NZ227367A

NZ227367A - Phenyl substituted ethanolamine derivatives containing a quaternary ammonium group

Info

Publication number: NZ227367A
Application number: NZ227367A
Authority: NZ
Inventors: Kurt Schromm; Anton Mentrup; Ernst-Otto Renth; Gojko Muacevic; Werner Traunecker
Original assignee: Boehringer Ingelheim Int
Priority date: 1987-12-19
Filing date: 1988-12-16
Publication date: 1990-07-26
Also published as: SU1628854A3; EP0321864A3; HU207283B; PT89234B; MX14253A; DK700788D0; ZA889387B; AU618302B2; NO885598D0; YU228688A; KR890009920A; EP0321864A2; DD280099A5; PL160685B1; PT89234A; PH27509A; NO885598L; FI885811A0; CZ843588A3; IL88707A0

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £27367 m 117367 # NO DRAWINGS Complete Specification Filed: 1*9.' Class: W. PM3/ '.V, £3X95/9 fcv P. . CoT? P^(p3/l Public&t.'cn Date: P.O. Journal. K'o: Patents Form No. 5 Class Cont: ... Ctf.Q&tf/pS; CcaV&tlf&y. NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION NEW QUATERNARY AMMONIUM COMPOUNDS/ THEIR PREPARATION AND USE 4 # )(/We, BOEHRINGER INGELHEIM INTERNATIONAL GMBH, A Body Corporate organised under the laws of the Federal Republic of Germany, of D-6507 Ingelheim am Rhein, FEDERAL REPUBLIC OF GERMANY hereby declare the invention, for which )(/we pray that a patent may be granted to rjfe/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - 1 - (followed by page la) 22 7 3 6 7 1 a- 20J 53 613 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 5 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 effective when inhaled makes it possible to 10 eliminate unwanted systemic side effects to a great extent whilst substantially retaining the broncholytic (topical) effect. We have found that the nature of the quaternary ammonium grouping may be selected from a wide range of^variations without crucially 15 affecting the differentiation between desirable and undesirable effects according to the invention. i According to the invention, we provide compounds of formula I A I4 Q - CH - CH - NH OH (I) 20 wherein Q represents a substituted phenyl group; 25 R represents a group, such as an alkoxy, arylalkoxy, aryloxyalkoxy, aryl, aryloxy, arylcarbonamido group, a heterocyclic group or a heterocyclically substituted carbonamido group, which includes (followed by page 2) 22 7 3 6 7 - 2 - also a quaternary ammonium grouping; R4 represents H, CHg or C2H5; R5 represents H or CH3; Rg represents H or CH^; 5 n represents an integer selected from 1, 2, 3, 4 and 5. The compounds of the invention may in one preferred embodiment be represented essentially by the formula la R R 2 11 R R 14 |S- >_ CH-CH-NH-C-(CH_) -R_- iT- (la) 1 1 2 n 7 I OH R 6 An 10 in which, unless otherwise stated, n represents an integer selected from 1, 2, 3, 4 and 5; R^ represents H, CH^, OCH^, CI, or F; R2 represents H, R3O-, -CH2OH, -NHCHO, -NHCOCH3, 15 -NHS02CH3, or -NHCONH2; R3 represents H, acyl, or N,N-dialkylcarbamoyl, the groups R30 being in the 4- or 5- positions; the group II m m 22 7 3 6 7 - 3 - (II) may also represent one of the groups O R and (I la) (Hb) (He) 5 wherein is as hereinbefore defined and Rg represents H or CH^; R^ represents H, CH-j, or C2H5; R^ represents H or CH^; Rg represents H or CH^; 10 R^ represents a single bond or a divalent bridging member which may also be bound to the ammonium nitrogen via ring atoms of a heterocyclic group; I m -N - represents a quaternary ammonium group; I 15 An® represents an anion. 22 7 3 6 - 4 - In a further preferred embodiment, the grouping I ® -Ry—N — primarily represents one of the groups -E (III a), 5 -Ar-B-E (III b), -O-Ar-B-E (III c), 10 -NH-CO-E (III d), -NH-CO-Ar-B-E (III e) , 15 ■°-(CmH2rr,)-A-E ' ("If), -0-(CmH2ln)-A-Ar-B-E (III g) r Het-\—B—E (III h) and N= 20 N-D-E (III i) , n and R^ to Rg being as defined hereinbefore. 25 In the above definitions of (Ilia) to (Illi), m represents an integer selected from 2, 3, 4, 5 and 6; 10 r=> N represents a nitrogen heterocycle which may be condensed with a benzene ring and which may be substituted or unsubstituted and may 35 optionally contain one or more additional heteroatoms in the ring; - 5 - 22 7 3 6 7 Ar represents arylene, preferably unsubstituted or substituted phenylene or naphthylene; A represents a single bond or a NH-CO--alkylene group; 5 B represents a single bond or an -0--alkylene, -NH-CO-(C-L_^)-alkylene, or --alkylene group; D represents a - (C^_^)-alkylene group; and 10 E represents one of the groups R9 -IP- Ri n ' _l Het i and I R11 (in which 15 Rg represents a (C^_4)-alkyl group; R ■j^g represents a (C-^_^)-alkyl group; or Rg and R-^g together represent a (C^g)-alkylene group; and R11 represents a (C^_^)-alkyl, (C^_^)-alkylene-COO®, 20 (C^_^)-alkylene-SO^®/ (cl_4)-alkylene-OHf or (C3_g)-cycloalkyl group; ( Het\ and the group N I is as defined above). - 6 - Typical examples of E include -|P(CH3)3, -N®(CH3) 2CH2CH2CH2so|>,--^I®(CH3)2-(CH2)4-so® -N®(CH3)2CH2CH2CO® 22 7 36 7 - 7 - 22 7 3 6 7 Particular mention should be made of the following IA preferred definitions for the grouping -R^-N in which the groupings and groups are as defined above: -^,RlORll r-B-lPf -Ar-B-rH9S10Rn -O-Ar-B-N^RgR10R11 -NH-CO -NH-CO-Ar-B- AnRinR 9 10 11 -°-(craH2ra)-A lPRgRioRll -O-(C H }-A-Ar-B-^.R. _R1 'm 2ra 9 10 11 -(^Het^ B-lPl N / R9R10R11 (III a 1) (III a 2) (III a 3) (III b 1) (III b 2) (III c 1) (III d 1) (III e 1) (III f 1) (III g 1) (III h 1) -N^%-D-tpR9R10R11 (III i ) 22 73 -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 5 also applies to the carbon chains which are components of other groups. Examples of substituents in aryl(ene) include, in particular, F, CI, CH^ and CH^O groups. The terms "aryl" and "arylene" refer to the appropriate groups derived from benzene or naphthalene. "Acyl 10 groups" in this case denote carboxylic acid groups with up to 7 carbon atoms, particularly acetyl. The bridge Ry may be linked to the nitrogen atom of the quaternary ammonium group. Alternatively, if the quaternary ammonium group is pafrt of a hetero-15 cyclic group, the bridge may be connected to another ring atom of the heterocyclic group. Groups falling into this latter category include in particular N. I 1 o R ii 22 7 3 6 7 - 9 - (in which R"^ represents H or C^_^-alkyl), and triazines. In a further preferred embodiment of the invention 5 represents H, CH^, OCH^r CI or F; R2 represents OH or, when R-^ equals CI or F, R2 may also represent H; or R ^ and R2 together may also represent ° Ro O (J HN 0 \ / or Hl^ / 10 (in which Rg is as hereinbefore defined) R 2 represents a hydrogen atom; 22 7 3 6.7 - 10 - represents H or R 2 and Rg both represent H or both represent CH^; n 5 R„ - represents an integer selected from 1, 2 and 3; CH - ■B " " " "11 R. ir) -N: CH B B O CH Het ; (s' N —' I CH . -» t . „ - W ~ R11 or CH. CH -N N - D - J*. R 11 o CH. 22 7 3 6 7 (in which ©N / CH Het1 here represents / CH. or represents -<V - N 5 whilst B, D and are as hereinbefore defined). Particular mention should be made of the compounds in which the following combinations of substituents occur: (a) represents a methyl or methoxy group, 10 R2 represents a hydroxyl group, and R^ represents a 4-hydroxyl group; (b) R^ represents a hydrogen atom, R2 represents a hydroxyl group, and represents a 4- or 5-hydroxyl group; 15 (c) R-, and R~ together represent % R 1 HN \) \ / R or HN , and Ill3fc7 - 12 - represents a 4- or 5-hydroxyl group; represents a hydrogen atom, if R5 and Rg represent methyl groups, but R5 anc^ R6 represent H; represents CH 3 nh - co "ch nh - co - ch2 \ CH ch 3 ch 3 o- ch 2 ch 3 - 13 - 22 7 3 6,: (in which R12 and R13 represent CH3, CH^COO0, CH2-CH2-COCP or ch2-ch2-ch2-so3®). 5 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 10 extends to all such forms of the "compounds of formula I. The compounds of the invention may be prepared by a variety of methods. Accordingly, in a further aspect of the invention, 15 we provide a process for preparing compounds of formula I as described above, wherein a) a compound of formula IV r r |4 |5 q - ch - ch - nh - c - (ch ) - r' (iv) , I I 2 n oh r 6 wherein n, Q, R^, R^ and Rg are as defined above, 20 R' is a tertiary amino group which corresponds at least in part to the quaternary ammonium group-containing group R, or a protected form thereof in which any hydroxyl group or amino group it is desired to protect is protected by hydrogenolytically-removable 25 protecting groups, is reacted with an alkylating agent, and any protecting groups present are removed by hydrogenolysis; 22 7 36 7 - 14 - or b) if it is desired to prepare a compound of formula VII 5 R5 Q - CH - 6H - NH - C - (CH.) - R, •_!!g!. it! k 2 " 7 I (VII) , 6 wherein n, R4, R5, Rg and Q are as defined above 10 and R^' represents a group Ry which is bound to the quaternary ammonium nitrogen via an aliphatic carbon atom, 15 a compound of formula VIII R„ Rr |4 ,5 Q - CH - CH - NH - C - (CH ) - R '-X I 2 n V /ttttti OH R (VIII) , 6 20 (wherein the symbols are all defined as above and X represents a leaving group j is reacted with a tertiary amine - N - to provide the desired quaternary ammonium compound, followed, if desired, by separation of any mixture 25 of enantiomers into pure enantiomeric forms or other enantiomeric mixtures, and formation of any desired acid addition salts. Process (a) above is suitable for preparing compounds 30 of formula I in which the quaternary ammonium group is not in the form - n 35 Compounds selected from CI—(C^_^)-alkylene-SO^Na and HO- (C1_4) -alkylene-S02-0- (C-L_4) -alkylene-S03Na - 15 - 22 7 3 6 7 are particularly suitable for the introduction of a (C^_4)-alkylene—SO® group. The reaction is expediently carried out in an inert 5 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 10 formula V ?4 ?S Q - CO - CH - NH - C - (CH ) - R' (V) , i 2 n R 6 15 4 5 6 1 wherein Q, R , R , R , R and n are as defined above, or Schiff bases of the formula VI 20 R " R | 4 i 5 -CO-C = N - C - (CH ) - R' I 2 n R 6 (VI) , 25 (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 30 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 (b) above, the leaving group X is preferably 35 a chlorine, bromine or iodine atom or an alkyl-or arylsulphonic acid group. 22 7 3 6 7 - 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 100°C. 5 Any hydrogenolytically-cleavable protecting groups present may be removed after the reaction if necessary or desired by conventional methods. 10 The starting compounds of formula VIII may be prepared, for example, from aminoketones of formula IX ?« ?s Q - CO - CH - NH - C - (CH ) - R •-X 15 I 2 n 7 R 6 (IX) by reaction thereof with a hydride such as sodium hydride or diborane. 20 The compounds of formula IX may in turn be obtained by methods known per se. Any protecting groups present which it is desired 25 to remove may expediently be removed by hydrogenolysis with palladium as catalyst in an inert solvent. The compounds according to the invention always will contain at least one asymmetric carbon atom. 30 In order to obtain compounds of formula I in the form of 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 X, in which the 35 desired configuration is already present at the - 17 - 22 7 3 6 7 centres of asymmetry in question. The compounds according to the invention may if desired be converted in a manner known per se into 5 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, 10 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. 15 The compounds of the invention are suitable for use in pharmaceutical compositions. In particular they have broncholytic, spasmolytic and anti-allergic activity, they increase ciliary activity and reduce inflammatory/ 20 exudative reactions. They may therefore be used inter alia for treating all types of asthma and bronchitis. The dosage for therapeutic and prophylactic use will in general depend on the nature and gravity 25 of the illness in question. For adults, the dosage for the preferred route of administration, namely inhalation, is preferably from 0.001 to 0.5 mg per day. The preparations 30 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 (e.g. ipratropium bromide, oxytropium bromide), 35 secretolytics (e.g. bromhexine, ambroxol), antibiotics (e.g. doxycycline), corticosteroids (e.g. beclomethasone dipropionate, flunisolide, budesonide) or other anti-asthma preparations such as disodium cromoglycate, nedocromil and anti-allergic substances. - 18 - 22 7 3 6 7 The following non-limiting examples illustrate formulations which incorporate the compounds of the invention: 1. Powder for inhalation 5 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 10 substances. The powder is inhaled from conventional inhaling devices, e.g. according to DE-A-3345722. * 2. Metering aerosol Active substance according 0.1% by weight to Example 8 hereinbelow 15 Sorbitane trioleate 0.5% by weight Monofluorotrichloromethane and difluorodichloromethane (2:3) 99.4% by weight The mixture is packed into metering aerosols of suitable type. The metering device is designed, 20 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 8-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. 22 7 3 6 7 - 19 - Some pharmacological activity data for compounds according to the invention are given hereinafter. The EC,-q 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 % 50 A 0,06 B 0,06 C 0 r 0 9 D 0-06 E 0.5 F Or 3 Gr\ r\ '7 H 0-05 I 0.02 J 0-004 K 0,02 - 20 - 22 7 3 6 7 Compounds tested CH Q-CHOH-CH2-ra-^-CH2-^^jy-NH-CO-CH2-^p- x HCl Compound Q -if®- J- % H O OH CH O HN O D: ) _ , - N(CH3)3Cr -<o -IP(ch. ) „ci® A: \ s -rr'(CH3)3cr HO B: \ / -® \ cP \ C: HO ([ ) V— -N^(CH3)3C1W ' -fP(CH^),Cl^ - 21 - 22 7 3 6 7 Compound Q -A® OH E: © © - N(CH3)3C1V;7 OH - 22 - 22 7 3 6 7 Compounds of formula 0 HN 0 ho X HCl choh-ch2-g Compound ch I 3 -nh-c-ch. I ch lP(CH3 ) 3 ci© C: cr ,e H: CH I 3 -NH-C-CH-I 2 CH 3 -CH2-CH2- fP(CH3)3 ClP CH I: -NH-C-CH. CH, CH -CH2-CH2-1RCH3 CH2-ch2-CO® CH J: -NH-C-CH. CH- CH CH.-CH^-lP-CH, 2 2 3 CH2-CH2-ch2-SO^ Compound - 23 -G 22 7 3 24 The following non-limiting examples illustrate processes whereby the compounds of the invention may be synthesised. 5 Example 1 0 /""A I! HN 0 ho ch-ch OH ch 2_nh- h2-ch2 [®-CH3 x HCl 1.9 g of 51-hydroxy-8'-[l-hydroxy-2-[4-(4-pyridyl)- 2-methyl-2-butylamino]-ethyl]-2H-l,4-benzoxazin- 3-(4H)-one-monohydrochloride are dissolved in a mixture of 3 ml of dimethylformamide and 1 ml of 10 water and 1.27 g of methyliodide are added. After 12 hours the solution is mixed with 5 ml of alcohol, acidified with conc. HCl and diluted with acetone; the crystals precipitated are suction filtered after about 1 hour and 1.2 g of the compound are 15 obtained by precipitation with water, conc. hydrochloric acid and alcohol. M.p. 207-209°C, 56% of theory. The starting compound may be prepared by the following method: O li 2 5 22 7 3 - 25 - O h hn 0 0 — O) CH3 :-ch=n-<!:-ch -ch„ in 2 2 3 NaBH (Mp. 170-171°C) u h hn o -O- i> C«3 h-ch2-nh-c-ch2-ch2 h ch 3 H /Pd/C 2 (Mp. 157-160°C) ch3 -ch-ch -nh-c-ch -ch-i 2 | Z / oh ch3 X HCl (Mp. 175°C (decomp.)) 26 22 7 3 Example 2 O hn O ho ch, I 3 ih-ch -nh-c-ch 2 | 2 ch 3 ch3 ®fcj-CH3 X HCl 3.7 g of 51-benzyloxy-8'-[l-hydroxy-2-[3-(4-dimethyl-aminophenyl)-2-methyl-2-propylamino]-ethyl]-2H-5 1,4-benzoxazin-3-(4H)-one-monohydrochloride are combined with 2.1 g of methyliodide in'7.4 ml of DMF 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 (m.p. 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: O - 27 - 22 7 3 6 7 k hn o .CH -O- ch_ 1 3 —c-ch=n-c-ch II i 2 o ch3 CH., NaBH. / 3 4 N } \ ch3 (Mp. 201-204°C) O ch HN O .ch. ,, ch -nh-c-ch 2 I 2 \ 2 \ 1 oh /H: N \ CH ch (Mp. 110-112°C, Mp. HCl salt 232-235°C) - 28 - 22 7 3 6 7 Example 3 CH I 3 CH-CH_-NH-C-CH i I | z OH CH 3 ?"3 0-CH_-CH_ -CH z Z \ CH 3 X HCl 2-ch2-co 3.2 g of 51-benzyloxy-81 -[l-hydroxy-2-[3-(4-dimethyl-amino-ethoxyphenyl)-2-methy1-2-propylamino]-ethyl]-2H-1,4-benzoxazin-2-(4H)-one-monohydrochlor ide 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, the crystals precipitated are suction filtered and 2.4 g of the compound are obtained (Mp. 123-126°C). 10 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. (Mp. 173-175°C, 94% of theory). - 29 - 22 7 3 6 7 The starting compound may be prepared by the following method: K HN 0 V / OH CH2o-/r Xv-Q-cu OC H 2 5 CH ^N-CH_ -CH.-0 2 2 CH CH„ / 3 CH -C-NH 2 \ - 2 CH 3 -> K Nf CH. -CH -O—'( YV—C-CH=N-C-CH —, v°^Qh i„ 2 CH \ 3 O-CH -CH -N 2 2/ CH 3 NaBH 4 > (MP- 153-155°C) CH. -CH-CH -NH-C-CH I 2 \ 2 OH CH CH \ 3 -CH -CH -N 2 2 i CH 3 X HCl (Mp. 176-178 °C) 22 7 3 6 - 30 - The following compounds may be synthesised analogously to the Examples given: K HO I c,z\ -ch-nh-ch2-ch2 X HCl ^3 0-ch2-ch2 ■sli -ch3 CH cr ,© o H.BX NH HO ch I 3 ch-ch--nh-c-ch-— I OH CH. X HCl" CH3 o-ch2-ch®n-ch2-ch2-ch2-s<^ ch 3 u K / hn o H q-^-ch- CH i 3 CH -NH-C-CH I OH CH. -ch -ch - . 2 2@ ,n cr ,© x HCl HN O HO — ^3 CH-CH -NH-C-CH -CH 2 CH, 4H Cl © X HCl 22 7 3 6 7 - 31 - K HN 0 ^ CH I 3 HO—< v—CH-CH -NH-C-CH -CH | 2 . T 2 2 CH I 3 N- OH CH. x HCl !~fc ° cp ch. 0 hn HO Jk N O —/ ]\—CH-CH -NH-C-CH -CH -N VJ/ ' 2 | 2 2 \ / OH CH 3 x HCl 0 ch CH I 3 H-CH- -NH-C-CH I 2 | 2 OH CH 3 X HCl CH CH2-CH2-^CH2-CH2"CH2-S4> CH 3 O HO CH. ch-ch_-nh-(!:-ch- i 2 i 2 oh ch 3 X HCl (Mp. 175 °C) CH —^CH2-cocP ch 3 JT\ CH t 3 HO—^^-CH-CH2 -NH-C-CH „-CH T 2 2 OH CH3 X HCl (Mp. 191-193°C) CH3 CH -CH -COCP C'H3 x HCl - 32 - 22 1 HO f3 f\ CH-CH--NH-C-CH - —a }V-f>H " ' CH. 2\Jf © CH, I 3 X HCl 0-CH?-CH2-CH2-CH2-^-ljJ-CH3 CH cP O (I r~\ HO CH. CH ch2-nh-^-ch2 CH -0-°- CH2-CH2-,j/N \J cr © X HCl - 33 - 22 73 HO ch. I 3 -ch-ch7-nh-c-ch t — 1 +* OH CH. X HCl f"3 —O-CH.-CH-- ®N -CH 2 2 i 3 (Mp. 23 5 ° C) cr HN HO CH. H-CH_-NH-C-CH i 2 | 2 OH CH 3 X HCl (Mp.. 173-175°C) CH. I CH 0-CH2-CH2-N^CH2CH2-C00 a CH OH l 2 HO- CH I 3 CH-CH--NH-C-CH-I 2 , 2 OH CH 3 X HCl CH3 0-CH--CH-- % -CH 2 2 | CH 3 CI © 22 - 34 - ho ?H3 ch-ch2-nh-c-ch2-ch_ CH3 nh-c0-cho-n®- <ch2)3sdf 2 , ch. x HCl x H20 (Mp. 250-255 °C) ch_ I 3 ch-ch0-nh-c-ch„ 2 | 2 ch„ ch3 0-cho-cho-#-ch_ 2 2 | 3 ch„ CI © x HCl flip. 158-162°C) OH CH, ho ch_ I 3 ch-ch -nh-^-ch _ OH ch. ch, v© 0-CH2-CH2-f,<CH2)3-sd3 ch0 hc - cooh hc - cooh (Mp. 220-223°C) - 35 - 22 7 3 IN O <fh3 ch-ch_-nh-c-ch_ I 2 I 2 oh ch ch -CH2-CH2-f-(CK2)4-SO{ CH_ f x HCl x 1/2 H20 (Mp. 231-234 °C) CH_ I 3 CHOH-CH -NH-(^-CH -a- CH ch3 w 0-CH_-CH_-tf^-CH„ in 3 x 1/2 H-SO. x 1/2 SO^ x H_0 2 4 4 2 (MP- 263-265 °C) oh ^^_CHOH-CH2-NH-(j:-CH2 _^^^-CH3 Ah x 1/2 h-so. x 1/2 so. 20 x h_0 2 4 4 2 (Mp. > 270°C) ch_ I 3 choh-ch--nh-c-ch-Z | z CH„ ^Qt^-cn 2-ch2-cocP x HCl x 2H20 (Mp. 171-174°C) ( DoOOT-96 *<3W) 0 hz x idh x .N rTi HO "hd HD Z ' Z N — hd-d-hn- hd-hohd £ 1 hd ho (DoOIZ *dw) O^H S'T x IDH X ho °Hp qOS-£(ZHD)-^-ZHD-ODHN hd hd zhd-d-hn-3hd-hohd Z 1 hd HD ' JpS-2(ZHD)ZHD-ZHDO EHD (Dot'EZ-ICZ *dw) IDH x 'HD Z 1 Z HD-D-HN- HD-HOHD" Z ' HD HO o HO (Oo9ZZ~VZZ *dw) 03H x ^0SZH Z/I x hd qos- ^ ( 3hd ) 3hd- 2hdo eHD hd 3hd-d-hn-3hd-hoh £ I ^HD ho L 9 £ L 11 ~ 9Z - 22 7 3 6 37 Example 4 0 HO -@-CO-CV^ CI® X HCl 4.4 g of 51-hydroxy-81 -[l-hydroxy-2-[3-(4-chloro-acetaminophenyl) -2-methyl-2-prof>ylamino]-ethyl]-2H-1,4-benzoxazin-3-(4H)-one-hydrochloride, 6 ml 5 of pyridine and 25 ml of methanol are refluxed for 6 hours, then after the methanol arid pyridine have been distilled off the oily residue is dissolved in alcohol and 3.8 g of the title compound are obtained. 10 (Mp. 190-192°C; 77.5% of theory). The starting compound may be prepared by the following processes: O > O 3 NO 2 NaBH 4 — > (Mp. 151-154*C) 22 7 3 6 7 - 38 - O HN 6 -O CHh- \—I OH (Mp. 214-216°C) ch3 CH -NH-C-CH —jfjL—NO H /Ni 2 2 \=T 2 3 x HCl CH I 3 CH-CH -NH-C-CH I 2 I 2 OH CH 3 H 2 X HCl chloroacetic anhydride (MP. 208-211°C) CH, I 3 H-CH -NH-C-CH — | 2 | 2 OH CH 3 NH-C-CH CI u 2 x HCl (Mp. 160°C (decomp.)) - 39 - 22 7 3 6 7 Example 5 O HN O 2.7 g of 6•-hydroxy-8'-[l-hydroxy-2-[3-(4-chloracetamino-phenyl)-2-methyl-2-propylamino]-ethyl]-2H-l,4-benzoxazin-5 3-(4H)-one-hydrochloride, 25 ml of methanol and 3 ml of 30% trimethylamine solution are stirred for 12 hours at ambient temperature, concentrated and the 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: 22 7 36 h H -O 2 <rh3 C-CH=N-C-CH II i : O CH NaBH NO (Mp. 14 0-142°C) K HN O CH2~° OH CHa —CH -NH-C-CH .2 I 2 c% X HCl H2/Pd/C NO -> (Mp. 232-234°C) u Jk HN O o CH. I 3 —CH-CH2-NH-<p-CH2 OH CH NH chloroacetic 2 anhydride HO x HCl -> (MP- 266-268°C) - 41 - 22 7 3 6 CH. CH-CH -NH-i-CH CH. H-jj-CH.-Cl 0 x HCl (Mp. 185-189°C) The following compounds are prepared analogously: H0-()>-^H~CH 2 _NH~ ( CH 2 } 6 "°~ ( C" 2) 4 x HCl NH-CO-CH -N~(CH Cl® CH-CH.-NH-(CH2)6-NH-CO-CH2-hr<CH,) 3 ' 3 Cl e x HCl 0 II NH-CO-CH2-N~(CH3)3 Cl0 X HCl 22 7 36 - 42 - -CH-CH2-NH-C(CH3)2-CH2 63 nh-co-ch.-n (ch ) © Cl^ OH CH HO—/T )V-CH-CH2-NH-C(CH3 ) 2-CH2 © NH-CO-CH -N (CH ) Cl® x HCl HN —S02CH3 ho—)V-ch-ch2-nh-c(ch3)2-ch2 OH x HCl (Mp. 164-167°C) © nh-cooch2-n o ch. /_ch 3 HN ho—. ch-ch2-nh-c(ch3)2-ch2-ch2-' oh x HCl Cl © NH-CO-CH2-N (CH3) Cl' © - 43 - 22 7 3 § 7 Example 6 ho CH 3 ho h oh h-ch2-nh-c(ch3)2-ch2 © nh-co-ch7-n (ch3) 4.2 g of dibenzyloxy compound (see below) are debenzylated with hydrogen in methanol with palladium charcoal as catalyst under normal conditions and 2.5 g of the title compound are obtained. (81% of theory). The starting compound may be prepared by the following method: Bz-0 CH (CH3)2N_CH2_CO_NH H2~C(CH3)2"NH2 7 NaBH4 (Bz equals c.h_-ch,-) 6 5 2 Bz-0 ch Bz- :h-ch2-nh-c<ch3)2-ch2 h-co-ch2-n(ch3) CH3,I / HCl (Mp. 115°C) - 44 BZ-0 Ctfj Ah 22 736 Bz-0 -/jV- ch-ch2-nh-c(ch3 ) 2~ch2 nh-co-ch2-n~(ch3 ) 3 Cl © (Mp. 210-212°C) Example 7 0 K hn 0 H 'Hj ho-/ j\-ch-ch2-nh-<j:-ch2- ?H3 o-ch2-ch2-#(ch2)3-so® ch 3 X HCl 10 3.5 g of benzoyloxy compound (see below) are debenzylated 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 90% 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°C; 93% of theory). 15 The starting compound may be prepared by the following process (Bz equals benzyl) Bz-O ?H3 h-ch--nh-c-ch. I 2 \ ' oh ch3 o-ch2-ch2-n (ch3)2 X HCl 22 7 3 - 45 - CH NH-C(CH3)2-CH2_^ _O-CH2-CH2>-(CH2)3-SO© 3 CH2-CHOH_( OBz x HCl 0 NH (Mp. 239-241°C) 0 Example 8 O 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°C, decomp., 71% of theory) 15 The starting compounds may be obtained by the following process: - 46 - 22 7 3 o h HN 0 H 'H3 Bz-o-/ J)\_-CH-CH2-NH-C-CH. \ / OH -N \ CH BrCH -COOC H 2 2 5 x HCl O Bz-0 <TH3 H-CH^-NH-^-CH^-OH CH 3 (Mp. 127-130°C) x HCl CH3 -CH -COOC_Hc 1. NaOH | / z ^ CH 2. HCl .© ^ Br Bz-0 fH3 CH-CH_-NH-C-CH0 I 2 I 2 OH CH 3 ch3 fP-CH„-cocP I 2 ch x HCl (Mp. 20 3-205°C) 22 7 3 6 7 - 47 - The following compounds may be synthesised analogously to the Examples: HN HO- ?"3 CH-CH2-NH-C-CH2-OH CH 3 x HCl (Mp. 17 3 -17 5 ° C ) o-ch2-ch2-n®(ch3)2-coo 0 O is, & CH I 3 CH-CH--NH-C-CH. I OH CH. X HCl (Mp. 187 °C) CH jP-CH, CH3 cr- HO OCH CH3 °-CH2-CH2)nS-(CH2>3-SC? CH 3 u h HN O HO—/(jL-CH- CH-I 3 CH,-NH-C-CH--NH Z I z CH3 X HCl 0-CH2-CH2-®N cr - 48 - 22 7 3 6 7 Jk hn 0 ho ch„ I 3 h-ch--nh-c-ch„ 2 I 2 OH CH. x HCl x H20 r-\ ch3 _^_nh-co-ch2-h®- (ch2) 3sdf (Mp. 250-255 °C) jk HN 0 ho CH-CH. I OH ch3 ch3 -NH-(j:-CH2^^U»0-CH2-CH2-N®-CH2-C0(P ch„ \_/ ch_ x HCl x H20 (Mp. 214 -216 °C) oh ch. ho :h. ,ch-ch2-nh-c-ch2 oh ch3 CH3 0-cho-ch_-n®-cho c1 2 2 | 3 CH„ / Hit— ico T r '» on \ V rip • x+j w J. u z. v, / © oh' ch. ho —^h™-CH2-NH-pH2-^y-0-CH2-CH2-tHCH2,3^SO? hc - cooh (Mp. 220-223 °c) hc - cooh - 49 - O 22 7 36 7 A hn 0 ch_ , ch. ho -o- ^:h-ch2-nh-c-ch2 -a- 0-ch2-ch2 -k(ch2)4-sc| oh ch3 \__/ ch3 x HCl x h20 (Mp. 23 1-234 °C) oh ch_ I 3 ..choh-ch--nh-c-ch 2 t ch3 )h CH3 0-ch_-cho-t\p-ch, 2 2 | CH„ x 1/2 H_SO x 1/2 SO. 2 4 4 2© x H20 oh (MP- 2G3-265°C) xhoh-ch2-nh-c- oh ch3 . ch3 -c-ch _ _/(u-_och_ -ch0 -kp- ( ch0 ) a -so® in, <k 2 4 3 x 1/2 H„SO. x H_0 2 4 2 (Mp. 234-236°C) x HCl (Mp. 231-234°C) </div>

Claims

<div class="application article clearfix printTableText" id="claims"> - 50 - 22 7 3 6 7 OH l- ch3 _ ch /^y_CHOH-CH2-NH-C-CH2_^y\-.NHC0-CH2-^-( CH2 ) 3-SO® *■' CH0 \- i CH3 oh x HCl x 1.5 H20 (Mp. 210 °C ) 22 7 36 7 WHAT ^WE CLAIM ISt- 51 •0jrQimD

1. Compounds of formula I R R I 4 |5 Q - CH - CH - NH - <j: - <CH2)n " R (I) , d)H 6 wherein 5 Q represents a substituted pfienyl group; R represents quaternary ammonium group-containing alkoxy, arylalkoxy, aryloxyalkoxy, aryl, aryloxy, arylcarbonamido, heterocyclic or heterocyclically substituted carbonamido 10 group; R^ represents H, CH^ or R^ represents H or CH^; Rg represents H or CH^; n represents an integer selected from 1, 2, 15 3, 4 and 5, optionally in the form of pure enantiomers or mixtures of one or more thereof, and salts, including internal salts, thereof.

2. Compounds of formula la t R 2 y—-1/ R4 20 /u)\-CH-i:H-NH-|:-(CH ) -R (Ia)' R O d>H t 2 n 7 I n 3 6 Atv® 22 7 3 6 7 - 52 - wherein n represents an integer selected from 1, 2, 3, 4 and 5; R-^ represents H, CH3, OCH^r Cl or F; 5 R2 represents H, R3O-, -Ct^OH, -NHCHO, -NHCOCH3, -NHS02CH3 or -NHCONH2? R3 represents H, acyl or N;N-dialkylcarbamoyl, the groups R3O- being in the 4- or 5-position; the group II 10 R o \v—' / (II) may also represent one of the groups O and (I la) (lib) (lie) (wherein R3 is as hereinbefore defined and Rg represents H or CH3) 15 R^ represents H, CH3 or C2H^; 22 7 36 - 53 - Rj- represents H or CH^; Rg represents H or CH^; 5 R7 represents a single bond or a divalent bridging member which may also be bound to the ammonium nitrogen via ring atoms of a heterocyclic group; 10 i represents a quaternary" ammonium group, An® represents an anion, 15 optionally in the form of pure enantiomers or mixtures thereof, and salts thereof.

3. Compounds as claimed in claim 2, wherein I © the group -R^-N - is selected from 20 -E (III a) , -Ar-B-E (III b), -O-Ar-B-E (III c), -NH-CO-E (III d), -NH-CO-Ar-B-E (III e), 25 30 -O-(CmH2m)-A-E (III f) , -0- (C H_ ) -A-Ar-B-E (HI g), 35 'm 2m Het^— B-E — n • (III h) and 2273G7 - 54 - -N—^ N-D-E I I (III i) , 5 n and to Rg being as hereinbefore defined and m represents an integer selected from 2, 3, 4, 5 and 6; 10 Ar represents a substituted or unsubstituted arylene group; 15 represents a nitrogen heterocycle which may be condensed with a benzene ring and which may be substituted or unsubstituted and may optionally contain one or more additional heteroatoms in the ring; 20 A represents a single bond or a NH-CO-(C^_^)-alkylene group; B 25 30 E 35 represents a single bond or an -0- (C-^_4) -alkylene, -NH-CO-(C^_^)-alkylene, or - (Ci_4)-alkylene group; represents a - (C-j^)-alkylene group; and represents one of the groups R« —N®-R 10 Het and *11 22 7 3 6 7 (in which Rg represents a (C-L_4)-alkyl group; R10 represents a (C^_4)-alkyl group; or Rg and R^q together represent (C^_g)-alkylene; and A 5 R-j^ represents a (c1_4) -alkyl, (C^_^)-alkylene-COO , (C^_4)-alkylene-SO^®, (C^_4)-alkylene-OH, or (C^g) -cycloalkyl group), optionally in the form of pure enantiomers 10 or mixtures thereof, and salts thereof.

4. The physiologically acceptable acid-addition salts of compounds of formula I as claimed in any of claims 1 to 3.

5. The compound of formula HN -o>- ho—\ ( )> choh-ch2-nh-c(ch3)2-ch2 ch3 fo e„ .... so3-(ch2)3-n^-ch2-ch2-o CH3 15 and the physiologically acceptable acid addition 22 7 3 - 56 - salts thereof.

6. The compounds of formula 0 HN ho- ?H3 choh-ch -nh-c-ch -w 2 | 2 ch . 3 wherein W represents © '© 0-ch2-ch2-N (ch3)3 x ArT -ch2-ch2-*p(ch3)2-(ch2)3-so^ ^^_NHCO-CH2-®Nj x AnP -CH - /( W^-CH„ X An° §- nhco-ch2-n®(ch3)2-(ch2)3-so® 5 (in which An represents an equivalent of an anion) and the acid addition salts thereof.

7. A pharmaceutical composition which comprises a compound as claimed in claim 1, in admixture 22 7 J - 57 - with a pharmaceutical^ acceptable excipient, carrier or diluent.

8. A compound as claimed in any one of claims 1 to 6 for use in therapy. 5

9. The use of a compound of formula I as defined in claim 1 in the preparation of a medicament having broncholytic, spasmolytic and anti-allergic activity.

10. A process for preparing compounds of formula I as claimed in claim 1 in which 10 a) a compound of formula IV R 14 0 -CH-CH - NH I OH wherein n, Q, R4, R5 and Rg are as defined in claim 1, R' is a tertiary amino group which corresponds at least in part to the quaternary ammonium group-15 containing group R, 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, and any protecting 20 groups present are removed by hydrogenolysis; or R l 5 C - (CH ) - R* I 2 n R (iv) , b) if it is desired to prepare a compound of formula VII 22 7 3 - 58 - ?« ?S , (VII), - CH - CH - NH - C - (CH.,) - I Y* 7 *~"2'n "7 OH R 6 wherein n, R^, R5, Rg and Q are as defined in claim 1 and R^1 represents a group R^ which is bound to the quaternary ammonium nitrogen via an aliphatic 5 carbon atom, a compound of formula VIII R R |4 | 5 Q - CH - CH - NH - C - (CH ) - R '-X i | 2 n 7 0H (VIII) , (wherein the symbols are all defined as above) and X represents a leaving group, 10 is reacted with a tertiary amine - N - to provide the desired quaternary ammonium compound R R R 1 4 114 I 5 CHOH - - CH - N C - I R - (CH ) -R 2 n (X) followed, if desired, by separation of any mixture of enantiomers into pure enantiomeric forms or 15 other enantiomeric mixtures, and formation of any desired acid addition salts. I 227367 - 59 -

11. A process as claimed in claim 10 substantially as herein disclosed in any one of the Examples. BOEHRINGER INGELHEIM INTERNATIONAL GMBH BALDWIN, SON & CAREY </div>