AU618302B2 - New quaternary ammonium compounds, their preparation and use - Google Patents

New quaternary ammonium compounds, their preparation and use Download PDF

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AU618302B2
AU618302B2 AU27022/88A AU2702288A AU618302B2 AU 618302 B2 AU618302 B2 AU 618302B2 AU 27022/88 A AU27022/88 A AU 27022/88A AU 2702288 A AU2702288 A AU 2702288A AU 618302 B2 AU618302 B2 AU 618302B2
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group
formula
alkylene
compound
groups
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Anton Mentrup
Gojko Muacevic
Ernst-Otto Renth
Kurt Schromm
Werner Traunecker
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Boehringer Ingelheim International GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Description

AUSTRALIA 7 PATENTS ACT 1952 6 0 COMPLETE SPECIFICATION
(ORIGINAL)
FOR OFFICE USE Short Title: Int. Cl: Application Number: Lodged: a .Complete Specification Lodged: SAccepted: o Lapsed: Published: Priority: Related Art: TO BE CCOMPLETED BY APPLICANT S Name of Applicant: Address of Applicant: Actual Inventors: BOEHRINGER INGELHEIM INTERNATIONAL GMBH D-6507 Ingelheim am Rhein, Federal Republic of Germany.
KURT SCHROMM, ANTON MENTRUP, ERNST-OTTO RENTH, GOJKO MUACEVIC and WERNER TRAUNECKER CALLINANS, Patent Attorneys, of 48-50 Bridge Road, Richmond 3121, Victoria, Australia.
Address for Service: Complete Specification for the invention entitled: NEW QUATERNARY AMMONIUM COMPOUNDS, THEIR PREPARATION AND USE The following statement is a full description of this invention, including the best method of performing it known to us:la- 53613-000.704 New quaternary ammonium compounds, their preparation and use The invention relates to quaternary ammonium compounds, and the preparation and use thereof. The compounds of the invention may be prepared by methods known per se and used as pharmaceuticals, particularly for inhalation.
We have found that the introduction of a quaternary ammonium group at a suitable point in the molecules of known broncholytically active compounds which are o 15 effective when inhaled makes it possible to eliminate o, o o unwanted systemic side effects to a great extent whilst substantially retaining the broncholytic (topical) S0"" effect. We have found that the nature of the quaternary 0o o ammonium grouping may be selected from a wide range of variations without crucially affecting the differentiation between desirable and undesirable effects according to the invention.
ooao o a o* According to the invention we provide compounds of formula Ia R2 R 1 CH-CH-NH-C-( -R -N (Ia) S 2 n 7 in which, unless otherwise stated, n represents an integer selected from 1, 2, 3, 4 and 4
I
I
I
-2 R 1 represents H, CH 3 OCH 3fCl, or F; R2 represents H, R30,-CH 2 OH, -HO,-NHCOCH 3 1 -NHSO 2 CH 3 or -NHCONH 2 R 3 represent 's H, acyl, or N,N-dialkylcarbanoyl, the groups R 30 being in the 4- or 5- positions; the group II R 30 (I I) a C I a Cl
CE',
I
44*
C,
a a a ,aa a may also represent one of the groups 0 R 0 0 R B HN 0 a 4~*4t a taOC a a 44 4 a a' C a Eta a aa a a I 4 41 41 a a 4 II and R 0 3 (lIa) (lI b) wherein R 3 is as hereinbefore defined and R 8 represents H or CH 3 R 4 represents H, CH 3 or C2 H; R 5 represents H or CH 3 (lIc) 4 6 represents H or CH 3 -R7? represents one of the groups 7-1
-E
-Ar-B-E (III a), (III b), -O--Ar-B-E (III C)
-NH-CO-E
-NH-CO-Ar-B-E mH 2m)-A-E mH 2m)-A-Ar-B-E (III d), (III e) 0 0 0400 0 0 (III if) (III g),
~~CI~I
4
-B-E
N
N-D-E
(III h) and (III i), n and R 1 to R 6 being as defined hereinbefore; Ane represents an anion.
ao 0 a e o 4 a ooo 0 4 4 9 o a os 4 9 a o e 0 o 0 a 4 6 044944 94 404 o 44 C L1O
C-
6 In the above definitions of (IIIa) to (IIIi), m represents an integer selected from 2, 3, 4, 5 and 15 6; represents a nitrogen heterocycle optionally 20 substituted by one or more C.1--alkyl groups which may be condensed with a benzene ring and which may optionally contain one or more additional heteroatoms in the ring; 25 Ar represents a substituted or unsubstituted arylene group, preferably an unsubstituted or substituted phenylene or naphthylene group; A represents a single bond or a NH-CO-(C_1 4 )-alkylene group; B represents a single bond or an -0-(C14 )-alkylene, -NH-CO-(C1- 4 )-alkylene, or -(C1- 4 )-alkylene group; D represents a l 4 )-alkylene group; and E3 k 0 represents one of the groups i li-- I L -1 N OR 1 0 liet- and Het: R 1 1 9 (in which 9 represents a (C 1 )-alkyl group; 1 represents a (C 1 )-alkyl group; or 9 and R 10 together represent a (C 4 )-alkylene group; 00 0 and R11 rersnsa(C 1 )-alkyl, (C 1 4 -alkylene-COO 00 00( 1 4 -alkylene- S0 3 (C 1 4 )-alkylene-OH, or (C 3 6 -cycloalkyl group; R et and the group NQ is as defined above).
0 I -6- Typical examples of E include N(Cl-I 3 )3' -N 0(CH )CH CH CH soe -N G(CH3 2 (CH 5 0 3 -Ne(CH 3 2 CH 2 CH 2CO 2 3
~N
H 3 -7 Particular mention should be made of the following preferred definitions for the grouping -R in which the groupings and groups are as defined above: 9 10 11 ;et N(4= (III a 1) (III a 2) Het
N
(III a 3) o- 0 0 0 9 C0 0 CIO 0 0 0' 00 000 o oa a ,0 00 0 a f 0 Dy 09 90 o a~ 0 0' 0: 0 0 9 c) 0 9' 000 O 0 -Ar-B-R 9
R
10 R 1 et
-AT-B-
-0-Ar-B-N-RR 9
R
1 0
R
11 -NH-CO Ret
R
9 (III b 1) (III b 2) (IfI c 1) (III d 1)
-NH-CO-A.-B-
9
R
1 0 R1 -0-(CmH 2
A-N'
9
R
9
R
1 0
R
m 2 )-A-Ar-B-N-R 9R 10R Het B-N R 1 0
R
1 1
N
0 N9101-N 9 10 1 (III e 1) (II1 f 1) (III g 1) (III h 1) (III i 4 A1 -8- The alkyl and alkylene groups in the above definitions may be straight-chained or branched. Unless otherwise stated, they contain 1 to 6, preferably 1 to 4, and most particularly 1 or 2 carbon atoms. This also applies to the carbon chains which are components of other groups.
A "substituted aryl(ene) group" denotes an aryl(ene) group substituted by a fluorine or chlorine atom or a
CH
3 or CH30 group. The terms "aryl" and "arylene" refer to the appropriate groups derived from benzene or naphthalene. "Acyl groups" in this case denote carboxylic acid groups with up to 7 carbon atoms, particularly acetyl. The bridge R 7 may be linked to the nitrogen atom of the quaternary ammonium group.
00 0 0 Alternatively, if the quaternary ammonium group is part oe M 15 of a hetero-cyclic group, the bridge may be connected to 0 oo 0 another ring atom of the heterocyclic group. Groups 0o o D falling into this latter category include in particular 0 00o o0
N
N a 0 0 00 0) I
N
N^
44 t.
4 9- 44 4 4 44 4 44 44 4 4 44 4 44 4g~8 4 4 4444 44 4 Si 444 44 0 4 44 4 44 4 44 4 4 44 4 44 0~ 4 44 4 44 4 44 44.~44~ 4 4 44* 44 4
~.J
4 4)
C
4 4 (in which R 1represents H or C 1 4 alkyl), ancd triazines.
In a further preferred embodiment of the invention~ 5 R 1 represents H, CH 3 OCH 3 r Cl or F; *2 represents OH or, when R 1 equals Cl or Ft R 2 may also represent H; or *and R 2together may also represent
R
8 0, or /0 (in which r8is as hereinbefore defined) R 3 represents a hydrogen atom; 0L 0 ./2 00 I I II p I, -10 R4 represents H or C 2 H 5 R and R both represent H or both represent CH-I 3 n represents an integer selected from 1, 2 and 3; R o-represents a group -NH-CO Het CeO
CH.
CH-
3 1-) *4 4 4 04 0 06 4 4.
'4 4 6 4~ 00 44 0 44 0 0 4 4.6 00 4 4 6 6 *4 .~-4040 4 4 0 ~0 4 4 ~4 6 6 6
GN~
ClI 3 0 CH3 113
CH
3
CH
CH3 11 (in which Het here represents
ON
CH 3 CH 3 CH 3 H-et or
-N
represents *4 a 4 At g 6 ~4 4* 4$$ 4 4 '4 ~i Q~jr 44 04 04 04 44 044 4 0 tO 4 0~4 44 4 44 4 4 r 4 *4444, 04 4 404 44
C
04 04 whilst B, D and R 1are as hereinbefcre defined).
Particular mention should be made of the compounds in which the following combinations of substituents occur: R 1 represents a methyl or methoxy group, 10 R 2r epresents a hydroxyl group, and R 3represents a 4-hydroxyl group; R 1 represents a hydrogen atom, R 2 represents a hydroxyl group, and R 3 represents a 4- or 5-hydroxyl group; 15 R, and R 2 together represent O R 8 HN \Oan and -12- R 3represents a 4- or 5-hydroxyl group7 R4 represents a hydrogen atom, if R 5and R6 6ehlgrus Ibut C 2 HT5, if R5and R 6 represent H; 1 7-N represents .1 CH j o NH CO0-CH C N 0
C-
3 3 -QNH CO C11 2 41Q 0 0 0 99 99 9 4 4t 4444 4 *44~ $9 4 9 I 944 *0 4 4 o 4 4* o 46 9 4 4-4 44 4 4 4 91 4 49 4 9 9 4049 *00.00
CH
12 C H S 0- CH 2- CH 2- 1' R 12
CH
3 CH 2 R1 Ik 13 (in which R2 and R13 represent CH CH 2 -COO CH -CH -COO' or CH -CH -CH -S 2 2 2 3 The compounds according to the invention may occur as mixtures of enantiomers, particularly as racemates, and optionally either as pairs of diastereoisomers or as pure enantiomers, and as salts with (preferably physiologically acceptable) acids, and the invention extends to all such forms of the compounds of formula Ia.
The compounds of the invention may be prepared by a variety of methods.
Accordingly, in a further aspect of the invention, we provide a process for preparing compounds of formula Ia "oo as described above, wherein a) a compound of formula IV 0u R R 4 Q CH CH NH (CH R 7 R' (IV), 0 2 n 7 o o OH R 6 6 So wherein n, R7, R 4 R and R 6 are as defined above, Q n 04 4 b represents one of the groups (IIa), (IIb) or (IIc)
/K
as defined above, R' represents the group -NL in which
IL
K and L represent any two of the groups carried by the quaternary nitrogen atom of the group R 7 as defined above or a protected form thereof in which any hydroxyl group or amino group it is desired to protect is protected by hydrogenolytically -removable protecting groups, is reacted with an alkylating agent serving to introduce that group carried by the quaternary nitrogen atom in the group R 7 as defined above not present in the group and any protecting groups present are S. ^<removed by hydrogenolysis; 4
C-S
14 or b) if it is desired to prepare a compound of formula Ia in which the nitrogen atom of the quaternary ammonium.
group in the group R 7 as defined above is directly bound to an aliphatic carbon atom, a compound of formula VIII R R i 4 Q CH CH NH C (CH2 R 7 X (VIII), OH R 6 (wherein n, R 4
R
5
R
6 and Q are all as defined above S 15 and R 7 X represents a group R as defined 07 7 i hereinbefore in which the quaternary nitrogen atom has been replaced by a leaving group X), is reacted with an appropriate tertiary amine to provide the desired quaternary ammonium compound of formula Ia; and in the case of either of steps a) or b) followed, if desired, by separation of any mixture of enantiomers Sinto pure enantiomeric forms or other enantiomeric mixtures, and formation of any desired acid addition salts.
Process above is suitable for preparing compounds of formula Ia in which the quaternary ammonium group is not in the form Het Compounds selected from Cl-(C 4 )-alkylene-SO Na and
HO-(C
1 _4)-alkylene-SO 2 O-(C1- 4 )-alkylene-SO3Na I~Y~ m-LIL___II L lC_
II
15 are particularly suitable for the introduction of a
(C
1 4 )-alkylene-SO group.
The reaction is expediently carried out in an inert polar solvent at ambient temperature or at an elevated temperature up to about 100"C.
The starting materials of formula IV may be obtained by methods known per se. Thus, aminoketones of formula V Q CO CH NH C (CH 2 n
R
7
R'
Q
a 0 o 0 0 0 a a S 30 o o 0 0 0 wherein Q, R 7 R4 R R 5
R
6 R' and n are as defined above, or Schiff bases of the formula VI R R S4 15 Q CO C N C (CH R R'
I
R
6
(VI)
(wherein the symbols are defined as hereinbefore) may be converted into compounds of formula IV by reduction with hydrogen in the presence of hydro- genation catalysts such as palladium, platinum or Raney nickel, or by reaction with hydrides such as sodium hydride in suitable solvents such as ethanol. Any protecting groups present may if necessary or desired be removed in the usual way.
In process above, the leaving group X is preferably a chlorine, bromine or iodine atom or an alkyl- or arylsulphonic acid group.
16 The reaction is preferably effected in a protic or aprotic solvent such as methanol or dimethylformamide at temperatures of between ambient temperature and about 100C.
Any hydrogenolytically-cleavable protecting groups present may be removed after the reaction if necessary or desired by conventional methods.
The starting compounds of formula VIII may be prepared, for example, from aminoketones of formula IX R R SI I 4 Q CO CH NH C (CH) R X (IX), 2in 7
R
*I by reaction thereof with a hydride such as sodium hydride or diborane.
The compounds of formula IX may in turn be obtained by methods known per se.
Any protecting groups present which it is desired to i remove may expediently be removed by hydrogenolysis with palladium as catalyst in an inert solvent.
SThe compounds according to the invention always will I contain at least one asymmetric carbon atom. In order I to obtain compounds of formula la in the form of 30 specific enantiomers or (in the case of several centres of asymmetry) diastereoisomeric pairs of antipodes, it is convenient to use starting materials, e.g. of formula IV or IX, in which the desired configuration is already present at the 17 centres of asymmetry in question.
The compounds according to the invention may if desired be converted in a manner known per se into salts. For pharmaceutical use these will preferably be formed with physiologically acceptable acids, and these may be either organic or inorganic.
Suitable acids for salt formation include, for example, inorganic acids such as hydrochloric, hydrobromic, sulphuric and phosphoric acids,-and organic acids such as methylsulphuric, tartaric, fumaric, citric, maleic, succunic, gluconic, malic, p-toluenesulphonic, methanesulphonic and amidosulphonic acids.
The compounds of the invention are suitable for use in o pharmaceutical compositions. In particular they have o broncholytic, spasmolytic and anti-allergic activity, they increase ciliary activity and reduce inflammatory/ 20 exudative reactions. They may therefore be used inter a °o alia for treating all types of asthma and bronchitis.
00 0 The dosage for therapeutic and prophylactic use will in general depend on the nature and gravity o' 25 of the illness in question.
For adults, the dosage for the preferred route 0 0 *0 of administration, namely inhalation, is preferably 1 from 0.001 to 0.5 mg per day. The preparations are obtained in conventional manner using normal diluents, excipients and/or carriers. The compounds according to the invention may also be combined with other active substances, e.g. parasympatholytics ipratropium bromide, oxytropium bromide), secretolytics bromhexine, ambroxol), antibiotics doxycycline), corticcsteroids beclomethasone dipropionate, flunisolide, budesonide) or other anti-asthma preparations such as disodium cromoglycate, nedocromil and anti-allergic substances.
u represents a -(C 1 4 )-alkylene group; and E represents one of the groups I L 1-i_ I r 18 The following non-limiting examples illustrate formulations which incorporate the compounds of the invention: 1. Powder for inhalation Micronised powdered active substance (compound of formula I; particle size about 0.5 to 7 microns) is packed into hard gelatine capsules in quantities of 0.02 mg with 10 mg of micronised lactose and, optionally, suitable quantities-of. other active substances. The powder is inhaled from conventional inhaling devices, e.g. according to DE-A-3345722.
2. Metering aerosol *0 4 4 *4 a i *9 t II t I (I9 9 1 4 9 490 a« 0 4 9i 9 4 04 0 I t C I 9*t 9 9 4 90 Active substance according to Example 8 hereinbelow 15 Sorbitane trioleate Monofluorotrichloromethane and difluorodichloromethane (2:3) 0.1% by weight 0.5% by weight 99.4% by weight Tie mixture is packed into metering aerosols of suitable type. The metering device is designed, for example, so as to release 0.05 ml of the preparation on each actuation.
The advantage of the compounds according to the invention is that, when they are inhaled, by comparison with known bronchospasmolytic 5-mimetics, they 25 show a particularly marked selectivity in the relationship between bronchospasmolysis and increased heart rate, positive inotropic effects and tremor. The broncholytic activity is achieved with low doses and the activity is long-lasting.
19 Some pharmacological activity data for compounds according to the invention are given hereinafter.
The EC50 by inhalation was determined on conscious, fasting guinea-pigs according to Kallos P. and Pagel, W. (Acta med. scand. 91, 292 (1937)) (histamine spasm). The substances were tested in the form of an aqueous solution.
EC
A 0,06 B 0,06 S° C 0,09 S D 0.06 E S" F 0 3 0 G 0.02 H 000005 I 0.02 J 0.004 4 0* K 0,02 a a O O B aa D 0 I e 20 Compounds tested
CH
Q-CHOH-CH 2 -N-H 2 K> NH-Co N®2-P x HC1 3_ Compound ri:G -N(S(CHi 3 3 c 00 0 0 00 0 00 00 0 o 0 0 0 00 000* 0 0000 00 0 0 0 000 00 0 00 0 00 0 00 00 0 0 00 0 00 00 0 O 00 0 I 0 4-.j 0000 0 0 0.0 00 0 0000
I
000* 00 0 0
CI
-^PCH 3 3C -PN(CH 3 3 C1I -21- Compound Q
OH
E: N(CH )C1
OH
0 ta at 4 a t I taI a a a a a a a lattO a a a 22 Compounds of formula 0 H-N x c C1 2-G Compound
G
CH
.3 F: -NH--C-CH 2
CH
-00-CN 3 ).3 C I '44 a '4 a a 0 '44 44 '4 '44 4 '49 '4444 '4 '4444 4'4 '4 4 ~'4'4 '44 '4 4 44 4 44 '4 44 a '4 '4 44 44 '4 4 '44 '44 4 '4 '44 '4 44 444444 '4 '4 '4 44 '4 '4 '4 '4444 '4 '444444 '4 '4
CH
c: NH-C'-CH
+C
CH
3 c
CH
1~CH) Cl H: -NH-C-CH C -C-H O C i 1 2 2 2 3 32 CH -D- I: TH3 C C
-NH-C-CH
2 .Q OC Z2C CH 3
CH
1 3 CH 2-CH 2-CO2
CH
1 3 :2 -CH 2 -CH 2 -So0 2 23 Compound G
CH-
3 iCH C 2 2 00 0 0 00 0 00 00 0 0 0 0 00 0000 0 0 0000 00 Oct o 00 0 00 0 013 00 0 13 0', 0 00 00 0 0 00 0 0 0 00 0 00 0~ 0 00 00 0 0 0 0 24 The following non-limiting examples illustrate processes whereby the compounds of the invention may be synthesised.
Example 1
O
HN 0 HO C HH-CH2-NH- H3 CH2 HC1 1.9 g of 5'-hydroxy-8'-[l-hydroxy-2-[4-(4-pyridyl)- 2-methyl-2-butylamino]-ethyl]-2H--1,4-benzoxazin- 3-(4H)-one-monohydrochloride are dissolved in a 0o mixture of 3 ml of dimethylformamide and 1 ml of 10 water and 1.27 g of methyliodide are added. After S4 12 hours the solution is mixed with 5 ml of alcohol, to acidified with conc. HCI and diluted with acetone; the crystals precipitated are suction filtered after about 1 hour and 1.2 g of the compound are obtained by precipitation with water, cone. hydrochloric acid and alcohol.
M.p. 207-209 0 C, 56% of theory.
4 4 The starting compound may be prepared by the following method:
O
CH
a HN H -CH -C-NH 2 2 1 2 OH CH3 -CH. CH OC
H
2 A
A
25 0 HN 0 O -CH- CH 3 -CH 2-CH2- 2HW~r NaBH4 (Mp. 170-171 0
C)
4 444 44 ~4 'I 4 441-4 I 44 44 4 44 4 44 4
V
44 4 4 4~41 4 *444 44 4 '4 cR -0 H 2/Pd/C 2- (MV. 157-1600C) 0 u 0 /CH 3 HO )-CH-CH -NHi-C-Gil -CH 2 2 2 2 OH CH3 x HCI.
(Mp. i75-C (decomp.)) 26 Example 2 x HC1
CH
:3 do 'ye e 4 ~'y 4 44 'ye t 4 4 4 4444 I I 4444 4.
4 44a 44 4 4 1 44 4 44 44 4 44 4 44 14 4 4 44 44 4 4' 4 44 444414 4 4 44 44 ~4 4 4b~ 44 3.7 g of 5'-benzyloxy-8'-[l-hydoxy-2-13-(4-dimetlhylaminophenyl) -2-methyl-2-propylamino 1-ethylil-2Hl,4-benzoxazin-3-(4H)-one-monolhydrochloride are combined with 2.1 q of methyliodide in'7.4 ml of DM1? and reacted for 12 hours. After dilution of the solution with acetone the ammonium iodide hydrochloride is obtained which is converted into the 10 ammonium chlorohydrochloride compound 195-197'C) by conversion with hydrochloric acid or by means of the ammonium hydroxide compound and treating with hydrochloric acid.
3.7 g of this benzyloxy compound are debenzylated 15 in 50 ml of methanol using palladium/charcoal as catalyst under normal conditions and 2 g of the title compound are obtained. M.p. 187'C (decomp.); (6.28% of theory).
The starting compound may be prepared by the following 20 method: 0
CH,
UNO0 zOR
CH~
c) C s-CH 0C
CR
~NO C -R-NR 2 3 3 27 HIN 0 CH CH 6> CH 0. (H N b 0 H3 CH3 NaBH 4 (mp. 201-204 0
C)
0 HN 0 CH 0- -C-CH 1O CpH 3
CH
00 o 0 4 0 04 0e 0 4 0 0 0 00 0000 0 00 4~ 0 4 0 40o 0 0 4 04 0 0 0 0 00 0 00 00 0 0 00 0* 0 0 1 0 it 000004 0 0 00 0 0400 00000~ 0 0 (Mp. 110-112 0 C, Mp. H1-i salt 232-235'C) 04 28 Example 3 OHCH CHi 1 3 3 x HCI 3.2 g of 5'-benzyloxy-8'-[l-hydr oxy-2--[3-(4-dimethylamino-ethoxyphenyl) -2-methiyl-*2--propylamino]-ethyl]- 2H-l, 4-benzoxazin-2- (4H) -one-monohydrochioride are combined with 0.41 g of 8-propiolactone in 6 ml of acetone and left to react for '12 hours at ambient temperature. After dilution with acetone, I the crystals precipitated are suction filtered and 2.4 g of the compound are obtained (Nip. 123-126'C).
2.3 g of the benzyloxy compound are debenzylated in 50 ml of methanol with the addition of palladium charcoal and 1.7 g of the title compound are obtained.
(Nip. 173-175 0 C, 94% of theory).
4 t 29 The starting compound may be prepared by the following method: 0
HN
ci) CH 2 Q- -CH H CH CH 3 NC H -CH -0 Q CHI -C-NH 2 2 2 2 CH CH3 41 4 4 44 44 4 4 44 4444 4 4 *444 44 4 4 444 44 4 4 4 4 44 44 4 4 4* 44 4 44 o 4 4 44 *4 4 4 4 4 4 44 444444 4 4 4 .4 44 4 444444 4 4 FCH -0 2 CH 3
C
C-CI -CC 0-CH -CHI N 4NCH(2 2 2/ 81 &CHI NaBH 4 (mP. 153-155"C) OCH -0
CHI
3 O-CII -CHI -N 2 2 1
CII
3 x HCI (Mp. 176-178 0
OC)
30 The following compounds may be synthesised analogously to the Examples given: 0
HN
C H
CH
HO 2 23 -H-O 2
QO
HH-I-NH-OH -OC OC CH NCl®
OH
x HCIlI 0 H NAL-NH 3 EDi13 HO4 1 OHC 2
-NHO-
2 Q 0O 2
OH
2 1 2
-C
2
-H
2 -SO3~ OH OH OH
HCII
HN4 0
C
OH
3 C 00 H) 0 C H 481 3 HO.- OCH-OH -NH -C-OH -C 2HC CH N(D \~iL O C 3 c-I x HO].
-31 0 H 2 0\ CH CH N 1 3 HO- Q9 H-CH 2 -NH- CFCH 2 -CH 2 7+ OH~H1 +0 33 0 HN
CH
13 HO- CH-CH -NH-C-CH -CH -N- 1 2 J 2 2 OH CH 3+ OCH x HC1 c 3 Cl 0
CH
44 a 3
HN
CH C 11 -HN-C-CH 2-l cf C -CH 2
-CH
1, 2- 01-C 2NH yOC 2
C
2 2C 2 2 -S3- 3 3 a1 4 44 0 44 0 CH CHH 6, 14 H0- CH-CH -NH- C CH -COo 2- 2 2- OH CEHC 44 43 3 44444w(Mp. 175 0
C)
444446 H 0 CH CH2 -C ui.n .yy. -Cn -CH 2 -C00 4 6 OH CH 3j CH 3 H CI x HCi (Mp. 191-193-C) *4 A e 32
CH
3 7-CH H 2 -CH 2 -CH 2 -CH 3
CH-
x HC1 HN 0
CH
HO~ -YH-CHI 2 -NH- -CH 2 -Ci OH CH 3 2 C H-s x HC1 40 0 0 04 0 00 00 o 0 00 00 0000 0 0 0000 00 00 0 Ooo 00 0 0 00 0 00 0 00 00 4 o 00 0 00 00 4 0 00 00 0 0 04 0 4~ 000040 0 0 00 00 0 000.
00 ~4 00 0 4 0 RN CH 3 HO- H -CH--H lc ~p H 6 1 H CH3 x HC1 0 HN 0
C
CH
HO H-CH 2 -NH- -CH O-CH 2 OH- CH3 c 1 x HG].
I 33 0
HN
CHi CH RO 3 3 OHCH 3CR x 1 (Mp. 235 0
C)
0 RO R-CR N 2 x RC1 I Q~O-CH 2 1{l 2 -c F1 2 C H 2 coo 173-175 0 C) 3 a, A a a *3 Ia I 4 4 I a.
4w;a a a I. 4 3 43 34 a 4 a a *4 a 4a 3 4 a a, a. 44 a a, 444444 4 4 4 44 44 33444 33 4~444 4 4 4 RO CH 2 CH 2 -s3 x RC1 CR OR 2H R 3
CR
0o CR-CH NR-C-CR 2 EIIH 3 H- C CR 2CR2 2 x HC1 Cl 0 -34 UN 0 OH OH OO H-CU -NH--OH K> NH-CO-OH 2 (FCH 2 3
SO
3 1 2 2 2 OUH CH 3 9-CU 3 xHCl x H 20 0 1-fN
HOQ
(mp. 250-255 0
C)
CH
O-C CH-1C p 3 i-cd 00 ao C) 00 00 0 0 C000
C.
00 a) 60 xHC1 x H 20 (Mp. 214-216-C) Oi OH
OHC
Q OH-OH 2-NH-C-OH 2~ 0-OH 2 OH 2-iNP'.L3 OH CH 3 O H 3 c l 0 x Hcl V P. 158-162oC) OH OH 3 OH CH OH-OH 2- -H2 H 2- (CH 2 3 so 3 OH 2- NcjCH 2 0-H3 2 CH 3 o 00 (C C) 0)00 0 000 (OC) HC- COOH HO COOH (Mp. 22O-223*O) 35 2 4 -S 3 x HCl x 1/2 H 20 (Mp. 231-234'C) x 2 2 4 x/S 4 x 2
O
04 4 (Mp. 263~265oC) 44 4 4 4, 4 44 4 4 4444 4' 4 0~0 44 0 4 40 4 4.4 4 ~4 4 4 44 6 44 44 4 4 44 44 4 44 4 ii 044404 4 4 4 44 0 0 4
OH
OH
3 CHIDC 2- QHYU 2CH 3 CH 3 x12H2so4 x12S 4 2H20 (MpD. >270-C)
CH
-NH-C-OH CH- CH- COO 1 2 x HC1 x 2H (Mp. 171-174-C) 36 (cH 2 )4503E x1/2 H 2so4 x HO2 (Mp. 234-236'C)
OH
.COH-CH(IIH
-COHCH
2 NlI--C-CH 2 OCH 2
-CH
2 2 3 -Sd3 Cil 3 -C 3 OHi x FCI (Mp. 231-234'C)
H
C3
C
D CHOH-CH 2
HCC
2 D NHC-CH 2 CH 2 )3 O0 CH 3 'H 3 O H xHC1 x 1,5 H 2 0 it S 4 4 0 44 4 4 4- 4454 44 4 5 4 4o~ 44 4 4 04 44 44 4 44 4 4 (Mp. 2 10 0 C.) 44 4 4 04 9 44 4 4 4 44 00 4 0 4.444445 4 4 O H O CHOH-CH 2
OH
x Hi('l x 2H (Mp. 95-100 0
C)
37 Example 4 H 3
C
A
4 4 Q 4 o 0 2 040 4 A 44 3 4 4 44 o 4 4 *34 44 4.4 g of 5'-hydroxy-8.'-[l-hydroxy-2-[3-(4-chloroacetaminophenyl) -2-methyl-2-propylaminolj-ethyl 1- 2H1I-,4-benzoxazin-3- (4I-)-one-hydrochloride,. 6 ml of pyridine and 25 ml of methanol are refluxed for 6 hours, then after the methanol ar~d pyridine have been distilled off the oily residue is dissolved in alcohol and 3.8 g of the title compound are obtained.
(Mp. 190-192-C; 77.5% of theory).
The starting compound may be prepared by the following processes: 0
HNIJ-
0 0CMH
CH
'3 0 N- -CH N H 22; 4, 0-4 4 00 4 4 4 O CHT-O (mp. 151-1546CI 4 1 38 O -CM -0 ClM 1'3 NH-C-CH NO2 H2/Ni 1 22 2
CH
3 x MCI (Mp. 214-216 0 C)
CH
1'3 -CM-CM -NMI-C-CM {v-NH 1 2 1 2 2 OH CHM 0 44 4 4 44 4* 44 4 4 4 4444 144k 4!~ ch loroace tic anhydride x MCI 208-211 0
C)
CH
HO H-CR -NHi-C-CM -qJN-C-CH Cl K~ I 2 12 OH CH 3 x MC I (Mp. 160-C (decomp.)) 1444~~ 4 4 4~ 44 4 4~4 4 S 4#~ 4 4
A
39 Example
CH-
NI{-CO-CH 3 C 2 3
CH
2.7 g of 6'-hydroxy-8'-[l-hydroxy-2-[3-(4-chloracetaminophenyl) -2-methyl-2-propylamino]P!-ethyl]-2H-l, 4-benzoxazin- 3-(4H)--one-hydrochloride, 25 ml of metha-nol and 3 ml of 30% trimethylamine solution are stirred for 12 hours at ambient temperature, concentrated adthe oil obtained is dissolved in alcohol.
After 1 hour the crystals precipitated are suction 10 filtered and 2 g of the title compound are obtained.
(Mp. 203-206'C, 65% of theory) The starting compound may be prepared by the following process: 04 4 4# 4 44 04 4 4 4 4 0~ 040, 4 4 044w 44 0 4 4 440 44 4 4 44 4 04 04 4 4 44 4 44 4 4 4 4 44 40 4 4 4 44 44444.
0 4 4 0009 4 0 0 HN 0
OH
CHQ c0 OC H Q CH-O 2
CH
'3 40 N a B 14 OCHl -0 2 cli3 (Mp. 140-142 0
C)
~4 4 44 o *4 44 4 4 4* 0*44 4 4 44 I 4 *44 44 4 4 4 44 O 44 4 4 4 4 44 4 44 4 4 4 4 44 4* 4 4 4 4 *4 444*44 4 4 44 4 4 4444 *4~ac 4 4 4 0 HN 0
CIH
3 H 2 /Pd/C Q H -CH -NH-C-CH Q NO OH 1n (Mp. 232-234 0
C)
0 IfN
NH
2 chioroacetic anhyd ride x HCI (Mp. 266-268*C) 41 0 I{N 0
CHR
3 -CR--CR -NH- -ClH 1 2 1 OH CH 3 NH-C-CH -C1 0 x HC1 (Mo. 185-189 0
C)
The following compounds are pr-epazred analogously: 0 RN 0 61 CR lox HCI 44 4 4 4 o 44 44 4 4 4 444, 4444 4.
4 4 4 444 44 4 1 4 4 4 44 4 1 4 44 4 44 4 4 44 44 4 4 4 4 4 44 444444 4 4 4 04 4 4 4 0444 4 .0 ~0 4 9 .CH-CR 2 -NH-(C 2 6 -NH-C0-CH 2 Ne(CH 3 3
OR
OH CCie 0 Hd 0 HO-6 ~C-CR 2-NH-C(CC 3 2 C 2 N-C-CH 2-NO(CH x HCI 1 42 01-i CH-CH -NH-(i -C HG-l N(CH 3 1 2 -C1 3 2
-C
2 2H-QO-3H 2 3 OH C 1 OH x HC1 OH CH 3 HO. yjCH-CH -NH-C(CR 3
-H
2 NH7CO-CH 2 -N @(CR OH c HC8 HN-SO 2CH3 HO- CH-ZH NH-COOCH N C Ci
G
x HC1 (Mp. 164-167 0
C)
O CH HN 0 0 90 0 00 000 o 0 o6 '0 0 00 0 -NH-C(CH -CH -C H 2 -I n NH-CO-CH 2 N"(CH 3 3 C 1 0 x HCl 43 Example 6 HO CH 3 lHo H-CH 2-NHI-C(CH 3) 2-CH NH-CO-CH 2-N e(CH3)3 OH Cl1 4.2 g of dibenzyloxy compound (see below) are debenzylated with hydrogen in methanol with palladium charcoal as catalyst under normal cond-it-t-ons and 2.5 g of the title compound are obtained.
(81% of theory).
The starting compound may be pre-pared hy the following method: 00 Q 0 00 0 ~0 00 0 00 0 00 o 0 O 0 4A 0 00 00 0 040 00 0 0 00 f, c,4 0 0* 00 0 0 00 00 0 0 0 0 00 00 0 0 00 0 0 0 0 ~4 00 0 0 0 40 0 00*~040 Bz-O Bz-O.
OHl D
CO-CH
OC (CH 3) 2N-CH 2-CO-NHi H 2-C(CiH 3 2-NH 2 NaBH4 (Bz equals C 6H 5-CH 2-
CH
3 H-CH 2 -NH-C(CH 3 -CH H-CO-CH 2 H32 CH IHCl (Mp. 115 0
C)
j i 44 CH-CH 2 -NH-C(CH3)2-CH 2 NH-CO-CH 2
-N
0
(CH
3 3 Cie (Mp. 210-212*C) Bz-0- Example 7 0 HN 0 C-I CH 3 3 CH-CH NH F -a O-CH 1 (CH -SOO 3 3 x HC1 uo a o 0 Or 0 O 0 0 a o0 o o 0 00 0 0 0 0 0 3.5 g of benzoyloxy compound (see below) are debenzylated 5 with hydrogen in 50 ml of methanol with the addition of 0.5 g of 5% palladium charcoal as catalyst under normal conditions. After the uptake has ceased the catalyst is removed by suction filtering, the methanol is distilled off under reduced pressure using a Rotavapor and the residue is dissolved in approximately alcohol. After seeding the crystals precipitated are suction filtered, washed with alcohol and dried.
2.9 g of the title compound are obtained, (Mp.
240 0 C; 93% of theory).
The starting compound may be prepared by the following process (Bz equals benzyl) 0 HN 0 H Bz-OH-CH -NH--CH -CH -CH2 -N (CH3)2 -6 COH CH_ 1 I K HC1 592 (MP. 191-193-C) 45
CH
NH-C(CH 2-CH 2 O-CH2-CN CH 2 3
-SO
3
CH
2 -CHOH- OBz O NH 0 x HC1 (Mp. 239-241 0
C)
44 4 4, 0 4 44 4 4L 0444 B 0 0404 006 44 04 0 4 4 4L 4 0 Sa Example 8 0 HN 0 CH CH HO )CH-CH 2 -NH- -CH 2
-CH
2
-COO
3 3 2.4 g of benzyloxy compound are debenzylated with 5 hydrogen in 50 ml of methanol and 10 ml of water with the addition of 0.5 g of palladium/charcoal as catalyst under normal conditions. After the uptake has ceased the catalyst is removed by suction filtering, the methanol is distilled off under reduced 10 pressure using a Rotavapor and the residue is triturated with alcohol. The crystals precipitated are suction filtered and reprecipitated once with water/alcohol.
1.6 g of the title compound are obtained, (mp.
175 0 C, decomp., 71'of theory) The starting compounds may be obtained by the following process: -,i 46 0 HI-i
CH
Bz-O CH-CH BrCH -COOC H I 22 \2 2 OH CHCH 3 3 x HG].
HN 0 Cif Bz-O HCH I U NO-CH -COOC H 1. NaOH 2- 2 2 5 4 HCH Ul 2. HG].
(Mp. 127-130 0 C) x HG].
I0
HH
Bz-O CU-CH -NH-C-C HJ bp-CH 2 -CocP OHCH CII 13 3 x HC1 (Mp. 203-205oC) 0 a 47 The following compounds may be synthesised analogously to the Examples:
RN
CH
HO-6 CI-1-CH C OCR C C N'(CH-coo~ OH 2 2 2 3 2 x RCI (Mp. 173-175 0
C)
If I I I I~ 4 14
II
I I I* I~ I~.
1 4 I 4; 44 4; 44 c~ 4 4 4
CR
-CR-CR 2-NH-C-_CHR 2 2 Or CR 3 x HCi C CRH IMP. 187 0
C)
OCR
'1 CH 3 CR-CR -NR-C-CR O-C 2 CH 0N- (CH SP- 2- 1 2 R1 CR CR 3 3 0
RN
CR
,13 RH -NR-C-CR NRH( O-C C2- CO 2 r X CR C lG 48 CH3 -CH-CH NH-C-OH (T NH-CO-OH 2 P(CH S0d- 1 2 1 2 2 2 3 OHt
OH
3 CHl3 x HCi x li 0 00 0 0 0 4 0 0 0 0o 0404 4,4, .4 444 4 0 4 4 40 O 00 4 0 0 40 4 4 4* 44 4 0 4 4 44 4*40.; 4 4 0 4 44 0 0000 000000 0 4 13 .jH-CH NH-cj- UH OH 2 2 x 1101 x H 2 0 OH OH HO O H-OH 2- NH-l_-CH 2 OH OH 3 x HC1 (Mp 250-2550C) O-Cli 2- C C 2 o 'if3 (Mp. 214-2160C) ;O H 0-OH 2-OCH 2-1 H 3 c I (Mp. 158-16'4"C) Q -OH C-C q O
H
3 ci3 HOc cOOOH x
OO
(Mp. 22O-223*C) 49 0 HN 0 CH CH 1 3 3H x IC x 1 2 0 xp 2/21S-234H0C 01- O CHOH1-CH 2 NHl-C-Cl OCHi 2 -CH 2 24H 3 2 2Y) 3 3 "000 OH.26-65C *Q0 02 4 2 (Mp. 234-2360C) 0
OHH
0 COHC HNH-?-CH 2 OCH -CH 2
(CH
2
)-O
0 0CH 3 CH3
OH
x IC 1 (Mp. 231-234 0
C)
50
C
2 3 -s0 3 CH 3 x Rd~ x 1.5 "2 (MP 2 10 c 6 0 0 0 0 0 0 0 00 ~O (~6 6666 66 0 0 6 60 0 6 0 0 0 &0 o 00 6 0 '4 6 00 00 0 0 64 66 4 0 00 0 St 0 66 6 0 6 0660 464066 6 6

Claims (3)

1. Compounds of formula Ia R R 2 1 a 4 R RO-H-H L-C )O- wherein n represents an integer selected from 1, 2, 3,4 and C, (4 o t o00 4, C, 0(4 (4 4~ 0(4 0 0 (44, 4 (4 *0 0 (4 (4 (4 0(40 0 44(4 0 0 (4 -'44 (4(4 0 o (4 44 R 1 represents H, CR 3 OCH 3 Cl or F; *R represents H, R301-CHR OR, -NHCHO, -NHCOCR 3 -NHSO 2CH 3or -NHCONH R represents H, acyl or N,N-dialkylcarbamoyl, the groups R 3 0- being in the 4- or the group II 2 R 3O' (II) may also represent one of the groups 0 0 R R 8 RN 0 H-N and R 0' 3 RO3 (IIc) (IIb) (I Ia) 52 (wherein RP 3 is as hereinbefore defined and R represents H or CHR 3 R 4 represents H, CR 3 or C R represents H or CH 3 R represents H or CH 3 -R ?-represents one of the groups o 0* 7 -E (III a), -Ar--B-B (III b), -0-Ar-B-B II 4*4~20-NH-CO-E (III d),
44-NH-CO-Ar-B-B (III e),
0400-0-(C mH 2m)-A-E (III f), 0: 25 H )-A-Ar-B-E (T mn 2m e t B-B- (III h) and N 0N-H- Li n and R1to R 6 being as hereinbefore defined and mn represents an integer selected fromt 2, 3, 4, 5 and 6; 000 53 Ar represents a substituted or unsubstituted arylene group; A represents a single bond or a NH-CO-(C 1 4 )-alkylene group; B represents a single bond or an -O-(C1-4 )-alkylene, -NH-CO-(C 1 4 )-alkylene, or -(C 1 4 )-alkylene group; D represents a 1 )-alkylene group; and E represents one of~ the groups R 9 "et and He GN R 9 (in which R9 represents a (C 1 )-alkyl group; R 10represents a (C 1 )-alkyl group; or R 9 and R 10 together represent (C 4 )-alkylene; and R 11represents a (C 1 )-alkyl, (C 1 4 )-alkylene-C0 9 (C 14 )-alkylene-SOCE 1-4 3,1 (C 1 )-alkylene-OH, or (C 3 6 -cycloalkyl group); -54 H e t N =---represents a nitrogen heterocycle optionally substituted by one or more C _4-alkyl groups which may be condensed with a benzene ring and which may optionally contain one or more additional heteroatoms in the ring; ArP represents an anion; optionally in the form of pure enantiomers or mixtures of one or more thereof, and salts including internal salts, thereof. a i 15 2. The physiologically acceptable acid-addition salts S« a o C3 2 i nd the physiologically acceptable acid in claddition salts thereof. S3. The compound of formula .H HN 3 SHOHH HCHOH-CH-NH-C(CH -C-C CH 3 and the physiologically acceptable acid addition salts thereof. 4. The compounds of formula O HO- CHOH-CH -NH-C-CH *I wherein W represents O-CH 2-CH 2-N *(C 0s 2 2 'e :H 3 3 An -Q -CH 2 CH 2- t(CH 3 2 -(CH 2 3 -SO 3 44 4 i* 4.f 4 i fi 0 0 4 o e o eb a B fie 6 6 ci) NHCO-CH 2 NQ -CU -CH 3x A x AnE NHCO-CH 2 CH 3 2 (CHi 2 3 -SO 3 (in the which Ar represents an equivalent of an anion) and acid addition salts thereof. 5. A pharmaceutical composition which comprises a 25 compound as claimed in claim 1, in admixture with a pharmaceutically acceptable excipient, carrier or diluent. 6. A process for preparing compounds of formula Ia as claimed in claim 1 in which a) a compound of formula IV R R (4 Q CH CH NH C (CH R R' (IV), O H R 6 56 wherein n, R 7 R 4 R 5 and R 6 are as defined in claim 1, Q represents one of the groups (IIa), (IIb) or (IIc) as defined in claim 1, R' represents the group K in which K and L represent any two of the groups carried by the quaternary nitrogen atom of the group R as defined in claim 1 or a protected form thereof 7) in which any hydroxyl group or amino group it is desired to protect is protected by hydrogenolytically-removable protecting groups, is reacted with an alkylating agent serving to introduce that group carried by the quaternary nitrogen atom in the group R as defined in claim 1 not present in the group and any protecting groups present are removed by hydrogenolysis; or oo0 b) if it is desired to prepare a compound of formula Ia 0 0 in which the nitrogen atom of the quaternary ammonium group in the group R 7 -N as defined in claim 1 is 0 20 directly bound to an aliphatic carbon atom, a compound of formula VIII R R 115 :00:0, 25 Q CH -CH-NH-C (CH R X (VIII), OH R 6 (wherein n, R 4 R 5 R 6 and Q are all as defined above and R X represents a group R as defined in claim 1 in which the quaternary nitrogen atom has been replaced by a leaving group X), is reacted with an appropriate tertiary amine to provide the desired quaternary ammonium compound of formula Ia; and in the case of either of steps a) or b) followed, if desired, by separation of any mixture of enantiomers into pure enantiomeric forms or other enantiomeric mixtures, and formation of any desired acid addition salts. )O x HC1 -2 0 i -IIU -II-I Il ^1L i- ~y -IOI 57 7. A process as claimed in claim 6 substantially as herein disclosed in any one of the Examples. 8. A method of treating bronchial conditions, conditions of spasm and allergic conditions in a human or non-human animal body which comprises adminstering to said body an effective amount of a compound of formula Ia as defined in claim 1. DATED this 8th day of October, 1991. BOEHRINGER INGELHEIM INTERNATIONAL GMBH By its Patent Attorneys: CALLINAN LAWRIE 0 J /74, L \L7
AU27022/88A 1987-12-19 1988-12-16 New quaternary ammonium compounds, their preparation and use Ceased AU618302B2 (en)

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DE69823858T2 (en) * 1997-10-17 2005-04-28 Yamanouchi Pharmaceutical Co., Ltd. AMID DERIVATIVES OR THEIR SALTS
KR20020093083A (en) * 2000-04-27 2002-12-12 베링거 잉겔하임 파르마 카게 Novel, slow-acting betamimetics, a method for their production and their use as medicaments
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
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US7307076B2 (en) 2004-05-13 2007-12-11 Boehringer Ingelheim International Gmbh Beta agonists for the treatment of respiratory diseases
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
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DE102004024453A1 (en) * 2004-05-14 2006-01-05 Boehringer Ingelheim Pharma Gmbh & Co. Kg New long-acting bronchodilators for the treatment of respiratory diseases
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DK700788D0 (en) 1988-12-16
PT89234B (en) 1993-07-30
AU2702288A (en) 1989-06-22
IL88707A0 (en) 1989-07-31
HUT53866A (en) 1990-12-28
NZ227367A (en) 1990-07-26
FI885811A (en) 1989-06-20
EP0321864A2 (en) 1989-06-28
NO885598L (en) 1989-06-20
YU228688A (en) 1990-08-31
PL160685B1 (en) 1993-04-30
ZA889387B (en) 1990-08-29
PT89234A (en) 1989-12-29
DD280099A5 (en) 1990-06-27
HU207283B (en) 1993-03-29
KR890009920A (en) 1989-08-04
MX14253A (en) 1993-09-01
EP0321864A3 (en) 1990-12-27
CZ843588A3 (en) 1996-08-14
DE3743265A1 (en) 1989-06-29
SU1628854A3 (en) 1991-02-15
DK700788A (en) 1989-06-20
JPH02239A (en) 1990-01-05
FI885811A0 (en) 1988-12-16
PH27509A (en) 1993-08-18
NO885598D0 (en) 1988-12-16
PL276549A1 (en) 1989-08-21

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