ZA200102565B - 2-oxo-2h-quinoline derivatives. - Google Patents

2-oxo-2h-quinoline derivatives. Download PDF

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Publication number
ZA200102565B
ZA200102565B ZA200102565A ZA200102565A ZA200102565B ZA 200102565 B ZA200102565 B ZA 200102565B ZA 200102565 A ZA200102565 A ZA 200102565A ZA 200102565 A ZA200102565 A ZA 200102565A ZA 200102565 B ZA200102565 B ZA 200102565B
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formula
compounds
group
physiologically acceptable
acceptable salts
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ZA200102565A
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Joachim Gante
Hanns Wurziger
Hans-Peter Buchstaller
Guido Melzer
Werner Mederski
Horst Juraszyk
Dorsch Dieter
Sabine Bernotat-Danielowski
Soheila Anzali
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Merck Patent Gmbh
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Publication of ZA200102565B publication Critical patent/ZA200102565B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • 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
    • C07D413/10—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 carbon chain containing aromatic rings
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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  • Pain & Pain Management (AREA)
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  • Quinoline Compounds (AREA)

Description

A _ 1 _ ) ’ . 2-0xo0-2H-quinoline derivatives
The invention relates to compounds of the formula I . rR }
R
AN
RZ—X—Y
Vo
ACH),
R3 wherein
R and R'in each case independently of one another are
H, A, -(CHz)n-R*, -(CH3)n-OA or - (CH,)n-Ar,
NH NH
N AN
WHO
6
R® is R® or
R? is Ar,
R? is CN, COQH, COA, CONH,, CONHA, CONA; or
C (=NH) -NH,,
R®> is -C (=NH) -NH,, -NH-C (=NH) -NH, or -C(=0) -N=C(NH,)>, which are unsubstituted or monosubstituted by -COA, -COOA, -OH or by a conventional amino-protective group,
N. N. a TE
HN—4 N= 0 CH, or
R® is H, A or NH,
Ar is phenyl, naphthyl or biphenyl, which are unsubstituted or mono-, di- or trisubstituted by A, cycloalkyl having 3-6 C atoms, OH, OA,
. ' - 2 =
Bn Hal, CN, NO, CFs, NH,, NHA, NA,, pyrrolidin- 3 1-vy1, piperidin-1-y1, benzyloxy, SO,NH,, Co
SO.NHA, SONA, - (CH) n-NHy, - (CHa) n-NHA, ke - (CH) n-NA;, -O- (CH) n-NH3, -O- (CHz) n-NHA, Co -O- (CHz) n-NA;, -0-(CH2)n-0- or R, - oo | A is alkyl having 1-6 C atoms, -
X is absent or is alkylene having 1-4 C atoms or oo carbonyl, oo
Co : Y is absent or is NH, O or S, oo
Hal is F, Cl, Br or I, E : mis 0, 1 or 2 and : n is 0, 71, 2 or 3 : and salts thereof. - ~ The invention also relates to the optically active : forms, the racemates, the diastereomers and the hydrates and solvates of these compounds.
The invention was based on the object of discovering new compounds with valuable properties, in particular those which can be used for the preparation of medicaments.
It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties, coupled with a good tolerability. In particular, they show Factor Xa-inhibiting properties and can therefore be used for combating and preventing thromboembolic diseases, such as thrombosis, myocardial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis following angioplasty and claudicatio intermittens.
Compounds of the formula I according to the invention can furthermore be inhibitors of the clotting factors
Factor VIIa, Factor IXa and thrombin of the blood clotting cascade.
: ® I.
Aromatic amidine derivatives having an antithrombotic : action are known, for example, from EP 0 540 051 Bl. E
Cyclic guanidines for treatment of thromboembolic diseases are described, for example, in WO 97/08165.
Aromatic heterocyclic compounds having a Factor ~ Xa-inhibitory activity are known, for example, from
WO 96/10022. Substituted N-[(aminoiminomethyl)phenyl- alkyl] -azaheterocyclylamides as Factor Xa inhibitors are described in WO 96/40679. : The antithrombotic and anticoagulating effect of the compounds according to the invention is attributed to the inhibiting action against the activated clotting protease, known by the name Factor Xa, or to the : 15 inhibition of other activated serine proteases, such as
Factor VIIa, Factor IXa or thrombin.
Factor Xa is one of the proteases involved in the complex process of blood clotting. Factor Xa catalyses the conversion of prothrombin into thrombin. Thrombin splits fibrinogen into fibrin monomers which, after crosslinking, make an elemental contribution to thrombus formation. Activation of thrombin can lead to the occurrence of thromboembolic diseases. However, an inhibition of thrombin can inhibit the fibrin formation involved in thrombus formation.
The inhibition of thrombin can be measured, for : example, by the method of G.F. Cousins et al. in
Circulation 1996, 94, 1705-1712.
An inhibition of Factor Xa can thus prevent thrombin being formed.
The compounds of the formula I according to the invention and their salts intervene in the blood clotting process by inhibiting Factor X and thus inhibit the formation of thrombi.
The inhibition of Factor Xa by the compounds according to the invention and the measurement of the
. { . anticoagulating and antithrombotic activity can be determined by customary in vitro or in vivo methods. A suitable method is described, for example, by iy
J. Hauptmann et al. in Thrombosis and Haemostasis 1990, 63, 220-223.
The inhibition of Factor Xa can be measured, for example, by the method of T. Hara et al. in Thromb. Co
Haemostas. 1994, 71, 314-319.
After binding to tissue factor, clotting Factor VIIa initiates the extrinsic part of the clotting cascade and contributes towards activation of Factor X to
Factor Xa. Inhibition of Factor VIIa thus prevents the formation of Factor Xa and therefore a subsequent formation of thrombin.
The inhibition of Factor VIIa by the compounds according to the invention and the measurement of the anticoagulating and the antithrombotic activity can be determined by customary in vitro or in vivo methods. A customary method for measuring the inhibition of Factor
VIIa is described, for example, by H.F. Ronning et al. in Thrombosis Research 1996, 84, 73-81.
Clotting Factor 1IXa 1s generated in the intrinsic : clotting cascade and likewise participates in the activation of Factor X to Factor Xa. An inhibition of
Factor IXa can therefore prevent formation of Factor Xa in another manner.
The inhibition of Factor IXa by the compounds according to the invention and the measurement of the anticoagulating and antithrombotic activity can be determined by customary in vitro or in vivo methods. A suitable method is described, for example, by J. Chang et al. in Journal of Biological Chemistry 1998, 273, 12089-12094.
The compounds of the formula I can be employed as medicament active compounds in human and veterinary
- } medicine, in particular for combating and preventing thromboembolic diseases, such as thrombosis, myocardial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis following angioplasty and 5 claudicatio intermittens. CL
The invention relates to the compounds of the formula I . and their salts and to a process for the preparation of compounds of the formula I according to Claim 1 and their salts, characterized in that a) they are liberated from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent in that i) an amidino group is liberated from its oxadiazole derivative or oxazolidinone derivative by hydrogenolysis or solvolysis, ii) a conventional amino-protective group is replaced by hydrogen by treatment with a solvolysing or hydrogenolysing agent, or an amino group protected by a conventional protective group is liberated, or b) in a compound of the formula I, one or more radical (s) R, R!, R? and/or R® is or are converted into one or more radical (s) R, R}, R? and/or R?, in that, for example, i) an ester group is hydrolysed to a carboxyl group, ii) a nitro group is reduced, iii) an amino group is acylated,
a iv) a cyano group 1s converted into an amidino group and/or c) a base or acid of the formula I is converted into So : - one of its salts. -
For all the radicals which occur more than once, such as, for example, Ar, the meanings thereof are independent of one another.
Unless expressly stated otherwise, the radicals and parameters R, X, Y, R', R? R® and n above and below have the meanings given in the case of formula I.
A is alkyl, is linear or branched and has 1 to 6, preferably 1, 2, 3, 4, 5 or 6 C atoms. A is preferably . methyl, and moreover ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, l-ethylpropyl, hexyl, 1-, 2-, 3- or 4 -methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, l-ethyl-1- methylpropyl, l-ethyl-2-methylpropyl or 1,1,2- or 1,2,2-trimethylpropyl. :
Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
Alkylene is preferably methylene, ethylene, propylene or butylene, or furthermore branched alkylene. :
CoA is acyl and is preferably formyl, acetyl or propionyl, or furthermore also butyryl, pentanoyl or hexanoyl.
Hal is preferably F, Cl or Br, or also I.
R is H, A, -(CHz)m-R?, -(CH;)n-OA or -(CH:)n-Ar, preferably H, A, -CH;-R* or R!, and R is particularly preferably H, A, -CH,-COOA, -CH,-COOH, -CH,-CONH,, COOH or COOA. . 5
SE R'® is H, A, -(CHy)n-R', -(CHy)q-OA or -(CHp)n-Ar, Co
Ce preferably H, A, -CH-R'-or R*, and R!' particularly = : preferably is H, A, -CH,-COOA, -CH,-COOH, -CH,-CONH;, : Co
E ) ‘COOH or COOA, and especially preferably H, A or COOH. oo oo | . R® is preferably Ar, particularly preferably phenyl . which is monosubstituted by RR’, and especially preferably phenyl which is monosubstituted by amidino. } 15 R?® is Ar, preferably phenyl which is unsubstituted or »
IK Co © mono-, di- or trisubstituted by A, OA, Hal, CN or CF,, = : B or phenyl, benzodioxol-5-yl, naphthyl or biphenyl, : which are unsubstituted or mono- or disubstituted by . | cycloalkyl having 3-6 C atoms, OH, NH,, NHA, NA, pyrrolidin-1-yl, piperidin-1-y1, benzyloxy, SO,NH,,
SO,NHA, SO;NA;, -(CH2)n-NH;, -(CHz)n~NHA, -(CHz),-NAy, -0- (CHz) n-NHz, -O- (CH) o-NHA, -0- (CH) n-NA;, or R’, naphthyl or biphenyl monosubstituted by amidino being preferred. Preferred substituents for biphenyl are amidino, fluorine, SO,NH, or SO,NHA.
Ar 1s phenyl, naphthyl of biphenyl, which are unsubstituted or mono-, di- or trisubstituted by A, cycloalkyl having 3-6 C atoms, OH, OA, Hal, CN, NO, : 30 CF3, NH, NHA, NA,, pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, SO,NH,, SO,NHA, SO;NA;, phenylsulfonamido, - (CHz) n-NH3z, - (CH) n-NHA, - (CH2) n-NA;, -0- (CHz) n-NH3, -0- (CHz) n-NHA, -O- (CHa)n-NA;, -O- (CHz)q-O- or R®.
Ar is preferably unsubstituted phenyl, naphthyl or biphenyl, and moreover preferably phenyl, naphthyl or biphenyl, which are mono-, di- or trisubstituted, for example by A, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy,
eo propoxy, butoxy, pentyloxy, hexyloxy, cyano, nitro, trifluoromethyl, amino, methylamino, ethylamino, 3 dimethylamino, diethylamino, pyrrolidin-1-y1, piperidin-1-y1, benzyloxy, sul fonamido, methyl - - sulfonamido, ethylsulfonamido, propylsul fonamido, butylsulfonamido, dimethylsulfonamido, phenyl - sul fonamido, aminomethyl, aminoethyl,
N-methylaminomethyl, N-ethylaminomethyl, N,N-dimethyl- aminomethyl, aminomethyloxy, aminoethyloxy or R®, and furthermore benzodioxolyl.
Ar is therefore preferably, for example, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or . 15 p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) -phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-(N,N-dimethylamino)-phenyl, o-, m- or p- (N-ethylamino) -phenyl, o-, m- or p-(N,N-diethyl- amino) -phenyl, o-, m- or p-fluorophenyl, o-, m- or : p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p- (methylsulfonamido) -phenyl, o-, m- or p-amidino- phenyl, 7-amidino-2-naphthyl, 3-fluoro-2'-sulfamoyl-
Dbiphenyl-4-yl, 3-fluoro-2’-N-tert-butyl-sulfamoyl- biphenyl-4-vy1, 2'-sulfamoyl-biphenyl-4-vy1, 2'-N-tert- butyl-sulfamoyl-biphenyl-4-yl, o-, m- or p-(pyrrolidin- 1-yl) -phenyl, o-, m- or p-(piperidin-1-yl)-phenyl, o-, m- or p-{S5-methyl-[1,2,4)oxadiazol-3-yl)}-phenyl, 7-{5- methyl-[1,2,4-oxadiazol-3-yl)}-napth-2-yl, o-, m- or p-{5-ox0-[1,2,4]-oxadiazol-3-yl) }-phenyl or 7-{5-oxo- [1,2,4] -oxadiazol-3-yl) } -naphth-2-y1, and also preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4- chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino- 5-chloro- or 2-amino-6-chlorophenyl, 2-nitro-4-N,N-
dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, : 5 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, : 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, : 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or _— 2,5-dimethyl-4-chlorophenyl. :
R* is preferably, for example, COOH, COOA or CONH,.
R® is preferably, for example, unsubstituted -C(=NH) -NH,, -NH-C(=NH) -NH,, -C(=0)-N=C(NH;),, which can also be monosubstituted by OH, t~Mo t~Mo
HN— N={
O or CH, especially preferably unsubstituted -C(=NH)-NH; or (~Mo =
CH,
X 1s preferably, for example, absent, or is carbonyl or alkylene, in particular methylene or -CH(CH,) -.
Y is preferably O. m is preferably 0 or 1, and furthermore also 2. n is preferably 0 or 1, and furthermore also 2 or 3.
The compounds of the formula I can have one or more chiral centres and can therefore occur in various stereoisomeric forms. Formula I includes all these forms.
® - 10 -
The invention accordingly particularly relates to those compounds of the formula I in which at least one of the radicals mentioned has one of the abovementioned preferred meanings. Some preferred groups of compounds can be expressed by the following part formulae Ia to . Ih, which correspond to the formula I and wherein the radicals not described in more detail have the meaning given in the case of formula I, but wherein in Ia R is H, A, -CH,-COOA, -CH,-COOH, -CH;-CONH,,
COOH or COOA; in Ib R is H, A, -CH,-COOA, -CH,-COOH, -CH,-CONH;,
COOH or COOA,
R' is H, A, -CH,-COOA, -CH,-COOH, -CH,-CONH,,
COOH or COOA; in Ic R is H, A, -CH,-COOA, -CH,-COOH, -CH,-CONH,,
COOH or COOA
R' is H, A, -CH,-COOA, -CH,-COOH, -CH,-CONH,,
COOH or COOA,
R? is phenyl which is monosubstituted by R®; in Id R is H, A, -CH,;-CO0OA, -CH,-COOH, -CH,-CONH,,
COOH or COOA,
R! is H, A, -CH,-COOA, -CH,-COOH, -CH;-CONH,,
COOH or COOA,
R?’ is phenyl which is monosubstituted by RZ,
R’ is phenyl or naphthyl, which are monosubstituted by CN or R®, or by phenyl which is mono - or disubstituted by R?, SO,NH,, SO,NHA or F; in Ie R is H, A, -CH,-COOA, -CH,-COOH, -CH,-CONH,,
COOH or COOA,
R' is H, A, -CH,-COOA, -CH,-COOH, -CH,-CONH,,
COOH or COOA,
R®’ is phenyl which is monosubstituted by R®,
R® is phenyl or naphthyl, which are monosubstituted by CN or R®, or biphenyl which is mono- or disubstituted by R®°, SO,NH,, SO,NHA or F, :
I R® is -C(=NH)-NH, or ~"o
N=
CH, Co in If R is H, A, -CH;-COOA, -CH,-COOH, -CH,-CONH;,
COOH or COOA,
R* is H, A, -CH,-COOA, -CH,-COOH, -CH,;-CONH,,
COOH or COO0A,
R? is phenyl which is monosubstituted by R®, iE rR? is phenyl or naphthyl, which are monosubstituted by CN or RS, biphenyl which is mono- or disubstituted by R°, SO.NH,, SO,NHA or F,
R> is -C(=NH)-NH; or =~
N={
Jo CH, nis 0 or 1; in Ig R is H, A, -CH,-COOA, -CH;-COOH, -CH,-CONH,,
COOH or COOA,
R! is H, A, -CH,-COOA, -CH;-COOH, -CH,-CONH,,
COOH or COOA,
R?> is phenyl which is monosubstituted by R®,
R®> is phenyl or naphthyl, which are monosubstituted by CN or R®, or biphenyl which is mono- or disubstituted by R®, SO,NH,, SO,NHA or F,
R> is -C(=NH)-NH, or
@ . t~Mo
N={ .
CH, nis 0 or 1, Ex ~ X is absent or is alkylene or carbonyl, )
Y is absent or is 0; So in Th R is H, A, -CH,-COOA, -CH,-COOH, -CH,-CONH,, -
COOH or COOA, .
R' is H, A, -CH,-COOA, -CH,-COOH, -CH,-CONH,, CL . 10 COOH or COOA, Co
R?> is phenyl which is monosubstituted by R®, ~
R?® is phenyl or naphthyl, which are . monosubstituted by CN or R?, or biphenyl ) which is mono- or disubstituted by R®, i ’ SO;NH,, SO,NHA or F,
R® is -C(=NH) -NH,, which can also be monosubstituted by OH, or —Mo
N={
CH, n is 0 or 1,
X 1s absent,
Y is 0.
The compounds of the formula I and also the starting substances for their preparation are moreover prepared by methods which are known per se, such as are described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry],
Georg-Thieme-Verlag, Stuttgart), and in particular under reaction conditions which are known and suitable for the reactions mentioned. It is also possible here
- @ to make use of variants which are known per se and are not mentioned in more detail here.
If desired, the starting substances can also be formed in situ, so that they are not isclated from the - reaction mixture but are immediately reacted further to give the compounds of the formula I. .
Compounds of the formula I can preferably be obtained : by liberating compounds of the formula I from their : functional derivatives by treatment with a solvolysing or hydrogenolysing agent.
Preferred starting substances for the solvolysis or - hydrogenolysis are those which otherwise correspond to the formula I but contain corresponding protected amino
To and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those which : carry an amino-protective group instead of an H atom bonded to an N atom, in particular those which carry an
R’-N group, wherein R’ is an amino-protective group, - instead of an HN group, and/or those which carry a hydroxyl -protective group instead of the H atom of a hydroxyl group, for example those which correspond to the formula I but carry a group -COOR”, wherein R” is a hydroxyl -protective group, instead of a group -COOCH.
Preferred starting substances are also the oxadiazole derivatives, which can be converted into the corresponding amidino compounds.
The liberation of the amidino group from its oxadiazole derivative can be carried out, for example, by treatment with hydrogen in the presence of a catalyst (for example Raney nickel). Suitable solvents are those mentioned below, in particular alcohols, such as methanol or ethanol, organic acids, such as acetic acid or propionic acid, or mixtures thereof. The hydrogenolysis is as a rule carried out at temperatures between about 0 and 100° under pressures between about
: ® 1 and 200 bar, preferably at 20-30° (room temperature) B under 1-10 bar. -
The oxadiazole group is introduced, for example, by reaction of the cyano compounds with hydroxylamine and reaction with. phosgene, dialkyl carbonate, chloroformic acid ester, N,N’ -carbonyldiimidazole or acetic anhydride. =
Several - identical or different - protected amino : and/or hydroxyl groups can also be present in the molecule of the starting substance. If the protective ‘groups present differ from one another, they can in many cases be split off selectively.
The term “amino-protective group” is generally known and relates to groups which are suitable for protecting (blocking) an amino group from chemical reactions but : can easily be removed after the desired chemical reaction has been carried out at other points of the molecule. Typical such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protective groups are removed after the desired reaction (or reaction sequence), their nature and size is moreover not critical; preferably, however, those having 1-20, in particular 1-8 C atoms are preferred. The term “acyl group” is to be interpreted in the broadest sense in : connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxycarbonyl, aryloxycarbonyl, and above all aralkoxy carbonyl groups. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl or toluyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert -butyloxycarkonyl) and 2-iodoethoxycarbonyl;
aralkyloxycarbonyl, such as CBZ (“carbobenzoxy”) , 4 -methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr. Preferred amino-protective groups are BOC and Mtr, and furthermore CBZ, Fmoc, benzyl and acetyl.
The term “hydroxyl-protective group” is also generally known and relates to groups which are suitable for . protecting a hydroxyl group from chemical reactions but
Co which can ‘easily be removed after the desired chemical reaction has been carried out at other points of the molecule. Typical such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, and furthermore also alkyl groups. The nature and size of the hydroxyl-protective groups is not critical, since they are removed again after the desired chemical reaction or reaction sequence; groups having 1-20, in particular 1-10 C atoms are preferred. : Examples of hydroxyl-protective groups are, inter alia, benzyl, 4 -methoxybenzyl, p-nitrobenzoyl, p-toluene- sulfonyl, tert-butyl and acetyl, benzyl and tert-butyl being particularly preferred.
The liberation of the compounds of the formula I from their functional derivatives is effected - depending on the protective group used - with, for example, strong acids, expediently with TFA or perchloric acid, or also with other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are, preferably, organic solvents, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as DMF, halogenated hydrocarbons, such as methylene chloride, and furthermore also alcohols, such as methanol, ethanol or isopropanol, as well as water. Mixtures of the abovementioned solvents are furthermore possible. TFA is preferably used in excess without addition of a further solvent, and ol perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9:1. The reaction , temperatures for the cleavage are expediently between : about 0 and about 50°, and the reaction is preferably carried out at between 15 and 30° (room temperature). BE
The groups BOC, OBut and Mtr can preferably be split off, for example, with TFA in methylene chloride or with about 3 to 5n HCl in dioxane at 15-30°, and the oo
FMOC group with an approximately 5 to 50% solution of To dimethylamine, diethylamine or piperidine in DMF at 15-30°. | Co
Protective groups which can be removed by hydrogenolysis (for example CBZ, benzyl or the liberation of the amidino group from its oxadiazole derivative) can be split off, for example, by treatment with hydrogen in the presence of a catalyst (for example a. noble metal catalyst, such as palladium, expediently on a support, such as charcoal). Suitable solvents here are those mentioned above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is as a rule carried out at temperatures between about 0 and 100° under pressures between about 1 and 200 bar, preferably at 20-30° under 1-10 bar. A hydrogenolysis of the CBZ group is effected particularly well, for example, on 5 to 10% Pd/C in methanol or with ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°.
Suitable inert solvents are, for example, hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbon tetra- chloride, trifluoromethylbenzene, chloroform or methylene chloride; alcohols, such as methanol, ethanol, isopropanol, n-propanol n-butanol or tert-
: @ butanol; ethers, such as diethyl ether, diisopropyl p ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether a (methylglycol or ethylglycol) or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or ! butanone; amides, such as acetamide, dimethylacetamide,
N-methylpyrrolidone (NMP) or dimethylformamide (DMF) ; oo nitriles, such as acetonitrile; sulfoxides, such as a . dimethylsulfoxide (DMSO); carbon disulfide; carboxylic : acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; a esters, such as ethyl acetate, or mixtures of the i solvents mentioned. : :
The conversion of a cyano group into an amidino group is carried out by reaction with, for example, hydroxylamine and subsequent reduction of the
N-hydroxyamidine with hydrogen in the presence of a catalyst, such as, for example, Pd/C.
For the preparation of an amidine of the formula I (for example Ar = phenyl which is monosubstituted by C(=NH)-
NH,), it is also possible to add ammonia onto a a nitrile. The addition reaction is preferably carried out in several stages, by, in a manner known per se, a) converting the nitrile into a thiocamide with H,S, which is converted with an alkylating agent, for example
CH3;I, into the corresponding S-alkylimido-thioester, which in turn reacts with NH; to give the amidine, b) converting the nitrile with an alcohol, for example ethanol, in the presence of HCl into the corresponding imido-ester and treating this with ammonia, or c) reacting the nitrile with lithium bis- (trimethylsilyl) - amide and subsequently hydrolysing the product.
It is furthermore possible to convert a compound of the © formula I into another compound of the formula I by converting one or more radical(s) R, R' R? and/or R? into one or more radical(s) R, R', R?* and/or R?, for example by acylating an amino group or reducing nitro

Claims (10)

oo - 43 - . Patent Claims
1. Compounds of the formula I E rR . R ’ IAN RZ—X —Y N fo) ICH), R3 wherein R and R®* in each case independently of one another are H, A, -(CH,)pn-R*, =-(CH,)n-OA or - (CHy) m-Ar, ’ NH NH v4 AN t= { . 6 6 R? is R® or R R® is Ar, R* is CN, COOH, COOA, CONH,, CONHA, CONA, or C(=NH) -NH,, R® is -C (=NH) -NH,, -NH-C (=NH) -NH, or -C(=0) -N=C(NH;),, which are unsubstituted or monosubstituted by -COA, -COOA, -OH or by a conventional amino-protective group,
N. { AN. eo TLL HN—4 N cn 0 or 3 R® is H, A or NH,
@ Ar is phenyl, naphthyl or biphenyl, which are : ) unsubstituted or mono-, di- or ) trisubstituted by A, cycloalkyl having - 3-6 C atoms, OH, OA, Hal, CN, NO,, CFs, oo . 5 NH,, NHA, NA,, pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, SO,NH;, SO,NHA, SO,NA;, -(CHp)a-NHp, -(CHp)n-NHA, BE - (CH) n-NA;, -0O-(CH;),-NH,, -0O-(CHa)n-NHA, 2 -0- (CHz) n-NA,, -0O-(CHz)q-0O- or R®, A is alkyl having 1-6 C atoms, X is absent or is alkylene having 1-4 C atoms or carbonyl, Y is absent or is NH, O or S, Hal is F, Cl, Br or I, m is 0, 1 or 2 and n is 0, "1, 2 or 3 and salts thereof. oo
2. Compounds according to Claim 1, a) 1l-(3-amidinobenzyl) -6- (3-amidinophenoxy) - 4-methyl-2-oxo-2H-quinoline, b) 1-(7-amidino-naphthalen-2-ylmethyl) -6-(3- amidino-phenoxy) -4-methyl-2-0oxo-2H-quinoline and salts thereof.
3. Process for the preparation of compounds of the formula I according to Claim 1 and their salts, characterized in that a) they are liberated from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent in that i) an amidino group is liberated from its oxadiazole derivative or oxazolidinone derivative by hydrogenolysis or solvolysis,
’ ii) a conventional amino-protective group is replaced by hydrogen by treatment with a solvolysing or hydrogenolysing agent, or a) an amino group protected by a conventional protective group is liberated, or b) in a compound of the formula I, one or more radical(s) R, R!, R? and/or R® is or are converted into one or more radical (s) R, R?, R? and/or RZ, in that, for example, i) an ester group is hydrolysed to a carboxyl group, : ii) a nitro group is reduced, iii) an amino group is. acylated, iv) a cyano group is converted into an amidino group and/or c) a base or acid of the formula I is converted into one of its salts.
4. Process for the preparation of pharmaceutical formulations, characterized in that a compound of the formula I according to Claim 1 and/or one of its physiologically acceptable salts is brought into a suitable dosage form together with at least one solid, liquid or semi-liquid excipient or auxiliary.
-e a Co
-
5. Pharmaceutical formulation, characterized by a content of at least one compound of the formula I according to Claim 1 and/or one of its physiologically acceptable salts.
6. Compounds of the formula I according to Claim 1 and their physiologically acceptable salts or : solvates as medicament active compounds. :
7. Compounds of the formula I according to Claim 1 and their physiologically acceptable salts for combating thrombosis, myocardial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis following ' angioplasty and claudicatio intermittens. : oo
8. Medicaments of the formula I according to Claim 1 : and their physiologically acceptable salts as inhibitors of coagulation factor Xa.
9. Use of compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts for the preparation of a medicament.
10. Use of compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts in combating thromboses, myocardial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis following angioplasty and claudicatio intermittens.
ZA200102565A 1998-08-29 2001-03-28 2-oxo-2h-quinoline derivatives. ZA200102565B (en)

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