United States Patent [19]
`Schromm et al.
`
`llllllllllllllllllllllIllllIllllIllllllllllllllIlllllllllllllllllllllllllll
`5,223,614
`Jun. 29, 1993
`
`USOO5223614A
`[11] Patent Number:
`[45] Date of Patent:
`
`[54] NEW QUATERNARY AMMONIUM
`COMPOUNDS, THEIR PREPARATION AND
`USE
`
`[75] Inventors: Kurt Schromm, Ingleheim am Rhein;
`Anton Mentrup, Wiesbaden;
`Ernst-Otto Renth; Gojko Mualcevic,
`both of Ingleheim am Rhein; Werner
`Traunecker, Munster-Sarrnsheim, all
`of Fed. Rep. of Germany
`Boehringer Ingelheim GmbH,
`Ingleheim am Rhein, Fed. Rep. of
`Germany
`[21] Appl. No.: 603,585
`[22] Filed:
`Oct. 25, 1990
`
`[73] Assignee:
`
`[63]
`
`Related US. Application Data
`Continuation of Ser. No.‘ 286,442, Dec. 19, 1988, aban
`doned.
`Foreign Application Priority Data
`[30]
`Dec. 19, 1987 [DE] Fed. Rep. of Germany ..... ., 3743265
`
`[51] Int. Cl.5 .......................................... .. C07D 265/36
`
`[52] U.S. Cl. . . . . . . .
`
`. . . .. 544/105; 546/184;
`
`546/221; 548/215; 548/221; 564/281; 564/282;
`564/291; 568/705
`
`[58] Field of Search ............. .. 564/283, 281, 282, 291;
`544/105; 546/184, 221; 548/215, 221;
`574/2305, 299, 330, 375; 568/705
`References Cited
`U.S. PATENT DOCUMENTS
`
`[56]
`
`4,599,335 7/1986 Rentzea et a1. ................... .. 564/282
`
`OTHER PUBLICATIONS
`Chemcial Abstracts, vol. 101, p. 772, 1919392, 1984.
`Chemical Abstracts, vol. 80, p. 274, N0. 7, 36875e, 1974.
`Primary Examiner-Jose G. Dees
`Assistant Examiner—Deb0rah D. Carr
`Attorney, Agent, or Firm-D. E. Frankhouser; A. R.
`Stempel; M-E. M. Timbers
`[57]
`ABSTRACT
`Compounds of formula
`
`wherein the substituents are de?ned hereinbelow, useful
`in the treatment of bronchospasm are described.
`
`5 Claims, No Drawings
`
`SAWAI EX. 1018
`Page 1 of 24
`
`

`

`1
`
`5,223,614
`
`2
`
`R: R1
`
`(11)
`
`(Ila)
`
`(Ilb)
`
`(Ilc)
`
`R30
`
`may also represent one of the groups
`
`0 R8
`ll
`R8
`
`HN
`
`0 hog
`
`?
`/\
`HN
`O
`
`
`
`@y R30
`
`0
`II
`
`“N;
`
`R30
`
`\;
`
`NEW QUATERNARY AMMONIUM COMPOUNDS,
`THEIR PREPARATION AND USE
`
`This is a continuation, of application Ser. No.
`286,442, filed Dec. 19, 1988, now abandoned.
`The invention relates to quaternary ammonium com
`pounds, and the preparation and use thereof. The com
`pounds 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
`effective when inhaled makes it possible to 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 ammo
`nium grouping may be selected from a wide range of
`variations without crucially affecting the differentiation
`between desirable and undesirable effects according to
`the invention.
`According to the invention, we provide compounds
`of formula I
`
`25
`
`11L;
`R5
`Q-<IIH—CH-NH—ClZ-(CHZ),,—R
`
`OH
`
`R5
`
`(I) 30
`
`35
`
`wherein
`Q represents a substituted phenyl group;
`R represents a group, such as an alkoxy, arylalkoxy,
`aryloxyalkoxy, aryl, aryloxy arylcarbonamido group,
`a heterocyclic group or a heterocyclically substituted 4O
`carbonamido group, which includes also a quaternary
`ammonium grouping;
`R4 represents H, CH3 or CZH5;
`R5 represents H or CH3;
`R6 represents H or CH3;
`n represents an integer selected from 1, 2, 3, 4 and 5.
`The compounds of the invention may in one pre
`ferred embodiment be represented essentially by the
`formula la
`
`45
`
`50
`
`wherein R3 is as hereinbefore de?ned and
`R8 represents H or CH3;
`R4 represents H, CH3, or C2H5;
`R5 represents H or CH3;
`R6 represents H or CH3;
`R7 represents a single bond or a divalent bridging mem
`ber which may also be bound to the ammonium nitro
`gen via ring atoms of a heterocyclic group;
`
`R2 R1
`
`R30
`
`R4
`|
`
`OH
`
`CH—CH-NH-(‘I-—(CHZ),,—R7—II~I$—
`
`R5
`
`R6
`
`l
`
`Arie
`
`(Ia)
`
`55
`
`represents a quaternary ammonium group;
`An9 represents an anion.
`In a further preferred embodiment, the grouping
`
`60
`
`in which, unless otherwise stated,
`n represents an integer selected from 1, 2, 3, 4 and 5;
`R1 represents H, CH3, OCH3, C1, or F;
`R2 represents H, R3O—, —CH2OH, —NHCHO,
`—NHCOCH3, ——-NHSO2CH3, 01' —NHCONH2;
`R3 represents H, acyl, or N,N-dialkylcarbamoyl, the
`groups R30 being in the 4- or 5- positions;
`the group II
`
`primarily represents one of the groups
`
`SAWAI EX. 1018
`Page 2 of 24
`
`

`

`3
`-continued
`—0-(c,,,1~1;,,,)—-A—Ar—B—E,
`
`—@-B—E and
`N
`
`0
`/“\
`-N
`N-D-E,
`L_____l
`
`5,223,614
`
`4
`-continued
`
`-—N
`
`k N9
`l
`CH3
`
`(III g)
`
`(III 11)
`
`(111 i)
`
`5
`
`Particular mention should be made of the following
`10 preferred de?nitions for the grouping
`
`n and R1 to R6 being as de?ned hereinbefore.
`In the above de?nitions of (IIIa) to (IIIi),
`m represents an integer selected from 2, 3, 4, 5 and 6;
`
`15
`
`_R7-]lq$_’
`l
`
`in which the groupings and groups are as de?ned above:
`
`Her
`
`N
`
`represents a nitrogen heterocycle which may be con
`densed with a benzene ring and which may be substi
`tuted or unsubstituted and may optionally contain
`one or more additional heteroatoms in the ring;
`Ar represents arylene, preferably unsubstituted or sub
`stituted phenylene or naphthylene;
`A represents a single bond or a NH-—-CO-—(C1.4)-alky
`lene group;
`B represents a single bond or an —O—-(C1_4)-alkylene,
`—-NH-CO-—(C1-4)-alkylene, or —(C14)-alkylene
`group;
`D represents a —(C1.4)-alkylene group; and
`E represents one of the groups
`
`20
`
`25
`
`35
`
`I
`-l'q$-R10, '-@N
`R11
`
`He!
`
`Her
`
`and 631?‘
`R9
`
`(in which
`R9 represents a (C1-4)‘alkyl group;
`R10 represents a (C1-4)-alkyl group; or
`R9 and R10 together represent a (C4-6)-alkylene group;
`and
`R11 represents a (C1.4)-alkyl, (C14)-alkylene-COO9,
`(C14)-alky1ene-SO39, (C14)-alkylene-OH, or (C345)
`cycloalkyl group; and the group
`
`45
`
`Het
`
`N
`
`is as de?ned above).
`Typical examples of E include
`—-N@(CH3)3,
`——N@(CH3)ZCHZCHZCHZSO3G,
`—N@(CH3)2—(CH2)4-—$039,
`—N@(CH3)2CH2CH2CO29,
`
`Mo ,
`
`Ida-CH3 and,
`
`55
`
`65
`
`The alkyl and alkylene groups in the above de?ni
`tions may be straight-chained or branched. Unless oth
`erwise 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. Examples of substituents in aryl(ene) include, in
`particular, F, C], CH3 and CH3O groups. 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 R7 may be
`
`SAWAI EX. 1018
`Page 3 of 24
`
`

`

`5,223,614
`
`5
`linked to the nitrogen atom of the quaternary ammo
`nium group. Alternatively, if the quaternary ammonium
`group is part of a heterocyclic group, the bridge may be
`connected to another ring atom of the heterocyclic
`group. Groups falling into this latter category include in
`particular
`
`5
`
`represents a group
`
`6
`
`_,L@_
`
`l
`
`@QQIQ
`
`10
`
`He‘
`
`__ _
`NH c0
`all‘!
`CH3
`
`,
`
`CH3
`I
`B-lltla-Ru.
`CH3
`
`N
`
`S, -’N
`
`N, _N
`
`NR",
`
`I!
`O
`
`-N
`
`0*
`T
`R”
`
`IN
`
`N
`
`N
`
`’
`
`N
`
`-N
`
`J\\
`R”
`N
`
`N
`
`R’
`
`R-N
`
`O:
`
`5
`
`0
`ll
`
`N
`|
`
`0
`II
`
`—N
`
`o=|\
`N
`l
`R,
`
`15
`
`2O
`
`25
`
`30
`
`35
`
`4O
`
`45
`
`(in which R11 represents H or C1_4-alky1), and triazines.
`In a further preferred embodiment of the invention
`R1 represents H, CH3, OCH3, Cl or F;
`R2 represents OH or, when R; equals C1 or F, R; may
`also represent H; or
`R1 and R2 together may also represent
`
`5O
`
`—®N
`
`,
`
`B—N$-— ,
`
`0
`
`CH
`3
`Het
`N—D-"N$_R1] or
`$1? _ , —N
`CH3
`LJ CH3
`
`0
`H
`CH3
`/\
`i
`—N
`N—D—N€B-—RH (in which
`I
`
`@ CH3
`
`6BN
`/
`CH3
`
`here represents
`
`,
`
`9N
`/
`CH3
`
`.
`
`5
`
`\
`
`X‘ lo, _
`@N
`K
`/
`N
`CH3
`GBI
`CH3
`
`Het
`
`—-$N
`
`represents —$N
`
`0 R3
`u
`| R
`g or
`
`rm
`\
`
`0
`/
`
`0
`]|
`HNAO,
`\ /
`
`(in which R3 is as hereinbefore de?ned)
`R3 represents a hydrogen atom;
`R4 represents H or C2H5;
`R5 and R6 both represent H-or both represent CH3;
`n represents an integer selected from 1, 2 and 3;
`R7
`
`55
`
`'
`
`whilst B, D and R11 are as hereinbefore de?ned).
`Particular mention should be made of the compounds
`in which the following combinations of substituents
`6O occur:
`.
`(a) R1 represents a methyl or methoxy group, R2 repre
`sents a hydroxyl group, and R3 represents a 4
`hydroxyl group;
`65 (b) R1 represents a hydrogen atom, R1 represents a
`hydroxyl group, and R3 represents a 4- or S-hydroxyl
`group;
`(0) R1 and R2 together represent
`
`SAWAI EX. 1018
`Page 4 of 24
`
`

`

`5,223,614
`
`8
`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 protect
`ing groups, is reacted with an alkylating agent, and any
`protecting groups present are removed by hydrogenol
`ysis;
`or
`b) if it is desired to prepare a compound of formula
`VII
`
`R3 represents a 4- or S-hydroxyl group;
`R4 represents a hydrogen atom, if R5 and R6 represent
`methyl groups, but C2I-I5, if R5 and R6 represent H;
`
`represents
`
`15
`
`25
`
`30
`
`35
`
`(in which R12 and R13 represent CH3, CHy-COOQ
`45
`CH2—CH2—CQOe OI‘ CH2——CH2—CH2-—SO39).
`The compounds according to the invention may
`occur as mixtures of enantiomers, particularly as race
`mates, 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
`I.
`
`The compounds of the invention may be prepared by
`a variety of methods.
`55
`Accordingly, in a further aspect of the invention, we
`provide a process for preparing compounds of formula
`I as described above, wherein
`a) a compound of formula IV
`
`50
`
`wherein n, R4, R5, R6 and Q are as de?ned above and
`R7’ represents a group R7 which is bound to the quater
`nary ammonium nitrogen via an aliphatic carbon atom,
`a compound of formula VIII
`
`(wherein the symbols are all de?ned as above and X
`represents a leaving group is reacted with a tertiary
`amine
`
`to provide the desired quaternary ammonium com
`pound, followed, if desired, by separation of any mix
`ture of enantiomers into pure enantiomeric forms or
`other enantiomeric mixtures, and formation of any de
`sired acid addition salts.
`Process (a) above is suitable for preparing com
`pounds of formula I in which the quaternary ammonium
`group is not in the form
`
`Compounds selected from Cl--(C1-4)-alkylene-SO3Na
`and
`HO-(C1.4)-alkylene-SO2—O-(C1.4)-alkylene
`SO3Na are particularly suitable for the introduction of a
`(C14)-alkylene-SO39 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 for
`mula V
`
`wherein :1, Q, R4, R5 and R6 are as de?ned above, R’ is
`a tertiary amino group which corresponds at least in
`part to the quaternary ammonium group-containing
`
`wherein Q, R‘, R5, R6, R1 and n are as de?ned above,
`or Schiff base of the formula VI
`
`65
`
`Rs
`
`Re
`
`(V)
`
`SAWAI EX. 1018
`Page 5 of 24
`
`

`

`(VI)
`
`5,223,614
`10
`The dosage for therapeutic and prophylactic use will
`in general depend on the nature and gravity of the ill
`ness in question.
`For adults, the dosage for the preferred route of ad
`ministration, namely inhalation, is preferably 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 in
`vention may also be combined with other active sub
`stances, e.g. parasympatholytics (e.g. ipratropium bro
`mide, oxytropium bromide), secretolytics (e.g. brom
`hexine, ambroxol), antibiotics (e.g. doxycycline), corti
`costeroids (e.g. beclomethasone dipropionate, fluniso
`lide, budesonide) or other anti-asthma preparations such
`as disodium cromoglycate, nedocromil and anti-allergic
`substances.
`The following non-limiting examples illustrate for
`mulations which incorporate the compounds of the
`invention:
`
`9
`
`R5
`
`Re
`
`R5
`
`Re
`
`(wherein the symbols are de?ned as hereinbefore) may
`be converted into compounds of formula IV by reduc
`tion with hydrogen in the presence of hydrogenation
`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 (b) above, the leaving group X is prefera
`bly a chlorine, bromine or iodine atom or an alkyl- or
`arylsulphonic acid group.
`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.
`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
`
`15
`
`20
`
`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. ac
`cording to DEA-‘3345722.
`
`25
`
`30
`
`(IX)
`
`2. Metering aerosol
`
`Active substance according
`to Example 8 hereinbelow
`Sorbitane trioleate
`Monofluorotrichloromethane and
`di?uorodichloromethane (2:3)
`
`0.l% by weight
`
`0.5% by weight
`
`99.4% by weight
`
`The mixture is packed into metering aerosols of suit
`able type. The metering device is designed, for example,
`so as to release 0.05 ml of the preparation on each actua
`tion.
`The advantage of the compounds according to the
`invention is that, when they are inhaled, by comparison
`with known bronchospasmolytic B-mimetics, they
`show a particularly marked selectivity in the relation
`ship between bronchospasmolysis and increased heart
`rate, positive inotropic effects and tremor. The bron
`cholytic activity is achieved with low doses and the
`activity is long-lasting.
`Some pharmacological activity data for compounds
`according to the invention are given hereinafter.
`The EC5Q 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.
`‘
`
`E O 50
`
`35
`
`40
`
`by reaction thereof with a hydride such as sodium hy
`dride or diborane.
`The compounds of formula IX may in turn be ob
`tained by methods known per se.
`Any protecting groups present which it is desired 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. In
`order to obtain compounds of formula I in the form of
`45
`speci?c 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 desired con?guration is already pres
`ent at the centres of asymmetry in question.
`The compounds according to the invention may if _
`desired by 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, methane
`sulphonic and amidosulphonic acids.
`The compounds of the invention are suitable for use
`in pharmaceutical compositions. In particular they have
`broncholytic, spasmolytic and anti-allergic activity,
`65
`they increase ciliary activity and reduce in?ammatory/
`exudative reactions. They may therefore be used inter
`alia for treating all types of asthma and bronchitis.
`
`50
`
`55
`
`SAWAI EX. 1018
`Page 6 of 24
`
`

`

`11
`-continued
`
`ECso
`
`5,223,614
`
`12
`
`0.02
`
`Compounds (ested
`
`Compound
`
`|
`CH 3
`
`HO
`
`HO
`
`HO
`
`OH
`
`Compounds of formula
`
`OH
`
`HN
`
`HO
`
`CHOH-CHZ-G
`
`Compound
`
`SAWAI EX. 1018
`Page 7 of 24
`
`

`

`5,223,614
`
`The following non-limiting examples illustrate pro- 35 solution is mixed with 5 ml of alcohol, acidi?ed with
`conc. HC] and diluted with acetone; the crystals precip
`cesses whereby the compounds of the invention may be
`synthesised.
`itated are suction ?ltered after about 1 hour and 1.2 g of
`the compound are obtained by precipitation with water,
`conc. hydrochloric acid and alcohol.
`
`EXAMPLE 1
`
`0
`||
`
`HN
`
`0
`
`HO
`
`‘EH3
`<l:H—cH1—NH—<|:—cHZ—cH2 0 N$—CH3 >< HC]
`OH
`CH3
`
`8 Cl
`
`1.9 g of 5'-hydroxy-8'-[l-hydroxy-2-[4-(4-pyridyD-2
`methyl-Z-butylarnino]-ethyl]-2H-1,4-benzoxazin-3
`(4H)-one-rnonohydrochloride are dissolved in a mixture
`of 3 m] of dimethylformamide and 1 ml of water and
`1.27 g of methyliodide are added. After 12 hours the
`
`M.p. 207°—209° C. 56% of theory.
`The starting compound may be prepared by the fol
`lowing method:
`
`0
`ll
`
`HN
`
`0
`
`CHZO
`
`CH3
`
`SAWAI EX. 1018
`Page 8 of 24
`
`

`

`15
`
`0
`ll
`
`5,223,614
`
`-continued
`
`16
`
`(Mp. 170-171’ C)
`
`0
`ll
`
`HN
`
`0
`
`cal-o
`
`9*
`(IIH—CH2-NH—-(II—-CHZ—CHZ 0 N —2—-—-9
`OH
`CH3
`
`H /Pd/C
`
`(Mp. 157-160’ c.)
`
`0
`||
`
`EN
`
`0
`
`CH3
`
`HO
`
`?H—CH2—NH—(II—CHZ—CH; O N x l-lCl
`OH
`CH3
`
`(Mp. 175° C. (decomp.))
`
`EXAMPLE 2
`
`ammonium h droxide com ound and treatin with
`h d
`. y -
`p
`g
`y rochlorlc acid.
`
`0
`ll
`
`EN
`
`0
`
`CH3
`
`H0
`
`(|:H—~cH2—NH-(l:—CH2
`OH
`CH3
`
`CH3
`/
`@N—CH3 >< HC]
`CH3
`
`C19
`
`3.7 g of 5’-benzyloxy-8’-[l-hydroxy-2-[3-(4-dime-
`
`_
`
`so willi?gi‘zzrssftszgp:11aa‘irmichziztizzyizizfyz
`are
`1dbmmim'3‘(4H)'°“e'm°‘!°h¥d‘9°h1°“de
`under normal conditions and 2 g of the title compound
`combined with 2.1 g of methyhodtde in 7.4 ml of DMF are obtained M p 187° c (decomp ), (6 28% of the_
`and reacted for 12 hours. After dilution of the solution
`my)
`'
`'
`'
`'
`'
`’
`'
`with acetone the ammonium iodide hydrochloride is
`The starting compound may bg prepared by the fol_
`obtained which is converted into the ammonium chlo- 55 lowing method
`rohydrochloride compound (m.p. 195°~197° C.) by
`'
`conversion with hydrochloric acid or by means of the
`
`-
`
`1
`
`C m n m
`
`-
`
`0
`II
`
`HN
`
`0
`
`cnzo
`
`C53
`N
`/
`CH3
`
`on
`/
`c-cn
`ll \
`O
`OCZH 5
`
`CH3
`CH;—C—NH2
`
`CH3
`
`\
`,
`
`SAWAI EX. 1018
`Page 9 of 24
`
`

`

`17
`
`0
`ll
`
`5,223,614
`
`-continued
`
`18
`
`(Mp. 201-204” c.)
`
`it’
`
`/
`
`(Mp. 110-112c C., Mp. HC] salt 232-235” C.)
`
`EXAMPLE 3
`
`precipitated are suction ?ltered and 2.4 g of the com
`pound are obtained (Mp. 123°-l26° c.).
`
`it’
`/—\
`HN
`0
`
`HO
`
`CH3
`CH-CH3—NH—C_CH2
`(In-l
`(‘31-13
`
`CH3
`O-CHZ—CH2—G3IL—CHZ—CHZ—COOG
`$143
`
`2.3 g of the benzyloxy compound are debenzylated in
`
`3.2 g of 5’-benzyloxy-8'-[1-hydroxy-2-[3-(4-dime- 40
`
`thylamino-ethoxypheny1)-2-methyl-2-propy1amino]-
`
`22.32:;‘is‘gasrlhtazzizzfsxzs 255222121232;
`
`-
`
`-
`
`-
`
`-
`
`_
`
`ride are combined with 0.41 g of B-propiolactone in 6
`1732175.. c‘ 94% of themy)
`ml of acetone and left to react for 12 hours at ambient
`’
`'
`The starting compound may be prepared by the fol
`temperature. After dilution with acetone, the crystals 45 10
`
`(Mp. 153-155“ C.)
`
`SAWAI EX. 1018
`Page 10 of 24
`
`

`

`5,223,614
`
`-continued
`
`20
`
`(Mp. 176-178'C.)
`
`The following compounds may be synthesised analo
`gously to the Examples given:
`
`15
`
`
`
`cum I
`
`0
`
`H
`
`o H
`
`N 0!
`
`
`
`
`
`m Cum Cum Cum
`
`N N N H H H . O O 0
`
`O 0 O
`
`H H H
`
`2
`
`CH3 2
`
`X HC]
`
`Cl-CI w 2
`
`r_. N N N 1
`
`W C|.C|C X C|C|C X H "r u.“ k
`
`w w W‘ w b2 m
`
`"_n w m w m w
`m _ w c
`H3 _ m m _ H3 3 3
`
`H H H H H
`
`JV “e we X
`
`
`
`C|O CIO WIO
`
`m H1 .w
`
`@N
`l
`
`+
`
`N
`l
`CH3
`
`SAWAI EX. 1018
`Page 11 of 24
`
`

`

`5,223,614
`
`-continued
`
`22
`
`Oo
`ll
`
`HN
`
`Oo
`
`21
`
`CH3
`
`HO
`
`HO
`
`HO
`
`HO
`
`(RTNBECCN
`OH
`CH;
`LL N@&
`x HC]
`
`|
`CH3
`
`ce
`
`O CH;
`il
`CH;
`oO
`
`HN
`
`GH
`CH—CHa—NH—C—CHa
`OH
`CH;
`x HCl
`
`CHs
`O™CHaCHNECHaCHCH2—S039
`CH3
`
`Oo
`ll
`
`HN
`
`Oo
`
`Oo
`Il
`
`HN
`
`Oo
`
`i
`CHCHz—NH—C—CH:
`OH
`CH3
`x HCl
`(Mp. 175° C.)
`
`NE—CHa—COOS
`CH3
`
`CHs
`CH—CH)—NH—C—CH2—CHe
`OH
`CH3
`x HCl
`(Mp. 191-193° C.)
`
`Bs
`N@—CH:—CH2—COO®
`CH3
`x HCl
`.
`
`CH
`CHCH2—NH—C—CHa
`OH
`CH3
`x HCl
`
`¢Hs
`.
`O—CHaCHaCHCH2~ONCH
`cle
`CH;
`
`.
`
`CH3
`
`CH™CH2—NH—C—CHa~CH
`OH
`CH3
`x HCl
`
`CH3
`|
`O™CHa~CH2~SNCHaCH2—CH2S039
`CH3
`
`°i
`
`l
`
`HN
`
`Oo
`
`°o
`Il
`
`HN
`
`Oo
`
`HO:
`
`HO
`
`SAWAI EX. 1018
`Page 12 of 24
`
`SAWAI EX. 1018
`Page 12 of 24
`
`

`

`ohm
`
`N H
`
`0
`
`o H
`
`OH
`
`Cum
`
`N H
`
`0
`
`23
`
`5,223,614
`
`continued
`
`24
`
`0
`
`C19
`
`(Mp. 235" c.)
`
`Cle
`
`Cum Gum
`
`N N H H
`
`O 0
`
`O O H H
`
`X HCI
`
`CHZOH
`
`CH1
`
`CH3
`
`C19
`
`SAWAI EX. 1018
`Page 13 of 24
`
`

`

`25
`
`5,223,614
`
`-continued
`
`26
`
`ve
`CHCHy—NH—C—CH
`OH
`CH3
`x HC! x H20
`
`CH3
`NH—CO—CH2—N®—(CH2)3S039
`CH3
`
`(Mp.250-255° C.)
`
`Oo
`It
`
`HN
`
`Oo
`
`HO
`
`Oo
`It
`
`HN
`
`Oo
`
`i
`CHCHaNH~C~CHa
`OH
`CH3
`x HCl x H20
`
`CH3
`O—CH2~-CH2—N®—CH2—-COooe
`CH3
`
`(Mp. 214-216° C.)
`
`OH
`
`CH3
`
`ois
`CH—CH—NHCCH:
`OH
`CH3
`x HCl
`
`CH3
`O—CHaCHz—NS—CHs cle
`CH3
`
`(Mp. 158-162° C.)
`
`OH
`
`CH3
`
`qi
`CH™CH2—-NH-C—CHa
`OH
`CH3
`
`x HC--COOH
`HC—COOH
`
`CH3
`O~CHaCH“NO(CH2)sS039
`CH3
`
`(Mp. 220-223° C.)
`
`Oo
`il
`
`HN
`
`0
`
`HO
`
`HO:
`
`HO
`
`HO
`
`OH
`
`OH
`
`OH
`
`OH
`
`im
`(TNCH
`OH
`CH3
`
`D CH3
`
`CH3
`O—CHaCHaNO—(CHS039
`
`x HCl x 4 H20
`
`(Mp. 231-234" C.)
`
`CH3
`CHOH—CH)—NH—o—CH,
`bus
`
`PD
`
`CH3
`o—-CHy—CHz—NO—CHs
`CH3
`
`X 4 H2SO4 x 4 SO42- x H20
`(Mp.263-265" C.)
`
`CH
`CHOH—CH)-NH—¢—CH;
`bu;
`
`oO
`
`N®—CH3
`
`X 4 H2SO4 x 4 S042 x H20
`(Mp. > 270° C.)
`
`SAWAI EX. 1018
`Page 14 of 24
`
`SAWAI EX. 1018
`Page 14 of 24
`
`

`

`27
`
`5,223,614
`
`-continued
`
`28
`
`'
`
`on
`
`on
`
`on
`
`OH
`
`CH3
`cnou-cm-mr-o-cnz G N®—-cri2—c1-12-c0o9
`CH3
`
`x HCl x 21120
`(Mp. 171-174" c.)
`
`CH3
`
`CHOH-CH2—NH—(|I—CH2
`
`CH3
`
`CH3
`
`ocm-cm-q?-mmn-so?
`
`CH3
`
`X Q H2504 X H1O
`(Mp. 234-236‘ 0)
`
`x HCl
`(Mpl 231434“ c.)
`
`OH
`
`on
`
`OH
`
`OH
`
`@r OH
`or
`gr?
`
`CH3
`
`CH3
`
`CH3
`
`CH3
`
`CH3
`
`CH3
`
`CH3
`
`CH3
`
`X HCl X ZHZO
`
`CHOH--CH2-NH-(II—CHZ-N®
`CH3
`k n
`
`H3
`
`N
`
`(Mp, 95-100" c‘)
`
`EXAMPLE 4
`
`distilled off the oily residue is dissolved in alcohol and
`3.8 g of the title compound are obtained.
`
`0
`ll
`/"_\
`RN
`0
`
`HO
`
`CH3
`('IH~—CH2-NH—(‘I-—CH2
`OH
`CH3
`
`NH—c0—cH2—@N 6
`
`C19 >< HCl
`
`5’-hydroxy-8'-[1-hydroxy-2-[3-(4
`of
`g
`4.4
`chloroacetaminophenyl)-2-methyl-2-propylamino]
`(Mp. l90°-l92° C.; 77.5% of theory).
`ethyl]-2H-l,4-benz0xazin-3-(4H)-one-hydrochloride, 6
`The starting compound may be prepared by the fol
`ml of pyridine and 25 ml of methanol are re?uxed for 6
`hours, then after the methanol and pyridine have been 65 lowing processes:
`
`SAWAI EX. 1018
`Page 15 of 24
`
`

`

`29
`
`5,223,614
`
`30
`
`T
`CH)—C—NH
`ON
`2
`j
`2
`2
`OH
`7
`CH3
`C—CH —_—
`oN
`Oo
`OC2Hs5
`
`ies
`c—chi=N—C—ch
`bus
`
`(Mp. 151-154° C.)
`
`aB)
`
`No)BS,
`
`CH3
`CH™CH2—NH~C~CH
`OH
`CH3
`
`(Mp. 214-216" C.)
`
`x HCl
`
`H2/Ni
`NOQ).———_>
`
`H2--O
`
`Oo
`ll
`
`CH2—o
`
`oO
`il
`
`HN
`
`oO
`
`CH2—-O
`
`oO
`ll
`
`HN
`
`oO
`
`chloroacetic
`qi
`
`HO NH)—2ahvdride3,CH—Ciy—NH—C—CHt
`
`
`
`OH
`
`CH3
`
`(Mp. 208-211" C.)
`
`x HCl
`
`Oo
`Il
`
`HN
`
`Oo
`
`CH3
`
`HO
`
`CH—CHy—NH—C—CHs
`OH
`CH3
`
`(Mp. 160° C. (decomp.))
`
`NH—E—CHACI
`
`x HCl
`
`SAWAI EX. 1018
`Page 16 of 24
`
`SAWAI EX. 1018
`Page 16 of 24
`
`

`

`31
`
`EXAMPLE 5
`
`5,223,614
`32
`concentrated and the oil obtained is dissolved in alco
`hol. After 1 hour the crystals precipitated are suction
`
`0
`ll
`
`HN
`
`0
`
`no
`
`CH3
`'iIH-CIh-NH-(f-CH;
`OH
`CH3
`
`CH3
`NH-c0—cH2—N6B—cI-13
`CH3
`
`Cle
`
`2.7
`g
`of
`6'-hydroxy-8’-[l-hydroxy-2-[3-(4- l5
`chloracetaminophenyl)-Z-methyl-Z-propylarnino]
`ethyl]-2H-l,4-benzoxazin-3-(4H)-one-hydrochloride, 25
`ml of methanol and 3 m1 of 30% trimethylamine solu-
`tion are stirred for 12 hours at ambient temperature,
`
`d
`-
`'
`g6gghgftltlizgg?pound are obmme ' (Mp.
`th f 1_
`-
`logglegsggégfséompound may be prepared by e 0
`'
`
`(Mp. 266468" C.)
`
`SAWAI EX. 1018
`Page 17 of 24
`
`

`

`5,223,614
`
`The following compounds are prepared analogously:
`
`15
`
`(Mp. 164-167’ C.)
`
`9
`C]
`
`SAWAI EX. 1018
`Page 18 of 24
`
`

`

`35
`
`O
`
`CH 3
`
`5,223,614
`
`-continued
`
`36
`
`HN
`
`o
`
`HOA©>fH-Clh-NH—C(CH3);—CH2-CH2
`
`on
`
`x HCl
`
`EXAMPLE 6
`
`15 addition of 0.5 g of 5% palladium charcoal as catalyst
`under normal conditions. After the uptake has ceased
`
`Cl9
`
`HO
`
`CH3
`
`HO@ eri—cn2—NH—c(cn3)2—cH2
`
`OH
`
`C16
`
`4.2 g of dibenzyloxy compound (see below) are
`debenzylated with hydrogen in methanol with palla- 25
`dium charcoal as catalyst under normal conditions and
`2.5 g of the title compound are obtained. (81% of the
`ory).
`The starting compound may be prepared by the fol
`lowing method:
`
`the catalyst is removed by suction ?ltering. the metha
`nol 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 ?ltered, washed with alcohol and dried. 2.9 g of
`the title compound are obtained, (Mp. 240° C.; 93% of
`theory).
`
`(Bz equals C5H5-CH2-)
`
`C19
`
`The starting compound may be prepared by the fol
`
`CH3
`
`CH 3
`
`X HC]
`
`3.5 g of benzoyloxy compound (see below) are deben
`zylated with hydrogen in 50 ml of methanol with the
`
`lowing process (Bz equals benzyl)
`
`SAWAI EX. 1018
`Page 19 of 24
`
`

`

`37
`
`5,223,614
`
`38
`
`0
`ll
`
`EN
`
`0
`
`Bz-O
`
`$143
`era-cm-nu-c-cu;
`OH
`CH3
`
`[ /SO2
`O-CHZ-CHZ—N(CH3)2——Oé
`
`X HCl
`
`NH_'C(CH3)2—CH2
`‘
`
`Cl-b-CHOH
`
`OBz
`
`0
`
`NH
`
`II
`o
`
`r";
`O—CH2-CH2—l|‘I$-(CH2)3—SO3e
`CH3
`
`X HCl
`
`(Mp. 239-241" C.)
`
`EXAMPLE 8
`
`Rotavapor and the residue is triturated with alcohol.
`The crystals precipitated are suction ?ltered and re
`
`11’
`
`HN
`
`0
`
`HO
`
`CH3
`(|IH'-CH2-NH—C—CH2
`0H
`CH3
`
`CH3
`l"~¢‘e9—Cl1I2—COOe
`CH3
`
`2.4 g of benzyloxy compound are debenzylated with
`hydrogen in 50 ml of methanol and 10 m1 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 ?ltering, the metha
`nol is distilled off under reduced pressure using a
`
`40 precipitated once with water/alcohol. 1.6 g of the title
`compound are obtained, (mp. 175° C., decomp., 71% of
`theory)
`The starting compounds may be obtained by the fol
`lowing process:
`
`OH
`
`CH3
`
`CH3
`
`'
`
`Bre
`
`(Mp. 127-130“ C.) X HCl
`
`SAWAI EX. 1018
`Page 20 of 24
`
`

`

`39
`
`Oo
`tl
`
`HN
`
`Oo
`
`Bz—-O
`
`5,223,614
`
`-continued
`
`40
`
`CH3
`FHTCHeTNBGCH
`OH
`CH3
`
`(Mp. 203-205° C.)
`
`CH3
`N®—CH2—Cooe
`CH3
`
`x HCl
`
`The following compounds may be synthesised analo-
`gously to the Examples:
`
`15
`
`Oo
`ll
`
`HN
`
`Oo
`
`oO
`Il
`
`HN
`
`oO
`
`tT
`FeNB O—CH2—CH2—N®(CH3)3-—-CO0S
`OH
`CH3
`
`x HCl
`
`(Mp. 173-175° C.)
`
`CH3
`CH—CH2?~NH~C—CHyz
`|
`OH
`CHa
`
`x HCl
`
`(Mp. 187° C.)
`
`HO
`
`OCH3
`
`ois
`NG—CH3
`|
`CH3
`
`ce
`
`Hs
`TeTNECH
`OH
`CH3
`
`CH3
`O—CHaCHTNO=(CHa)803°
`CH3
`
`0 I
`
`t
`
`HN
`
`0
`
`HO
`
`HO
`
`HO
`
`HO
`
`HO
`
`FoCRTNBOCRNB
`
`CH3
`
`CH3
`
`OH
`
`O-—CH)—CH2-—-®N C) ce
`
`:
`
`x HCl
`
`Oo
`ll
`
`HN
`
`oO
`
`CH3
`eeNBFh
`OH
`CH3
`
`< HCl x H20 (Mp. 250-255° C.)
`
`CH3
`NH—CO™CHy~N@—(CH2)3S03°
`CH;
`
`SAWAI EX. 1018
`Page 21 of 24
`
`SAWAI EX. 1018
`Page 21 of 24
`
`

`

`Oo
`
`HO:
`
`HO
`
`HO
`
`HO:
`
`OH
`
`OH
`
`OH
`
`OH
`
`OH
`
`OH
`
`41
`
`5,223,614
`
`-continued
`
`42
`
`on3
`CHCHaNH~C—CHo
`OH
`CH3
`
`x HCI x H20 (Mp. 214-216" C)
`
`ra
`O~CHaCHNE~CHz—COOS
`CH3
`
`t
`CHTCHINAe—CH
`OH
`CH3
`
`T
`O~CHCH2—NO—CHs ce
`CH3
`
`x HCl
`
`(Mp. 158-162° C.)
`
`T
`GeNOCH
`OH
`CH3
`
`x
`
`HC—COOH
`il
`HC—COOH
`
`T
`OTCHaCHaN&(CHa)s~S039
`CH3
`
`(Mp. 220-223° C.)
`
`I
`(RTNBeB
`OH
`CH3
`
`xX HC! x H20 (Mp. 231-234° C.)
`
`T.
`O—CH2—CHaNO—(CH2)4¢—S039
`CH3
`
`crtirntfrom{()ochre
`
`CH3
`
`buy
`x 4 H2SO4 x 4 SO42S x H2O
`(Mp. 263-265° C.)
`
`CH3
`
`bu,
`
`crttmon{(O)octets
`
`CH;
`
`bu,
`X 4 H2SO4 x H20
`(Mp. 234-236" C.)
`
`CH3
`
`bu,
`
`is
`CHOCHa—NATECH
`CH3
`
`ois
`OCH~CHy—NS—(CHa)s—$039
`CH3
`
`x HCl
`(Mp. 231-234" C.)
`
`SAWAI EX. 1018
`Page 22 of 24
`
`SAWAI EX. 1018
`Page 22 of 24
`
`

`

`43
`
`CH3
`
`5,223,614
`
`-continued
`
`CH3
`
`44
`
`CHOH—CH)—~NH=-C—-CH?
`bu3
`x HC] x 1.5 H20
`(Mp. 210° C.)
`
`NHCO—CH2—N®—(CH2)3--S039
`bat,
`
`OH
`
`OH
`
`Whatis claimedis:
`1. A compoundof formula
`
`R Ri
`
`Ris a single bond or a divalent bridging member which
`may also be bound to the ammonium nitrogen via
`ring atomsof a heterocyclic group;
`Rg is H, or —CH3;
`
`da) 15
`
`Rs
`
`Rg
`|
`I
`CH--CH-~ NH~-C—(CH2),;—R7—-N®O—
`|
`l
`| An®
`OH
`
`20
`
`R30
`
`wherein
`n is an integer 1, 2, 3, 4 or 5;
`R, is H, CH3, OCH3, Cl or F;
`R2 is H, R30, CH2OH, NHCHO, NHCOCH:, 55
`NHSO2CH3, or NHCONH?;
`R3 is H, acyl, N,N-dialkylcarbamoyl, the group R30
`being in the 4 or 5 position; or the group
`
`R2 Ri
`
`ay 30
`
`R30
`
`Rg
`O
`Ip,
`0
`
`HN
`
`35
`
`(Ia)
`
`is a quaternary ammonium group,
`An-— is 1 equivalent of an anion, a pure enantiomer
`thereof, or a mixture of enantiomers, or a salt with
`inorganic or organic acids.
`2. The compoundsasrecited in claim 1, wherein the
`group
`
`|
`RI-NS— is
`
`—E
`—Ar—B—E
`—O—Ar—B—-E
`—NH—CO—E
`—NH—CO—Ar—B—E
`—O—(Cm— Hm) AE
`—O— (CHa)AAr BE
`
`(HI a)
`(III b)
`(Il c)
`(III d)
`(III e)
`duh
`(HI g)
`
`(HI h)
`
`ye:
`:
`—fwe)3-2
`
`R30
`
`
`
`N
`
`1
`os
`
`oO
`
`HN
`
`(Ib) 45
`
`q
`a
`
`—N’
`
`N~-D-—E
`
`L__]
`
`(HT i)
`
`°
`
`uw
`
`N
`
`R30
`
`R30
`
`wherein n and R; to R¢are as recited in claim 2 and
`m is an integer 2, 3, 4, 5 or 6;
`A is a single bond or NH—CO—(C).4)-alkylene;
`B is a single bond, —O—(C).4)-alkylene, —(C).4)-alky-
`lene, or —-NH--CO—(C}.4)-alkylene;
`D is —(C).4)-alkylene
`E is
`
`(Ic)
`
`55
`
`Rs
`THE-Rio
`Riy
`
`Het
`
`
`or ON
`
`Het
`
`
`
`or
`
`oN
`Ro
`
`wherein R3 is as defined above and Rg is H or CH3;
`Ry is H, CH3, or C2Hs;
`Rs is H or CH3;
`Re is H or CH3;
`
`65
`
`wherein
`R9 is (Cj-4)-alkyl;
`R10 is (Cy-4)-alkyl;
`
`SAWAI EX. 1018
`Page 23 of 24
`
`SAWAI EX. 1018
`Page 23 of 24
`
`

`

`5,223,614
`
`45
`Ril is (C).4)-alkyl, (Cy-4)-alkylene-COO—(C.4)-alky-
`lene-SO3—,
`(C}.4)-alkylene-OH,
`(Cj.4)-cycloalkyl,
`Rg and Rio together are (C4.¢)-alkylene.
`Ar is arylene, and
`
`Het
`N
`
`is N-heterocycles which may be condensed with a
`benzene ring and maybe substituted or unsubstituted
`
`5
`
`46
`and may optionally contain one or more additional
`heteroatomsin the ring.
`3. The compoundasrecited in claim 2 wherein Aris
`unsubstituted or substituted phenylene or naphthylene.
`4. A pharmaceutical composition of matter useful in
`the treatment of bronchospasm comprising a therapeuti-
`cally effective amount of a compound as recited in
`claim 2 and a pharmaceutically acceptable carrier.
`5. A method of treating bronchospasm in a warm-
`10 blooded animal comprising administering to said animal
`a therapeutically effective amount of a compound as
`recited in claim 1.
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`65
`
`*_* es *
`
`SAWAI EX. 1018
`- Page 24 of 24
`
`SAWAI EX. 1018
`Page 24 of 24
`
`