DD280099A5 - PROCESS FOR PRODUCING NEW AMMONIUM COMPOUNDS - Google Patents
PROCESS FOR PRODUCING NEW AMMONIUM COMPOUNDS Download PDFInfo
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- DD280099A5 DD280099A5 DD88323312A DD32331288A DD280099A5 DD 280099 A5 DD280099 A5 DD 280099A5 DD 88323312 A DD88323312 A DD 88323312A DD 32331288 A DD32331288 A DD 32331288A DD 280099 A5 DD280099 A5 DD 280099A5
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- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/40—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton with quaternised nitrogen atoms bound to carbon atoms of the carbon skeleton
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
- C07D213/20—Quaternary compounds thereof
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- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/10—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
- C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
Die Erfindung betrifft ein Verfahren zur Herstellung von Verbindungen der Formel (I), nach an sich bekannten Verfahren sowie ihre Verwendung zur Herstellung von Arzneimitteln. Die erfindungsgemaess hergestellten Verbindungen haben vor allem broncholytische, spasmolytische und antiallergische Wirkung, erhoehen die Ciliartaetigkeit und verringern entzuendlich-exsudative Reaktionen. Sie sind daher u. a. fuer die Behandlung aller Formen von Asthma und Bronchitis verwendbar. Formel (I)The invention relates to a process for the preparation of compounds of the formula (I), to processes which are known per se and to their use for the preparation of medicaments. The compounds prepared according to the invention have, above all, broncholytic, spasmolytic and antiallergic action, increase ciliary activity and reduce inflammatory exudative reactions. They are therefore u. a. suitable for the treatment of all forms of asthma and bronchitis. Formula (I)
Description
Die neuen Verbindungen lassen sich im wesentlichen durch die FormelThe new compounds can be essentially by the formula
ArAr
wiedergeben.play.
Soweit nichts anderes angegeben ist, bedeutet in dieser Formel und im folgendenUnless otherwise indicated, means in this formula and in the following
n: \2,3,4oder5;n: \ 2,3,4 or 5;
R1: H, CH3, OCH3, Cl, F; R2: H, R3O, CH2OH, NHCHO, NHCOCH3, NHSO2CH3, NHCONH2;R 1: H, CH 3, OCH 3, Cl, F; R 2 : H, R 3 O, CH 2 OH, NHCHO, NHCOCH 3 , NHSO 2 CH 3 , NHCONH 2 ;
R3: H, Acyl, Ν,Ν-Dialkylcarbamoyl, wobei sich die Gruppe R3O in 4- oder 5-Stellung befindet; die GruppeR 3 : H, acyl, Ν, Ν-dialkylcarbamoyl, wherein the group R 3 O is in the 4- or 5-position; the group
R _ R,R _ R,
steht außerdem für O Ralso stands for O R
(Ha)(Ha)
(Hb)(Hb)
(lic)(Lic)
R4: H, CH3, C2H^; R5: H,CH3; R6: H, CH3, R7: eine Eiiifachbindung oder ein zweibindiges Brückenglied, das auch über Ringatome eines Heterocyclus an denR 4 : H, CH 3 , C 2 H ^; R5: H, CH 3; R 6 : H, CH 3 , R 7 : a single bond or a divalent bridge member, which can also be attached via ring atoms of a heterocycle to the
Ammoniumstickstoff gebunden sein kann; R8: H oder 'JH3; -N®-: einequartäreAmmoniumgruppe.Ammonium nitrogen may be bound; R 8 : H or 'JH 3 ; -N®-: a quaternary ammonium group.
ΑηΘ: 1 ÄquivalenteinesAnionsΑη Θ : 1 equivalent of an anion
Die Gruppierung -R7-N* - steht (während η und Ri bis R6 die obige Bedeutung hauen), hauptsächlich fürThe grouping -R 7 -N * - stands (while η and Ri to R 6 have the meaning given above), mainly for
B-EB-E
(HIh)(HIH)
Dabei bedeutenMean
2,3,4,5 oder 6; eine Ein "achbinding oder NH-CO-(C)-C4)-Alkylen; eine Einfachbindung oder-O-ICr-C^-Alkylen-.-NH-CO-ICi-Cjl-Alkylen-.-IC-Cil-Alkylen- -(C,-C)-Alkylendie Gruppen2,3,4,5 or 6; achbinding a "or NH-CO- (C) -C 4) alkylene represents a single bond or-O-ICR-C ^ alkylene -.- NH-CO-ICI Cjl alkylene -.- IC CIL Alkylene- (C, -C) -alkyl groups
1IO oder 1 IO or
oderor
1111
Arylen, insbesondere unsubstituiertes oder substituiertes Phenylen oder Naphthylen;Arylene, in particular unsubstituted or substituted phenylene or naphthylene;
N-Heterocyclen, die mit einem Benzolring kondensiert und unsubstituiert oder substituiert sein können und die gegebenenfalls ein oder mehrere zusätzliche Heteroatome im Ring enthalten können;N-heterocycles which may be condensed with a benzene ring and may be unsubstituted or substituted and which may optionally contain one or more additional heteroatoms in the ring;
(C,-C)-Alkyl; (C-Cl-Alkyl;(C, -C) alkyl; (C-Cl-alkyl;
(C,-C)-Alkyl, (C-O-Alkylen-COO®, (C^-Ql-Alkylen-SOa0, (C,-C4)-Alkylen-OH, (C4-C6)-Cycloalkyl, R9 und(C 1 -C 4 ) -alkyl, (CO-alkylene-COO®, (C 1 -C 4 -alkylene-SOA 0 , (C 1 -C 4 ) -alkylene-OH, (C 4 -C 6 ) -cycloalkyl, R 9 and
R10gemeinsam auch (C4-C6)-Alkylen.R 10 together also (C 4 -C 6 ) -alkylene.
-Ar-B-Ar-B
-NH-CO f- Het-NH-CO f- Het
9 10 119 10 11
(III a I)(III a I)
(III a 2)(III a 2)
(in a ;)(in a)
(III b 1)(III b 1)
(III b 2)(III b 2)
(III c 1)(III c 1)
(III d 1)(III d 1)
(III e 1) (III f 1)(in g D(III h 1)(III e 1) (III f 1) (in g D (III h 1)
(III i )(III i)
Die orfindungsgemäßen Verbindungen können als Enantiomerengemische, insbesondere als Racemate, gegebenenfalls auch Diastereomerenpaare, und als reine Enantiomere vorliegen, jeweils auch als Salze mit (vorzugsweise physiologisch verträglichen) Säuren.The compounds according to the invention can be present as enantiomer mixtures, in particular as racemates, if appropriate also pairs of diastereomers, and as pure enantiomers, in each case also as salts with (preferably physiologically compatible) acids.
Die Alkyl- und Alkylengruppen in dan obigen Definitionen können geradkettig oder verzweigt sein. Soweit keine näheren Angaben gemacht sind, enthalten sie 1 bis 6, vorzugsweise 1 bis 4, insbesondere 1 bis 2 C-Atome. Dies gilt auch für die C-Ketten, die Bestandteil anderer Reste sind. Als Substituenten in Aryl(en) kommen vor allem F, Cl, CH3, CH3O in Betracht, wobei mit „Aryl" bzw. „Arylen" die entsprechenden von Benzol bzw. Naphthalin abgeleiteten Reste gemeint sind. „Acylreste" sind hier Carbonsäurereste mit bis zu 7 C-Atomen, insbesondere Acetyl. Die Brücke R7 kann mit dem N-Atom der quartären Ammoniumgruppe verknüpft sein. Falls die quartäre Ammoniumgruppe Bestandteil eines Heterocyclus ist, kann die Brücke auch mit einem anderen Ringatom des Heterocyclus verbunden sein. Reste der FormelThe alkyl and alkylene groups in the above definitions may be straight-chain or branched. Unless otherwise specified, they contain 1 to 6, preferably 1 to 4, in particular 1 to 2, C atoms. This also applies to the C chains, which are part of other radicals. Suitable substituents in aryl (s) are, in particular, F, Cl, CH 3 , CH 3 O, where by "aryl" or "arylene" is meant the corresponding radicals derived from benzene or naphthalene. Here, "acyl radicals" are carboxylic acid radicals having up to 7 carbon atoms, in particular acetyl The bridge R 7 may be linked to the nitrogen atom of the quaternary ammonium group If the quaternary ammonium group is part of a heterocycle, the bridge may also be linked to another ring atom of the heterocycle
sind vor allemare especially
-N-N
N-N-
ferner Triazine; R" gleich H oder C,-C4-Alkyl)furthermore triazines; R "is H or C, -C 4 -alkyl)
In einer bevorzugten Ausführungsform der Erfindung steht R, für H, CH3, OCH3, Cl, F; R2 für OH oder-im Falle R1 gleich Cl, F-für H; Typische Beispiele für E sind z. B.In a preferred embodiment of the invention R, is H, CH 3 , OCH 3 , Cl, F; R 2 is OH or-in the case of R 1 is Cl, F is -H; Typical examples of E are z. B.
-N®(CH3)3,-N® (CH 3 ) 3 ,
-N®(CH3)2CH2CH2CH2SOf, -M0ICH3I2-(CH2I4-SOf, -N®(CH3)2CH2CH2CO?,-N® (CH 3 ) 2 CH 2 CH 2 CH 2 SOf, -M 0 ICH 3 I 2 - (CH 2 I 4 -SOf, -N® (CH 3 ) 2 CH 2 CH 2 CO ?,
— N-- N-
R, und R2fjemeinsam fürR, and R 2 are the same for
0 R o Il I 8 0 R o Il I 8
Χ" "β Χ "" β
R3 für H,;R 3 for H ,;
R4 für H, C2H5;R 4 is H, C 2 H 5 ;
R5, R6: beidefürHoderbeidefürCH3;R 5 , R 6 : either or both of CH 3 ;
η für1,2oder3;η is 1,2 or 3;
oderor
R7- N+- fürR 7 - N + - for
-NH-CO-NH-CO
CH3 CH 3
B -B -
CHCH
HetHet
Of-of-
oderor
CHCH
- D - if- R- D - if- R
CHCH
1111
CHCH
1Il 1 Il
steht hier fürstands for
oder -Nor -N
-M-M
fürFor
während B, D und R11 die obige Bedeutung haben.while B, D and R 11 have the above meaning.
Besonders hervorzuheben sind die Verbindungen, in denen sich die nachstehenden Substituentenkombinationen finden:Particularly noteworthy are the compounds in which the following substituent combinations are found:
(a) CH3 oder OCH3/OH/4-OH(a) CH 3 or OCH 3 / OH / 4-OH
(b) H/OH/4-oder5-OH(b) H / OH / 4 or 5-OH
O RO R
HNHN
oder HNor HN
[ I[I
(R1 und R2 gemeinsarn)/4-oder S-OH(R 1 and R 2 in common) / 4 or S-OH
R4: H,wenn R5 und R6CH3;R 4 is H when R 5 and R 6 are CH 3 ;
und C2H5, wenn R5 und R6 H sind;and C 2 H 5 when R 5 and R 6 are H;
R7-IjK:R 7 -IjK:
-CO - CH„ --CO - CH "-
- CH.- CH.
__NH - CO - CH„ -__NH - CO - CH "-
1212
O- CH2 -CH2-O-CH 2 -CH 2 -
- R- R
1313
R12, Rn: CH3,R 12 , R n : CH 3 ,
CHj-CHj-COÜ®, -CH2-CH2-CH2-SOf;CHj-CHj-COÜ®, -CH 2 -CH 2 -CH 2 -SOf;
Die erfindungsgemäßeh Verbindungen können als Enantiomerengemische, insbesondero als Racemate, gegebenenfalls auch Diastereomeronpaare, und als reine Enantiomere vorliegen, jeweils auch als Salze mit (vorzugsweise physiologischThe compounds according to the invention can be present as mixtures of enantiomers, in particular as racemates, if appropriate also diastereomerone pairs, and as pure enantiomers, in each case also as salts with (preferably physiologically
\ erträglichen) Säuren.\ tolerable) acids.
Die neuen Verbindungen können nach an sich bekannten Methoden horgestellt werden:The novel compounds can be prepared by methods known per se:
1. Quaternierung von Verbindungen der Formel1. Quaternization of compounds of the formula
|4| 4
CHCH
| I| I
il 2 ηil 2 η
H RMR
(IV),(IV),
in der n, R4, R5 und R6 die obige Bedeutung haben und R' für einen Rest steht, der mit R übereinstimmt, außer daß er anstelle der quartären Ammoniumgruppe eine tertiäre Arninogruppe enthält, und in der Q' die gleiche Bedeutung wie Q hat, woboi jedoch etwa darin vorhandene OH-Grup/en, wie auch die zentrale NH-Gruppe, durch hydrogenoiytisch abspaltbare Schutzgruppen gecchützt sein können, mit geeigneten Alkylierungsmitteln umsetzt und gegebenenfalls vorhandene Schutz{iruppen mit Wasserstoff/Κε:alysator entfernt.in which n, R 4 , R 5 and R 6 are as defined above and R 'is a radical which is identical to R, except that it contains a tertiary amino group instead of the quaternary ammonium group, and the same meaning in Q' However, Q, where OH groups present therein, as well as the central NH group, may be protected by hydrogenolysis-releasable protective groups, are reacted with suitable alkylating agents and any protective groups present are removed with hydrogen / ethyl acetate.
Das Verfahren eignet sich zur Herstellung derjenigen Verbindungen der Formel I, in denen die quartäre Ammoniumgruppe nicht die FormThe process is suitable for the preparation of those compounds of formula I in which the quaternary ammonium group is not the form
Her -V=lhat.Her -V = l has.
Zur Einführung von (C|-C4)-Alkylen-SOf eignen sich vor allem CI-(Ci-C4)-Alkylen-SO3Na und HO-(Ci-C4)-Alkylen-SO2-O-(C,-C4)-Alkylen-SO3Na.For the introduction of (C | -C 4) -alkylene SOF mainly CI (Ci-C4) alkylene-SO 3 Na and HO (C 4) -alkylene-SO2-O- (C are , -C 4 ) -alkylene-SO 3 Na.
Die Umsetzung erfolgt zweckmäßig in einem inerten polaren Lösungsmittel bei Raumtemperatur oder erhöhter Temperatur (bis etwa 1000C).The reaction is expediently carried out in an inert polar solvent at room temperature or elevated temperature (up to about 100 ° C.).
Die Ausgangsstoffe der Formel IV können ebenfalls nach an sich bekannten Methoden erhalten werden. So können Aminoketone der FormelThe starting materials of formula IV can also be obtained by methods known per se. Thus, aminoketones of the formula
R4 R5 R 4 R 5
oder Schiffsche Basen der Formelor Schiff bases of the formula
ι 55
- (CH ) 2 η- (CH) 2 η
I ιI ι
- CO - C - N - C - (CH ) - R1 (Vl).- CO - C - N - C - (CH) - R 1 (VI).
I 2 ηI 2 η
worin die Symbole die oben angegebene Bedeutung haben, durch Reduktion mit Wasserstoff und Hydrierungskatalysatoren wie Palladium, Platin oder Ranoy-Nickel oder mit Hydriden wie NaH in geeigneten Lösungsmitteln, z. B. Ethanol in Verbindungen der Formel IV umgewandelt werden. Schutzgruppen können gewünschtenfalls in üblicher Weise entfernt werdenwherein the symbols have the meaning given above, by reduction with hydrogen and hydrogenation catalysts such as palladium, platinum or Ranoy nickel or with hydrides such as NaH in suitable solvents, for. For example, ethanol can be converted into compounds of formula IV. If desired, protective groups can be removed in the usual way
2. Zur Herstellung von Verbindungen der Formel 2. For the preparation of compounds of the formula
I4 ι 5 I^I4 ι 5 I ^
OH R 'OH R '
worin die Symbole die obige Bedeutung haben, R;' eine solche Gruppe R7 darstellt, die über ein aliphatisches C-Atom an den quartären Ammoniumstickstoff gebunden istwherein the symbols have the above meaning, R; ' represents such a group R 7 , which is bonded via an aliphatic carbon atom to the quaternary ammonium nitrogen
Umsetzung einer Verbindung der Formel Reaction of a compound of the formula
R4 R5 R 4 R 5
OH R£ OH R £
worin die Symbole die obige Bedeutung habe1" jnd X eine Gruppe bedeutet, die unter Bindung von R7' (und damit Quaternisierung) an das Stickstoffetom eines entsprechenden tertiären Amins abgespalten wird.in which the symbols have the above meaning 1 "and X denotes a group which is split off with the bond of R 7 '(and thus quaternization) to the nitrogen atom of a corresponding tertiary amine.
Die abspaltbare Gruppe X ist bevorzugt Chlor, Brom oder Jod oder ein Alkyl- oder Arylsulfonsäu.rerest.The cleavable group X is preferably chlorine, bromine or iodine or an alkyl or Arylsulfonsäu.rerest.
Die Komponenten werden in einem protischen oder aprotischen Lösungsmittel wie Methanol oder Dimethylformamid bei Temperaturen zwischen Raumtemperatur und etwa 1000C zur Reaktion gebracht.The components are reacted in a protic or aprotic solvent such as methanol or dimethylformamide at temperatures between room temperature and about 100 ° C.
Evfi.v-jell vorhandene hydrogenolytisch abspaltbare Schutzgruppen werden nach der Umsetzung nach üblichen Methoden entfernt.Evifi.v-jell existing hydrogenolytically removable protecting groups are removed after the reaction by conventional methods.
Die Ausgangsstoffe der Formel VIII lassen sich z. B. aus Aminoketonen der FormelThe starting materials of the formula VIII can be z. B. from aminoketones of the formula
R RR R
14 Ϊ514 Ϊ5
mit Hydriden wie Natriumhydrid oder Diboran herstellen.with hydrides such as sodium hydride or diborane.
Die \ erbindungen der Formel IX sind ihrerseits nach an sich bekannten Methoden erhältlich. 3. Entfernung von hydrogenolytisch abspa!;baren Schutzgruppen aus einer Verbindung der FormelThe compounds of the formula IX are in turn obtainable by methods known per se. 3. Removal of hydrogenolytically removable protective groups from a compound of the formula
R. R, · R»R. R, · R »
I 4 l14 15 I 4 l14 15
I I 2 η (X)1 II 2 η (X) 1
OH Rc OH R c
in der R14 für Wasserstoff oder eine hydrogenolytisch abspaltbare Schutzgruppe steht und die übrigen Symbole die oben angegebene Bedeutung haben, wobei die Verbindung X jedoch mindestens eine abzuspaltende Schutzgruppe enthält, mit Wasserstoff in Gegenwart eines Hydrierungskatalysators.in which R 14 is hydrogen or a hydrogenolytically removable protective group and the other symbols have the abovementioned meaning, but the compound X contains at least one protective group to be removed, with hydrogen in the presence of a hydrogenation catalyst.
Die Entfernung der Schutzgruppen wird zweckmäßig mit Palladium als Katalysator in einem inerten Lösungsmittel vorgenommen.The removal of the protective groups is expediently carried out with palladium as catalyst in an inert solvent.
Die Ausgangsstoffe können nach üblichen Methoden, z. B. analog den obigen Verfahren 1 und 2 gewonnen werden.The starting materials can be prepared by customary methods, for. B. are obtained analogously to the above methods 1 and 2.
Die erfindungsgemäßen Verbindungen enthalten mindestens ein asymmetrisches C-Atom. Zur Gewinnung bestimmter Enantiomerer bzw. (im Fall mehrerer Asymmetriezentren) diastereomerer Antipodenpaare verwendet man zweckmäßig Ausgangsstoff*1. -. B. der Formel IV oder X, in denen an den betreffenden Asymmetriezentren von vornherein die gewünschte Konfiguration vorliegt.The compounds according to the invention contain at least one asymmetric carbon atom. To obtain certain enantiomers or (in the case of several centers of asymmetry) diastereomeric antipode pairs, it is expedient to use starting material * 1 . -. B. the formula IV or X, in which the desired configuration is present at the asymmetry centers in question from the outset.
Die erfindungsgemäßen Verbind'ingen werden gewünschtenfalls in an sich bekannter Weise in Salze mit physiologisch verträglichen Säuren übergeführt.If desired, the compounds according to the invention are converted into salts with physiologically tolerated acids in a manner known per se.
Die neuen Verbindungen sind als Arzneistoffe verwendbar. Sie haben vor allem broncholytische, spasmolytische und antiallergische Wirkung, erhöhen die Ciliartätigkeit und verringern entzündlich-exsudative Reaktionen. Sie sind daher u.a. für die Behandlung aller Formen von Asthma und Bronchitis verwendbar.The new compounds are useful as drugs. In particular, they have broncholytic, spasmolytic and anti-allergic effects, increase ciliary activity and reduce inflammatory-exudative reactions. They are therefore u.a. suitable for the treatment of all forms of asthma and bronchitis.
Die therapeutische und prophylaktische Dosis ist abhängig von der Beschaffenheit und Ernsthaftigkeit des Krankheitszustandes. Für einen Erwachsenen beträgt die Dosis bei der bevorzugten inhalativen Anwendung 0,001-0,5mg pro die. Die Zubereitung der Präparate erfolgt in der galenisch üblichen Weise mit gebräuchlichen Hilfs- und/oder Trägerstoffen, wobei die erfindungsgemäßen Verbindungen auch mit anderen Wirkstoffen kombiniert werden können, z. B. mit Parasympatholytika (z. B. Ipratropiumbromid, Oxitropiumbromirl), Selcretolytika (z. B. Bromhexin, Ambroxol), Antibiotika (z. B. Doxycyclin), Corticosteroiden (z. B. Beclomethasondipropionat, Flunisolid, Budesonid), anderen Asthmamitteln wie Dinatriumcromoglicat, Nedocromil und AntiallergikaThe therapeutic and prophylactic dose depends on the nature and severity of the condition. For an adult, the preferred inhalative dose is 0.001-0.5 mg per day. The preparation of the preparations is carried out in the usual galenic manner with conventional excipients and / or carriers, wherein the compounds of the invention can also be combined with other active ingredients, for. With parasympatholytics (eg, ipratropium bromide, oxitropium bromine), selcretolytics (eg, bromhexine, ambroxol), antibiotics (eg, doxycycline), corticosteroids (eg, beclomethasone dipropionate, flunisolide, budesonide), other asthma agents such as Disodium cromoglycate, nedocromil and antiallergic agents
Ausführungsbeispieleembodiments
1. Inhalationspulver1. Inhalation powder
Mikronisiertes Wirkstoffpulver (Verbindung der Formel I; Teilchengröße etwa 0,5 bis 7 pm) werden in einer Menge von 0,02 mg mit 10 mg rnikronisierter Lactose und gegebenenfalls geeigneten Mengen weiterer Wirkstoffe in Hartgelatinekapseln abgefüllt. Das Pulver wird aus üblichen Inhalationsgeräten, z. B. gemäß DE-A 3345722, inhaliert.Micronised active ingredient powder (compound of formula I, particle size about 0.5 to 7 pm) are filled in an amount of 0.02 mg with 10 mg of nicronized lactose and optionally suitable amounts of further active ingredients in hard gelatin capsules. The powder is from conventional inhalers, z. B. according to DE-A 3345722, inhaled.
2. Disieraerosol2. Disieraerosol
WiiKstoff gemäß Beispiel 8 0,1 Gew.-%WiiKstoff according to Example 8 0.1 wt .-%
Sorbitantrioleat 0,5Gew.-%Sorbitan trioleate 0.5% by weight
MonofluortrichlormethanundDifluordichlormethan(2:3) 99,4 Gew.·%Monofluorotrichloromethane and difluorodichloromethane (2: 3) 99.4% by weight.
Die Mischung wird in Dosieraerosolgeräte üblicher Art abgefüllt. Die Dosiervorrichtung wird beispielsweise so ausgelegt, daß pro Hub 0,05 ml der Zubereitung abgegeben werden.The mixture is filled into metered dose inhalers of conventional type. The dosing device is designed, for example, so that 0.05 ml of the preparation are dispensed per stroke.
Der Vorteil der erfindungsgemäßen Verbindungen besteht darin, daß bei der inhalativen Applikation im Vergleich zu bekannten bronchospasmolytischen ß-Mimetika eine besonders ausgeprägte Selektivität im Verhältnis Bronchospasmolyse zu Herzfrequenzsteigerung, positiv inotropen Effekten und Tremor festzustellen ist. Die broncholytische Wirkung mit geringen Dosen erzielt, die Wirkung hält lange an.The advantage of the compounds according to the invention is that a particularly pronounced selectivity in the ratio of bronchospasmolysis to increase in heart rate, positive inotropic effects and tremor can be ascertained during inhalative administration in comparison with known bronchospasmolytic β-mimetics. The broncholytic effect achieved with low doses, the effect lasts for a long time.
Im folgenden sind einige pharmakologische Wirkungsangaben für erfindungsgemäße Verbindungen zusammengestellt. Es wurde die inhalative EC50 am wachen, nüchternen Meerschweinchen nach Kallos P. und Pagel, W. (Acta med. scand. 91, 292 [1937I) ermittelt (Histaminspasmus). Die Substanzen wurden in Form einer wäßrigen Lösung geprüft. 'In the following some pharmacological effects are compiled for compounds according to the invention. The inhalative EC 50 was determined in the guinea pig guinea pigs according to Kallos P. and Pagel, W. (Acta med. Scand., 91, 292 [1937I] (histamine spasm). The substances were tested in the form of an aqueous solution. '
EC60 %EC 60 %
Geprüfte VerbindungenTested connections
CHCH
2 CH ' 2 CH '
Verbindung QConnection Q
HOHO
er-he-
OH CHOH CH
-N®-N®
( CH3J3C(CH 3 J 3 C
>N(CH> N (CH
OHOH
Verbindung d9r FormelConnection of the formula
X HClX HCl
CHOH-CH-GCHOH-CH-G
Verbindung Verbin dung
lP(CHa), Cl®IP (CH a ), Cl®
3)3 3 ) 3
G: -NH-C-CH,G: -NH-C-CH,
ι ' CH3 ι 'CH 3
ClSClS
H: -NH-C-CH2 /Γ J \H: -NH-C-CH 2 / Γ J \
CH3 CH 3
I: -NH-C-CH.I: -NH-C-CH.
CH,CH,
CHCH
lr+\ -CH-CH-I^-CHlr + \ -CH-CH-I ^ -CH
it it «J it it «J
CHCHCHCH
CH,CH2-CH2-CH2-SO-CH, CH 2 -CH 2 -CH 2 -SO-
CHCH
K: -NH-C-CHK: -NH-C-CH
JH.CHJH.CH
CH2-CH2-CH2-SOTCH 2 -CH 2 -CH 2 -SOT
Zu Verfahren 1: Beispiel 1For method 1: example 1
-CH2-NH-C-CH2-CH2 -CH 2 -NH-C-CH 2 -CH 2
CH,CH,
x HClx HCl
ClCl
monohydrochlond wfirden in einer Mischung von 3ml Dimethylformamid/1 ml Wasser gelöst und mit 1,27g Methyljodid zersetzt. Nach 12 Stunden wird die Lösung mit 5 ml Alkohol versetzt, mit konz. HCI angesäuert und mit Aceton verdünnt; die ausgefallenen Kristalle werden nach ~ 1 Stunde abgesaugt und durch Umfallen am Wasser, konz. Salzsäure und Alkohol erhältmonohydrochloride was dissolved in a mixture of 3 ml of dimethylformamide / 1 ml of water and decomposed with 1.27 g of methyl iodide. After 12 hours, the solution is mixed with 5 ml of alcohol, with conc. HCI acidified and diluted with acetone; The precipitated crystals are filtered off with suction after ~ 1 hour and by precipitation on the water, conc. Hydrochloric acid and alcohol
man 1,2g der Verbindung.1.2 g of the compound.
Fp.207-209°C,56%d.Th.Fp.207-209 ° C, 56% d.Th.
Die Ausgangsverbindung kann nach folgendem Verfahren hergestellt werden:The starting compound can be prepared by the following procedure:
-CH O-CH O
HN OHN O
•Qt• Qt
OC H 2 5OC H 2 5
CH -CH -C-NH 2 ι 2CH-CH -C-NH 2 ι 2
CH3 CH 3
HN 0HN 0
H-O—{( Yy-C-CH=N-C CH -CH 2 \V )l\\ ι 2 2H-O-{(Yy-C-CH = N-CCH-CH2 \ V) l \\ 2 2
0 CH0 CH
NaBHNaBH
(Fp. 170-1710C)(Mp 170-171 0 C)
.CH-CH -NH-C-CH -CH -I 2 ι 2 2.CH-CH-NH-C-CH-CH-I 2 ι 2 2
OH CHOH CH
H /Pd/CH / Pd / C
(Fp. 157-1600C)(Mp 157-160 0 C)
HO —HO -
-CH-CH0-NH-C-CH -CH -ι 2 ι 2 2 -CH-CH 0 -NH-C-CH-CH 2 ι 2 2
OH CHOH CH
X HCl X HCl
(Fp. 175°C (Zers.)(Mp 175 ° C (decomp.)
<ίΗ3<ί Η 3
-CH0-NH-C-CH0 2 ι 2-CH 0 -NH-C-CH 0 2 ι 2
OH CHOH CH
monohydrochlorid werden in 7,4ml DMF mit 2,1g Methyljodid versetzt und 12 Stunden reagieren lassen. Nach Verdünnender Lösung mit Aceton erhält man das Ammoniumjodid-hydrochlorid, welches duich Umsätzen mit Salzuaure oder über die Ammoniumhydroxydverbindung und Behandeln mit Salzsäure in die Ammonium-Chlor-hydrochlorid-Verbindung (Fp. 195-1970C) überführt wird.monohydrochloride are added in 7.4 ml of DMF with 2.1 g of methyl iodide and allowed to react for 12 hours. After diluting the solution with acetone to obtain the ammonium iodide hydrochloride, which duich transactions with Salzuaure or the Ammoniumhydroxydverbindung and treating with hydrochloric acid in the ammonium-chloride hydrochloride compound (mp. 195-197 0 C) is transferred.
3,7g dieser Benzyloxyverbindung werden in 50ml Methanol mit Palladiumkohle als Katalysator unter Normalbedingungen entbenzyliert und man erhält 2g der Titelverbindung.3.7 g of this benzyloxy compound are debenzylated in 50 ml of methanol with palladium carbon as a catalyst under standard conditions, giving 2 g of the title compound.
Fp. 1870C (Zers.); 6,28% d. Th.Mp 187 0 C (Zers.); 6.28% d. Th.
Die Ausgangsverbindung kann nach folgendem Verfahren hergestellt werden:The starting compound can be prepared by the following procedure:
HNHN
Γ\Γ \
_O-CH_O-CH
CHCH
.OH.OH
OC2H5 OC 2 H 5
CH3 CH 3
:-CH=N-C-CH-I ι 2: -CH = N-C-CH-I 2
) CH) CH
CH. /3CH. / 3
CHCH
(Fp. 2O1-2O4°C)(Mp 2O1-2O4 ° C)
(Fp. 110-1120C, Fp. HCl Salz 232-235°C)(HCl mp. 110-112 0 C, mp. 232-235 ° C salt)
HN bHN b
CH-CH2-NH-C-CH2-/ OH CHCH-CH 2 -NH-C-CH 2 - / OH CH
O-CH_-CH,.-®N-CH_-CH_-COci) L I ι 2 ZO-CH_-CH, .- ®N-CH_-CH_-COci ) LI ι 2 Z
CHCH
X HClX HCl
3,2g 5'-Benzyloxy-8'-{1-hydroxy-2-[3-{4-dimethylamino-ethoxyphenyl)-2-methyl-2-propylamino|-ethyl}-2H-1,4-benzoxazin-2-(4H)-on-monohydrochlorid werden in 6ml Acoton mit 0,41 g ß-Propiolacton versetzt und 12 Stunden bei Raumtemperatur reagieren lassen. Nach dem Verdünnen mit Aceton werden die ausgefallenen Kristalle abgesaugt und man erhält 2,4g der Vorbindung (Fp. 123-126°C).3.2 g of 5'-benzyloxy-8 '- {1-hydroxy-2- [3- {4-dimethylamino-ethoxyphenyl) -2-methyl-2-propylamino-ethyl} -2H-1,4-benzoxazine-2 - (4H) -one monohydrochloride are added in 6 ml of Acoton with 0.41 g ß-propiolactone and allowed to react for 12 hours at room temperature. After dilution with acetone, the precipitated crystals are filtered off with suction, giving 2.4 g of the pre-bond (mp 123-126 ° C).
2,3g der Benzyloxyverbindung werden in 50 ml Methanol unter Zusatz von Palladiumkohle entbenzyliert und man erhält 1,7g der Titelverbindung.2.3 g of the benzyloxy compound are debenzylated in 50 ml of methanol with addition of palladium carbon, giving 1.7 g of the title compound.
Fp. 173-1750C, 94% d. Th.Mp 173-175 0 C, 94% d. Th.
Die Ausgangsverbindung kann nach folgendem Verfahren hergestellt werden:The starting compound can be prepared by the following procedure:
HNHN
(OV- ™>° (OV ™> °
V / ^0HV / ^ 0H
7 ί7 ί
OC2H5 OC 2 H 5
-CH -CH -O 22-CH -CH -O 22
CHCH
-CH -C-NH 2 \ CH-CH -C -NH 2 \ CH
IlIl
r-\r \
HN O /HN O /
CH -O 2CH -O 2
CH r-. CHCH r -. CH
C-CH=N-C-CH - ξ Λν-0-CH -CH -N Il I 2 \Jl 2 2/ C-CH = N-C-CH -ξΛν-0-CH-CH-N il I 2\ Jl 2 2 /
O CH Υ-/ CHO CH Υ- / CH
NaBH,NaBH,
(Fp. 153-155°C)(Mp 153-155 ° C)
HNHN
-O--O-
,-CH-CH.-NH-C-CH —/, -CH-CH.-NH-C-CH - /
-CH -CH -N 2 2 ι-CH -CH -N 2 2 ι
CH X HClCH x HCl
(Fp. 176-178°C)(Mp 176-178 ° C)
Entsprechend den angegebenen Beispielen werden synthetisiert: OAccording to the examples given are synthesized: O
O H.H-1O H.H-1
NHNH
-CH-NH-CH9-CH--CH-NH-CH 9 -CH-
X HClX HCl
CHCH
O-CH_-CH,-^1N-CH-2,3O-CH_-CH, - ^ 1 N-CH-2,3
OHOH
CH X HClCH x HCl
CHCH
CHCH
HN OHN O
CHCH
-CH-CH -NH-C-CH I 2 ι 2-CH-CH-NH-C-CH I 2 ι 2
OH CHOH CH
χ HClχ HCl
2 . +2. +
HN OHN O
HO—.HO.
CH-CH -NH-C-CH -CH / I 2 ι 2CH-CH-NH-C-CH-CH / I 2 ι 2
/ oh GH. *n/ oh GH. * n
3 I CH 3 I CH
OHOH
X HClX HCl
<rH3<r H 3
CH3 N-CH 3 N-
HO—/Γ ^V-£H-CH -NH-C-CH -CH Δ \ ί Ι» HO- / Γ ^ V- £ H-CH-NH-C-CH-CHΔ \ ί Ι "
OH CH3 OH CH 3
χ HCl CF CH3 χ HCl CF CH 3
N ΟN Ο
'a'a
2 \T7 OH CH. 2 \ T7 OH CH.
X HClX HCl
H, CrH, Cr
O CHO CH
HNHN
--M--M
CH,CH,
1,^.3 ο1, ^. 3 ο
^-O-CH--CH0-N-"^, -CH0-CH0-SCY K^// 2 2 ι 2 2 2 3^ -O-CH - CH 0 -N - "^, -CH 0 -CH 0 -SCY K ^ // 2 2 ι 2 2 2 3
OH CH \—1 CHOH CH\-1 CH
X HClX HCl
O HN OO HN O
ι 2 ι 2 \ // ιι 2 ι 2 \ // ι
OH CH VT/ CHOH CH VT / CH
X HClX HCl
CH.CH.
JP-iJP-i
(Fp. 175°C)(Mp 175 ° C)
HN OHN O
CH-CH.-NH-C-CH_-CH_-/\_N^)-CHO-CH.-COCP I 2 ι 2 2 \νν/ 2 2CH-CH.-NH-C-CH_-CH _- / \ _ N ^) -CH O -CH.-COCP νν ι I 2 2 2 \ / 2 2
VT7 X HClVT7 X HCl
OHOH
x HClx HCl
(Fp. 191-193°C)(Mp 191-193 ° C)
HNHN
HO--HO--
Γ3 Γ 3
H-CH2-NH-C-CH, H CH.H-CH 2 -NH-C-CH, H CH.
OHOH
X HClX HCl
0-CH2-CH2-CH2-CH2-0-CH 2 -CH 2 -CH 2 -CH 2 -
?H3? H 3
τ τ
-CH.CH.
CH.CH.
HN 0HN 0
HOHO
CH.CH.
CH-CH -NH-C-CH -CHCH-CH-NH-C-CH-CH
I 2 T 2I 2 T 2
OHOH
CHCH
X HClX HCl
HNHN
HO—HO
fH3 H-CH2-NH-C-CH2-CHf H 3 H-CH 2 -NH-C-CH 2 -CH
CHCH
χ KClχ KCl
HN OHN O
HO—,'!HO '!
CHCH
I 3I 3
,^-CH-CH.-NH-C-CH., ^ - CH-CH.-NH-C-CH.
OHOH
CHCH
-C2H5- C 2 H 5
cr: cr :
CH.CH.
-0-CHo-CHo--N O-0-CH o -CH o - NO
'2 ^"2'2 ^ "2
X HClX HCl
ΓΛ HN 0 ΓΛ HN 0
HO-HO
?H3? H 3
-CH-CJI_-NH-C-CH_ ι 2 :-CH-CJI_-NH-C-CH_ ι 2:
OHOH
CH.CH.
-O-CH_-CH_-®N-CH. 2 2 ι 3-O-CH_-CH_-CH ®N. 2 2 ι 3
X HCl (Fp. 235°C)X HCl (mp 235 ° C)
HO—* HO- *
CHCH
CH_CH_
.H-CH2-NH-C-CH2-Z^)V-O-CH2-CH2-N^(.H-CH 2 -NH-C-CH 2 -Z ^) VO-CH 2 -CH 2 -N ^ (
OH CH V^/ CHOH CH V ^ / CH
3 33 3
X KCl (Fp. 173-175°C)X KCl (mp 173-175 ° C)
,-C00v: , -C00v :
Jkjk
HN OHN O
HO — ((V-CH-CH9 -NH-C -CH0 -CH0-'( N^-CH0-CH0-CH0-SO-X HClHO - ((V-CH-CH-C 9 -NH -CH -CH 0 0 - '(N ^ CH 0 CH 0 CH 0 -SO-X HCl
CH OH 2CH OH 2
CHCH
HO—/f )V_CH-CH0-NH-C-CH0-<( W0-CHo-CHo--N-CH. Jf I 2 I 2 y_>/ 2 2 3HO- / f) V_CH-CH 0 -NH-C-CH 0 - <(W0-CH o o --N -CH-CH Jf I 2 I 2 y _.> / 2 2 3
V- / OHV- / OH
CHCH
CHCH
X HClX HCl
:ii
HN OHN O
I 3 I 3
—/jOy CH-CH0-NH-C-CH2-- / jOy CH-CH 0 -NH-C-CH 2 -
.•7. • 7
OHOH
I CHI CH
CHCH
•i¥)3 Q• i ¥) 3 Q
-NH-CO-CH2-N^-(CH )S0^; -NH-CO-CH 2 -N ^ - (CH) S0 ^ ;
χ HCl xχ HCl x
(Fp. 250-2550C)(Mp 250-255 0 C)
-©ι- © ι
CH0 I 3 CH 0 I 3
CH0-NH-C-CH0. δ jCH 0 -NH-C-CH 0 . δ j
CH^CH ^
CH3 CH 3
J-CH0-CH0-N^-CH0-OXf 2 jJ-CH 0 -CH 0 -N ^ -CH 0 -OXf 2 j
CH^CH ^
χ HCl χχ HCl χ
(Fp. 214-216°C)(Mp 214-216 ° C)
OH CH,OH CH,
HO _HO _
CH0 I 3 CH-CH2-NH-C-CICH 0 I 3 CH-CH 2 -NH-C-CI
CH0 CH 0
CH0 CH 0
, CH3 CH3 , CH 3 CH 3
χ HClχ HCl
(Fp. 158-162°C)(Mp 158-162 ° C)
OH CH,OH CH,
HOHO
CHCH
OHOH
CH,CH,
KC - COOHKC - COOH
HC - COOHHC - COOH
HN OHN O
CH-CH0-NH-C-CH,CH-CH 0 -NH-C-CH,
i OHi OH
CH, (Fp. 220-2230C)CH, (mp 220-223 0 C)
fH3 -CH2-CH2-N®-f H 3 -CH 2 -CH 2 -N®-
CH3 CH 3
X HCl X 1/2 (Fp. 231-234°C)X HCl X 1/2 (mp 231-234 ° C)
CHOH -CHCHOH-CH
CH3 CH 3
,-NH-C-CH2-. CH0 , -NH-C-CH 2 -. CH 0
CH,CH,
0-CH0-CH0-N^-CH,. 2 ι0-CH 0 -CH 0 -N ^ -CH ,. 2 ι
CH3 CH 3
2_2_
χ .l/2 H2SO4 x 1/2 SO4 χχ .l / 2 H 2 SO 4 x 1/2 SO 4 χ
(Fp. 263-265°C)(Mp 263-265 ° C)
CH0 CH 0
I 3 I 3
-CH0H-CH2-NH-C-(-CHO-CH 2 -NH-C- (
-CH,CH,
χ 1/2 H3SO4 χ 1/2 SO4 (Fp. > 2700C)χ 1/2 H 3 SO 4 χ 1/2 SO 4 (mp> 270 ° C.)
CHOH-CH2-NH-C-CH2-, CH0 -CH2-CH2-COO0 CHOH-CH 2 -NH-C-CH 2 -, CH 0 -CH 2 -CH 2 -COO 0
χ HCl χ 2H2O (Fp. 171-174°C)χ HCl χ 2H 2 O (mp 171-174 ° C)
HOH-CH0-NH-C-CH * IHOH-CH0-NH-C-CH* I
CH3 CH 3
χ 1/2 H?SO4 χ (Fp. 234-2360C)χ 1/2 H ? SO 4 χ (mp 234-236 0 C)
CH,CH,
u A-CHOH-CH0-NH-C-CH, u A-CHOH-CH 0 -NH-C-CH,
\w/ 2 ι\ w / 2 ι
, CH3, CH 3
(O(O
χ HClχ HCl
(Fp. 231-2340C)(Mp 231-234 0 C)
, y_CHOH-CH2-NH-C-CH2 , y_CHOH-CH 2 -NH-C-CH 2
CH,CH,
,-N®-(CH?: CH0 , -N®- (CH ?: CH 0
CHCH
CHCH
CH„CH "
\ I C \ IC
NHCO-CH2-N -(CH2)3-SO3 NHCO-CH 2 -N - (CH 2 ) 3 -SO 3
CH3 CH 3
χ HCl χ 1,5 H2O (Fp. 2100Cχ HCl χ 1.5 H 2 O (mp 210 ° C
CH CH I 3 I+ 3 CH CH I 3 I + 3
CH0H-CHo-NH-C-CHo-Nl-2 ι χ HCl χCHOH-CH o -NH-C-CH o -Nl-2 ι χ HCl χ
(Fp. 95-1000C(Mp 95-100 0 C
J~\J ~ \
/VU-CH-CH2-NH-C-CH2 / VU-CH-CH 2 -NH-C-CH 2
έΗ3 έΗ 3
C)V-CH J in C) V-CH J in
H-CO-CH2-H-CO-CH 2 -
X HClX HCl
4,4g5'-Hydroxy-8'-{1-hydroxy-2-[3-(4-chloracetaminophenyl)-2-methyl-2-propylaminol-ethyl}-2H-1,4-benzoxazin-3-(4H)-onhydrochlorid, 6 ml Pyridin und 25ml Methanol werden 6 Stunden refluxiert, nach dem Abdestillieren des Methanols und Pyridins wird der ölige Rückstand in Alkohol gelöst und man erhält 3,8g der Titelverbindung.4,4g5'-hydroxy-8 '- {1-hydroxy-2- [3- (4-chloracetaminophenyl) -2-methyl-2-propylamino-ethyl} -2H-1,4-benzoxazin-3- (4H) -one hydrochloride, 6 ml of pyridine and 25 ml of methanol are refluxed for 6 hours, after distilling off the methanol and pyridine, the oily residue is dissolved in alcohol to give 3.8 g of the title compound.
(Fp. 190-192T; 77,5% d. Th.).(Mp 190-192T, 77.5% of theory).
Die Ausgangsverbindung kann nach folgenden Verfahren hergestellt werden:The starting compound can be prepared by the following methods:
HNHN
OHOH
OC H 2 5OC H 2 5
O N-O N-
HN O WHN O W
CHCH
NaBH,NaBH,
-NO-NO
(Fp. 151-154°C) O(Mp 151-154 ° C) O
ohOh
CHCH
-NO H /Ni-NO H / Ni
X HClX HCl
(Fp. 214-216°C)(Mp 214-216 ° C)
CH-CH-NH-C-CHCH-CH-NH-C-CH
I 2 I 2 νI 2 I 2 ν
OH CHOH CH
Chloressigsäureanhydridchloroacetic
X HClX HCl
(Fp. 208-2110C)(Mp 208-211 0 C)
JH,JH,
OHOH
?H3? H 3
[ -NH-C-CH 2 I 2[-NH-C-CH 2 I 2
CH3 CH 3
(Fp. 1600C Zers.)(Fp. 160 0 C Zers.)
Γ3 Γ 3
CH-CH,-NH-C-CH,-2 ι 2CH-CH, -NH-C-CH, -2 ι 2
OH OHOH OH
NH-C-CH ClNH-C-CH Cl
X HClX HCl
CH.CH.
NH-CO-CH-N^-OUNH-CO-CH-N ^ ou
CH ^ 3CH ^ 3
2,7g6'-Hydroxy-8'-{1-hydroxy-2-[3-(4-chloracetaminophenyl)-2-methyl-2-propylamino)-ethyl)-2H-1,4-benzoxazin-3-(4H)-onhydrochlorid, 25ml Methanol und 3ml 30%ige Trimethylaminlösung werden 12 Stunden bei Raumtemperatur gerühi t, konzentriert und das erhaltene Öl in Alkohol gelöst. Nach 1 Stunde werden die ausgefallenen Kristalle abgesaugt und man erhält 2g der Titelverbindung.2,7g6'-hydroxy-8 '- {1-hydroxy-2- [3- (4-chloracetaminophenyl) -2-methyl-2-propylamino) -ethyl) -2H-1,4-benzoxazin-3- (4H ) -one hydrochloride, 25ml of methanol and 3ml of 30% trimethylamine solution are stirred for 12 hours at room temperature, concentrated and the resulting oil dissolved in alcohol. After 1 hour, the precipitated crystals are filtered off with suction and 2 g of the title compound are obtained.
(Fp. 203-2060C. 65% d. Th.)(Mp 203-206 0 C. 65% of theory)
Die Ausgangsverbindung kann nach folgendem Verfahren hergestellt werden:The starting compound can be prepared by the following procedure:
/ HN O/ HN O
3-3
ChKChK
OHOH
CH -O'CH-O '
CHCH
-C-NH-C-NH
2 ι2 ι
CHCH
IlIl
?H3? H 3
C-CH=N-C-CH -C-CH = N-C-CH -
Il I O CH.Il I O CH.
.NO.NO
NaBHNaBH
(Fp. 140-1420C)(Mp 140-142 0 C)
-CH -NH-C-CH 2 I 2-CH-NH-C-CH 2 I 2
H2/Pd/CH 2 / Pd / C
X HClX HCl
(Fp. 232-234°C)(Mp 232-234 ° C)
HN OHN O
?H ? H
ohOh
X HCl ChloressigsäureanhydridX HCl chloroacetic anhydride
(Fp. 266-268°C)(Mp 266-268 ° C)
IlIl
HN OHN O
?H3? H 3
CH-CH -NH-C-CH I 2 I 2 OH CHCH-CH-NH-C-CH I 2 I 2 OH CH
H-C-CH -Cl Ο 2 OH-C-CH-Cl Ο 2 O
X HClX HCl
(Fp. 185-189°C)(Mp 185-189 ° C)
In analoger Weise werden folgende Verbindungen hergestellt: OIn an analogous manner, the following compounds are prepared: O
HN OHN O
ClCl
X HClX HCl
HN OHN O
HO-4 ,W-CH-CH-NH-(CH, ) ,-NH-CO-CH0-N^(CH ) \ Δ δ ο 2 3 3HO-4, W-CH-CH-NH- (CH,), -NH-CO-CH0-N ^ (CH)\ Δ δ ο 2 3 3
OHOH
Cl: Cl :
X HClX HCl
ΓΛΓΛ
HN ΟHN Ο
HO-.Y ^-CH-CH0-NH-(CH. U I 2HO-.Y ^ -CH-CH 0 -NH- (CH 2 UI 2
—} OH -} Oh
.NH-CO-CH2 .NH-CO-CH 2
X HClX HCl
CH-CH2-NH-C(CH3 CH-CH 2 -NH-C (CH 3
OH OH χ HClOH OH χ HCl
-NH-CO-CH9-N^(CH.). C1G -NH-CO-CH 9 -N ^ (CH.). C1 G
OH CH,OH CH,
α-·· α-
~i J)-CH-CH -NH-C(CH )-CH / OH~ i J) -CH-CH-NH-C (CH) -CH / OH
)-CH,-(( I) -CH, - ((I
X HClX HCl
HNHN
N Γ)} N Γ)}
2 Ν±/ 2 Ν ± /
CH-CH-NH-C(CH ) -CH-CH-OHCH-CH-NH-C (CH) -CH-CH-OH
X HClX HCl
NH-CO-CH0-N^(CH-) Cl0'NH-CO-CH 0 -N ^ (CH-) Cl 0 '
Zu Verfahren 3 Beispiel 6To method 3 example 6
HO CHHIGH
Η'Η '
ZjL-CH-OHZJL-CH-OH
-NH-C (CH3 ) 2 --NH-C (CH 3 ) 2 -
NH-CO-CH0-N (CH-), C1J NH-CO-CH 0 -N (CH-), C1 J
4,2g der Dibenzyloxyverbindung (siehe unten) werden in Methanol mit Palladiumkohle als Katalysator unter Normalbedingungen entbenzyliert und man erhält 2,5g der Titelverbindung.4.2 g of the dibenzyloxy compound (see below) are debenzylated in methanol with palladium carbon as the catalyst under standard conditions, giving 2.5 g of the title compound.
Die Ausgangsverbindung kann nach folgendem Verfahren hergestellt werden:The starting compound can be prepared by the following procedure:
Bz-O CHBz-O CH
O CHO CH
CO-CHCO-CH
OC2H5 OC 2 H 5
(CH )(CH)
N-CH -CO-NH-/|f~\N-CH-CO-NH- / | f ~ \
,,;^CH2-C (CH3J2-NH2 / NaBH4 ,,; ^ CH 2 -C (CH 3 J 2 -NH 2 / NaBH 4
(Bz gleich C^H-CH.-)(Bz is equal to C ^ H-CH.-)
Bz-O CHBz-O CH
Bz-O-,/f K-CH-CH0-NH-C(CH0 J-CH, / 2 3 2Bz-O-, / f K-CH-CH 0 -NH-C (CH 0 J-CH, / 2 3 2
^-NH-CO-CH0-N(CH ) 2 3 L ^ -NH-CO-CH 0 -N (CH) 2 3 L
CH3J / HClCH 3 J / HCl
(Fp. 115°C)(Mp 115 ° C)
Bz-OBz-O
ClCl
(Fp. 210-2120C)(Mp 210-212 0 C)
HN OHN O
CH.CH.
CHCH
CHCH
X HClX HCl
3,5g Benzyloxyverbindung (siehe unten) werden in 50 ml Methanol unter Zusatz von 0,5g Palladiumkohle (5%ig) als Katalysator unter Normalbedingungen entbenzyliert. Nach beendeter Aufnahme wird der Katalysator abgesaugt, das Methanol unter vermindertem Druck am Rotavapor abdestilliert und der Rückstand in etwa 90%igem Alkohol gelöst. Nach dem Animpfen werden die ausgefallenen Kristalle abgesaugt, mit Alkohol gewaschen und getrocknet. Man erhält 2,9g der Titelverbindung, (Fp. 24O0C; 93% d. Th.) Die Ausgangsverbindung kann nach folgendem Verfahren hergestellt werden (Bz gleich Benzyl)3.5 g of benzyloxy compound (see below) are debenzylated in 50 ml of methanol with the addition of 0.5 g of palladium carbon (5%) as catalyst under normal conditions. After completion of the recording, the catalyst is filtered off, the methanol was distilled off under reduced pressure on a rotary evaporator and the residue dissolved in about 90% strength alcohol. After inoculation, the precipitated crystals are filtered off with suction, washed with alcohol and dried. This gives 2.9 g of the title compound, (mp 24O 0 C, 93% of theory) The starting compound can be prepared by the following process (Bz is benzyl)
HN OHN O
Ez-OEz-O
.OH-CH9-NH-C-CH9-1 2 1 2.OH-CH 9 -NH-C-CH 9 -1 2 1 2
OH CHOH CH
ilil
X HClX HCl
NH-C(CH3 )2-CH2-NH-C (CH 3 ) 2 -CH 2 -
CH-CHOHCH-CHOH
itit
O NHO NH
OBZOBZ
b3 9b 3 9
CH3 CH 3
X HClX HCl
(Fp. 239-241°C)(Mp 239-241 ° C)
CH-CH2-NH-C-CH2-OH CHCH-CH 2 -NH-C-CH 2 -OH CH
-CH2-COO0 -CH 2 -COO 0
2,4g Benzyloxyverbindung werden in 50ml Methanol und 10ml Wasser unter Zusatz von 0,5g Palladiumkohle als Katalysator unter Normalbedingungen entbenzyliert. Nach beendeter Aufnahme wird der Katalysator abgesaugt, das Methanol unter vermindertem Druck am Rotavapor abdestilliert und der Rückstand mit Alkohol verrieben. Die ausgefallenen Kristalle werden abgesaugt und einmal mit Wasser/Alkohol umgefällt. Man erhält 1,6g der Titelverbindung (Fp. 175°CZers.,71%d.Th.)2.4 g of benzyloxy compound are debenzylated in 50 ml of methanol and 10 ml of water with addition of 0.5 g of palladium carbon as catalyst under normal conditions. After completion of the recording, the catalyst is filtered off, the methanol was distilled off under reduced pressure on a rotary evaporator and the residue triturated with alcohol. The precipitated crystals are filtered off and reprecipitated once with water / alcohol. 1.6 g of the title compound are obtained (mp 175 ° C, 71% of theory).
Die Ausgangsverbindungen werden nach folgendem Verfahren hergestellt:The starting compounds are prepared by the following procedure:
Bz-OBz-O
?H3 -CH-CH -NH-C-CH? H 3 -CH-CH-NH-C-CH
ι 2 ι :ι 2 ι:
OH CHOH CH
/CH3/ CH 3
CHCH
BcCH -COOC H 2 2BcCH-COOC H 2 2
x HClx HCl
•-o • - o
.-CH-CH0-NH-C-CH0. OH CH-CH-CH 0 -NH-C-CH 0 . OH CH
N-CH,-COOC0H.. CH 2N-CH, -COOC 0 H. CH 2
1. w'aOH HCl1. W'aOH HCl
(Fp. 127-1300C) X HCl(Mp. 127-130 0 C) X HCl
HN \HN \
Βζ-0-Βζ-0-
\ZJ OH \ ZJ OH
CH3 CH-CH0-NH-C-CH0-/ JV-CH 3 CH-CH 0 -NH-C-CH 0 - / JV-
CH V—ί CHCH V- CH
X HCl (Fp. 2O3-2O5°C)X HCl (mp 2O3-2O5 ° C)
-CH_-CO( 2-CH_-CO (2
Entsprechend den angegebenen Beispielen werden synthetisiert: OAccording to the examples given are synthesized: O
HN Ο HO-Z)V- CH-CH0-NH-C-CH0 -.HN Ο HO-Z) V-CH-CH 0 -NH-C-CH 0 -.
\ 2 J 2 \ 2 J 2
X HCl (Fp. 173-175°C) O-CH2-CH2-N®(CH3)2-C00~X HCl (mp 173-175 ° C) O-CH 2 -CH 2 -N® (CH 3 ) 2 -CO 2
HN \HN \
-CH-CH0-NH-C-CH--CH-CH 0 -NH-C-CH-
2 I 2 OH CH3 2 I 2 OH CH 3
χ HClχ HCl
(Fp. 187°C)(Mp 187 ° C)
CHn CH n
NT- CH, I 3 CHNT-CH, I 3 CH
r. Cl" r. cl "
HO OCHHO OCH
HO-Q-CH-HO-Q-CH
V-/ OH V- / OH
C I CHC I CH
CHCH
CHCH
CH- -CH-
I 3 /I 3 /
CH-CH0-NH-C-CH0-NH-,,CH-CH 0 -NH-C-CH 0 -NH- ,,
Ι 2 1 2 Ι 2 1 2
OH CH3 X HClOH CH 3 X HCl
λ \- Ολ \ - Ο
CH2-CHCH 2 -CH
,Λί, Λί
HN 0HN 0
OHOH
CHCH
CHCH
x HCl χ HO (Fp. 250-2550C)x HCl χ H 2 O (mp 250-255 0 C)
HN OHN O
HO-HO
OHOH
CH3 V_,CH 3 V_,
X HCl χ (Fp. 214-2160C)X HCl χ (mp 214-216 0 C)
OHOH
CH,CH,
-CH-CH2-NH-C-CH2 -CH-CH 2 -NH-C-CH 2
OHOH
CH,CH,
0-CH0-CH0-N^-CH0-CH 0 -CH 0 -N ^ -CH
CH3 -N^-CH 3 -N ^ -
c1' c1 '
χ HClχ HCl
(Fp. 158-162°C)(Mp 158-162 ° C)
OHOH
CH,CH,
HO —HO -
ohOh
CH3 .-0-CHo-CHo-N®(CHo),-ίCH 3. - O -CH o -CH o -N® (CH o ), - ί
HC - COOHHC - COOH
HC - COOHHC - COOH
(Fp, 220-2230C)(Mp, 220-223 0 C)
KN OKN O
CHCH
CH CHCH CH
)4-S0( ) 4 -S0 (
x HCl χ H2O (Fp. 231-234°C)x HCl χ H 2 O (mp 231-234 ° C)
OHOH
irir
CHOH-CH0-NH-C-CH0 2 ιCHOH-CH 0 -NH-C-CH 0 2 ι
CH0 CH 0
?Η ? Η
Ah.Ah.
χ 1/2 H2SO4 χ 1/2χ 1/2 H 2 SO 4 χ 1/2
(Fp. 263-2650C)(Mp 263-265 0 C)
OHOH
CHOH-CH0-NH-C-CH0 2 ιCHOH-CH 0 -NH-C-CH 0 2 ι
Γ OHOH
χ 1/2 H2SO4 χ (Fp. 234-236°C)χ 1/2 H 2 SO 4 χ (mp 234-236 ° C)
-CH0-N^- (CH0) ,-SO® 2 ι 2 M 3-CH 0 -N ^ - (CH 0 ), -SO® 2 ι 2 M 3
OHOH
OHOH
OHOH
OHOH
CH,CH,
CHCH
χ HClχ HCl
(Fp. 231-234°C)(Mp 231-234 ° C)
CH,CH,
CH,CH,
(O(O
χ HCl χ 1,5 H2O (Fp. 2100C CH,χ HCl χ 1.5 H 2 O (mp 210 ° C. CH,
CH„CH "
-N1^-(CH2 )3-S0®-N 1 ^ - (CH 2 ) 3 -SO®
CH.CH.
Claims (5)
oder1 amine, with a tertiary amine -N-reacted
or
R5: H, CH3;
Re'. H, CH3;
n: 1,2,3,4oder5Carbonamido radical containing a quaternary ammonium moiety; R «j: H, CH3, C2H5;
R5: H, CH3;
Re'. H, CH3;
n: 1,2,3,4 or 5
b) daß man zur Herstellung einer Verbindung der Formelin which η, R 4 , R 5 and R 6 are as defined above and R 'is a radical which is identical to R, except that it contains a tertiary amino group instead of the quaternary ammonium group, and the same meaning in Q' Q has, but about OH groups present therein, as well as the central NH group may be protected by hydrogenolytically cleavable protecting groups, reacted with suitable alkylating agents and optionally removed protecting groups with hydrogen / catalyst or
b) that for preparing a compound of formula
B: eine Einfachbindung oder -O-(C,-C4)-Alkylen-,NH-CO- (C, -C 4 ) -alkylene;
B: a single bond or -O- (C, -C 4 ) -alkylene,
D: -(C,-C4)-Alkylen~
E: die Gruppen- (C 1 -C 4 ) -alkylene;
D: - (C, -C 4 ) -alkylene ~
E: the groups
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19873743265 DE3743265A1 (en) | 1987-12-19 | 1987-12-19 | NEW AMMONIUM COMPOUNDS, THEIR MANUFACTURE AND USE |
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| Publication Number | Publication Date |
|---|---|
| DD280099A5 true DD280099A5 (en) | 1990-06-27 |
Family
ID=6343092
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DD88323312A DD280099A5 (en) | 1987-12-19 | 1988-12-16 | PROCESS FOR PRODUCING NEW AMMONIUM COMPOUNDS |
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|---|---|
| EP (1) | EP0321864A3 (en) |
| JP (1) | JPH02239A (en) |
| KR (1) | KR890009920A (en) |
| AU (1) | AU618302B2 (en) |
| CZ (1) | CZ843588A3 (en) |
| DD (1) | DD280099A5 (en) |
| DE (1) | DE3743265A1 (en) |
| DK (1) | DK700788A (en) |
| FI (1) | FI885811L (en) |
| HU (1) | HU207283B (en) |
| IL (1) | IL88707A0 (en) |
| MX (1) | MX14253A (en) |
| NO (1) | NO885598L (en) |
| NZ (1) | NZ227367A (en) |
| PH (1) | PH27509A (en) |
| PL (1) | PL160685B1 (en) |
| PT (1) | PT89234B (en) |
| SU (1) | SU1628854A3 (en) |
| YU (1) | YU228688A (en) |
| ZA (1) | ZA889387B (en) |
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| DE3918834A1 (en) * | 1989-01-26 | 1990-08-02 | Bayer Ag | ARYL- AND HETEROARYLETHANOL-PYRIDYLALKYLAMINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A PERFORMANCE IN ANIMALS AND AS A MEDICINE AGAINST ADIPOSITAS |
| PT1028111E (en) * | 1997-10-17 | 2004-09-30 | Yamanouchi Pharma Co Ltd | DERIVATIVES OF AMIDA OR ITS SALTS |
| EA200201056A1 (en) * | 2000-04-27 | 2003-04-24 | Бёрингер Ингельхайм Фарма Кг | NEW, OWNED BY THE LONG-TERM EFFECT OF BETAMIMETIC, THE METHOD OF THEIR PREPARATION AND THEIR APPLICATION AS A MEDICINE |
| DE10246374A1 (en) * | 2002-10-04 | 2004-04-15 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New 4-(2-alkylamino-1-hydroxyethyl)-3-alkoxy-benzene-1,2-diol derivatives, are beta-mimetics having a long duration of action, useful e.g. for treating asthma, chronic obstructive pulmonary disease or arrhythmia |
| US6951888B2 (en) | 2002-10-04 | 2005-10-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Betamimetics with a prolonged duration of activity, processes for preparing them, and their use as pharmaceutical compositions |
| US7056916B2 (en) | 2002-11-15 | 2006-06-06 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Medicaments for the treatment of chronic obstructive pulmonary disease |
| DE10253282A1 (en) * | 2002-11-15 | 2004-05-27 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Treatment of chronic obstructive pulmonary disease, using new or known N-substituted 2-amino-1-(benz-(1,4)-oxazin-3-on-8-yl)-ethanol derivative beta-mimetic agents, suitable for once-daily administration |
| CN100577633C (en) * | 2003-04-23 | 2010-01-06 | 日本烟草产业株式会社 | CaSR antagonists |
| US7307076B2 (en) | 2004-05-13 | 2007-12-11 | Boehringer Ingelheim International Gmbh | Beta agonists for the treatment of respiratory diseases |
| DE102004024453A1 (en) * | 2004-05-14 | 2006-01-05 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New long-acting bronchodilators for the treatment of respiratory diseases |
| US7745621B2 (en) | 2004-05-14 | 2010-06-29 | Boehringer Ingelheim International Gmbh | Long acting bronchodilators for the treatment of respiratory diseases |
| DE102004024454A1 (en) * | 2004-05-14 | 2005-12-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Novel enantiomerically pure beta agonists, process for their preparation and their use as pharmaceuticals |
| US7220742B2 (en) | 2004-05-14 | 2007-05-22 | Boehringer Ingelheim International Gmbh | Enantiomerically pure beta agonists, process for the manufacture thereof and use thereof as medicaments |
| PL1917253T3 (en) | 2005-08-15 | 2015-06-30 | Boehringer Ingelheim Int | Method for producing betamimetics |
| EP2057152A1 (en) * | 2006-08-07 | 2009-05-13 | Boehringer Ingelheim International GmbH | Single enantiomer beta-agonists, methods for the production thereof and the use thereof as medication |
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| DE2429253A1 (en) * | 1974-06-19 | 1976-01-15 | Boehringer Sohn Ingelheim | PHENYLAL CANOLAMINE |
| DE3134590A1 (en) * | 1981-09-01 | 1983-03-10 | Boehringer Ingelheim KG, 6507 Ingelheim | NEW BENZO HETEROCYCLES |
| EP0105053B1 (en) * | 1982-10-01 | 1988-01-20 | Merck & Co. Inc. | Aralkylaminoethanol heterocyclic compounds |
| GB8426200D0 (en) * | 1984-10-17 | 1984-11-21 | Glaxo Holdings Ltd | Chemical compounds |
-
1987
- 1987-12-19 DE DE19873743265 patent/DE3743265A1/en not_active Withdrawn
-
1988
- 1988-12-15 ZA ZA889387A patent/ZA889387B/en unknown
- 1988-12-15 EP EP19880121011 patent/EP0321864A3/en not_active Withdrawn
- 1988-12-16 NO NO88885598A patent/NO885598L/en unknown
- 1988-12-16 YU YU02286/88A patent/YU228688A/en unknown
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- 1988-12-16 IL IL88707A patent/IL88707A0/en unknown
- 1988-12-16 DK DK700788A patent/DK700788A/en not_active Application Discontinuation
- 1988-12-16 FI FI885811A patent/FI885811L/en not_active IP Right Cessation
- 1988-12-16 PT PT89234A patent/PT89234B/en not_active IP Right Cessation
- 1988-12-16 SU SU884613149A patent/SU1628854A3/en active
- 1988-12-16 DD DD88323312A patent/DD280099A5/en not_active IP Right Cessation
- 1988-12-16 AU AU27022/88A patent/AU618302B2/en not_active Ceased
- 1988-12-17 KR KR1019880016884A patent/KR890009920A/en not_active Application Discontinuation
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Also Published As
| Publication number | Publication date |
|---|---|
| NZ227367A (en) | 1990-07-26 |
| SU1628854A3 (en) | 1991-02-15 |
| EP0321864A3 (en) | 1990-12-27 |
| HU207283B (en) | 1993-03-29 |
| PT89234B (en) | 1993-07-30 |
| MX14253A (en) | 1993-09-01 |
| DK700788D0 (en) | 1988-12-16 |
| ZA889387B (en) | 1990-08-29 |
| AU618302B2 (en) | 1991-12-19 |
| NO885598D0 (en) | 1988-12-16 |
| YU228688A (en) | 1990-08-31 |
| KR890009920A (en) | 1989-08-04 |
| EP0321864A2 (en) | 1989-06-28 |
| PL160685B1 (en) | 1993-04-30 |
| PT89234A (en) | 1989-12-29 |
| PH27509A (en) | 1993-08-18 |
| NO885598L (en) | 1989-06-20 |
| FI885811A0 (en) | 1988-12-16 |
| CZ843588A3 (en) | 1996-08-14 |
| IL88707A0 (en) | 1989-07-31 |
| DK700788A (en) | 1989-06-20 |
| AU2702288A (en) | 1989-06-22 |
| DE3743265A1 (en) | 1989-06-29 |
| FI885811L (en) | 1989-06-20 |
| PL276549A1 (en) | 1989-08-21 |
| JPH02239A (en) | 1990-01-05 |
| HUT53866A (en) | 1990-12-28 |
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