drop~, ln partlcular, aro ueed for oral admlnlotratlons ~pocl-l lacquorod tablet- and cap~ulos wlth coatlng~ or sh-ll~ rooletant to ga~trlc ~ulce- ar~
of lntor~t ~uppo~ltorlo~ ar- used for rectal adblnl~-tratlon and ~olutlon-, proforably olly or aqueou~ aolu-tlon~, a~ woll a~ ~u~pon~lon~ uls~onc or lmplant~, ar-u~ed for paronteral adm~nl~trat$on For admlnlotratlon as lnhalatlon ~pray~, lt ~ po~lblo to uso opray~ contaln-lng tho actlv~ ingr-dlent olth-r d~s~olved or su~pended ln a propollant ga- ~lxtur- It 1~ con~onlont hor- to u~e tho actlv- lngr-dl-nt ln lcronl~od for~, lt bolng po~lbl- for ono or ~or- addltlonal phyclologlcally compatlbl- ~olvont-, for oxa pl- othanol, to bo pro~ont Inhalatlon ~olutlon~ c~u bo admlnlatorod wlth th- ald of conventlonal lnhalor~ Tho nov-l compounds can bo lyo-phllla-d nd th- r--ultlng lyophlllrat-- u~od for oxa~pl-for th- nuf-ctur- of ln~-ctabl- proparatlon~ Th lndlcat-d for~ul-tlon- c~n b- ~t-rllleod and/or can contaln ad~unet~ ~uch a- pr---rv tlvoc, ~tablll~or~
nd/or ~ ttlng ago~t-, ooulclfl-ra, a~lta for l~flu~ncing th- o-~otle pr-a-ur-, buff-r ubat ncoa and eolouro a~d/or flavourlnga If doalrod, th-y ean al80 coutaln ono or moro oth-r actlv- lngrodlont-, for oxamplo ono or ~oro vltamlna, dlur-tlea or antlphloglatlea Th- aub~tanc-a aecordlng to tho lnvention ar-normally admln~atorod nalogoualy to oth~r known, coomorclally avallablo pr-paratlon~, for exumpl- cap-toprll or nalaprll, but ln p rtlcular nalogoualy to th~
compounda d-acrlb-d ln ~ patent ~ 880 80~, pr-forably lu dos-a of bot~oon about 1 ~g and 1 g, o~p~c~ally of botwoon 50 nd 500 m~ por aoaag- unlt Th~ dally do~o 1 prof-rably b-t~-on bout 0 1 and 50 mg/~g, ~p-clally botwoon 1 and 10 ~g/~g of body ~$ght ~ow v~r, th-2133933 : ~:
~ 15 -partlcular dose for each ~ndividu~l patient deponds on a very wide variety of factor~, for example on the eficacy of tho partlcular compound u~ed, age, body weight, genoral ~tate of health, sox, diot, time and mode of adminietration, rat- of excretlon, drug co~bination and soverity of th- particular disea~e to which the therapy ie applied Oral administration ~ preferred Above and below, all temporatures aro givon in C ~n the following examples, ~conventional wor~ing-up~
mean~ Water i8 add-d if noc-soary, the p~ is ad~usted to between 2 and 10 if necessary, depending on the con~titution of th- end product, extraction 1~ carried out with ethyl ac-tate or ~ethylen- chlorlde and the organic phase i8 ~eparat-d off, dried ovor sodium ~ulfate, evaporated and purifi~d by chromatography on eillca g-l and/or by cry~talllzation FAB ~ molecul-r ion pea~ (M~ ~ 1) obtain-d ~a~ pectroecoplcally by the ~fa~t ato~ bombardment~ mothod Exampl- 1 A olutlon of 2 72 g of 1,2-dihydro-2-oxo-3-N-m thyl-N-~ethyl~ulfonylamino~ thyl-6-butylpyrldln- (PAB
273~ obtalnable by r-actlon of 1,2-dlhydro-2-oxo-6-butylpyrldln--3-carboxald-hyd- wlth ~ethylam~n-/E~ to glve 1,2-dlhydro-2-oxo-3-~ethylaminomethyl-6-butyl-pyrldln- and ~ub~-gu-nt roactlon wlth methan-~ulfonyl chlorld-) ln 30 ~1 of DMP 1~ treated wlth 1 12 g of t-rt-butoxld- and th- mixtur- 1- stlrred at 20 for 1 hour A eolutlon of 3 31 g of ~-bromomethyl-2'-~,5-dlhydro-5-oxo-1,2,~-oxodlazol-3-yl)blphenyl (obtalnable by reactlon of 4-methyl-2'-cyanobiphenyl with hydroxylamin- to glv- ~-~ethyl-2'-(am~nooxtminomethyl)-blph-nyl, reaotlon wlth ethyl chloroformat- to glve ~-~othyl-2'-(~,5-dlhydro-5-oxo-1,2,~-oxadlazol-3-yl)-blphenyl and brom$nat$on) ln 35 ml of DM~ lo then added dropw~s- at 0 wlth ~tirrlng The m~xture lo otirr~d at 20 for 16 hour- and evaporat-d, and the re~ldu~
wor~ed up ln th- cu-tomary m~nn-r and 1,2-dihydro-1-(2~-(~,5-dlhydro-S-oxo-1,2,~-oxad~azol-3-yl)biphenyl-~-.r~ 2133939 ylmethyl)-2-oxo-3-N-methyl-N-methylsulfonyl~nomethyl-6-butylpyridino ~Ix~), m p 207 i8 obtained ~ salt, Rf 0 27 on silica gol (ethyl acetate) ExamDl- 2 S 1 5 ml of 1 N NaO~ are added dropwlee w$th lce cooling to a ~olutlon of 1 g of 1,2-dihydro-1-(2'-(5-trichloromethyl-1,2,~-oxadiazol-3-yl)biphenyl-4-yl-methyl)-2-oxo-3-N-~ethyl-N-methylsulfonylaminomethyl-6-butylpyrid~n- (obtalnable from 3-(4'-bromomethyl-2-bi-ph-nylyl)-5-trichloromethyl-1,2,~-oxadiazole (~P-A2-520423, ~xamplo 22 c) and 1,2-dihydro-2-oxo-3-N-methyl-N-methylsulfonylaminomethyl-6-butylpyrldine analogously to Bxampl- 1) in a mixtur~ of 8 ml of dioxane and 2 ml of water, and the d xture ~8 stlrred for 30 min w~th lce-coollng, wor~-d up ln the customary manner (dllute hydrochlor~c ac$d/othyl acetate) and ~Ix~ i~
obtaln-d, m p 207 ExamDle 3 (a) A ~olution 7 1 g of hydroxylammonium chloride ln 30 ml of DMSO 1~ tr-ated wlth 14 4 ml of tri-thylamln- ln 40 ml of T~F Th- solut~on 1~ filt-red, and th- flltrat-i~ vaporat-d and tr-at-d with 4 63 g of 1,2-dihydro-1-(2'-oyanoblph-nyl-~-ylmothyl)-2-oxo-3-N-methyl-N-m thyl-~ulfonylaminom thyl-6-butylpyrldln- (Rf 0 35 (p-troleum ther/othyl acetat- ~ 6); obtalnabl- by reaction of 1,2-dihydro-2-oxo-3-N-methyl-N-methylsulfonylaminomethyl-6-butylpyrldin- with ~'-bromom thyl-2-cyanobiphenyl) and a furth-r 3 5 ~1 of tri-thylamine The solution ia stirr-d for 16 hour- at 75 It 18 cooled, poured into water, and the proolpltat-d 1,2-dihydro-1-(2'-( d noox~nomethyl)-biphenyl-~-ylmethyl)-2-oxo-3-N-methyl-N-methyl~ulfonyl-aminomothyl-6-butylpyridine (~A ) is filtered off and drl-d (b) A suspension of ~ 96 g of A (crude) in 32 ml of ~EF ie treat-d with 2 ~ g of l,l'-carbonyldilmldazolo and h-atod wlth ~tlrrlng for 7 hour~ Ths mi~ture 18 e~apor-atod and wor~ed up ln th- cu~tomary (ethyl acetate/dilute ~ ~133939 H2S0~, and ~Ix~ i~ obtained m.p. 207.
Analogou~ly to a~, fro~ tho 1,2-dlhydro-1-(2'-cyanobiphenyl-4-ylmsthyl)-2-oxo-3-N-R3-N-mothyleulfonyl-aminomethyl-6-butylpyridino~ below (obtainable by S reaction of 1,2-dihydro-2-oxo-6-butylpyridine-3-carbox-aldehydo with amine~ of the formula R3-NH2/H2 to give 1,2-dlhydro-2-oxo-3-N-R3-aminomethyl-6-butylpyridines, reac-tion with methane~ulfonyl chloride/pyridino to give 1,2-dihydro-2-oxo-3-N-R3-N-~ethyl~ulfonylamlnomethyl-6-butyl-pyridino- and reaction with ~'-bromomethyl-2-cyano-biphenyl):
-3-N-ethyl--3-N-propyl--3-N-i~opropyl--3-N-butyl--3-N-i~obutyl--3-N-cyclopropylmothyl-wlth hydroxyla~monium chloride/trlethylam~ne th- 1,2-dihydro-1-(2'-(aminooxim~no~thyl)blphenyl-4-ylmethyl)-2-oxo-3-N-R3-N-methyl-ulfonylaminomethyl-6-butylpyridlne~
below aro obtain-d: -~
-3-N-othyl--3-N-propyl--3-N-l~opropyl--3-N-butyl--3-N-i-obutyl--3-N-cyclopropylmethyl-and from tho~o analogou~ly to b) wlth 1,1'-carbonyldi-imldazolothol,2-dihydro-1-(2'-(4,5-dlhydro-S-oxo-1,2,4- ;
oxadiazol-3-yl)biphenyl-4-ylmethyl)-2-oxo-3-N-R3-N-meth- -~
yl~ulfonylamlnomethyl-6-butylpyridines below: -~ ~--3-N-othyl--3-N-propyl--3-N-isopropyl--3-N-butyl- ~ ---3-N-isobutyl--3-N-cyclopropylmothyl.
. 2133939 - le-Exampl~ ~
(a) 550 ~g of ethyl chloroformato ar~ added to a 801u-tion of 527 ~g of 1,2-dlhydro-1-(2'-amino~ulfo~yl-biphenyl-4-yl~ethyl)-2-oxo-3-N-mothyl-N-methyl-~ulfonylamlnomothyl-6-butylpyrldine(~B~;obtainabls by roaction of 1,2-dihydro-2-oxo-3~N-msthyl-N-methylsulfonylaminomethyl-6-butylpyr~d~no with N-tort-butyl-4~-bromomethylblphenyl-2-sulfonamide to g~e 1,2-d~hydro-1-(2'-N-tert-butylaminosulfonyl-biphenyl-~-ylmethyl)-2-oxo-3-N-mothyl-N-methyl-sulfonylAm~nomethyl-6-butylpyrid~ne and remo~al of tho t-rt-butyl group using CF3COO~/anl~ole) and 360 ~ of 4-d~methylaminopyr~dine in 12 ml of pyridine, the mixture 1B stirred for 48 hours at 20, 8 ml of methanol are addod and it i~ wor~ed up in th- customary manner 1,2-D~hydro-1-(2'-(N-etho~cycarbonyl~m~no~ulfonyl)blphonyl-4-ylmethyl)-2-oxo-3-N-thyl-N-m-thyl~ulfonylaoino~et~yl-6-butyl-pyridin- 1B obtained 1,2-Dihydro-1-(2'-(N-buto~ycarbonylamino-~ulfonyl)blph nyl-4-ylm-thyl)-2-oxo-3-N-mothyl-N-methyl-~ulfonylaminomethyl-6-butylpyridin~ 1~ obtalnsd analo-gously from ~ and butyl chlorofor~ate The 1,2-dlhydro-1-(2'-R2-biphenyl-4-ylmethyl)-2-oxo-3-N-m~thyl-N-methyl~ulfonylaminomethyl-6-butyl-pyridlne~ b-low ar- obtalned analogou~ly using acetyl chloride, propionyl chlorld~, butyryl chlorlde, cyclo-propylcarbonyl chlorld~, cyclopropylacotyl chlorld-, cyclopsntylcarbonyl chlorid-, bsnzoyl chlorids, p-meth-oxybsnzoyl chlorid-, p-chlorobonzoyl chlorld~ or 2-thlenylcarbonyl chloride inst-ad of ethyl chloroformat--3-(2'-(acetylaminosulfonyl)blphenyl-4-ylm~thyl)--3-(2'-(propionylaminosulfonyl)biphenyl-4-ylmethyl)--3-(2'-(butyrylaminosulfonyl)blphenyl-4-ylmet~yl)--3-(2'-(cyclopropylcarbonylaminosulfonyl)blphenyl-4-ylmothyl)--3-(2'-(cyclopropylacetyl~nosulfo~yl)blphsnyl-~-ylmethyl)-f~
.~.;,~............................ g -3-(2'-(cyclopentylcarbonylam~nosulfonyl)biphenyl-4-ylmethyl)--3-(2'-(benzoylaminosulfonyl)b$phenyl-4-ylmethyl)--3-(2'-(p-methoxybenzoylaminosulfonyl)blphenyl-4-ylmethyl)--3-(2'-(p-chlorobenzoylamlnosulfonyl)biphenyl-4-ylmethyl)--3-(2'-(2-thienylcarbonylaminosulfonyl)b~phenyl-4-ylmethyl)-. ~-10 (b) A solution of 598 mg of the ethoxycarbonyl ~ A'' compound obtalned a~ in (a) and 108 mg of 2-aminomethyl-pyridine ln 30 ml of tolue~e i~ heated for 2 hours, cooled and wor~ied up in th- customary manner. 1,2-Di-hydro-1-(2~-N-(N-2-pyridylmethylcarbamoyl)amlnosulfonyl-biphenyl-4-ylmethyl)-2-oxo-3-N-methyl-N-methylsulfonyl-aminomethyl-6-butylpyridine 18 obtained.
Example 5 A mlxture of 527 mg of ~B~ and 7 ml of phenyl lsocyanate i~ heated for 4 hour~ at 80. It i8 cooled, the exces~ phenyl isocyanato 18 di~tilled off and 1,2-dihydro-1-(2'-N-(N-phenylcarbaooyl)ami~osulfonylbiphenyl-4-ylmethyl)-2-oxo-3-N-methyl-N-m~thylsulfonyl-amino-methyl-6-butylpyrldine is obtained aft~r chromatographic puriflcation.
xample 6 496 mg of A- are suspended under argon ln 7 ml of pyridlne and treated dropwise at 0 wlth ~tlrrlng with a ~olution of 0.09 ml of ~OC12 in 3.5 ml of CH2C12. The mixture ~ 8 stirred for a further 2 hours at 0, poured into 500 ml of water and wor~ed up ln tho customary manner, and 1,2-dlhydro-1-(2'-(2-oxo-3~-1,2,3,5-oxathia-diazol-4-yl)biphenyl-4-ylmethyl)-2-oxo-3-N-m-thyl-N-mothylsulfonylaminomethyl-6-butylpyrldine is obtalned.
Bxample 7 1,2-Dlhydro-1-(2'-(2,2-dioxo-3~-1,2,3,5-oxa-thiadiazol-4-yl)biphe~yl-~-ylmothyl)-2-oxo-3-N-methyl-N-~ ~r .
methylsulfonylami~omethyl-6-butyl-pyr$dine i8 obtained analogou~ly to Example 6 from A- and S02C12.
.. . '.
Example 8 A mixture of 496 ~g of A-, 10 ~1 of TaP and S 180 mg of l,l'-thiocarbonyldlimidazole i8 st$rred for 30 min at 20 and evaporated. The re~idue i~ dissolved in ethyl ac~tate, washed with dilute hydrochlor$c acid and then with water, dried and evaporated agaln. The resldue ;~
thu~ obtalned i~ d~s~olved in a m$~tur~ of 60 ml of chloroform and 12 ml of methanol. 3.5 g of silica gel are added to thi~ solutlon, th~ mlxture 1~ stirred for 48 hours at 20, filtered and ovaporated and the residue ~e purified by chromatography on ~$1$ca gel. 1,2-Dihydro-l-(2'-(4,5-dihydro-5-oxo-1,2,4-thlad$azol-3-yl)blphenyl-4-ylmethyl)-2-oxo-3-N-methyl-N-metbylsulfonylamln~m^thyl-6-butylpyr$dine i~ obta$ned.
' ' : ~ . :-Example 9 4.96 g of A- are d$scolved in 50 ml of dichloro-mothane, 1.15 g of tr$etbylamine and 1.15 g of acetic anbydride ar- add-d and th- mlxtur- is stirred for 2 hours at 20. It ic evaporat-d and the res$due $e wor~ed up in the cu~tomary manner (ethyl acetat-/water;
washing with NaHC03 solution) and th- result$ng crude acetyl derivativ- ia d$ssolved ln 30 ~1 of DMP. 4 g of CS2 are added f$rct, then, ln the cour~e of 10 m~nutee, NaH (60 %, ln o$1; 1.4 g) and th~ mixture $8 stirred for 2 hours at 20. After cuotomary wor~ng up (pH 3, lce water), 1,2-dihydro-1-(2'-(4,5-dlhydro-5-thloxo-1,2,4-oxad$azol-3-yl)b$phenyl-4-ylmethyl)-2-oxo-3-N-metbyl-N-methyleulfonylamlnomethyl-6-butylpyrld$ne 18 obta$ned.
~, 21 2133939 E~ample 10 a) Analogously to E~arnple 3a), 1,2-dihydro 1-(2'-(a nino-oximino-methyl)-biphenylyl4-methyl)-2- o~o-3-N-methyl-N-methylsulfonyl-aminomethyl-~
propyl-pyridineisobtainedfrom 1,2-dihydro-1~2'-cyano-biphenylyl4- ~ ~ -methyl)-2-oxo-3-N-methyl-N-methylsulfonyl-aminomethyl-~propyl-pyridine (obtainable by reaction of 1,2-dihydr~2-oxo-3-N-methyl-N-methylsulfonyl-aminornethyl-~propyl-pyridine with 4'-bromomethyl-2-cyano-biphenyl) with hydro~ylammoniumchoride/triethylamine.
b) Analogously to E-~ample 3b), 1,2-dihydr~1-(2'-(4,5-dihydro-5-oxo-1,2,4-o~adiazol-3-yl)-biphenylyl-4-methyl)-2-oxo-3-N-methyl-N-methylsulfonyl-aminomethyl-~propyl-pyridine is obtained from the compound prepared according to a) with 1,1 carbonyldiimidazole.
Analogously to there are obtained from the following 1,2-dihydro-1-(2'-cyano-biphenylyl4-methyl)-2-o~o-3-N-R3-N-methylsulfonyl-amjnomethyl- .
~propyl-pyridines (obtainable by reaction of 1,2-dihydro-2-o~lo~propyl-pyridine-3 carbo~caldehyde with amines of formula R3-NH2/H2 to 1,2-dihydro-2-o~o-3-N-R3-aminomethyl-~propyl-pyridines, conversion with methanesulfonyl chloride/pyridine to 1,2 dihydro 2-oxo-3-N-R3-N-methyl-sulfonyl-aminomethyl~propyl-pyridines and reaction with 4'-bromomethyl-2-cyano-biphenyl):
-3-N~yl--3-N-propyl--3-N-isopropyl--3-N-butyl--3-N-isobutyl--3-N-cyclapropylmethyl-wi~ hydrw~ylarnmonjum chloride/triethylamine the following 1,2-dihydro-1-(2'-an~ino-o~imino-methyl)-biphenylyl~-methyl~2-o~o-3-N-R3-N-methylsulfonyl-aminomethyl-~propyl-pyridines:
~ , .
"` -22- 2133939 ... -. ~.
-3-N-ethyl- .; .. :.
-3-N-propyl--3-N-isopropyl- , -3-N-butyl--3-N-isobutyl -3-N-cyclopropylmethyl-,. . ;.
and from these, in analogy to b), with l,1'4arbonyldiimidazole the following 1,2-dihydr~1-(2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenylyl-4-methyl)-2-oxo-3-N-R3-N-methylsulfonyl-aminomethyl-~propyl-pyridines~
-3-N-ethyl--3-N-propyl- ~: ::
-3-N-isopropyl--3-N-butyl--3-N-isobutyl--3-N-cyclopropylmethyl-, oil.
Th- followlng axampl-- rol~t~ to pharmac-utlc~
for~ul~tlon~ contalnlng actlv lngredl-nt~ of th- formula ;~
I or tholr ~lt~
ExamDl- A Ta~l-tc and coat d tabl-t~
Tabl~t~ of tho follo~lng co~po~lt~on aro produc-d .:
.
,~ .
by compr-aaion in conventional mannor and, whero rogulr-d, are provlded with a conventional eucrose-baaed coating Activo lngredient of tho formula I100 mg 5 Microcry~talline celluloae 278 8 mg Lactoao 110 mg ~alze atarch 11 mg Magnoaium atearat- 5 mg Finely divlded eilicon dloxido0 2 mg ~xamplo ~ ~ard golatin cap~ulea Convent$onal two-part hard gelatin cap~ules are each filled with Actlvo lngrediont of tho formula I100 mg ~actoao 150 mg 15 Celluloao 50 mg Magnealum atearat- 6 mg Exampl- Cs Soft gelatin cap~uloa Conv-ntional aoft gelatin capaule~ aro filled with a mixturo of 50 mg of actlve ~ngrediont and 250 mg of ollvo oll ln oach ca~e Exampl- D~ Ampoul-a A ~olutlon of 200 g of actlvo lngredlent in 2 ~g of propano-1,2-diol 1~ mado up to 10 1 with ~at-r and flllod into a~pouloa ~o that oach ampoulo containa 20 mg of activo lngrodient ~xampl- ~ Aquooua au-penaion for oral adminiatration An aquooua au~pension of the activo ingrodient iB
propared i~ conventional manner Tho unit doao (5 d ) containa 100 mg of active lngr-dlent, 100 mg of Na carboxymothylcolluloao, 5 mg of Na benzoato and 100 mg of sorbitol ., '~ . '
Claims (8)
1. 1,2-Dihydro-2-oxopyridines of the formula I
I
wherein R is , R1 is H, A, C2-C6-alkenyl or C2-C6-alkynyl, is -SO2NH-COOR5, -SO2NH-COR5, -SO2NH-SO2R5, -SO2NH-CONR5R6, -C(NH)=NOH, 4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, 4,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl, 2-oxo-3H
1,2,3,5-oxathiadiazol-4-yl, 2,2-dioxo-3H-1,2,3,5-oxothiadiazol-4-yl, 2,3-dihydro-3-oxo-1,2,4-oxadiazol-5-yl, 2,5-dihydro-
I
wherein R is , R1 is H, A, C2-C6-alkenyl or C2-C6-alkynyl, is -SO2NH-COOR5, -SO2NH-COR5, -SO2NH-SO2R5, -SO2NH-CONR5R6, -C(NH)=NOH, 4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, 4,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl, 2-oxo-3H
1,2,3,5-oxathiadiazol-4-yl, 2,2-dioxo-3H-1,2,3,5-oxothiadiazol-4-yl, 2,3-dihydro-3-oxo-1,2,4-oxadiazol-5-yl, 2,5-dihydro-
2,5-dioxo-1H-imidazol-4-yl, 4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl, 4,5-dihydro-5-thioxo-1H-1,2,4-triazol-3-yl, 2,3-dihydro-2-oxo-1,3,4-thiadiazol-5-yl or 4,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl, R3 is H, A, C3-C8-cycloalkyl-CnH2n- or Ar-CnH2n-, R4 is A-CO-, Ar'-CO-, Ar'-CmH2m-C-O-, R9-SO2-or Ar'-SO2-, R5 and R6 are each H, a C1-C6-alkyl group, wherein one CH2 group can also be replaced by O or S or an additional C-C double bond can be contained and which can additionally be substituted by OH, OR7, Ar, Het, NR7R8, NR7-COOR8, NR7-COO-CtH2t-Ar, NR7-COO-CtH2t-Het and/or COOR7, or are C3-8-cycloalkyl, Ar or Het, R7 and R8 are each A, C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl-CkH2k- or C1-C6-alkyl, wherein one CH2 group is replaced by O or S, R9 is C1-C6-alkyl, wherein one or more H
atoms can also be replaced by F, A is C1-C6-alkyl, Ar and Ar' are each an unsubstituted phenyl group or a phenyl group monosubstituted or disub-stituted by R9, OH, OR9, COOH, COOA, CN, NO2, NH2, NHA, N(A)2, NHCOR9, NHCOOA, NHSO2R9, Hal and/or 1H-tetrazol-5-yl, Het is a five- or six-membered heteroaromatic radical having 1 to 3 N, O and/or S
atoms, which can also be fused with a benzene or pyridine ring, Hal is F, Cl, Br or I, k is 0, 1, 2, 3 or 4 m and n are each 1, 2, or 3 and t is 1, 2, 3 or 4, and their salts.
2. 1,2-Dihydro-1-(2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-ylmethyl)-2-oxo-3-N-methyl-N-methylsulfonylaminomethyl-6-butylpyridine and its K salt.
atoms can also be replaced by F, A is C1-C6-alkyl, Ar and Ar' are each an unsubstituted phenyl group or a phenyl group monosubstituted or disub-stituted by R9, OH, OR9, COOH, COOA, CN, NO2, NH2, NHA, N(A)2, NHCOR9, NHCOOA, NHSO2R9, Hal and/or 1H-tetrazol-5-yl, Het is a five- or six-membered heteroaromatic radical having 1 to 3 N, O and/or S
atoms, which can also be fused with a benzene or pyridine ring, Hal is F, Cl, Br or I, k is 0, 1, 2, 3 or 4 m and n are each 1, 2, or 3 and t is 1, 2, 3 or 4, and their salts.
2. 1,2-Dihydro-1-(2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-ylmethyl)-2-oxo-3-N-methyl-N-methylsulfonylaminomethyl-6-butylpyridine and its K salt.
3. Process for the preparation of 1,2-dihydro-2-oxopyridines of the formula I according to Claim 1, and their salts, characterized in that (a) a compound of the formula II
II
wherein E is Cl, Br, I, a free OH group or an OH
group which has been functionally modified to acquire reactivity, and R2 is as defined in Claim 1, is reacted with a compound of the formula III
H-R III
wherein R is as defined in Claim 1, or (b) a compound of the formula I is freed from one of its functional derivatives by treatment with a solvo-lysing or hydrogenolysing agent, (c) to prepare a compound of the formula I wherein R2 is -C(NH2)=NOH, a compound which corresponds to formula I but in which the radical R2 is replaced by a CN
group, is reacted with hydroxylamine or (d) to prepare a compound of the formula I wherein R2 is -SO2-NH-COOR5, -SO2NH-COR5, -SO2NH-SO2R5 or -SO2NH-CONR5R6, a compound which corresponds to the formula I but in which the radical R2 is replaced by an -SO2NH2 group, is reacted with a compound of the formula E-COOR5, E-COR5, E-SO2R5, E-CONR5R6 or O=C=NR5 and/or in that one or more radicals R and/or R2 in a compound of the formula I are converted to one or more different radicals R and/or R2, and/or a base or acid of the formula I is converted to one of its salts.
II
wherein E is Cl, Br, I, a free OH group or an OH
group which has been functionally modified to acquire reactivity, and R2 is as defined in Claim 1, is reacted with a compound of the formula III
H-R III
wherein R is as defined in Claim 1, or (b) a compound of the formula I is freed from one of its functional derivatives by treatment with a solvo-lysing or hydrogenolysing agent, (c) to prepare a compound of the formula I wherein R2 is -C(NH2)=NOH, a compound which corresponds to formula I but in which the radical R2 is replaced by a CN
group, is reacted with hydroxylamine or (d) to prepare a compound of the formula I wherein R2 is -SO2-NH-COOR5, -SO2NH-COR5, -SO2NH-SO2R5 or -SO2NH-CONR5R6, a compound which corresponds to the formula I but in which the radical R2 is replaced by an -SO2NH2 group, is reacted with a compound of the formula E-COOR5, E-COR5, E-SO2R5, E-CONR5R6 or O=C=NR5 and/or in that one or more radicals R and/or R2 in a compound of the formula I are converted to one or more different radicals R and/or R2, and/or a base or acid of the formula I is converted to one of its salts.
4. Process for the preparation of pharmaceutical formulations, characterized in that a compound of the formula I according to Claim 1, and/or one of its physio-logically acceptable salts, are incorporated into a suitable dosage form together with at least one solid, liquid or semi-liquid excipient or adjunct.
5. Pharmaceutical formulation, characterized in that it contains at least one compound of the formula I
according to Claim 1, and/or one of its physiologically acceptable salts.
according to Claim 1, and/or one of its physiologically acceptable salts.
6. Compound of the formula I according to Claim 1, and its physiologically acceptable salts, for the control of diseases.
7. Use of compounds of the formula I according to Claim 1, and/or their physiologically acceptable salts, for the preparation of a drug.
8. Use of compounds of the formula I according to Claim 1, and/or their physiologically acceptable salts, in the control of diseases.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4336051A DE4336051A1 (en) | 1993-10-22 | 1993-10-22 | 1,2-Dihydro-2-oxopyridines |
| DEP4336051.3 | 1993-10-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2133939A1 true CA2133939A1 (en) | 1995-04-23 |
Family
ID=6500753
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002133939A Abandoned CA2133939A1 (en) | 1993-10-22 | 1994-10-20 | 1,2-dihydro-2-oxo-pyridines |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0657435A3 (en) |
| JP (1) | JPH07242664A (en) |
| KR (1) | KR950011409A (en) |
| CN (1) | CN1106388A (en) |
| AU (1) | AU7593294A (en) |
| CA (1) | CA2133939A1 (en) |
| CZ (1) | CZ258594A3 (en) |
| DE (1) | DE4336051A1 (en) |
| HU (1) | HU9403060D0 (en) |
| NO (1) | NO944024L (en) |
| PL (1) | PL305514A1 (en) |
| RU (1) | RU94037954A (en) |
| SK (1) | SK128594A3 (en) |
| ZA (1) | ZA948311B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE0100873D0 (en) * | 2001-03-13 | 2001-03-13 | Astrazeneca Ab | Method of treatment |
| JP6281735B2 (en) * | 2013-03-19 | 2018-02-21 | トーアエイヨー株式会社 | Method for evaluating therapeutic agent for acute heart failure and method for producing acute heart failure model |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2037630C (en) * | 1990-03-07 | 2001-07-03 | Akira Morimoto | Nitrogen-containing heterocylic compounds, their production and use |
| NZ238624A (en) * | 1990-06-19 | 1994-08-26 | Meiji Seika Co | Pyridine derivatives, compositions, preparations and use thereof |
| IL100917A0 (en) * | 1991-02-16 | 1992-11-15 | Fisons Plc | Pyridinone and pyrimidinone derivatives,their preparation and pharmaceutical compositions containing them |
| DE4129340A1 (en) * | 1991-09-04 | 1993-03-11 | Merck Patent Gmbh | 1,2-dihydro-2-OXOPYRIDINE |
| DE4334308A1 (en) * | 1993-10-08 | 1995-04-13 | Merck Patent Gmbh | 1,2-dihydro-2-oxo-3-pyridine-methylsulfonylaminomethyl |
-
1993
- 1993-10-22 DE DE4336051A patent/DE4336051A1/en not_active Withdrawn
-
1994
- 1994-10-10 EP EP94115937A patent/EP0657435A3/en not_active Withdrawn
- 1994-10-19 AU AU75932/94A patent/AU7593294A/en not_active Abandoned
- 1994-10-20 CN CN94117572A patent/CN1106388A/en active Pending
- 1994-10-20 JP JP6255555A patent/JPH07242664A/en active Pending
- 1994-10-20 PL PL94305514A patent/PL305514A1/en unknown
- 1994-10-20 CZ CZ942585A patent/CZ258594A3/en unknown
- 1994-10-20 CA CA002133939A patent/CA2133939A1/en not_active Abandoned
- 1994-10-21 HU HU9403060A patent/HU9403060D0/en unknown
- 1994-10-21 ZA ZA948311A patent/ZA948311B/en unknown
- 1994-10-21 SK SK1285-94A patent/SK128594A3/en unknown
- 1994-10-21 RU RU94037954/04A patent/RU94037954A/en unknown
- 1994-10-21 KR KR1019940026911A patent/KR950011409A/en not_active Application Discontinuation
- 1994-10-21 NO NO944024A patent/NO944024L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| RU94037954A (en) | 1996-10-27 |
| EP0657435A3 (en) | 1996-03-06 |
| JPH07242664A (en) | 1995-09-19 |
| AU7593294A (en) | 1995-05-11 |
| NO944024D0 (en) | 1994-10-21 |
| SK128594A3 (en) | 1995-05-10 |
| ZA948311B (en) | 1995-06-14 |
| PL305514A1 (en) | 1995-05-02 |
| CZ258594A3 (en) | 1995-07-12 |
| DE4336051A1 (en) | 1995-04-27 |
| NO944024L (en) | 1995-04-24 |
| EP0657435A2 (en) | 1995-06-14 |
| HU9403060D0 (en) | 1994-12-28 |
| CN1106388A (en) | 1995-08-09 |
| KR950011409A (en) | 1995-05-15 |
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