CA1079739A - Basically substituted indole derivatives and process for their manufacture - Google Patents
Basically substituted indole derivatives and process for their manufactureInfo
- Publication number
- CA1079739A CA1079739A CA268,139A CA268139A CA1079739A CA 1079739 A CA1079739 A CA 1079739A CA 268139 A CA268139 A CA 268139A CA 1079739 A CA1079739 A CA 1079739A
- Authority
- CA
- Canada
- Prior art keywords
- phenyl
- indole
- chloro
- resultant
- carbon atoms
- 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.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- A61P9/06—Antiarrhythmics
-
- 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
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Abstract:
The present invention relates to basically substituted indole derivatives and to a process for their manufacture.
The novel compounds are valuable medicaments.
The present invention relates to basically substituted indole derivatives and to a process for their manufacture.
The novel compounds are valuable medicaments.
Description
1~'79735~ ~
The pres~nt irlvention relato~ to new ba~ieally ~ub-stituted indolo derivatives and to the phy~iologically aeeept-~ble acid addition ~al-ts thore~ s well ~ to a proe~s for th~ manufaeture of th~se compounds and to th~ pharmaceutieal compo~itions thereof.
It has now been found that indole d~rivati~es that carry basie sub~tituents in 3 position ha~e v~luable pharmacological properties, especially on ~ho l~art~ circulatory system.
H~nce, object o~ this invention ar~ indole derivative~ of 10 the ~ormula I
(R3)m :ln whieh R1 ~t~ ds f'or a ehlor:Lno or bromLno atom, , ~2 stands for a) an aminogroup of the formula -N~ 6 ~ wherein R5 is hydrogen and R6 is . . 7 , I) an aminoa].kyl group of the formula -A1-N~ 8 wherein A1 is a single bond or represents a straight-chained or branched low-molecular-weight-alkylene group having up to 6 carbon atoms,. .:
. which may be substituted by hydroxy or alkoxy or : ;D I acyloxy groups both having 1 to 4 carbon atoms, and whereln , , --. , , . :. . .
.. , . . . - . , ~ ~ :
: : .
- ~ . . ` ,. ', . .
~LO'7~73g R7 and R8 may be identical or different and each represents 1. hydrogen
The pres~nt irlvention relato~ to new ba~ieally ~ub-stituted indolo derivatives and to the phy~iologically aeeept-~ble acid addition ~al-ts thore~ s well ~ to a proe~s for th~ manufaeture of th~se compounds and to th~ pharmaceutieal compo~itions thereof.
It has now been found that indole d~rivati~es that carry basie sub~tituents in 3 position ha~e v~luable pharmacological properties, especially on ~ho l~art~ circulatory system.
H~nce, object o~ this invention ar~ indole derivative~ of 10 the ~ormula I
(R3)m :ln whieh R1 ~t~ ds f'or a ehlor:Lno or bromLno atom, , ~2 stands for a) an aminogroup of the formula -N~ 6 ~ wherein R5 is hydrogen and R6 is . . 7 , I) an aminoa].kyl group of the formula -A1-N~ 8 wherein A1 is a single bond or represents a straight-chained or branched low-molecular-weight-alkylene group having up to 6 carbon atoms,. .:
. which may be substituted by hydroxy or alkoxy or : ;D I acyloxy groups both having 1 to 4 carbon atoms, and whereln , , --. , , . :. . .
.. , . . . - . , ~ ~ :
: : .
- ~ . . ` ,. ', . .
~LO'7~73g R7 and R8 may be identical or different and each represents 1. hydrogen
2. a cycloalkyl group of 5 to 7 carbon atoms
3. a straight-chained or branched alkyl group of 1 to 6 carbon atoms,
4. a phenyl group which may carry one or more alkyl groups of 1 to 4 carbon atoms, alko~y groups of 1 to 4 carbon atoms, methylene-dioxy, hydroxy, nitro, amino groups or halo-gen atoms and if .~ n R' and Ru represent alkyl groups, these groups may O~) form together with the nitrogen atom a S-, 6- or 7-membered heterocyclic ring which may be substituted by alkyl groups of 1 to 4 carbon atoms, alkoxy groups of 1 to 4 carbon atoms, hydroxy groups or alkoxy carbonyl groups groups o:E 1 to 4 carbon atoms, or B) form together with the nitrogen atom a
5-, 6- or 7-membered heterocyclic ring wherein one of the carbon atoms is re-~ placed by oxygen, sulfur or nitrogen atom, this latter may be substituted by 1. hydrogen ~ ~ 3 ~
''.
.
, ' . , ~ ' , .
. . .
.~ , . . . . .
'79739 2. a phenyl group which may be substituted by one or more alkyl groups of 1 to 4 carbon atoms, alkoxy groups of 1 to 4 car-bon atoms, methylene-dioxyr hydroxy, nit-ro or amino groups or halogen atoms, ~ 3. an alkenyl group of 3 to 8 carbon atoms, 4. an alkinyl group of 3 to 8 carbon atoms, :~
5u the formyl group,
''.
.
, ' . , ~ ' , .
. . .
.~ , . . . . .
'79739 2. a phenyl group which may be substituted by one or more alkyl groups of 1 to 4 carbon atoms, alkoxy groups of 1 to 4 car-bon atoms, methylene-dioxyr hydroxy, nit-ro or amino groups or halogen atoms, ~ 3. an alkenyl group of 3 to 8 carbon atoms, 4. an alkinyl group of 3 to 8 carbon atoms, :~
5u the formyl group,
- 6. an alkyl group of 1 to 4 carbon atoms, . which may be subs-tituted by one or more hydroxy, alkoxy groups of 1 to 4 carbon atoms, ethylene-dioxy, trimethylene~di-oxy, phenyl groups hav~ng the substitu-ents men~ioned above (item 2) or amino-oarbonyl groups of the formula - 3a -' .1 . .
.
.. ~ .: . .....
-.
~'79~39 ~ . .
-CO-N~ , wherein ~R1 0 R9 and R10 have the same meanings as R7 and R~ with the proviso that they ~ay form to-gether with the nitrogen atom a 5-, 6- or
.
.. ~ .: . .....
-.
~'79~39 ~ . .
-CO-N~ , wherein ~R1 0 R9 and R10 have the same meanings as R7 and R~ with the proviso that they ~ay form to-gether with the nitrogen atom a 5-, 6- or
7-membered ring which may be substituted as defined above (itemOC) and wherein one ; of the carbon atoms may be replaced by an oxygen, sulfur or nitrogen atom, this latter being, however, unsubstituted II) a cycloalkyl group o~ 5 to 7 carboll atoms, whi.ch may be substitut~d by dialky:Lamino cJroups o 1 to 4 carbon atoms, or III) R6 forms together with R5 and the nitrogen atom a 5- or 6-membered ring, in which one of the carbon atoms may be replaced by a nitrogen atom which may be substituted as mentioned for R7 and R8 (item B, 1. to 6.) ~11 , b) an.aminoalkoxy .. group ofthe formula-O-A2-N\
, wherein R
A2 stands for a straight-chained or.branched low-molecular-weight alkylene group of 2 to 6 carbon atoms which may be substituted by alkyl of 1 to 4 carbon atoms or by phenyl optionally having .~ the substituents mentioned above (item B) 2.) and ' R11 and R12 have the same meanings as R7 and R8, ~: .
~ ~ .
1~7S~739 c) a ba~ic radical of the formula -o-(CH2)n-R13, wh~rein R13 stands for a 5- or 6-memb~red heterocycl1c ring containing a nitrogerl atom and S n stands for zero or 1.
R3 stands for a hydrogen atom, the hydroxy group, an alkoxy group of 1 to 5 carbon atoms, a fluorlne, chlorine or bro-mine atom, the nitro, amino or benzyloxy group, m stands for the integer 1, 2 or 3, lO R stancls for a hydrogen atom, a saturatsd or unsaturated, ~,
, wherein R
A2 stands for a straight-chained or.branched low-molecular-weight alkylene group of 2 to 6 carbon atoms which may be substituted by alkyl of 1 to 4 carbon atoms or by phenyl optionally having .~ the substituents mentioned above (item B) 2.) and ' R11 and R12 have the same meanings as R7 and R8, ~: .
~ ~ .
1~7S~739 c) a ba~ic radical of the formula -o-(CH2)n-R13, wh~rein R13 stands for a 5- or 6-memb~red heterocycl1c ring containing a nitrogerl atom and S n stands for zero or 1.
R3 stands for a hydrogen atom, the hydroxy group, an alkoxy group of 1 to 5 carbon atoms, a fluorlne, chlorine or bro-mine atom, the nitro, amino or benzyloxy group, m stands for the integer 1, 2 or 3, lO R stancls for a hydrogen atom, a saturatsd or unsaturated, ~,
8 tral~ht-ch~.i.ned or branched allphat:Lc hyclrocarbon radi-ca:L haYirl~ 1 to 5 carbon ~toms, the benzyl or phonyl ~roup, o~ wh~ch the phony:L nuclou~ may bo sub~t:Ltuted ag de~`lnod for R2, and the physiologically acceptable salts of the said com-pound~ o~ formula I.
Preferred sub~tituents are the follow:ing: for R the chlorine atom; for R the radical ~NH-N ~ 8 ~ wherein R7 and , R to~ether wlth the nltrogen atom form a 6- or 7-mambered r:Ln~ ~or example ll-rnetllyl~ ipara~inylamino or plpexidino-amlno; ~urthermore, tlle racllcal -N~ -N~'~ , wherein Al stands for a strai~ht-chainad or branchcd alk~lene group of 2 or 3 car~on atom~, which may bo subs-tituted by hydro~y and . ' ' ' . . . . .
. - - 4a -w. ~ - . , ~ ' .
- , .
.
. . ~ .
.~ .
, . .
Preferred sub~tituents are the follow:ing: for R the chlorine atom; for R the radical ~NH-N ~ 8 ~ wherein R7 and , R to~ether wlth the nltrogen atom form a 6- or 7-mambered r:Ln~ ~or example ll-rnetllyl~ ipara~inylamino or plpexidino-amlno; ~urthermore, tlle racllcal -N~ -N~'~ , wherein Al stands for a strai~ht-chainad or branchcd alk~lene group of 2 or 3 car~on atom~, which may bo subs-tituted by hydro~y and . ' ' ' . . . . .
. - - 4a -w. ~ - . , ~ ' .
- , .
.
. . ~ .
.~ .
, . .
9~3~ ~[o~ ~
wherein, if R7 and R8 are dLfrer~n-t from each other, R7 i~
hydrogen ~nd R a linear or branched alkyl group of 1 to 3 carbon atoms, or :Lf R7 and R are identical, they stand *or tlle same alky.l groups of l -to ll carbon a-toms or togsth~r with g the ni-trogen atolll-th~y foral a 5- OI` 6-m~mbered ring which may contain anothor hetero a-tom, for example thv morpholino, pi-per:idlno, pipsra~GinO, l~-methyl-plp~ra~ino or pyrrolidino group.
Fur-ther pre~errecl substituent~ t`or R are the l-pipera~inyl ~roup - ~ ~I-Y, whorein Y is hydrogen, alky:L of 1 to l~ carbon atoms3 B-hydroxyethyl, 2-(1,3-~:lioxola~-2~yl)--~thy.L, 2-(1,3-dioxan-2-yl)-ethyl, 3,l~-methyLene-cliocy-ben2yl, pyrrolidino-ca.rbonylmot}lyL, phenyl, phenyl which is ~ubstituted by metho.Yy, chl.oro or n~tro, a:Lly:L,2-nlethy.Lal.Ly.L o:r prol)arg,y.l, the amino-~lJ. Icy l. O Xy ~L'O L~ ~ _o_~2_N R1 whore:ln A2 L d t:ra:Lght-ohn.Lrlocl or brnllc}locl n.l.~cy.Leno group or 2 or 3 on.r.~bon aLorll~, and .I~ 1l ancl:RI2 are d:Lr:f`eI-erlt frorn oaeh othel, Rll i9 hydrogen and R12 a linear or branch~d al]cyl group of 1 to l~ carbon atoms or a oycloalkyL group oP 5 to 7 carbon a-toms, or ir Rll ancl R12 aro ldentical, th2y 9 tand for alk~.L groups o-.~ 1 to 4 carbon atoms, or -togethsr with -the ni-trogon atoms they stand for a 5- or 6-rnembered rlng which lilay contain anothe.r hetoro atom, for exarnple the morpho:LLno, 4-lnethy:L-p:lperaY.:Lrlo~ plpe:ridlno or pyrro.L.Ld:Lno ~roup.
Li:kewise preferred i9 the radical -0-~C1l2)n-nl3 , wherein 2$ n is an integer of 1 or zero and R13 stands for a 6-membered ; cyclic basic radical, for example 1-methyl-l~-piperidyLoxy, l-msthyl-3-piperidyloxy, 1-mcthyl~3~piperidyl~-methyloxy, 2-pyridyloxy, ~-pyr:idyloxy.
. 29 Tho pre~erred substi-tuents -for R3 are hydroglen and alko~y _ g _ :
.: .''. ' ' : . ' . . :
.: ~ : .. ,
wherein, if R7 and R8 are dLfrer~n-t from each other, R7 i~
hydrogen ~nd R a linear or branched alkyl group of 1 to 3 carbon atoms, or :Lf R7 and R are identical, they stand *or tlle same alky.l groups of l -to ll carbon a-toms or togsth~r with g the ni-trogen atolll-th~y foral a 5- OI` 6-m~mbered ring which may contain anothor hetero a-tom, for example thv morpholino, pi-per:idlno, pipsra~GinO, l~-methyl-plp~ra~ino or pyrrolidino group.
Fur-ther pre~errecl substituent~ t`or R are the l-pipera~inyl ~roup - ~ ~I-Y, whorein Y is hydrogen, alky:L of 1 to l~ carbon atoms3 B-hydroxyethyl, 2-(1,3-~:lioxola~-2~yl)--~thy.L, 2-(1,3-dioxan-2-yl)-ethyl, 3,l~-methyLene-cliocy-ben2yl, pyrrolidino-ca.rbonylmot}lyL, phenyl, phenyl which is ~ubstituted by metho.Yy, chl.oro or n~tro, a:Lly:L,2-nlethy.Lal.Ly.L o:r prol)arg,y.l, the amino-~lJ. Icy l. O Xy ~L'O L~ ~ _o_~2_N R1 whore:ln A2 L d t:ra:Lght-ohn.Lrlocl or brnllc}locl n.l.~cy.Leno group or 2 or 3 on.r.~bon aLorll~, and .I~ 1l ancl:RI2 are d:Lr:f`eI-erlt frorn oaeh othel, Rll i9 hydrogen and R12 a linear or branch~d al]cyl group of 1 to l~ carbon atoms or a oycloalkyL group oP 5 to 7 carbon a-toms, or ir Rll ancl R12 aro ldentical, th2y 9 tand for alk~.L groups o-.~ 1 to 4 carbon atoms, or -togethsr with -the ni-trogon atoms they stand for a 5- or 6-rnembered rlng which lilay contain anothe.r hetoro atom, for exarnple the morpho:LLno, 4-lnethy:L-p:lperaY.:Lrlo~ plpe:ridlno or pyrro.L.Ld:Lno ~roup.
Li:kewise preferred i9 the radical -0-~C1l2)n-nl3 , wherein 2$ n is an integer of 1 or zero and R13 stands for a 6-membered ; cyclic basic radical, for example 1-methyl-l~-piperidyLoxy, l-msthyl-3-piperidyloxy, 1-mcthyl~3~piperidyl~-methyloxy, 2-pyridyloxy, ~-pyr:idyloxy.
. 29 Tho pre~erred substi-tuents -for R3 are hydroglen and alko~y _ g _ :
.: .''. ' ' : . ' . . :
.: ~ : .. ,
10 ~ 7~9 ~lo~ '~5/F 130 groups of 1 to 4 carbon atoms, ~speclally the mcthoxy group, pref-rlrably ~n the ll_, 5_ and/or 6-position. . ~
~4 proferably stancls ~or hydrogrerl, methyl, phenyl or benzyl, or a o-, m- or p-(Cl-CIl)-alkoxyphenyl group1 e~pecial1y tho methoxy-pheny:L group.
Further object o.~ this inven-tion i.s a process for th~
manu.~ac-ture of the compounds of formula I as we:ll as pharrna-cQutical colllpositions of these compouncls. ~' The process for the manufac-ture o r the compounds of the invention comprises (a1) reacting a compound of the formula II
, ~0 ~ R~
:Ln wh.ich ~, R~ and m are c~le:fin~d as ln ~`ormu.la I, with phosphorus oxychloride or -bromide and dimethylformamlde to yi~ld an alcle~lydo of the form~lla III
. . ' //o ,C~I
)m ~a2~ oxidi~ling ~h~ ald~h~rd~ o~t~in~d to y1ulc~ th~3 oarqoxyllG
acid of *he ~ormu:L~ IV
COOH
~ R1 ''' ' ~
" (P~ )m R
w 6 --.
: . ... :
. .. . . . .
': '" ' ' . . ',' ~
~lO~ 'f5/I~` 330 1~79~39 in which R3, R and m are def'ined as 7 n formt~tla I, and (a3) roac-ting tho ~o-obtained compound of formula IV ~ith an amine o~ the fornlula ~IN ~R6 or with an alcohol of the fo~lnu.la ~O-A -N ~ -l2 or -~10-t~Cfl~)nE~ 3 , whercin A2, R5, R , R11, R~2 and R13 and rl are defined as in formula I, or (bl) reac-ting a compound of the formula II as defln~d sub (al) w:i-th phosp~lo~ls oxych:loride/dimethylformamlde first to yleld the 3-dimethyLam:Lno-methy.lene compotlnd of the formula V
~;~C~ "Cr}13 V
and (~2) converting the resulting compound of formula V by roaction with phosphorus oxytrichloride or -bromide into a compound o~ the formula VI
H Vl (R3 )m n and converting this compo~tncl according to steps (a2) and (a3) into a compound o~ forlllula I, or (c) reacting a compound of the formula I, in which R to R
and m are dcf:ined as above with -the proviso that R
contains a s~condary amino group, ~ith an alkylating agent of the formula R1 X7 wherein X stands for a ~ 7 ~-.
~79739 ~IOE 75~
chlori~e or bromitl~ atom and R1 for an alkcnyl group of 3 to 8 carbon atoms or ~or an alkinyl group of 3 to 8 carbon atom~ or for an ~lkyl group of 1 to 6 carbon atols-s ~hlch may be substituted by hydroxy, alkoxy o~ 1 to 4 carbon atoms, ffthylene~dio~y, trime-thylene-dioxy, optioncally ~ubstituted phenyl or by -the group -CO-N ~ 10 ~ whereill ~9 and R are defined a~ abo~e, The oxo-indole of formula II used zls star-l;:ing compound for the proces~ of the invention i9 known in th~ art and may be prepare~ accordillg to t~l~ method of 1~.E.Sch~1lte, J. Reisch and U. Stoess (Arch. Pharm. ~0~, ( 1972), p. 523) and }I.A.H.
Beclcett, R.W. Dalsl~y, J. WaLk2r (Tetrah~dron 24 (1968), p.
6093), ~ocor~lLr~t,~ to methocl (a)~ ~ho oxo Lndolo o~' ~orl1lu1a :C:C i~
1~ ~eactod Ln knowr1ll~ar1llor nccoxclll1~r to 'Vll~imo;i.er tLaaolc (O, Bayor in llouben-Weyl: Me-thod~n deI organlschen Chernie, 4th edition, Y. Tlliome, Stuttgart, 1954, Vol, 7/1 p. 29). The a'Ldehyde of formula III is then oxidized according to known methods, for oxample u~ing po-tassium pormanganate, to yield the car'hoxylic acid of formuLa IV, Thc compound of ~orn1ula II'L (~ C6~5, R3 i~ }1) is cllsclo~ecl in tho art, Its prep,lratlon by kho Vllsmoier ~orlny-latlon of' N-phenyl-oxo-indole (K.E. SchuLte, J. I~Qisch and U. Stoess, Arch. Pharm. 305, p. 523 (1972)), howeYer, leads to mixtures of products, from whlch the pure compound of formula III can be obtained only aftar complicated pur~fication opera-tions (L. Marchetti and A. Andreani, Annali di Chimica ~ , p. 681 (1973)).
29 ' When, howevar, according to method (b), N-phenyl-oxo-.
.~. . .
.
'~ ' , " " . ' : . ' , : ' . ' ~ ' , , ~7~739 ~ F~30 indole is react~d wLth dim~thylformamido/p}losphorus oxychlo-ride at a t~rnperature of from O C to 30 C, the rosul-t ia a puro product Or formula V iith a very good yield. As solvents, there are mentioned inert anhydrous organic so.Lvonts, such as chloroform, carbon tetrach.Loride, dio~a~, berlzena, to.Lu~ne, chlorobenzene, N,N dimethylformaillide. The compowld of formula V .is then convorted into th~ compound of fo.rmula YI by reae tion ~i-th POC13 or POBr3, using the phosphorus oxychloride or -bromide in at least equi.valerlt amounts, pr0f~rab.Ly :Ln a 3-tO to 5-fold excess. ~s so.lvents, there are used inHrt apro-tie solvents such as ben~.ene, to:luo.ne, chloroben~ene, chloroform or carbon tetrachloride. 'l`he .roact.Lon ls generally carriecl out nL -tolllperatllr~s o~`.t`rolll 30 to l()f)C, r>roE`~:r~b.l.y *rom 50 to f3 ~l5 Utlcl~r t~lo ~lL~l oollcL:LL.Lorls, aL.L the ol;ho.r oompourlds o~
rormu.La Il may also b~ reacted to yie:l.d compouncls of formula I.
T.he compounds Or formula V.l obta.lnecl according to (b) aro then converte(l according to methods (a2) and (a~) into cornpounds of t`ormula I.
Aeeording to method step (a3), the earboxyl:Le ae;Lcls o~
formu.La IV are eonverted aceordLng to thc usual mothods of ostor or an~ o format.lon, for exalrlp.l.e v:La aaid eh:Lor-idc~ o:r mixed allhydrides, lnto the e.st~r~ o.r am:Lclos. I~`or esteri~l-ca-tion with a.leollols stil.L conta:Lning seeondary amino groups, the salts of the am:Lno aleohols are used.
According to method (c), the secondary amino groups are alkylated aceording to known methods usin~ alkylating agents Or the de~ined ~ormula XR
i~
29 The co~pound.s of the inventlon have valuable p.harma-- 9 ~
.
'' ' ~
.: , :, . . . :
:, . .
, .. . .
1~7g73~
cological. propertles. Thu~ ~or example, ln addition to other properties, they have an ef~ect on th~ coronary circulation, which appears :in a hy~otensive effect and especially in an antiarrhy-thmic activity. These compounds are the:rafore suit-ab.Le for the troatmen-t of disturbances in the cardiac rhythmQ
This antiéarrhythTnic activity was establish~d on a dog that had been poisoned with s-trophanthln, on a cat exposed to hypo-thermia and by means of the cllgltoxin-acon:i-tin fibrillat-ion test on -the guinea pig-Langendorff heart.
The novel compourlds may bo used aLone or lrl actn~ixture with pharmacologically acc~ptable carrier materia:L. l~`or oral ad~
mini.stration, the acti~e compounds are mixed with the usual substances a~cl brought lnto thi~ us-~a:L closa~e un.iL .~orms by Icnown mo thocl~, .f`o.t.~ ~xartlp.l.o l~f.~b l.c ts, ge La t:Ln onpsu.Lo4, a~ eo-l~, ls al.oo~lo.l.lo or o:L:ly :~u.3[~n~:Lolls or nclu~ou3, a.Lco~lol.Le or o:l..ly so~ t.lon~ .Lr~xt oarr:lor materLa.L, thore mé~y be u9ecl, for example, magnesium carbonate, lactose or corn 9 tarch, in con-junetion with other ~ubstances, ~or example magnesLum stea-rate, T.he eom2os:Lti.orl may be ln the form of dry or mois-t granuLes. As oily carrier material or solvents, -there are ospecially usod vegotable and animal oils, for example sun-rlower ol:L or castor oL:L.
~ peo.ially aclvantagrcous 19 t~lo :Lntrav~xlous adm:Lnistrat.ioxl.
~or this purpo4e, the active compounds or the physiologically acoeptable salts thereof are dls.solved together with -the usual subst~nces .
Such physiologically acceptable sal-ts are foulld with the -~ollowing acids, fo.r example: hydrochloric aoid, hydrobromic 29 acid or hydrolodic acid, phosphoric acid, sulfuric aoid, , -- 10 ~
~.. ;, . . .
"~ ' ' . : .
.
' ' : ' ~IOE 7 ~F~
methylsulfur~c acicl, amidosulfonic aci~l, ni.trlc acid; formic ac:lcl, acet.~c atid, propionic acld, s~lccin.ic ac-i.d, tartaric acid, lactic ac:id, malonic acid, ~umaric aclcl, oxalic ac.id, citric acid, ma.Lic acid, mucic acld, ben~Joic acicl, salicylic acid, aceturlc acid, embonic acid, napht}lalene-1,5-disulfonic acid, ascorbic acid, phenylacetlc acldl p-amino-salicylic acid, hydroxyethane-sulfonie acid, benzone-sulfor1ic acid, or syn--thetic resins containing acid groups, for example thosa having an ion exchanger effect.
~s solvents of the corresponding ph~ls.iolog:ical.ly ~ccept-able .sa.Lts Or the actlve compounds suitable for intravenolls admin:i~tratLon, thero are mentloned,~ for exaltlple, water, a phy~:Lo;log.ica:L socl:L~Inl ch.l.orldo ~o.l.utios) or tl:Lcl)ho:Ls~ Por examF)lo oth~ ol, r)ro~nallo cl:l.ol or ~:Lycero:l; rurtlle:rllloro, ~u~;ar so.lut:l0ns, f~or ex;.lmp.Lo ~I.U~O~Jt~ 0~ Inar~ .Lto.l. sol.ut:Lon~, or Inlxtu.res o~' t.tlo varlous solvents rlleIIt.tolled.
~or oral administrat-ion, the sing:Le dose Ls wi-thin the range o~` from 50 - 1,000 mg, preferably from 100 - 500 mg, for the intra~enotns o.r intramu~scular admlni.stra-tion, it i~s within -the range of froln 20 - 100 mg, proferably 50 mg, The da.ily dose ln each case is ~or t.he oral admll1is-tra-t:l.on w:Ltllln t}l~ range of frolll 50 - 2,00() mg" preferably 500 Ing, ~or the lntravonous or lntrallluscu:Lar adm:LI1Lstrat:Lon wlth:Ln the range o~ from 20 - 500 mg, preferably 100 mg.
The pharmacolog.ical effeet has been tested on rats.
The compounds of formula I may also be ~1sed as inter- `
msdiate produets for the manufacture of i~dolo derivativv~ -which carry basie substi-tuents in -the 2~ and 3-positions.
29 The following Examp:Les lllustrate the invention.
': ' , ' , " , . :
. ., ' . ~ ' ~ , '' ' ' ~79739 E X A ~I P L E 1: , 2-Chloro-1~pherly.L-:indole 3-earboxy.lic aeid ~-m~thyl) pipera- -~ f3 (a) 2-Chloro-l-phe~.l-indo.Le ~-carb~a~ cll etlvde To 130 ml o-f N,N-dimethy:Lf'orma~ .do, 130 ml Or phosp~lorus oxych.Lorlcle were aclcled dropw:i~e whl.le eooling, so that the temp~rature di~l not exce~d ~25C. S~irring was con-t:inued ror 30 tllinU te~ at room te~nperaturf3, L~oO rnl of an-hydro~ls -toluerle w~re adcled, and then 209 g (1 mol) of N-p}lenyl~oxo-inclole wero :int:roducecl portions~.Lse wh-ile eoolLng to ma:in~;ain the -telllpera-tL~re between 30 and 35 C.
Stirring was eont:irlued :~or 2 hours at room tempera-turo, 1 .l Or eh;Lo~o.,ornl wa~ aclclud, arl(l tho m.Lxture was ~ash~d sov~ral t:lm~3~ wi.th wate.r, at ,I.ast w:lttl an iaqueou~ socllum b:l-earL)ollato st)'l.ut.Lo~ lo so.Lvl3rlt w~l~ f3.Llm.lnatocl ln VUCUO, and tho erystall.L~ed r~esldlle was washf3d with dii~oproprl ether to yie.Ld 230 g of a brown-colored 3 climethylamino-methylene-1-pllenyl-2-indolinone melting at 130 - 132 C
(87 ~ of t.he theoretiea:L y:Lold).
The produet was heated to the boil .E'or 6 hours .Ln a `
mixture of l~50 ml o~ ehloro~orm and 225 m:L o~ pho.sphorus oxyeh.l.orldo, tho ooo.l0d solut:l.on wa9 washed wLth water, arlcl tho solvent was ellm:Lnatod ln vaeuo. The erystal:Li~d residuo (1~2 g _ 86 ~ of -the theoretieal yie:Ld) melted upon washing with diisopropyl ether at 132 - 134 C.
~b) 2-Chloro-1-phenyl-indole ~-carboxy.Lie aeid .
256 g (1mol) of 2-ehloro-1-phenyl-incloLe 3-earboxaldehyde were suspended in a mixture of 3.5 1 of aeetone, 2.5 l of 29 Im phosphate buffer (pH 7) and 1.7 1 of wa-ter, and 230 g ~ _ 12 -... : . .
... . . .
"....................... .
1~73739 ~0~ ` 3 ~o Or pota~siUnl permarlganate were added portions-~ise while stirring a-t 40 C within ~ hours. 5t:irring was continusd for 2 hours, and ,'0 g of sodium b:lsu,Lfate wero added. The precipitate was ~uction-flltered, washed -tw:lca with 300 mL .' o:f water each time, the faintly ye.llow Piltrate was s-trong- , ly acidified with concerltrated hycl:rochlorid acicl. The pre-, cipi-tated acid was suct:ion-f`iltered and washed with va-ter until neutral.
Yield: 190 g (7-i ~ of the theoret:ical yi~ld), m.p. 220 -221C.
(c) 2-Chloro 1-phenyl-indole 3-carboxy'Lic ac:icl (4-mQthyl)-a~,:ide ~
135.5 ~ (0.5 mo:L) of' 2-o~lt.oro~ erlyl-Lrlclo:Le 3-carboxyl.Lc ~c:ld ~ d 110 Inl. ('I.5'mol.9) o:f th:Lo.rly:l. c~ rlcl~ w~ro hocit~d I ~; E.lt t.llO ~ .1 Lul~.L.'I. tho ovo:Lut:Lon o.t` tra~ oea,~cl; ~XC~9~thlonyl chlorlcle wa~s e,l:llll:Lnated ln vacuo, and the crude crystalli~ed acicl ch,Lorîde was dissol.vod :in 500 ml of chloroform. J~t -20C, a mixture of 75 g (0.75 mol) of N-methyl-pipora~irle and 55 m:L (0.7 mol) of pyridine in lO0 ml o-f chloroform was added while coo.lLng and stirring, so that tho temperLIture did not exceQcl-~10 C~ St:i.rrin~ was cont:L;nuo~ ~or.~ 3 hours at room tempora-ture, the solution wa~ wash~d three tLnlos w:l.-th wa-tor, Qnd th~ 301vent was eliminated :Ln vacuo. The residue was freed from pyridine sti'Ll present by dlsso1ving it twice in -toluene and eva- .
porating the toluene in ~acuo. The crude resinous base was dissol~ed in 250 ml of acetone, and an excess of ethanolic ', hydrochloric acid was added. 1`he crvstal. mass was suction-29 fil-tered and washed with acetone.
.
. , 13 . ' ~ :
!
.. . .
;
~V7~739 ~OI~ 5 ~
Yielcl: 1~8 g (8G 'J.q of the theoretica:l yield), m.p. 248 -25()C.
E ~ A ~1 ? L E 2;
2-Chloro-1-T)herly.l.-.incLol.Q ~-carbox~ic acid pi~eraz.ide S (a) 2-Chloro-l-pherlyl-inclole 3-carboxylLc acid (4-formyl)-pi~erazide _ _ _ ~ __ _ Th:is compound was prcparecl as in Examp:Le 1 (c) from 2-chloro-1-pheny.L-iIl(lole 3-carboxylic acicl chloride and N-fornly:L-plpera~.ine. Tho react.ion solution was washed successive.Ly with water, 2N hydroch:Loric acicl and water.
After the so:Lvent had been e1:Lminatccl an amorphous brown COlllpOUnd l~aS obtained, w}l:Lch was un:L.form accorcling to the thisl.Layor chrolllatotsralll.
(~)) ?-C~Ir~~!~L~ r~ r. ~ lcL~ r~ L~Io, 1.5 0.l3 mo.L o~` tho N-f`ot~myL co~ )o~ncl obtalned sub (a) was cllssolved J.n 350 nl.L o~` ethlrlo'L, and after acLcll*ion of lOO
ml of a 30 % sodium hydro~icle so:Lu-tion, the solu-tion was stirrecl for 6 hours at roorll terllpera-ture. Then, 400 ml of water were add~d, and the mix-ture was ext,racted three -times wi.th methylene ch:Loride. ThQ res.inous res:Ldue o:f t}le or-ganic phase was clissolved in acetone, ancl a so:Lut:lon of an ~quiva.1ent alllollnt o.~ rmale:1c ac:ld in acetono wa~ ad~ed.
T.he cry6tal mas~ was suction-fi.Ltered and wa~hecl with acetone.
Yield- 54 g (91 % o~ the theoretical yield), m.p. 147 C
(maleinatc).
The substi-tuted 2-chloro~1-phenyl~indole 3 carboxylic acid . ~ derivatlve~ Or the Examples listed in Table 1 and the pharma-29 colo~ically useful salts were prepared from 2~chloro-1-pIle~yl-- 14 _ , . .
lV~739 llo_z.~ ~ :
i ndo l ~ 3- c arbo xyl i c ac i d ch L o ri do and thc c o rrc sponding . .
bascs accord;.ng to Examplc 1 (c).
T A :B I, E
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~ 9739 ?
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~IOE 7 ~F ~0 1~79739 X A ~I r L E 26: ~
2-Chloro-5-1netlloxy-1-rll~thyL-lndole 3-carboxylic acid (l~-me-th ~ p pera~ido _ ~ _ (a) ?-C~Iloro-5-rnothox~- ! -me-tllyJ -irldo Lc _~-carh ald~x~
To a mixturs of 33 ml of N N-dimethylforlllalllide and 30 ml of chloroforn~, 22 ml of phosphorll~ oxychloride were add~cl dropw:iso, whi;L~ cooling wi-th ic~. A~-ter 20 minu-t~s, a solutLon of 20 g o~ 5-methoxy-1-mothyl-oxo-indoLe in 30 ml of chloroform was added dropwisc so a~ to maintclin -the temperature bctwson 25 and 30C. Th~ mixture was alLowed to stand for 3 hours ~t room temperatur~, and then a mix-turo of l~oo ml of sa-turr-ltod aqUeOIlS ';OdiLllll biCarbOrla te solution wa~ acldocl~hil~ stlrrlng. r~ or~;anic phase was r~opar.ltocl, waflil~d with wator rlncl ttlo solverll; wa~ ol;lml-slatol in ~nc~lo. Tll~ claLIc-r~l olly ~o~l.clue wa~ oklromtlto~
grapsled l)y mearl~ o~` ~illca geL 60 (o.o6 - 0.2 mm, do-activatecl by 10 ~ of watcr, column siYe 3.5 x 80 cm) and a toluene/ei;}lyl acetaie 8~1 mixture. After a first frac--tion of 200 ml, the abo~ro-specifiod compound was elut~d.
Yield: 1 1 g of light ysllow crys-tals, m.p. 115 C.
(b) 2-Chloro-5-me-t~ __clole_~____b~ io aoicl ~1 ~ of potas~lunl pcrlllanganato wer~ adcled portions~lse at 35C wlthLn 1~ hours to a susporlsiorl of t6 g o~ 2-chloro-5-methoxy~ ethyL-indole-3-carb aLdehydo in 280 ml of ac~tone, 210 ml of phosphate buffer (pH 7) and 140 ml of`
. ., water. Stirri~g was continued for 2 hours until the vio-let color had disappeared, 3 g of sodium bisulfite were ~ added, and artsr standing overni~ht, the precipita-te wa9 29 soparated by suction-filtration. A~ter acidiflca-tion, ,`
1~79739 ~
1 g of` carboxflic acid WCa9 precipltatd from th~ ~iltrat~.
Tho preclpitatc was dig~-ted twice with 100 ml o:f N,N- -climetllyl.-~ormalnidc CaC}1 time, undi.sctolv~d ~substance was separa-ted by filtre~tion, ancl tho.fi.ltrat~ was diluted with /~00 ml Or water. The s~para-t~cl crye;tal mass was ~uc-tion-f`iltcred and t~ashcci with wat~r -to yiold 10 g.
The ove:rall -yielcl~as l1 g (6l~ % o~' th~ theorctical yi~lcl), m.p. 2It2 - 24ltC.
Acid ch.Loricl~: f`rom the acid alld thionyl chlor:ide~ :
~I.P. 132 - l3ll C
(c) 2-Chloro-5-m~-thoxy-l-mothyl-inclole 3-carboxy:Lic acld __ido _ _ Tllo abovo ..l~lb~t ta~lco ~ S p.r~JI)arQcl acco:r~l.l.llg to l~xanlp.Le I ~o) f`rotrl 2-cil.Loro-5-nl~tho:xy~l-nlot}ly.L-ll1clo.Lo 3-carboxyL:Lc ac.kl cll.l.or.Lclo arlcl N-rrlothy.L-~ )oraY~:ltlo :LII o~l.Lo:roro.rrll, rn.p. l2l~ - l25C.
M~ E_ ~I~
The substitu-tod 2-chLoro-5-mc-thoxy-l-mothyl-inclole 3-carboxy.Lic aci.ds of ~ormula I and t,ho pharm~co.Logiccllly U90-:~ul salts theroo~ woro proparod ~rom 2-chloro-5-mo thoxy- 1-rn~thy.L-indolo 3~carboxy.L.Lc acid chloricio and tho correspondLn~
~acto~ ~ocordlrlg to th~ ~`xartlplos ~ (c), 2 (a) ancl 2 (~). Tho basos arld tho racllcals ~2 a:r.~o ll~tec~ :Ln Tab..Lo 1.
CII30 ~ ~ ~ COR' 'N~ Cl C~I3 E X ~ M P L E 28:
~-C.hloro- 1- ( 3-mc thox~flvhenyl ) -indolo 3-carboxylic acid (I~-Tni~ -, '' ,'' ' ' ' '~ ' . ,' . " ' "1~79~39 t~
_ . _ (a) 1~ lothox-~ph ny.L)-2-indol.lnone To a stirred mi~cture o:f ~15 g~ (1.5 mo:ls) o~ N-pheny:L-N ~ :
(3-methoxy-l~heny:L)-chloroace-tic acid amido and 600 m.L of o-dichLoroberl~etle, 300 g of ~lCl3 wore addcd at room tern- ;
pera-tu-re. After the exothermi.c reaction had died down, duri:ng which the temperature had r:Lsen to 100 C, another 300 g of AlCl3 -we.re acldccl. The m:ixture WQS heated to -the boil and mai.TItai.rled there at 180 C :for 30 m:inutes. The m:ix-ture was t.hell placed oll ice, the preclpitate was stirred several times with wa-ter, and after aclclltion of 500 m:L of ethex, :it was suct.Lon-f':i:LterQd, Tho fil-trato ~as wa~shed w:lth ~thor ancl ~tharlo.l, ~le:l.d: 30() g~ (~6 ~ o:~ tl~e theorQI::laa:l y~ l.cl) o:~ clarlc-r~ ~rowrl cry~tn:ls~ n~E). 20fi - 20r~ a. Af`tot- rec.ry~t.l:l.'l:L~.~at:l.or ~`rorn ethano:L the me.Ltlng point was 2'l4)C.
(b) 1- ~ n th ~ 2~indol.inone 23 ml (o.24 mol) of dimethylsu:L.ra-te were added dropwise to a solution of ~5 g (0.2 moJ.) o~ (3-hydroxypheny:L)-2--:indolinone in 150 m:L of 2N NaOlI and 50 InL of` water. Cooling kept the temperiltllre between 25 ancl 30 C. Stlrr:Lng was con-t:lnuod ~`o:r 'l7 hour~ at rooln temp~ratll:ro, thQ p:reclp:ltate was suct:Lon-~l.Ltered, wn~hecl with water ullti.L neutral and then washed twice with 20 ml of othanol each time.
Yield: 32 g (68 ~0 of the theoretical yield), m.p. 104 -1 o6c .
(c) 2-Chloro- ~ ~ indole 3 c~arb a].clsh~de To a reaction product according to Vilsmei~r prepared 29 according to Example 1 from 30 ml of N,N-clir.lethy:Lf`ormamide .
'~ . - 21 -- ' . : ' . , . ' ,: . : :, .. . .. .. .
~ 5/F 330 ~L~7~73~
ancl 30 m.L o~ phosphoru~ oxychlorid~, 80 ml of anhydrous to'l.uene we.re added, arld whi.Le ~t,irringr L~8 g (O.Z mol) of 'I-(3-methoxypherlyl)-2-indol1none were introduced portions-wi~e so as to maintain tho temperal~ure betweerl 25 and 30 C, wh~n Coo~ }g slight:Ly. S-tirr:ing was cont:lnued for 30 minut~s, the nlixturo ~a~ di.luted wi-th 500 m:L of chlo-roform, and the ~OlUtiOII was wa~hec~ ~everal tlmes with water and aqueous sodium b:icarbonato solut:ion. After the solvent had been evaporatecl in vacuo, 3-clime-thylalJJino-methylcne-l (3-rsle-ttloxy-pheny.L) 2~:inclol:Lnone remalnod a3 a crystQlli~ecl re~-Ldue which me:Lted at 98 - 99 C
The crys-tn1.li.~ed product wa~ d:i.s~.;olved :in 200 ml o:f to-.L~eno, an-l a.fter acld,lt:Lorl o:f 70 Itl.l O f l~ho~ o:ru~ oxy-ohlorl.do, t~lo so.l~lt.lotl ~a~ ~t;,l.rrod .t`-.~r l~5 ll~i,.rlute~ at 75 C.
I5 ~:t`tor coc1L:Ln~, 5~ r O~` Lco arlcl ~00 Ill.l of` Lco wnl;o.t~ w0 adclocl in OtlQ po:rt:Lon to th~ so.Lul;Lorl, wller~upon tha -temperQture of tho mixture reached 55C af-ter 10 minutes hen stirring. The cry~tal mass which had f`ormecl at the ~am~ timo ~la~ S~lC tion~`i.l.-tered afte~r addi-t:Lon o:f 'lOO ml of ethcr, wa~hecl~i,t}l wa-ter un-til neutral ar~cl washed twico w:ith ether.
Y.lelcl: 29 g, rll.p. 'l67C. Concentrat:i.o~ of the mother .Llquor yl,olclo~ :~urther 9 ~r~ m. p~ 166 ~ 167C~
Overall yiolcl: 38 g (70 ~o Or the t~eoretical y~eld).
(d) 2-Chloro-- ~ etho~-yphenyl)-indole 3-carbox~.lic acid This compound was obtained as in Example -I (b) from 27 g ~0.1 mol) of 2-chloro~ (3-methoxyphenyl) indole 3-carb aldehyde in 500 ml o.f acetone, 3GO ml of im pho~-29 phate buf~er (pH 7) and tOO ml of water by o~yclation . - 22 - ' , : ' ', .
.. . . .
', .' , : ' :
_ 1 lV797~3~
w:ith 40 g of potassiulll permatlganato.
Yie.Ld: 18 g (60 ~ of the theoretlca:L yie].d), m.p. 196 -Ac:id chlo~:icle: From the ac:id and thlony.l chloride, m.p. 1l~2 ~ 3C.
~e) 2-Chloro-1-(3~methoxyphenyl)-:Lndole 3-carboxyLic acid era~.-icle _ _ _ Thi.s compo~ncl was prepared as in Exarllpls 1 (c) from 2-chloro-l-(3-methox~ phenyl)-indole-3-carboxylic acid chlorido and M-methyl-p:i.per.lz:i.ne.
Yield: resin, hydroch.loricle; decomposition above 250 C, 85 ~ of th~ thooretical yi.o:ld.
X A M P 1, E ~9:
~___._... __ .
Thc sub~it~ltocl 2-ohl.o .t`O- t ~ ( '3-nlethoxyl~llerly~ nclol~
3-cnrboxyl;i.o ao:ld.~ o~ .fox~lllu.l.~ :~ aslcl ~h~ rmaco.lo~.~lc~.L:Ly use.f'ul ~alt~ thereof' wero p:repar~d f:rom 2-chloro-l-(3-nlethoxy-phenyl)-indole 3-carbo~ylic acid chloride and the correspon- .
d:ing bases accordiJIg to Examples 1 (c), 2 (a) and Z (b). The ~:
ba~es and ~;he rad:icals R aro li~ted in Table 1.
~$ ~ I
OClf3 E X A ~
The following 2-chloro-indole carboxyl:ic acids of formula I listed in Table 2 were prepared according -to Exatnples 1, 2, 27 and 29 from the corrasponding carboxylic acid chloridos and th~ amines oP the rormula HR2.
. ' ' ' .
_ 23 - ~
, . , .. ~ . : . : . ; : . . . ~:.
. .~. . . . . .
:.: . : . . . . . .
, . , . : . ~
~!!~ 3 30 2 .
1~3~lCl _ .~
~3 n R2 _ ~ _ _ 4-C:L f[ 4~ thyl-l-pip~raz~ y:L
s-Br H 4-11yclroxy~t~lyl l-piperazinyl 7 Cl H I-piporazinyl 5 N02 H 1~ hyL-l-p:Lperayinyl 5-N112 H Il-nlo thyl~ l-plporaz,:lrly:L
~,7-D:I-Br ~1 4~1l~L~yl. I~plE)oraY,~rly.L
tl 6 5 2 I ~Ll)~ L`~Z.. ltl~ L
s-F C~ I~-mothy.L-I-plporaz:lnyL
s-F c2~[5 I-piperazinyl 5-Cl 3 7 4 motl~yl l piperazinyl s-Br n-C4~1g die-thylaminoethylam:ino S-~N2 C~13 4-methy:L-1-pipo:razinyl 5-NH2 C~13 4-methyl~l-p:LE~oraY.irly:l 4 CH 0 C~13 I-p:iporaz:LIly.L
7-CH~0 CH3 morpho.LinoHthy:Lalll:Lno 5 C2H5 CH3 4-hydroxyothy:L-l-piporazinyl 5-C3H70 CH3 4-phonyl-1-pipera~inyl S-CL~H90 6 5 4-m~thyl~1-piperazinyl 5-C5H11 C~13 4-methyl-1 piperazinyl 6 C2H5 C6H5 l-piperaziIIyl 6-C3H70 C6H5 piper:idinoamino _ 24 _ '` ' ~ . ' ' : , . .
~4 proferably stancls ~or hydrogrerl, methyl, phenyl or benzyl, or a o-, m- or p-(Cl-CIl)-alkoxyphenyl group1 e~pecial1y tho methoxy-pheny:L group.
Further object o.~ this inven-tion i.s a process for th~
manu.~ac-ture of the compounds of formula I as we:ll as pharrna-cQutical colllpositions of these compouncls. ~' The process for the manufac-ture o r the compounds of the invention comprises (a1) reacting a compound of the formula II
, ~0 ~ R~
:Ln wh.ich ~, R~ and m are c~le:fin~d as ln ~`ormu.la I, with phosphorus oxychloride or -bromide and dimethylformamlde to yi~ld an alcle~lydo of the form~lla III
. . ' //o ,C~I
)m ~a2~ oxidi~ling ~h~ ald~h~rd~ o~t~in~d to y1ulc~ th~3 oarqoxyllG
acid of *he ~ormu:L~ IV
COOH
~ R1 ''' ' ~
" (P~ )m R
w 6 --.
: . ... :
. .. . . . .
': '" ' ' . . ',' ~
~lO~ 'f5/I~` 330 1~79~39 in which R3, R and m are def'ined as 7 n formt~tla I, and (a3) roac-ting tho ~o-obtained compound of formula IV ~ith an amine o~ the fornlula ~IN ~R6 or with an alcohol of the fo~lnu.la ~O-A -N ~ -l2 or -~10-t~Cfl~)nE~ 3 , whercin A2, R5, R , R11, R~2 and R13 and rl are defined as in formula I, or (bl) reac-ting a compound of the formula II as defln~d sub (al) w:i-th phosp~lo~ls oxych:loride/dimethylformamlde first to yleld the 3-dimethyLam:Lno-methy.lene compotlnd of the formula V
~;~C~ "Cr}13 V
and (~2) converting the resulting compound of formula V by roaction with phosphorus oxytrichloride or -bromide into a compound o~ the formula VI
H Vl (R3 )m n and converting this compo~tncl according to steps (a2) and (a3) into a compound o~ forlllula I, or (c) reacting a compound of the formula I, in which R to R
and m are dcf:ined as above with -the proviso that R
contains a s~condary amino group, ~ith an alkylating agent of the formula R1 X7 wherein X stands for a ~ 7 ~-.
~79739 ~IOE 75~
chlori~e or bromitl~ atom and R1 for an alkcnyl group of 3 to 8 carbon atoms or ~or an alkinyl group of 3 to 8 carbon atom~ or for an ~lkyl group of 1 to 6 carbon atols-s ~hlch may be substituted by hydroxy, alkoxy o~ 1 to 4 carbon atoms, ffthylene~dio~y, trime-thylene-dioxy, optioncally ~ubstituted phenyl or by -the group -CO-N ~ 10 ~ whereill ~9 and R are defined a~ abo~e, The oxo-indole of formula II used zls star-l;:ing compound for the proces~ of the invention i9 known in th~ art and may be prepare~ accordillg to t~l~ method of 1~.E.Sch~1lte, J. Reisch and U. Stoess (Arch. Pharm. ~0~, ( 1972), p. 523) and }I.A.H.
Beclcett, R.W. Dalsl~y, J. WaLk2r (Tetrah~dron 24 (1968), p.
6093), ~ocor~lLr~t,~ to methocl (a)~ ~ho oxo Lndolo o~' ~orl1lu1a :C:C i~
1~ ~eactod Ln knowr1ll~ar1llor nccoxclll1~r to 'Vll~imo;i.er tLaaolc (O, Bayor in llouben-Weyl: Me-thod~n deI organlschen Chernie, 4th edition, Y. Tlliome, Stuttgart, 1954, Vol, 7/1 p. 29). The a'Ldehyde of formula III is then oxidized according to known methods, for oxample u~ing po-tassium pormanganate, to yield the car'hoxylic acid of formuLa IV, Thc compound of ~orn1ula II'L (~ C6~5, R3 i~ }1) is cllsclo~ecl in tho art, Its prep,lratlon by kho Vllsmoier ~orlny-latlon of' N-phenyl-oxo-indole (K.E. SchuLte, J. I~Qisch and U. Stoess, Arch. Pharm. 305, p. 523 (1972)), howeYer, leads to mixtures of products, from whlch the pure compound of formula III can be obtained only aftar complicated pur~fication opera-tions (L. Marchetti and A. Andreani, Annali di Chimica ~ , p. 681 (1973)).
29 ' When, howevar, according to method (b), N-phenyl-oxo-.
.~. . .
.
'~ ' , " " . ' : . ' , : ' . ' ~ ' , , ~7~739 ~ F~30 indole is react~d wLth dim~thylformamido/p}losphorus oxychlo-ride at a t~rnperature of from O C to 30 C, the rosul-t ia a puro product Or formula V iith a very good yield. As solvents, there are mentioned inert anhydrous organic so.Lvonts, such as chloroform, carbon tetrach.Loride, dio~a~, berlzena, to.Lu~ne, chlorobenzene, N,N dimethylformaillide. The compowld of formula V .is then convorted into th~ compound of fo.rmula YI by reae tion ~i-th POC13 or POBr3, using the phosphorus oxychloride or -bromide in at least equi.valerlt amounts, pr0f~rab.Ly :Ln a 3-tO to 5-fold excess. ~s so.lvents, there are used inHrt apro-tie solvents such as ben~.ene, to:luo.ne, chloroben~ene, chloroform or carbon tetrachloride. 'l`he .roact.Lon ls generally carriecl out nL -tolllperatllr~s o~`.t`rolll 30 to l()f)C, r>roE`~:r~b.l.y *rom 50 to f3 ~l5 Utlcl~r t~lo ~lL~l oollcL:LL.Lorls, aL.L the ol;ho.r oompourlds o~
rormu.La Il may also b~ reacted to yie:l.d compouncls of formula I.
T.he compounds Or formula V.l obta.lnecl according to (b) aro then converte(l according to methods (a2) and (a~) into cornpounds of t`ormula I.
Aeeording to method step (a3), the earboxyl:Le ae;Lcls o~
formu.La IV are eonverted aceordLng to thc usual mothods of ostor or an~ o format.lon, for exalrlp.l.e v:La aaid eh:Lor-idc~ o:r mixed allhydrides, lnto the e.st~r~ o.r am:Lclos. I~`or esteri~l-ca-tion with a.leollols stil.L conta:Lning seeondary amino groups, the salts of the am:Lno aleohols are used.
According to method (c), the secondary amino groups are alkylated aceording to known methods usin~ alkylating agents Or the de~ined ~ormula XR
i~
29 The co~pound.s of the inventlon have valuable p.harma-- 9 ~
.
'' ' ~
.: , :, . . . :
:, . .
, .. . .
1~7g73~
cological. propertles. Thu~ ~or example, ln addition to other properties, they have an ef~ect on th~ coronary circulation, which appears :in a hy~otensive effect and especially in an antiarrhy-thmic activity. These compounds are the:rafore suit-ab.Le for the troatmen-t of disturbances in the cardiac rhythmQ
This antiéarrhythTnic activity was establish~d on a dog that had been poisoned with s-trophanthln, on a cat exposed to hypo-thermia and by means of the cllgltoxin-acon:i-tin fibrillat-ion test on -the guinea pig-Langendorff heart.
The novel compourlds may bo used aLone or lrl actn~ixture with pharmacologically acc~ptable carrier materia:L. l~`or oral ad~
mini.stration, the acti~e compounds are mixed with the usual substances a~cl brought lnto thi~ us-~a:L closa~e un.iL .~orms by Icnown mo thocl~, .f`o.t.~ ~xartlp.l.o l~f.~b l.c ts, ge La t:Ln onpsu.Lo4, a~ eo-l~, ls al.oo~lo.l.lo or o:L:ly :~u.3[~n~:Lolls or nclu~ou3, a.Lco~lol.Le or o:l..ly so~ t.lon~ .Lr~xt oarr:lor materLa.L, thore mé~y be u9ecl, for example, magnesium carbonate, lactose or corn 9 tarch, in con-junetion with other ~ubstances, ~or example magnesLum stea-rate, T.he eom2os:Lti.orl may be ln the form of dry or mois-t granuLes. As oily carrier material or solvents, -there are ospecially usod vegotable and animal oils, for example sun-rlower ol:L or castor oL:L.
~ peo.ially aclvantagrcous 19 t~lo :Lntrav~xlous adm:Lnistrat.ioxl.
~or this purpo4e, the active compounds or the physiologically acoeptable salts thereof are dls.solved together with -the usual subst~nces .
Such physiologically acceptable sal-ts are foulld with the -~ollowing acids, fo.r example: hydrochloric aoid, hydrobromic 29 acid or hydrolodic acid, phosphoric acid, sulfuric aoid, , -- 10 ~
~.. ;, . . .
"~ ' ' . : .
.
' ' : ' ~IOE 7 ~F~
methylsulfur~c acicl, amidosulfonic aci~l, ni.trlc acid; formic ac:lcl, acet.~c atid, propionic acld, s~lccin.ic ac-i.d, tartaric acid, lactic ac:id, malonic acid, ~umaric aclcl, oxalic ac.id, citric acid, ma.Lic acid, mucic acld, ben~Joic acicl, salicylic acid, aceturlc acid, embonic acid, napht}lalene-1,5-disulfonic acid, ascorbic acid, phenylacetlc acldl p-amino-salicylic acid, hydroxyethane-sulfonie acid, benzone-sulfor1ic acid, or syn--thetic resins containing acid groups, for example thosa having an ion exchanger effect.
~s solvents of the corresponding ph~ls.iolog:ical.ly ~ccept-able .sa.Lts Or the actlve compounds suitable for intravenolls admin:i~tratLon, thero are mentloned,~ for exaltlple, water, a phy~:Lo;log.ica:L socl:L~Inl ch.l.orldo ~o.l.utios) or tl:Lcl)ho:Ls~ Por examF)lo oth~ ol, r)ro~nallo cl:l.ol or ~:Lycero:l; rurtlle:rllloro, ~u~;ar so.lut:l0ns, f~or ex;.lmp.Lo ~I.U~O~Jt~ 0~ Inar~ .Lto.l. sol.ut:Lon~, or Inlxtu.res o~' t.tlo varlous solvents rlleIIt.tolled.
~or oral administrat-ion, the sing:Le dose Ls wi-thin the range o~` from 50 - 1,000 mg, preferably from 100 - 500 mg, for the intra~enotns o.r intramu~scular admlni.stra-tion, it i~s within -the range of froln 20 - 100 mg, proferably 50 mg, The da.ily dose ln each case is ~or t.he oral admll1is-tra-t:l.on w:Ltllln t}l~ range of frolll 50 - 2,00() mg" preferably 500 Ing, ~or the lntravonous or lntrallluscu:Lar adm:LI1Lstrat:Lon wlth:Ln the range o~ from 20 - 500 mg, preferably 100 mg.
The pharmacolog.ical effeet has been tested on rats.
The compounds of formula I may also be ~1sed as inter- `
msdiate produets for the manufacture of i~dolo derivativv~ -which carry basie substi-tuents in -the 2~ and 3-positions.
29 The following Examp:Les lllustrate the invention.
': ' , ' , " , . :
. ., ' . ~ ' ~ , '' ' ' ~79739 E X A ~I P L E 1: , 2-Chloro-1~pherly.L-:indole 3-earboxy.lic aeid ~-m~thyl) pipera- -~ f3 (a) 2-Chloro-l-phe~.l-indo.Le ~-carb~a~ cll etlvde To 130 ml o-f N,N-dimethy:Lf'orma~ .do, 130 ml Or phosp~lorus oxych.Lorlcle were aclcled dropw:i~e whl.le eooling, so that the temp~rature di~l not exce~d ~25C. S~irring was con-t:inued ror 30 tllinU te~ at room te~nperaturf3, L~oO rnl of an-hydro~ls -toluerle w~re adcled, and then 209 g (1 mol) of N-p}lenyl~oxo-inclole wero :int:roducecl portions~.Lse wh-ile eoolLng to ma:in~;ain the -telllpera-tL~re between 30 and 35 C.
Stirring was eont:irlued :~or 2 hours at room tempera-turo, 1 .l Or eh;Lo~o.,ornl wa~ aclclud, arl(l tho m.Lxture was ~ash~d sov~ral t:lm~3~ wi.th wate.r, at ,I.ast w:lttl an iaqueou~ socllum b:l-earL)ollato st)'l.ut.Lo~ lo so.Lvl3rlt w~l~ f3.Llm.lnatocl ln VUCUO, and tho erystall.L~ed r~esldlle was washf3d with dii~oproprl ether to yie.Ld 230 g of a brown-colored 3 climethylamino-methylene-1-pllenyl-2-indolinone melting at 130 - 132 C
(87 ~ of t.he theoretiea:L y:Lold).
The produet was heated to the boil .E'or 6 hours .Ln a `
mixture of l~50 ml o~ ehloro~orm and 225 m:L o~ pho.sphorus oxyeh.l.orldo, tho ooo.l0d solut:l.on wa9 washed wLth water, arlcl tho solvent was ellm:Lnatod ln vaeuo. The erystal:Li~d residuo (1~2 g _ 86 ~ of -the theoretieal yie:Ld) melted upon washing with diisopropyl ether at 132 - 134 C.
~b) 2-Chloro-1-phenyl-indole ~-carboxy.Lie aeid .
256 g (1mol) of 2-ehloro-1-phenyl-incloLe 3-earboxaldehyde were suspended in a mixture of 3.5 1 of aeetone, 2.5 l of 29 Im phosphate buffer (pH 7) and 1.7 1 of wa-ter, and 230 g ~ _ 12 -... : . .
... . . .
"....................... .
1~73739 ~0~ ` 3 ~o Or pota~siUnl permarlganate were added portions-~ise while stirring a-t 40 C within ~ hours. 5t:irring was continusd for 2 hours, and ,'0 g of sodium b:lsu,Lfate wero added. The precipitate was ~uction-flltered, washed -tw:lca with 300 mL .' o:f water each time, the faintly ye.llow Piltrate was s-trong- , ly acidified with concerltrated hycl:rochlorid acicl. The pre-, cipi-tated acid was suct:ion-f`iltered and washed with va-ter until neutral.
Yield: 190 g (7-i ~ of the theoret:ical yi~ld), m.p. 220 -221C.
(c) 2-Chloro 1-phenyl-indole 3-carboxy'Lic ac:icl (4-mQthyl)-a~,:ide ~
135.5 ~ (0.5 mo:L) of' 2-o~lt.oro~ erlyl-Lrlclo:Le 3-carboxyl.Lc ~c:ld ~ d 110 Inl. ('I.5'mol.9) o:f th:Lo.rly:l. c~ rlcl~ w~ro hocit~d I ~; E.lt t.llO ~ .1 Lul~.L.'I. tho ovo:Lut:Lon o.t` tra~ oea,~cl; ~XC~9~thlonyl chlorlcle wa~s e,l:llll:Lnated ln vacuo, and the crude crystalli~ed acicl ch,Lorîde was dissol.vod :in 500 ml of chloroform. J~t -20C, a mixture of 75 g (0.75 mol) of N-methyl-pipora~irle and 55 m:L (0.7 mol) of pyridine in lO0 ml o-f chloroform was added while coo.lLng and stirring, so that tho temperLIture did not exceQcl-~10 C~ St:i.rrin~ was cont:L;nuo~ ~or.~ 3 hours at room tempora-ture, the solution wa~ wash~d three tLnlos w:l.-th wa-tor, Qnd th~ 301vent was eliminated :Ln vacuo. The residue was freed from pyridine sti'Ll present by dlsso1ving it twice in -toluene and eva- .
porating the toluene in ~acuo. The crude resinous base was dissol~ed in 250 ml of acetone, and an excess of ethanolic ', hydrochloric acid was added. 1`he crvstal. mass was suction-29 fil-tered and washed with acetone.
.
. , 13 . ' ~ :
!
.. . .
;
~V7~739 ~OI~ 5 ~
Yielcl: 1~8 g (8G 'J.q of the theoretica:l yield), m.p. 248 -25()C.
E ~ A ~1 ? L E 2;
2-Chloro-1-T)herly.l.-.incLol.Q ~-carbox~ic acid pi~eraz.ide S (a) 2-Chloro-l-pherlyl-inclole 3-carboxylLc acid (4-formyl)-pi~erazide _ _ _ ~ __ _ Th:is compound was prcparecl as in Examp:Le 1 (c) from 2-chloro-1-pheny.L-iIl(lole 3-carboxylic acicl chloride and N-fornly:L-plpera~.ine. Tho react.ion solution was washed successive.Ly with water, 2N hydroch:Loric acicl and water.
After the so:Lvent had been e1:Lminatccl an amorphous brown COlllpOUnd l~aS obtained, w}l:Lch was un:L.form accorcling to the thisl.Layor chrolllatotsralll.
(~)) ?-C~Ir~~!~L~ r~ r. ~ lcL~ r~ L~Io, 1.5 0.l3 mo.L o~` tho N-f`ot~myL co~ )o~ncl obtalned sub (a) was cllssolved J.n 350 nl.L o~` ethlrlo'L, and after acLcll*ion of lOO
ml of a 30 % sodium hydro~icle so:Lu-tion, the solu-tion was stirrecl for 6 hours at roorll terllpera-ture. Then, 400 ml of water were add~d, and the mix-ture was ext,racted three -times wi.th methylene ch:Loride. ThQ res.inous res:Ldue o:f t}le or-ganic phase was clissolved in acetone, ancl a so:Lut:lon of an ~quiva.1ent alllollnt o.~ rmale:1c ac:ld in acetono wa~ ad~ed.
T.he cry6tal mas~ was suction-fi.Ltered and wa~hecl with acetone.
Yield- 54 g (91 % o~ the theoretical yield), m.p. 147 C
(maleinatc).
The substi-tuted 2-chloro~1-phenyl~indole 3 carboxylic acid . ~ derivatlve~ Or the Examples listed in Table 1 and the pharma-29 colo~ically useful salts were prepared from 2~chloro-1-pIle~yl-- 14 _ , . .
lV~739 llo_z.~ ~ :
i ndo l ~ 3- c arbo xyl i c ac i d ch L o ri do and thc c o rrc sponding . .
bascs accord;.ng to Examplc 1 (c).
T A :B I, E
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~ 9739 ?
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~IOE 7 ~F ~0 1~79739 X A ~I r L E 26: ~
2-Chloro-5-1netlloxy-1-rll~thyL-lndole 3-carboxylic acid (l~-me-th ~ p pera~ido _ ~ _ (a) ?-C~Iloro-5-rnothox~- ! -me-tllyJ -irldo Lc _~-carh ald~x~
To a mixturs of 33 ml of N N-dimethylforlllalllide and 30 ml of chloroforn~, 22 ml of phosphorll~ oxychloride were add~cl dropw:iso, whi;L~ cooling wi-th ic~. A~-ter 20 minu-t~s, a solutLon of 20 g o~ 5-methoxy-1-mothyl-oxo-indoLe in 30 ml of chloroform was added dropwisc so a~ to maintclin -the temperature bctwson 25 and 30C. Th~ mixture was alLowed to stand for 3 hours ~t room temperatur~, and then a mix-turo of l~oo ml of sa-turr-ltod aqUeOIlS ';OdiLllll biCarbOrla te solution wa~ acldocl~hil~ stlrrlng. r~ or~;anic phase was r~opar.ltocl, waflil~d with wator rlncl ttlo solverll; wa~ ol;lml-slatol in ~nc~lo. Tll~ claLIc-r~l olly ~o~l.clue wa~ oklromtlto~
grapsled l)y mearl~ o~` ~illca geL 60 (o.o6 - 0.2 mm, do-activatecl by 10 ~ of watcr, column siYe 3.5 x 80 cm) and a toluene/ei;}lyl acetaie 8~1 mixture. After a first frac--tion of 200 ml, the abo~ro-specifiod compound was elut~d.
Yield: 1 1 g of light ysllow crys-tals, m.p. 115 C.
(b) 2-Chloro-5-me-t~ __clole_~____b~ io aoicl ~1 ~ of potas~lunl pcrlllanganato wer~ adcled portions~lse at 35C wlthLn 1~ hours to a susporlsiorl of t6 g o~ 2-chloro-5-methoxy~ ethyL-indole-3-carb aLdehydo in 280 ml of ac~tone, 210 ml of phosphate buffer (pH 7) and 140 ml of`
. ., water. Stirri~g was continued for 2 hours until the vio-let color had disappeared, 3 g of sodium bisulfite were ~ added, and artsr standing overni~ht, the precipita-te wa9 29 soparated by suction-filtration. A~ter acidiflca-tion, ,`
1~79739 ~
1 g of` carboxflic acid WCa9 precipltatd from th~ ~iltrat~.
Tho preclpitatc was dig~-ted twice with 100 ml o:f N,N- -climetllyl.-~ormalnidc CaC}1 time, undi.sctolv~d ~substance was separa-ted by filtre~tion, ancl tho.fi.ltrat~ was diluted with /~00 ml Or water. The s~para-t~cl crye;tal mass was ~uc-tion-f`iltcred and t~ashcci with wat~r -to yiold 10 g.
The ove:rall -yielcl~as l1 g (6l~ % o~' th~ theorctical yi~lcl), m.p. 2It2 - 24ltC.
Acid ch.Loricl~: f`rom the acid alld thionyl chlor:ide~ :
~I.P. 132 - l3ll C
(c) 2-Chloro-5-m~-thoxy-l-mothyl-inclole 3-carboxy:Lic acld __ido _ _ Tllo abovo ..l~lb~t ta~lco ~ S p.r~JI)arQcl acco:r~l.l.llg to l~xanlp.Le I ~o) f`rotrl 2-cil.Loro-5-nl~tho:xy~l-nlot}ly.L-ll1clo.Lo 3-carboxyL:Lc ac.kl cll.l.or.Lclo arlcl N-rrlothy.L-~ )oraY~:ltlo :LII o~l.Lo:roro.rrll, rn.p. l2l~ - l25C.
M~ E_ ~I~
The substitu-tod 2-chLoro-5-mc-thoxy-l-mothyl-inclole 3-carboxy.Lic aci.ds of ~ormula I and t,ho pharm~co.Logiccllly U90-:~ul salts theroo~ woro proparod ~rom 2-chloro-5-mo thoxy- 1-rn~thy.L-indolo 3~carboxy.L.Lc acid chloricio and tho correspondLn~
~acto~ ~ocordlrlg to th~ ~`xartlplos ~ (c), 2 (a) ancl 2 (~). Tho basos arld tho racllcals ~2 a:r.~o ll~tec~ :Ln Tab..Lo 1.
CII30 ~ ~ ~ COR' 'N~ Cl C~I3 E X ~ M P L E 28:
~-C.hloro- 1- ( 3-mc thox~flvhenyl ) -indolo 3-carboxylic acid (I~-Tni~ -, '' ,'' ' ' ' '~ ' . ,' . " ' "1~79~39 t~
_ . _ (a) 1~ lothox-~ph ny.L)-2-indol.lnone To a stirred mi~cture o:f ~15 g~ (1.5 mo:ls) o~ N-pheny:L-N ~ :
(3-methoxy-l~heny:L)-chloroace-tic acid amido and 600 m.L of o-dichLoroberl~etle, 300 g of ~lCl3 wore addcd at room tern- ;
pera-tu-re. After the exothermi.c reaction had died down, duri:ng which the temperature had r:Lsen to 100 C, another 300 g of AlCl3 -we.re acldccl. The m:ixture WQS heated to -the boil and mai.TItai.rled there at 180 C :for 30 m:inutes. The m:ix-ture was t.hell placed oll ice, the preclpitate was stirred several times with wa-ter, and after aclclltion of 500 m:L of ethex, :it was suct.Lon-f':i:LterQd, Tho fil-trato ~as wa~shed w:lth ~thor ancl ~tharlo.l, ~le:l.d: 30() g~ (~6 ~ o:~ tl~e theorQI::laa:l y~ l.cl) o:~ clarlc-r~ ~rowrl cry~tn:ls~ n~E). 20fi - 20r~ a. Af`tot- rec.ry~t.l:l.'l:L~.~at:l.or ~`rorn ethano:L the me.Ltlng point was 2'l4)C.
(b) 1- ~ n th ~ 2~indol.inone 23 ml (o.24 mol) of dimethylsu:L.ra-te were added dropwise to a solution of ~5 g (0.2 moJ.) o~ (3-hydroxypheny:L)-2--:indolinone in 150 m:L of 2N NaOlI and 50 InL of` water. Cooling kept the temperiltllre between 25 ancl 30 C. Stlrr:Lng was con-t:lnuod ~`o:r 'l7 hour~ at rooln temp~ratll:ro, thQ p:reclp:ltate was suct:Lon-~l.Ltered, wn~hecl with water ullti.L neutral and then washed twice with 20 ml of othanol each time.
Yield: 32 g (68 ~0 of the theoretical yield), m.p. 104 -1 o6c .
(c) 2-Chloro- ~ ~ indole 3 c~arb a].clsh~de To a reaction product according to Vilsmei~r prepared 29 according to Example 1 from 30 ml of N,N-clir.lethy:Lf`ormamide .
'~ . - 21 -- ' . : ' . , . ' ,: . : :, .. . .. .. .
~ 5/F 330 ~L~7~73~
ancl 30 m.L o~ phosphoru~ oxychlorid~, 80 ml of anhydrous to'l.uene we.re added, arld whi.Le ~t,irringr L~8 g (O.Z mol) of 'I-(3-methoxypherlyl)-2-indol1none were introduced portions-wi~e so as to maintain tho temperal~ure betweerl 25 and 30 C, wh~n Coo~ }g slight:Ly. S-tirr:ing was cont:lnued for 30 minut~s, the nlixturo ~a~ di.luted wi-th 500 m:L of chlo-roform, and the ~OlUtiOII was wa~hec~ ~everal tlmes with water and aqueous sodium b:icarbonato solut:ion. After the solvent had been evaporatecl in vacuo, 3-clime-thylalJJino-methylcne-l (3-rsle-ttloxy-pheny.L) 2~:inclol:Lnone remalnod a3 a crystQlli~ecl re~-Ldue which me:Lted at 98 - 99 C
The crys-tn1.li.~ed product wa~ d:i.s~.;olved :in 200 ml o:f to-.L~eno, an-l a.fter acld,lt:Lorl o:f 70 Itl.l O f l~ho~ o:ru~ oxy-ohlorl.do, t~lo so.l~lt.lotl ~a~ ~t;,l.rrod .t`-.~r l~5 ll~i,.rlute~ at 75 C.
I5 ~:t`tor coc1L:Ln~, 5~ r O~` Lco arlcl ~00 Ill.l of` Lco wnl;o.t~ w0 adclocl in OtlQ po:rt:Lon to th~ so.Lul;Lorl, wller~upon tha -temperQture of tho mixture reached 55C af-ter 10 minutes hen stirring. The cry~tal mass which had f`ormecl at the ~am~ timo ~la~ S~lC tion~`i.l.-tered afte~r addi-t:Lon o:f 'lOO ml of ethcr, wa~hecl~i,t}l wa-ter un-til neutral ar~cl washed twico w:ith ether.
Y.lelcl: 29 g, rll.p. 'l67C. Concentrat:i.o~ of the mother .Llquor yl,olclo~ :~urther 9 ~r~ m. p~ 166 ~ 167C~
Overall yiolcl: 38 g (70 ~o Or the t~eoretical y~eld).
(d) 2-Chloro-- ~ etho~-yphenyl)-indole 3-carbox~.lic acid This compound was obtained as in Example -I (b) from 27 g ~0.1 mol) of 2-chloro~ (3-methoxyphenyl) indole 3-carb aldehyde in 500 ml o.f acetone, 3GO ml of im pho~-29 phate buf~er (pH 7) and tOO ml of water by o~yclation . - 22 - ' , : ' ', .
.. . . .
', .' , : ' :
_ 1 lV797~3~
w:ith 40 g of potassiulll permatlganato.
Yie.Ld: 18 g (60 ~ of the theoretlca:L yie].d), m.p. 196 -Ac:id chlo~:icle: From the ac:id and thlony.l chloride, m.p. 1l~2 ~ 3C.
~e) 2-Chloro-1-(3~methoxyphenyl)-:Lndole 3-carboxyLic acid era~.-icle _ _ _ Thi.s compo~ncl was prepared as in Exarllpls 1 (c) from 2-chloro-l-(3-methox~ phenyl)-indole-3-carboxylic acid chlorido and M-methyl-p:i.per.lz:i.ne.
Yield: resin, hydroch.loricle; decomposition above 250 C, 85 ~ of th~ thooretical yi.o:ld.
X A M P 1, E ~9:
~___._... __ .
Thc sub~it~ltocl 2-ohl.o .t`O- t ~ ( '3-nlethoxyl~llerly~ nclol~
3-cnrboxyl;i.o ao:ld.~ o~ .fox~lllu.l.~ :~ aslcl ~h~ rmaco.lo~.~lc~.L:Ly use.f'ul ~alt~ thereof' wero p:repar~d f:rom 2-chloro-l-(3-nlethoxy-phenyl)-indole 3-carbo~ylic acid chloride and the correspon- .
d:ing bases accordiJIg to Examples 1 (c), 2 (a) and Z (b). The ~:
ba~es and ~;he rad:icals R aro li~ted in Table 1.
~$ ~ I
OClf3 E X A ~
The following 2-chloro-indole carboxyl:ic acids of formula I listed in Table 2 were prepared according -to Exatnples 1, 2, 27 and 29 from the corrasponding carboxylic acid chloridos and th~ amines oP the rormula HR2.
. ' ' ' .
_ 23 - ~
, . , .. ~ . : . : . ; : . . . ~:.
. .~. . . . . .
:.: . : . . . . . .
, . , . : . ~
~!!~ 3 30 2 .
1~3~lCl _ .~
~3 n R2 _ ~ _ _ 4-C:L f[ 4~ thyl-l-pip~raz~ y:L
s-Br H 4-11yclroxy~t~lyl l-piperazinyl 7 Cl H I-piporazinyl 5 N02 H 1~ hyL-l-p:Lperayinyl 5-N112 H Il-nlo thyl~ l-plporaz,:lrly:L
~,7-D:I-Br ~1 4~1l~L~yl. I~plE)oraY,~rly.L
tl 6 5 2 I ~Ll)~ L`~Z.. ltl~ L
s-F C~ I~-mothy.L-I-plporaz:lnyL
s-F c2~[5 I-piperazinyl 5-Cl 3 7 4 motl~yl l piperazinyl s-Br n-C4~1g die-thylaminoethylam:ino S-~N2 C~13 4-methy:L-1-pipo:razinyl 5-NH2 C~13 4-methyl~l-p:LE~oraY.irly:l 4 CH 0 C~13 I-p:iporaz:LIly.L
7-CH~0 CH3 morpho.LinoHthy:Lalll:Lno 5 C2H5 CH3 4-hydroxyothy:L-l-piporazinyl 5-C3H70 CH3 4-phonyl-1-pipera~inyl S-CL~H90 6 5 4-m~thyl~1-piperazinyl 5-C5H11 C~13 4-methyl-1 piperazinyl 6 C2H5 C6H5 l-piperaziIIyl 6-C3H70 C6H5 piper:idinoamino _ 24 _ '` ' ~ . ' ' : , . .
11:979739 ~3 R R2 ~_~
~-CI~I90 CH3 ~-methyl-l-p:ipera~.inyl 6-C6l-[5CI-I20 C6~I5 I~-methyl-l-piperazirlyl an~ino 5,6~Di-CH30 CI13 4-rnQthy:L-l-piperazinyl 5,6-Di-C2~I50 C6H5 l-~)iperil~i.nyl 5-C2I~50,6-C~I30C~l3 ll-methy.L-l-piE~erzlzinyl 5,6-D.i-C3~T70 ~ ~ Il-methyl.-l-p:Lperazinyl E X A ~I P L, E 31:
2-Chloro-l-phel1yl-ir~clol.o 3-carboxyl:ie ~ei.d 2-d.iethyLi~mino ethy:L
ostor 27.l ~ no.L) o.~ 2-ol~;Lot~ovl-E~horly.L-lrldol.~.3 ~-eLI:rboxyl:le aol.cl w(l;re ro~`.Luxocl w.i.t.h 30 m.l. o:t' lvhLorly.L oh:l.or.i.(.lo ~rltl.L tlle ovolut:Lorl Or ~as had eoasocl. Excoss t.h:Lony.L oh.lor~ was el~
minatod in vaeno, ancl the crude acid ch:Loride was d:Lsso:lvod in lO0 ml of anhydrous chloroform. After cooling to 20 C', a mixture of 15.2 g (0.l3 mo:L) of d:Lothyla~Lno-othanol and 15 ml (0v1~ Mol) of' pyri.d:ino in 50 ml of chlorororrn was ad-lod, and tho m.Lxturo was stirred ror 3 hou:rs at room tonlporature. The so-lutlorl ~/as di:Lutod with eh:lorof`orlll ancl wcashod throo timos wLth wator. Tho so:lvont WQ~ o.LLminato~ :ln vacuo, tho r~:Lcluo wai d:lssolved in tolueno and agaln eoncentratod ln vaeuo. T}le re-isinous crude baso was dii~so:Lved in 100 m:L of ch:loroform and ethanolie hydrochloric acid was added unti~t a pII of 1 was reaehed. Tho solvent was eliminated in vacuo, and the residue wa~ digested thrao times with acotono and concentrated. The precipitate va9 thon suction-filtered and washed wlth aeetono.
.
.
.. . . . . . . .
.
: . ., :, ' : . , , ~ : ' ". .;
.:, . . , . ' '.:
~1;37~739 Yie:Ld: 21 g (52 ~ of:' thc theor~t:ical yia:lcl) of colorless cryst~ls, 11l.p. 162 - 163C.
The substltu-ted 2-chloro-:indolc 3-carboxylic ac-id estors of tho E~amplos lis-t~d in Tablo 3 and the pharmacologically usef`u~ salts -thcreof were preparad ~9 :~1 EXaTllpl~ 31 rrom -the :indole carboxylic acid chlorido ancl thc corrcspondlng basic est~r of -thereor.
T A ~ I, E '3:
Cl l~xamplo No R m. pO C C; sa:L t (m. p . C ) 3~ 0C112Cll2~(aEl3)2 ro,~ y~ ocllL-):r.l.cl~ (171-173) 33o(a;~ N(c~l3)2 127~13o; hyclrooh.Lo.r:Lclo (228-229) 31~-OC'I-I2C~lz ~ resin; hydroch:Lor:ido (248) 35C~l2 ~2 ~ rosin; hydrochloridc (250-251 ) 36OCH~CH2 ~ :r~s:Ln; hyclroch:Loriclo (230 - 232) 37-0 ~ C}13 amorphous, hydrochlorido clocomp. ~250 38 -0 ~ amoI p~lVUS; hyclrochloridv ~ ~ docomp. >265 .
C~13 39 . amorphous; hydrochloride -0 ~ dQcomp. ~230 N
- 26 _ .
' , ,. . ~ ~ ' . : ' . ' ;..
.. ..
' ' ' : ' : ., ' ,, .
., i ' , ~ 7~739 F Y A ~l P 1 ~ ~0 :
2-ChLoro-1-pheny.l :indol~ 3-carbo~ylic acid 2-cyclo:hoxy:Lamlno-~y~ e t~r hyclrochLor:ide CTC1 eoUs llydrog~n ch.Lor:icle Wl~ introducecl:Ln-to .a solution of 30 g (0.2l mo:L) o:f 2-cyc.lohexyLa~ o-ethano:L in 300 ml of ~thyl aceta~c unt:il the so:Lutlc,n roached a p~l of 1. The so-obta:ine~ su~peris:iorl of`-the am1rla hydrochLorids was then added to 0.2 mol of 2-chloro 1-ptleny.L .indol.e 3-carboxy.Lic ac:id chlor:ido which hcld been l3r~pared from 5ll.2 g of the correspon-d:ing acid accorclirlg to Iixamp:Le 5, .,tld the ~ hlro W<l5 hocltec -to the boil ~or 17 hours ~hil.e sti:rring. I~.ftor cooLi.ng, -tho precipitate ~/as suction-fL.Lterod and w~shed w.i.-th ethyl aceta-te.
~lolti.ng t)oint~ 212 - 2-l5C. .~:t`tor .recrysta.l.L.i.~.at.l.on :from eth.lr1o.l., tllo mo:ltlrlg t)o:Lrlti wa~g 21~ - ~l7C.
Y.l.o.L~l5 ~ r (~0 ~J~ ~.)t` i~ lo~roii.lc~~.1. y.Lo.~cl)~
f~ M P J I~
The sub~-titu-ted 2-chLoro-~in~o:l.e 3-ca:rboxyLic acid cster~
of formula I listocl in Table 4 were prep~recl ~ccording to ~Xalllp1e ]10 f`l'Oltl 2-ch:loro-i.rlclole 3-carbo~yl.ic acid e.hlorides ancl the hydrochlor.ides of the corre3ponding ba~ic am:ino a.Lcohols.
T A }I L E /l~
~;ou2 . - 27 -, . .
, . .
:: . : - :
.
',~1 ~
____ _____ _~_ 5-C~I30 C~3 -OCH2CH2N~
6-CH30 C6 5 -C~'2Cfl2 __, 5,6~DiCM30 C~3 ~OC~-I2CH2N~
6-C21150 C6H5 -OCII~CH2NIL-{~
II C6~5 -OC~T2C~I
~[ C6~ _OCf-I(6~l5)C~I2N~I
~t . a2l'l5 _OC~12Cl12~lla~l(a~l3)2 ~I C6~I5 _o ~ NH
Fl C6~[5 -O-fH c~l2N~12 C~I~CL
X ~ ~I P L E l~24 -2-Chloro-1-phony:L-Ln~oLo 3-oarboxyllc ac:Ld /~-(Z-(1,3 cl.Loxolan-2-y:L)-ethylypiperazide A tnixture 0~ 13.6 (40 mmols) of 2-chLoro-1-phenyl-indole 3-carboxylic acid piperazide (Example 2~, 17 g (0.125 mol) of ~-(2-chloroethyl)-1,3-dioxolane, 20 ml of trie-thylamine and 120 ml of toluene wera kep-t boiling for ~8 hours while s tir-:,. ' , :
.. . . ..
. ~ ..
.
~/1? 3 3 o '1~379739 ring. Tile coo.led IlliX ture was d:LLuted ~ith o-thyl acc-tate, washf,~d throe -tinle~ ~JiLh wa-ter, and the resinous residtle of the or~an:ic phase was cl-lromatographed us1ng s:Llica gel 60 (o.o6 -~.2 mm, clf3act-i.vatf3cl by tO ',~ of wa-ter; co.lumrl s1zc: 3.5 x 100 cm) and ethy.l acetate. ~`ter a firs-t fract.ion o:f I l, the above compouncl was f~lutecl a~ a res:Ln, T:l1c hydrochloride melted a-t 230 - 23ZC, Yielfl: 9.5 g o~ hydroc.ilLoricle (~0 ~h of tho theoretical yicld).
E X A ~I P I,E ~
2-Chloro-1-ph~nyl-:indol~ 3-car.i)o.xy.l.:Lc ac:;cl ~-(3,~ mf3-thylene-c~ f~ )Z-~:L~f,~r~ le _____________. __ ~ mixt~ro o:i-` l2 ~; (35 mlllols) o:~' 2~ahLf).t~o-1-phf3rlyl-~irldolf3 3-~ L)oxy.l.;i.c .lc:Lcl p.l~)f~ Lcl~ (E`~ f).l.f3 2), 17 g (0.l Illo.l) of`
pl.~f)~o~ly.L ch.Lo.r.l.cle, l'7 nl.L o.i.' I;:rl.etlly:l.a~LIle arlcl l~0 Ill;L oE' l;o lS Luf3rl0 we.re rf.~ Luxod f`or 2ll llou.r..c.~. The coo.l.ed so:Lut:Lon wa~ cll-luted with f~tllyl aceta~,e, wQshed with water and the solven~
tras e~ Liminated in vacuo . The resirlous rcsidue was clissolved in acotoJ1e, exccss othanolic hyclrochlorlc ac:id (40 nmlols) was added, and tho prec:Lpitate :~o:rmeclt~as suc-tion-f:i.l.-tored and ~ashed w:Lth acotono.
Tl1o ylo.Ld of co.Lor.lo~ product was 15.2 g (85 $ o~` tho theo-rot:Leal y:Lo.L~) nl.p. 24l - 2l~(~.
E X A M P ~ _F, 4l~
The compounds o~ Table 5 were prepared ~rom the carboxy-lic acid piperazides and the corresponding alkyl halides according to Examp:Lcs 42 and 43.
' ' ' , .
- _ 29 -,' ' ~
1~973't3 llor 7~
T A B 1, R3 ~'i ~Cl nlJr R3 ~V N~
R3 E~ R
~ _ __ ___ ~1 C~15 ~C~12C:~12C~o_~
~1 C6~15 -C1~2C ~ Cfl }I C6~15 -C~12 C:~l=C}12 6--C11 0 ~ C fl -~Cft2Cl~
5-Cfs30 C~S3 -C1~12CO-~3 5, 6 D1-C1130 C1~13 -CH2C6~I5 2 5 C6H5 -CH2CONHC}13 ~ a2~lS -OH2'~ 'C-a'~l3 .' H C6H5 - C}12C~S2N ( CZH5 ) 2 J"
. ::
': ~ : ,i :
~-CI~I90 CH3 ~-methyl-l-p:ipera~.inyl 6-C6l-[5CI-I20 C6~I5 I~-methyl-l-piperazirlyl an~ino 5,6~Di-CH30 CI13 4-rnQthy:L-l-piperazinyl 5,6-Di-C2~I50 C6H5 l-~)iperil~i.nyl 5-C2I~50,6-C~I30C~l3 ll-methy.L-l-piE~erzlzinyl 5,6-D.i-C3~T70 ~ ~ Il-methyl.-l-p:Lperazinyl E X A ~I P L, E 31:
2-Chloro-l-phel1yl-ir~clol.o 3-carboxyl:ie ~ei.d 2-d.iethyLi~mino ethy:L
ostor 27.l ~ no.L) o.~ 2-ol~;Lot~ovl-E~horly.L-lrldol.~.3 ~-eLI:rboxyl:le aol.cl w(l;re ro~`.Luxocl w.i.t.h 30 m.l. o:t' lvhLorly.L oh:l.or.i.(.lo ~rltl.L tlle ovolut:Lorl Or ~as had eoasocl. Excoss t.h:Lony.L oh.lor~ was el~
minatod in vaeno, ancl the crude acid ch:Loride was d:Lsso:lvod in lO0 ml of anhydrous chloroform. After cooling to 20 C', a mixture of 15.2 g (0.l3 mo:L) of d:Lothyla~Lno-othanol and 15 ml (0v1~ Mol) of' pyri.d:ino in 50 ml of chlorororrn was ad-lod, and tho m.Lxturo was stirred ror 3 hou:rs at room tonlporature. The so-lutlorl ~/as di:Lutod with eh:lorof`orlll ancl wcashod throo timos wLth wator. Tho so:lvont WQ~ o.LLminato~ :ln vacuo, tho r~:Lcluo wai d:lssolved in tolueno and agaln eoncentratod ln vaeuo. T}le re-isinous crude baso was dii~so:Lved in 100 m:L of ch:loroform and ethanolie hydrochloric acid was added unti~t a pII of 1 was reaehed. Tho solvent was eliminated in vacuo, and the residue wa~ digested thrao times with acotono and concentrated. The precipitate va9 thon suction-filtered and washed wlth aeetono.
.
.
.. . . . . . . .
.
: . ., :, ' : . , , ~ : ' ". .;
.:, . . , . ' '.:
~1;37~739 Yie:Ld: 21 g (52 ~ of:' thc theor~t:ical yia:lcl) of colorless cryst~ls, 11l.p. 162 - 163C.
The substltu-ted 2-chloro-:indolc 3-carboxylic ac-id estors of tho E~amplos lis-t~d in Tablo 3 and the pharmacologically usef`u~ salts -thcreof were preparad ~9 :~1 EXaTllpl~ 31 rrom -the :indole carboxylic acid chlorido ancl thc corrcspondlng basic est~r of -thereor.
T A ~ I, E '3:
Cl l~xamplo No R m. pO C C; sa:L t (m. p . C ) 3~ 0C112Cll2~(aEl3)2 ro,~ y~ ocllL-):r.l.cl~ (171-173) 33o(a;~ N(c~l3)2 127~13o; hyclrooh.Lo.r:Lclo (228-229) 31~-OC'I-I2C~lz ~ resin; hydroch:Lor:ido (248) 35C~l2 ~2 ~ rosin; hydrochloridc (250-251 ) 36OCH~CH2 ~ :r~s:Ln; hyclroch:Loriclo (230 - 232) 37-0 ~ C}13 amorphous, hydrochlorido clocomp. ~250 38 -0 ~ amoI p~lVUS; hyclrochloridv ~ ~ docomp. >265 .
C~13 39 . amorphous; hydrochloride -0 ~ dQcomp. ~230 N
- 26 _ .
' , ,. . ~ ~ ' . : ' . ' ;..
.. ..
' ' ' : ' : ., ' ,, .
., i ' , ~ 7~739 F Y A ~l P 1 ~ ~0 :
2-ChLoro-1-pheny.l :indol~ 3-carbo~ylic acid 2-cyclo:hoxy:Lamlno-~y~ e t~r hyclrochLor:ide CTC1 eoUs llydrog~n ch.Lor:icle Wl~ introducecl:Ln-to .a solution of 30 g (0.2l mo:L) o:f 2-cyc.lohexyLa~ o-ethano:L in 300 ml of ~thyl aceta~c unt:il the so:Lutlc,n roached a p~l of 1. The so-obta:ine~ su~peris:iorl of`-the am1rla hydrochLorids was then added to 0.2 mol of 2-chloro 1-ptleny.L .indol.e 3-carboxy.Lic ac:id chlor:ido which hcld been l3r~pared from 5ll.2 g of the correspon-d:ing acid accorclirlg to Iixamp:Le 5, .,tld the ~ hlro W<l5 hocltec -to the boil ~or 17 hours ~hil.e sti:rring. I~.ftor cooLi.ng, -tho precipitate ~/as suction-fL.Lterod and w~shed w.i.-th ethyl aceta-te.
~lolti.ng t)oint~ 212 - 2-l5C. .~:t`tor .recrysta.l.L.i.~.at.l.on :from eth.lr1o.l., tllo mo:ltlrlg t)o:Lrlti wa~g 21~ - ~l7C.
Y.l.o.L~l5 ~ r (~0 ~J~ ~.)t` i~ lo~roii.lc~~.1. y.Lo.~cl)~
f~ M P J I~
The sub~-titu-ted 2-chLoro-~in~o:l.e 3-ca:rboxyLic acid cster~
of formula I listocl in Table 4 were prep~recl ~ccording to ~Xalllp1e ]10 f`l'Oltl 2-ch:loro-i.rlclole 3-carbo~yl.ic acid e.hlorides ancl the hydrochlor.ides of the corre3ponding ba~ic am:ino a.Lcohols.
T A }I L E /l~
~;ou2 . - 27 -, . .
, . .
:: . : - :
.
',~1 ~
____ _____ _~_ 5-C~I30 C~3 -OCH2CH2N~
6-CH30 C6 5 -C~'2Cfl2 __, 5,6~DiCM30 C~3 ~OC~-I2CH2N~
6-C21150 C6H5 -OCII~CH2NIL-{~
II C6~5 -OC~T2C~I
~[ C6~ _OCf-I(6~l5)C~I2N~I
~t . a2l'l5 _OC~12Cl12~lla~l(a~l3)2 ~I C6~I5 _o ~ NH
Fl C6~[5 -O-fH c~l2N~12 C~I~CL
X ~ ~I P L E l~24 -2-Chloro-1-phony:L-Ln~oLo 3-oarboxyllc ac:Ld /~-(Z-(1,3 cl.Loxolan-2-y:L)-ethylypiperazide A tnixture 0~ 13.6 (40 mmols) of 2-chLoro-1-phenyl-indole 3-carboxylic acid piperazide (Example 2~, 17 g (0.125 mol) of ~-(2-chloroethyl)-1,3-dioxolane, 20 ml of trie-thylamine and 120 ml of toluene wera kep-t boiling for ~8 hours while s tir-:,. ' , :
.. . . ..
. ~ ..
.
~/1? 3 3 o '1~379739 ring. Tile coo.led IlliX ture was d:LLuted ~ith o-thyl acc-tate, washf,~d throe -tinle~ ~JiLh wa-ter, and the resinous residtle of the or~an:ic phase was cl-lromatographed us1ng s:Llica gel 60 (o.o6 -~.2 mm, clf3act-i.vatf3cl by tO ',~ of wa-ter; co.lumrl s1zc: 3.5 x 100 cm) and ethy.l acetate. ~`ter a firs-t fract.ion o:f I l, the above compouncl was f~lutecl a~ a res:Ln, T:l1c hydrochloride melted a-t 230 - 23ZC, Yielfl: 9.5 g o~ hydroc.ilLoricle (~0 ~h of tho theoretical yicld).
E X A ~I P I,E ~
2-Chloro-1-ph~nyl-:indol~ 3-car.i)o.xy.l.:Lc ac:;cl ~-(3,~ mf3-thylene-c~ f~ )Z-~:L~f,~r~ le _____________. __ ~ mixt~ro o:i-` l2 ~; (35 mlllols) o:~' 2~ahLf).t~o-1-phf3rlyl-~irldolf3 3-~ L)oxy.l.;i.c .lc:Lcl p.l~)f~ Lcl~ (E`~ f).l.f3 2), 17 g (0.l Illo.l) of`
pl.~f)~o~ly.L ch.Lo.r.l.cle, l'7 nl.L o.i.' I;:rl.etlly:l.a~LIle arlcl l~0 Ill;L oE' l;o lS Luf3rl0 we.re rf.~ Luxod f`or 2ll llou.r..c.~. The coo.l.ed so:Lut:Lon wa~ cll-luted with f~tllyl aceta~,e, wQshed with water and the solven~
tras e~ Liminated in vacuo . The resirlous rcsidue was clissolved in acotoJ1e, exccss othanolic hyclrochlorlc ac:id (40 nmlols) was added, and tho prec:Lpitate :~o:rmeclt~as suc-tion-f:i.l.-tored and ~ashed w:Lth acotono.
Tl1o ylo.Ld of co.Lor.lo~ product was 15.2 g (85 $ o~` tho theo-rot:Leal y:Lo.L~) nl.p. 24l - 2l~(~.
E X A M P ~ _F, 4l~
The compounds o~ Table 5 were prepared ~rom the carboxy-lic acid piperazides and the corresponding alkyl halides according to Examp:Lcs 42 and 43.
' ' ' , .
- _ 29 -,' ' ~
1~973't3 llor 7~
T A B 1, R3 ~'i ~Cl nlJr R3 ~V N~
R3 E~ R
~ _ __ ___ ~1 C~15 ~C~12C:~12C~o_~
~1 C6~15 -C1~2C ~ Cfl }I C6~15 -C~12 C:~l=C}12 6--C11 0 ~ C fl -~Cft2Cl~
5-Cfs30 C~S3 -C1~12CO-~3 5, 6 D1-C1130 C1~13 -CH2C6~I5 2 5 C6H5 -CH2CONHC}13 ~ a2~lS -OH2'~ 'C-a'~l3 .' H C6H5 - C}12C~S2N ( CZH5 ) 2 J"
. ::
': ~ : ,i :
Claims (24)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula I
I
wherein R1 represents a chlorine or bromine atom, R2 represents a) an aminogroup of the formula , wherein R5 is hydroyen and R6 is I) an aminoalkyl group of the formula , wherein A1 is a single bond or represents a straight-chained or branched low-molecular-weight-alkylene group having up to 6 carbon atoms, which may be substituted by hydroxy or alkoxy or acyloxy groups both having 1 to 4 carbon, atoms, and wherein R7 and R8 may be identical or different and each represents 1. hydrogen 2. a cycloalkyl group of 5 to 7 carbon atoms 3. a straight-chained or branched alkyl group of 1 to 6 carbon atoms, 4. a phenyl group which may carry one or more alkyl groups of 1 to 4 carbon atoms, alkoxy groups of 1 to 4 carbon atoms, methylene-dioxy, hydroxy, nitro, amino groups or halo-gen atoms and if R7 and R8 represent alkyl groups, these groups may .alpha.) form together with the nitrogen atom a 5-, 6- or 7-membered heterocyclic ring which may be substituted by alkyl groups of 1 to 4 carbon atoms, hydroxy groups or alkoxy carbonyl groups of 1 to 4 carbon atoms, or .beta.) form together with the nitrogen atom a 5-, 6- or 7-membered heterocyclic ring wherein one of the carbon atoms is re-placed by oxygen, sulfur or nitrogen atom, this latter may be substituted by
1. hydrogen 2. a phenyl group which may be substituted by one or more alkyl groups of 1 to 4 carbon atoms, alkoxy groups of 1 to 4 car-bon atoms, methylene-dioxy, hydroxy, nit-ro or amino groups or halogen atoms, 3. an alkenyl group of 3 to 8 carbon atoms, 4. an alkinyl group of 3 to 8 carbon atoms, 5. the formyl group, 6. an alkyl group of 1 to 4 carbon atoms, which may be substituted by one or more hydroxy, alkoxy groups of 1 to 4 carbon atoms, ethylene-dioxy, trimethylene-di-oxy, phenyl groups having the substitu-ents mentioned above (item 2) or amino-carbonyl groups of the formula.
, wherein R9 and R10 have the same meanings as R7 and R8 with the proviso that they may form to-gether with the nitrogen atom a 5-, 6- or 7-membered ring which may be substituted as defined above (item .alpha.) and wherein one of the carbon atoms may be replaced by an oxygen, sulfur or nitrogen atom, this latter being, however, unsubstituted II) a cycloalkyl group of 5 to 7 carbon atoms, which may be substituted by dialkylamino groups of 1 to 4 carbon atoms, or III) R6 forms together with R5 and the nitrogen atom a 5- or 6-membered ring, in which one of the carbon atoms may be replaced by a nitrogen atom which may be substituted as mentioned for R7 and R8 (item .beta., 1. to 6.) b) an aminoalkoxy group of the wherein A2 stands for a straight-chained or branched low-molecular-weight alkylene group of 2 to 6 carbon atoms which may be substituted by alkyl of 1 to 4 carbon atoms or by phenyl which may have the substituents mentioned above (item .beta.) 2.) and R11 and R12 have the same meanings as R7 and R8, c) a basic radical of the formula -O-(CH2)n-R13, wherein R13 stands for a 5- or 6-membered heterocyclic .
ring containing a nitrogen atom and n stands for zero or 1.
R3 represents a hydrogen atom, the hydroxy group, an alkoxy group of 1 to 5 carbon atoms, a fluorine, chlorine or bromine atom, the nitro, amino or benzyloxy group, m represents the integer 1, 2 or 3, R4 represents a hydrogen atom, a saturated or unsaturated, straight-chained or branched aliphatic hydrocarbon radical having 1 to 5 carbon atoms, the benzyl or phenyl group, of which the phenyl nucleus may be substituted as defined for R2, and the physiologically acceptable salts of the said compounds of formula I, in which (a1) a compound of the formula II
II
wherein R3, R4 and m are as defined above, is reacted with phosphorous oxychloride or -bromide and dimethylformamide to yield an aldehyde of the formula III
III
(a2) the aldehyde obtained is oxidized to yield the carboxylic acid of the formula IV
IV
wherein R3, R4 and m are as defined above, and (a3) the so-obtained compound of the formula IV is reacted with an amine of the formula or with an alcohol of the formula or -HO-(CH2)nR13, wherein A2, R5, R6, R11, R12 and R13 and n are defined as above, or (b1) a compound of the formula II as defined above is reacted with phosphorus oxychloride/dimethylformamide first to yield the 3-dimethylamino-methylene compound of the formula V
V
and (b2) the resulting compound of the formula V is converted, by reaction with phosphorous oxytrichloride or -bromide, into a compound of the formula VI
VI
and this compound is converted according to steps (a2) (a3) into a compound of the formula I, or (c) a compound of the formula I, wherein R1 to R4 and m are as defined above, with the proviso that R2 contains a secondary amino group, is reacted with an alkylating agent of the formula R14X, wherein X represents a chlorine or bromine atom and R14 represents an alkenyl group of 3 to 8 carbon atoms or an alkinyl group of 3 to 8 carbon atoms or an alkyl group of 1 to 6 carbon atoms which may be substituted by hydroxy, alkoxy of 1 to 4 carbon atoms, ethylene-dioxy, trimethylene-dioxy, phenyl or substituted phenyl or by the group , wherein R9 and R10 are as defined above, and the compound of the formula I may be converted into a physiologically acceptable salt by reaction with a suitable acid or suitable acid group-containing synthetic resin.
, wherein R9 and R10 have the same meanings as R7 and R8 with the proviso that they may form to-gether with the nitrogen atom a 5-, 6- or 7-membered ring which may be substituted as defined above (item .alpha.) and wherein one of the carbon atoms may be replaced by an oxygen, sulfur or nitrogen atom, this latter being, however, unsubstituted II) a cycloalkyl group of 5 to 7 carbon atoms, which may be substituted by dialkylamino groups of 1 to 4 carbon atoms, or III) R6 forms together with R5 and the nitrogen atom a 5- or 6-membered ring, in which one of the carbon atoms may be replaced by a nitrogen atom which may be substituted as mentioned for R7 and R8 (item .beta., 1. to 6.) b) an aminoalkoxy group of the wherein A2 stands for a straight-chained or branched low-molecular-weight alkylene group of 2 to 6 carbon atoms which may be substituted by alkyl of 1 to 4 carbon atoms or by phenyl which may have the substituents mentioned above (item .beta.) 2.) and R11 and R12 have the same meanings as R7 and R8, c) a basic radical of the formula -O-(CH2)n-R13, wherein R13 stands for a 5- or 6-membered heterocyclic .
ring containing a nitrogen atom and n stands for zero or 1.
R3 represents a hydrogen atom, the hydroxy group, an alkoxy group of 1 to 5 carbon atoms, a fluorine, chlorine or bromine atom, the nitro, amino or benzyloxy group, m represents the integer 1, 2 or 3, R4 represents a hydrogen atom, a saturated or unsaturated, straight-chained or branched aliphatic hydrocarbon radical having 1 to 5 carbon atoms, the benzyl or phenyl group, of which the phenyl nucleus may be substituted as defined for R2, and the physiologically acceptable salts of the said compounds of formula I, in which (a1) a compound of the formula II
II
wherein R3, R4 and m are as defined above, is reacted with phosphorous oxychloride or -bromide and dimethylformamide to yield an aldehyde of the formula III
III
(a2) the aldehyde obtained is oxidized to yield the carboxylic acid of the formula IV
IV
wherein R3, R4 and m are as defined above, and (a3) the so-obtained compound of the formula IV is reacted with an amine of the formula or with an alcohol of the formula or -HO-(CH2)nR13, wherein A2, R5, R6, R11, R12 and R13 and n are defined as above, or (b1) a compound of the formula II as defined above is reacted with phosphorus oxychloride/dimethylformamide first to yield the 3-dimethylamino-methylene compound of the formula V
V
and (b2) the resulting compound of the formula V is converted, by reaction with phosphorous oxytrichloride or -bromide, into a compound of the formula VI
VI
and this compound is converted according to steps (a2) (a3) into a compound of the formula I, or (c) a compound of the formula I, wherein R1 to R4 and m are as defined above, with the proviso that R2 contains a secondary amino group, is reacted with an alkylating agent of the formula R14X, wherein X represents a chlorine or bromine atom and R14 represents an alkenyl group of 3 to 8 carbon atoms or an alkinyl group of 3 to 8 carbon atoms or an alkyl group of 1 to 6 carbon atoms which may be substituted by hydroxy, alkoxy of 1 to 4 carbon atoms, ethylene-dioxy, trimethylene-dioxy, phenyl or substituted phenyl or by the group , wherein R9 and R10 are as defined above, and the compound of the formula I may be converted into a physiologically acceptable salt by reaction with a suitable acid or suitable acid group-containing synthetic resin.
2. A process as claimed in claim 1 in which the preparation is carried out according to reaction (a1) to (a3).
3. A process as claimed in claim 1 in which the prepara-tion is carried out according to reaction (b1) and (b2).
4. A compound of the formula I as defined in claim 1, whenever obtained according to a process as claimed in claim 1, claim 2 or claim 3 or by an obvious chemical equivalent thereof.
5. A process as claimed in claim 1 in which the prepara-tion is carried out according to reaction (c).
6. A compound of the formula I as defined above, whenever obtained according to a process as claimed in claim 5 or by an obvious chemical equivalent thereof.
7. A process as claimed in claim 1 for the preparation of 2-chloro-1-phenyl-indole 3-carboxylic acid (4-methyl)-piperazide in which N-phenyl-oxo-indole is reacted with phos-phorus oxychloride and dimethylformamide, the resultant 3-dimethylaminomethylene-1-phenyl-2-indolinone is subsequently isolated and heated with phosphorus oxychloride in chloroform to yield the 2-chloro-1-phenyl-indole-3-carbaldehyde which is subsequently isolated and oxidized in solution using potassium permanganate, the resultant 2-chloro-1-phenyl-indole 3-carboxylic acid and thionyl chloride are reacted, excess thionyl chloride is eliminated, N-methyl-piperazine and pyridine are added to the product in solution and the resultant product is subsequently isolated.
8. 2-Chloro-1-phenyl-indole 3-carboxylic acid (4-methyl)-piperazide whenever obtained according to a process as claimed in claim 7 or by an obvious chemical equivalent thereof.
9. A process as claimed in claim 1 for the preparation of 2-chloro-1-phenyl-indole 3-carboxylic acid piperazide in which N-phenyl-oxo-indole is reacted with phosphorus oxychloride and dimethylformamide, the resultant 2-chloro-1-phenyl-indole 3-carbaldehyde is subsequently isolated and oxidized in solution using potassium permanganate, the resultant 2-chloro-1-phenyl-indole 3-carboxylic acid and thionyl chloride are reacted, excess thionyl chloride is eliminated, N-formyl-piperazine and pyridine are added to the product in solution, the resultant 2-chloro-1-phenyl-indole 3-carboxylic acid (4-formyl)-piperazide is dissolved in ethanol, treated with sodium hydroxide and the resultant product is subsequently isolated.
10. 2-Chloro-1-phenyl-indole 3-carboxylic acid piperazide whenever obtained according to a process as claimed in claim 9 or by an obvious chemical equivalent thereof.
11. A process as claimed in claim 1 for the preparation of in which N-phenyl-oxo-indole is reacted with phosphorus oxychloride and dimethylformamide, the resultant 2-chloro-1-phenyl-indole 3-carbaldehyde is subsequently isolated and oxidized in solution using potassium permanganate, the resultant 2-chloro-1-phenyl-indole 3-carboxylic acid and thionyl chloride are reacted, excess thionyl chloride is eliminated, the compound and pyridine are added to the product in solution and the resultant product is subsequently isolated.
12. whenever obtained according to a process as claimed in claim 11 or by an obvious chemical equivalent thereof.
13. A process as claimed in claim 1 for the preparation of in which N-phenyl-oxo-indole is reacted with phosphorus oxychloride and dimethylformamide, the resultant 2-chloro-1-phenyl-indole 3-carbaldehyde is subsequently isolated and oxidized in solution using potassium permanganate, the resultant 2-chloro-1-phenyl-indole 3-carboxylic acid and thionyl chloride are reacted, excess thionyl chloride is eliminated, the compound and pyridine are added to the product in solution and the resultant product is subsequently isolated.
14. whenever obtained according to a process as claimed in claim 13 or by an obvious chemical equivalent thereof.
15. A process as claimed in claim 1 for the preparation of 2-chloro-1-phenyl-indole 3-carboxylic acicl 2-diethylamino ethyl ester in which N-phenyl-oxo-indole is reacted with phosphorus oxychloride and dimethylformamide, the resultant 2-chloro-1-phenyl-indole 3-carbaldehyde is subsequently isolated and oxidized in solution using potassium permanganate, the resultant 2-chloro-1-phenyl-indole 3-carboxylic acid and thionyl chloride are reacted, excess thionyl chloride is eliminated, diethylamino-ethanol and pyridine are added to the product in solution and the resultant product is subsequently isolated.
16. 2-Chloro-1-phenyl-indole 3-carboxylic acid 2-diethylamino ethyl ester whenever obtained according to a process is claimed in claim 15 or by an obvious chemical equivalent thereof.
17. A process as claimed in claim 1 for the preparation of in which N-phenyl-oxo-indole is reacted with phosphorus oxychloride and dimethylformamide, the resultant 2-chloro-1-phenyl-indole 3-carbaldehyde is subsequently isolated and oxidized in solution using potassium permanganate, the resultant 2-chloro-1-phenyl-indole 3-carboxylic acid and thionyl chloride are reacted, excess thionyl chloride is eliminated, the compound and pyridine are added to the product in solution and the resultant product is subsequently isolated.
18.
whenever obtained according to a process as claimed in claim 17 or by an obvious chemical equivalent thereof.
whenever obtained according to a process as claimed in claim 17 or by an obvious chemical equivalent thereof.
19. A process as claimed in claim 1 for the preparation 2-chloro-1-phenyl-indole 3-carboxylic acid 2-cyclohexylamino-ethyl ester hydrochloride in which N-phenyl-oxo-indole is reacted with phosphorus oxychloride and dimethylformamide, the resultant 2-chloro-1-phenyl-indole 3-carbaldehyde is subsequently isolated and oxidized in solution using potassium permanganate, the resultant 2-chloro-1-phenyl-indole 3-carboxylic acid and thionyl chloride are reacted, excess thionyl chloride is eliminated, 2-cyclohexylamino-ethanol after being treated with gaseous hydrogen chloride until a pH of 1 is reached is added to the product in solution and the resultant product is subsequently isolated.
20. 2-Chloro-1-phenyl-indole 3-carboxylic acid 2-cyclohexyl-amino-ethyl ester hydrochloride whenever obtained according to a process as claimed in claim 19 or by an obvious chemical equivalent thereof.
21. A process as claimed in claim 1 for the preparation of 2-chloro-1-phenyl-indole 3-carboxylic acid [4-(2-(1,3-dioxolan-2-yl)-ethyl)]piperazide in which N-phenyl-oxo-indole is reacted with phosphorus oxychloride and dimethylformamide, the resultant 2-chloro-1-phenyl-indole 3-carbaldehyde is sub-sequently isolated and oxidized in solution using potassium permanganate, the resultant 2-chloro-1-phenyl-indole 3-carboxylic acid and thionyl chloride are reacted, excess thionyl chloride is eliminated, N-formyl-piperazine and pyridine are added to the product in solution, the resultant 2-chloro-1-phenyl-indole 3-carboxylic acid (4-formyl)-piperazide is dissolved in ethanol and treated with sodium hydroxide, the resultant 2-chloro-1-phenyl-indole 3-carboxylic acid piperazide is boiled with a mixture of 2-(2-chloroethyl)-1,3-dioxolane, triethylamine and toluene, the cooled mixture is diluted with ethyl acetate and the resultant product is subsequently isolated.
22. 2-Chloro-1-phenyl-indole 3-carboxylic acid [4-(2-(1,3-dioxolan-2-yl)-ethyl)]piperazide whenever obtained according to a process as claimed in claim 21 or by an obvious chemical equivalent thereof.
23. A process as claimed in claim 1 for the preparation of 2-chloro-1-phenyl-indole 3-carboxylic acid [4-(3,4-methylene-dioxy-benzyl)]-piperazide in which N-phenyl-oxo-indole is reacted with phosphorus oxychloride and dimethylformamide, the resultant 2-chloro-1-phenyl-indole 3-carbaldehyde is subsequently isolated and oxidized in solution using potassium permanganate, the resultant 2-chloro-1-phenyl-indole 3-carboxylic acid and thionyl chloride are reacted, excess thionyl chloride is eliminated, N-formyl-piperazine and pyridine are added to the product in solution, the resultant 2-chloro-1-phenyl-inaole 3-carboxylic acid (4-formyl)-piperazide is dissolved in ethanol and treated with sodium hydroxide, the resultant 2-chloro-1-phenyl-indole 3-carboxylic acid piperazide is boiled with a mixture of piperonyl chloride, triethylamine and toluene, the cooled mixture is diluted with ethyl acetate and the resultant product is subsequently isolated.
24. 2-Chloro-l-phenyl-indole 3-carboxylic acid [4-(3, 4-methylene-dioxy-benzyl)]-piperazide, whenever obtained according to a process as claimed in claim 23 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19752557342 DE2557342A1 (en) | 1975-12-19 | 1975-12-19 | BASIC SUBSTITUTED INDOLDER DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1079739A true CA1079739A (en) | 1980-06-17 |
Family
ID=5964905
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA268,139A Expired CA1079739A (en) | 1975-12-19 | 1976-12-17 | Basically substituted indole derivatives and process for their manufacture |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS5277060A (en) |
| AT (1) | ATA936276A (en) |
| BE (1) | BE849626A (en) |
| CA (1) | CA1079739A (en) |
| DE (1) | DE2557342A1 (en) |
| DK (1) | DK571376A (en) |
| FR (1) | FR2335216A1 (en) |
| GB (1) | GB1566307A (en) |
| IT (1) | IT1065683B (en) |
| LU (1) | LU76427A1 (en) |
| NL (1) | NL7614050A (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5936675A (en) * | 1982-07-13 | 1984-02-28 | サンド・アクチエンゲゼルシヤフト | Cyclic carboxylic acid piperidyl ester and amide derivative |
| US4879391A (en) * | 1982-09-20 | 1989-11-07 | Pfizer Inc. | 1-Phenyl-2(1H,3H)-indolone psychotherapeutic agents |
| US4861880A (en) * | 1982-09-20 | 1989-08-29 | Pfizer Inc. | 1-phenyl-2(1H,3H)-indolone psycho-therapeutic agents |
| US4476307A (en) * | 1982-09-20 | 1984-10-09 | Pfizer Inc. | Heteroylidene indolone compounds |
| US4977178A (en) * | 1982-09-20 | 1990-12-11 | Pfizer Inc. | Method of treating anxiety and depression with 1-phenyl-2(1H,3H)-indolone psycho-therapeutic agents |
| JPS6084281A (en) * | 1983-09-14 | 1985-05-13 | Yoshitomi Pharmaceut Ind Ltd | 3-indolecarboxamide |
| DE3445377A1 (en) * | 1983-12-23 | 1985-07-04 | Sandoz-Patent-GmbH, 7850 Lörrach | CARBOCYLIC AND HETEROCYCLIC CARBONIC ACID ESTERS AND AMIDES OF BRIDGED AND NON-BRIDGED CYCLIC NITROCYLINE AMINES OR ALCOHOLS |
| US5852014A (en) * | 1992-03-12 | 1998-12-22 | Smithkline Beecham P.L.C. | Condensed indole derivatives as 5HT4 -receptor antagonists |
| ES2132223T3 (en) * | 1992-03-12 | 1999-08-16 | Smithkline Beecham Plc | INDOL DERIVATIVES CONDENSED AS ANTAGONISTS OF THE 5-HT4 RECEPTOR. |
| PT802183E (en) * | 1996-04-19 | 2002-03-28 | American Home Prod | ESTROGENIC AGENTS |
| US6069153A (en) * | 1998-05-12 | 2000-05-30 | American Home Products Corporation | Indenoindoles and benzocarbazoles as estrogenic agents |
| US6479535B1 (en) | 1998-05-15 | 2002-11-12 | Wyeth | 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole and estrogen formulations |
| US6159959A (en) * | 1999-05-06 | 2000-12-12 | American Home Products Corporation | Combined estrogen and antiestrogen therapy |
| EA015252B1 (en) | 2005-05-10 | 2011-06-30 | Интермьюн, Инк. | Method of modulating stress-activated protein kinase system |
| KR101020351B1 (en) * | 2005-07-29 | 2011-03-08 | 에프. 호프만-라 로슈 아게 | Indol-3-yl-carbonyl-piperidin and piperazin derivatives |
| EP1924557A2 (en) * | 2005-09-16 | 2008-05-28 | Serenex, Inc. | Carbazole derivatives |
| AU2008286946B2 (en) * | 2007-08-10 | 2013-11-21 | H. Lundbeck A/S | Heteroaryl amide analogues |
| CN102099036B (en) | 2008-06-03 | 2015-05-27 | 英特芒尼公司 | Compounds and methods for treating inflammatory and fibrotic disorders |
| AR092742A1 (en) | 2012-10-02 | 2015-04-29 | Intermune Inc | ANTIFIBROTIC PYRIDINONES |
| CN110452216B (en) | 2014-04-02 | 2022-08-26 | 英特穆恩公司 | Anti-fibrotic pyridinones |
-
1975
- 1975-12-19 DE DE19752557342 patent/DE2557342A1/en not_active Withdrawn
-
1976
- 1976-12-17 NL NL7614050A patent/NL7614050A/en not_active Application Discontinuation
- 1976-12-17 LU LU76427A patent/LU76427A1/xx unknown
- 1976-12-17 DK DK571376A patent/DK571376A/en not_active Application Discontinuation
- 1976-12-17 IT IT30582/76A patent/IT1065683B/en active
- 1976-12-17 AT AT936276A patent/ATA936276A/en not_active Application Discontinuation
- 1976-12-17 CA CA268,139A patent/CA1079739A/en not_active Expired
- 1976-12-18 JP JP51151501A patent/JPS5277060A/en active Pending
- 1976-12-20 BE BE173447A patent/BE849626A/en unknown
- 1976-12-20 GB GB53124/76A patent/GB1566307A/en not_active Expired
- 1976-12-20 FR FR7638400A patent/FR2335216A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| FR2335216A1 (en) | 1977-07-15 |
| IT1065683B (en) | 1985-03-04 |
| LU76427A1 (en) | 1977-07-05 |
| JPS5277060A (en) | 1977-06-29 |
| GB1566307A (en) | 1980-04-30 |
| NL7614050A (en) | 1977-06-21 |
| DE2557342A1 (en) | 1977-06-30 |
| ATA936276A (en) | 1980-02-15 |
| DK571376A (en) | 1977-06-20 |
| BE849626A (en) | 1977-06-20 |
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