(cid:9) (cid:9)
`
`[54] ADHESION RECEPTOR ANTAGONISTS
`
`[75] Inventors: Peter Raddatz, Seeheim-Jugenheim;
`Joachim Gante, Darmstadt; Horst
`Juraczyk, Seeheim; Hanns Wurziger,
`Darmstadt; Helmut Pitcher,
`Heppenheim; Sabine
`Bernotat-Danielowski, Bad Naumheim;
`Guido Melzer, Hotheim/Ts., all of
`Germany
`
`[73] Assignee: Merck Patent Gesellschaft mit
`beschrankter Haftung, Darmstadt,
`Germany
`
`[ * ] Notice: (cid:9)
`
`The portion of the term of this patent
`subsequent to Jul. 21, 2014, has been
`disclaimed.
`
`[21] Appl. No.: 234,691
`
`[22] Filed: (cid:9)
`
`Apr. 29, 1994
`
`[30] (cid:9)
`
`Foreign Application Priority Data
`
`May 1, 1993 [DE] Germany (cid:9)
`Feb. 22, 1994 [DE] Germany (cid:9)
`
` 43 14 378.4
` 44 05 633.8
`
`[51] Int. C1.6
`
` A61K 31/42; A61K 31/445;
`CO7D 413/06
`[52] U.S. Cl.
` 514/326; 514/210; 514/212;
`514/255; 514/278; 514/376; 540/200; 540/362;
`540/603; 544/369; 546/18; 546/229; 548/229;
`548/962
` 540/603, 200,
`[58] Field of Search (cid:9)
`540/362; 546/209, 18; 548/229, 962; 544/369;
`514/210, 212, 255, 278, 326, 376
`
`[56] (cid:9)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`United States Patent [19]
`Raddatz et al. (cid:9)
`
`1111111111111111111111111111,11!101101!1,1121211,1151),111111111111111111111111111
`
`[11] Patent Number: (cid:9)
`[45] Date of Patent: (cid:9)
`
`5,532,255
`* Jul. 2, 1996
`
`4,886,794 12/1989 Walsh (cid:9)
`4,970,217 11/1990 (cid:9) Priicher et al. (cid:9)
`5,084,466
`1/1992 (cid:9) Alig et al. (cid:9)
`5,086,055 2/1992 Walsh (cid:9)
`5,232,931
`8/1993 (cid:9) Priicher et al. (cid:9)
`
` 514/211
` 514/327
` 514/353
` 514/252
` 514/321
`
`FOREIGN PATENT DOCUMENTS
`
`0381033 8/1990 European Pat. Off. .
`0459256 12/1991 European Pat. Off. .
`0462960 12/1991 European Pat. Off. .
`
`OTHER PUBLICATIONS
`
`Ruoslahti et al "New Perspective in Cell Adhesion: RGD
`and Integrins" Science 238 491-496 (1987).
`Bajnsz et al "High Active and Selective Anticoagulants" J.
`Med. Chem. 33 pp. 1729-1735 (1990).
`Hartman et al "Non—Peptide Fibrinogen Receptor Antago-
`nists" J. Med. Chem. 35 4640-4642 (1992).
`Born. Nature, 194(4832):927-929 (Jun. 9, 1962).
`
`Primary Examiner—Ceila Chang.
`Attorney, Agent, or Firm—Millen, White, Zelano & Brani-
`gan
`
`[57] (cid:9)
`
`ABSTRACT
`
`Compounds of the formula
`
`CH2 —Y
`
`RI —N
`
`X
`
`0
`in which R', X and Y have the meanings defined herein, and
`their salts, inhibit the binding of fibrinogen to the fibrinogen
`receptor and can be used for treating thrombosis, stroke,
`cardiac infarction, inflammations, arteriosclerosis,
`osteoporosis and tumors.
`
`3,687,965 8/1972 Fauran et al. (cid:9)
`
` 260/307 C
`
`22 Claims, No Drawings
`
`MYLAN - EXHIBIT 1019
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`5,532,255
`
`1
`ADHESION RECEPTOR ANTAGONISTS
`
`The invention relates to novel compounds of the formula
`
`CH2 —Y
`
`Ri —N (cid:9)
`
`X
`
`0
`
`5 (cid:9)
`
`25 (cid:9)
`
`30
`
`2
`to the fibrinogen receptor (glycoprotein Ilb/Ina) on activated
`platelets, fibrinogen-binding inhibitors are expected to be
`effective as antimetastatics.
`Also, since fibrinogen-binding inhibitors are ligands with
`fibrinogen receptor on platelets, they can be used as diag-
`nostic tools for detection and localization of thrombi in the
`vascular in vivo. Thus, for example, in accordance with
`known procedures, the fibrinogen-binding inhibitors can be
`labeled with a signal generating or detectable moiety
`10 whereby, once the labeled fibrinogen-binding inhibitor is
`bound to a fibrinogen receptor on platelets, it is possible to
`detect and locate thrombi.
`Fibrinogen-binding inhibitors are also very effective as
`research tools for studying the metabolism of platelets in the
`different activation states or intracellular signalling mecha-
`15 nisms of the fibrinogen receptor. For example, as described
`above, fibrinogen-binding inhibitor can be labeled with a
`signal generating or detectable moiety. The fibrinogen-
`binding inhibitor-signal generating/detectable moiety con-
`jugate can then be employed in vitro as a research tool. By
`20 binding the conjugate to fibrinogen receptors, it is possible
`to monitor and study the metabolism of platelets, as well as
`the activation states and signalling mechanisms of the
`fibrinogen receptors.
`The compounds are also suitable as anti-microbial active
`substances which are able to prevent infections, for example,
`those initiated by bacteria, fungi or yeasts. The substances
`can therefore preferably be given as accompanying anti-
`microbial active substances, when organisms are subjected
`to interventions in which exogenous, for example, bioma-
`terials, implants, catheters, or pacemakers, are employed.
`They act as antiseptics. Antimicrobial activity of the com-
`pounds can be demonstrated by the procedure described by
`P. Valentin-Weigand et al., Infection and Immunity,
`2851-2855 (1988).
`The properties of the compounds can be demonstrated by
`methods which are described in EP-Al-0 462 960. The
`inhibition of the binding of fibrinogen to the fibrinogen
`receptor can be demonstrated by the method given in
`EP-Al-0 381 033. The inhibitory effect on blood platelet
`40 aggregation can be demonstrated in vitro by the method of
`Born (Nature, 4832, 927-929, 1962).
`The invention relates additionally to a process for pre-
`paring a compound of the given formula I, and its salts,
`characterized in that
`(a) a compound of the formula I is liberated from one of
`its functional derivatives by treating with a solvolyzing
`or hydrogenolyzing agent, or in that
`(b) a compound of the formula II
`
`in which
`X is 0, S, NH or NA,
`Y is an aziridino, azetidino, pyrrolidino, piperidino,
`1-oxa-8-azaspiro[4.5]dec-8-yl, hexahydroazepino or
`4-R4-piperazino radical which is unsubstituted or sub-
`stituted once by R2 and optionally additionally substi-
`tuted by an OZ, SZ or N(Z)2 group and/or by carbonyl
`oxygen,
`Z is in each case H, A, phenyl-CkH2k or Ac,
`R1 is a phenyl radical which is substituted once by CN,
`H2N—CH2—, (A)2N—CH2—, H2N—C(=NH)—,
`H2N—C(=NH)—NH—, H2N—C(=NH)—NH—
`CH2—, HO—NH—C(=NH)— or HO—NH—
`C(=NH)—NH—,
`R2 is —C11112„,—COOR3 or _ —C„112„—O—CpH2p—
`COOR3,
`R3 is H, A or benzyl,
`R4 is H, A, benzyl or —Cm1-12,„—COOR3,
`A is in each case alkyl having 1-6 C atoms,
`Ac is acyl having 1-11 C atoms,
`k and m are in each case 0, 1, 2 or 3,
`n is 0, 2 or 2, and
`p is 1, 2 or 3,
`and salts thereof.
`An object of the invention is to provide novel compounds
`with valuable properties, especially those which can be used
`for the preparation of drugs.
`Similar compounds are known from EP-A1-0 381 003.
`Upon further study of the specification and appended
`claims, further objects and advantages of this invention will
`become apparent to those skilled in the art.
`These objects have been achieved by the compounds
`according to the invention. It has been found that the
`compounds of formula I and their solvates and salts possess
`valuable pharmacological properties coupled with a good
`tolerance. In particular, they inhibit the binding of fibrino-
`gen, fibrinonectin and the von Willebrand factor to the
`fibrinogen receptor of blood platelets (glycoprotein (cid:9)
`as well as the binding of these proteins, and further adhesive
`proteins, such as vitronectin, collagen and laminin, to the
`corresponding receptors on the surface of various cell types.
`The compounds consequently influence cell-cell and cell-
`matrix interactions. They prevent the development of blood- 55
`platelet thrombi in particular, and can therefore be used for
`the treatment of thrombosis, stroke, cardiac infarction,
`inflammations and arteriosclerosis. In addition, the com-
`pounds have an effect on tumor cells, by preventing them
`from forming metastases. Consequently, they can also be
`employed as anti-tumor agents.
`There is evidence that tumor cells spreading from a solid
`tumor into the vasculature are carried by microthrombi and
`thus are protected from being detected by cells of the
`immune system. The second step of attachment to the vessel
`wall seems to be facilitated by microthrombi as well. Since
`the formation of thrombi is mediated by fibrinogen binding
`
`35 (cid:9)
`
`45
`
`so
`
`60 (cid:9)
`
`65 (cid:9)
`
`CH2—E (cid:9)
`
`II
`
`R1 —N (cid:9)
`
`F
`X
`Y
`
`0
`in which
`E is Cl, Br, I, or a reactive esterified OH group, and
`R1 and X have the abovementioned meanings,
`is reacted with an amino compound of the formula HI
`
`H—Y
`
`III
`
`in which
`Y has the abovementioned meaning,
`or in that
`(c) a compound of the formula IV
`
`(cid:9)
`

`
`5,532,255
`
`5 (cid:9)
`
`15 (cid:9)
`
`20
`
`IV
`
`3
`R'-NH-C1-12-CH(XH)-CH2-Y (cid:9)
`in which
`R', X and Y have the abovementioned meanings, or one
`of its reactive derivatives,
`is reacted with a reactive derivative of carbonic acid, or in
`that
`(d) in order to prepare a guanidino compound of the
`formula I (R1=phenyl radical substituted once by
`H2N-C(=NH)-NH-), an amino compound corre-
`sponding to the formula I, which, however, contains an
`aminophenyl group in place of the radical R1, is treated
`with an amidinating agent,
`and/or in that, in a compound of the formula I, one or both
`radicals R' and/or Y is/are transformed into (an) other
`radical(s) R1 and/or Y, and/or a compound of the formula I
`is converted into one of its salts by treatment with an acid or
`a base.
`The compounds of the formula I possess at least one chiral
`center and can therefore occur in several enantiomeric
`forms. All these forms (e.g., D and L forms), and their
`mixtures (e.g., the DL forms), are included in the formula I.
`Both in the above and in the following, the radicals or
`parameters X, Y, Z, R' to R4, A, Ac, k, m, n, p and E have
`the meanings given in the formulae I or II, unless otherwise
`expressly indicated. In the case where several groups A
`and/or Z are present in the molecule I, II and/or III, they can
`be identical or different from one another.
`In the above formulae, the group A has 1-6, preferably
`1,2, 3 or 4, C atoms. Specifically, A preferably is methyl,
`ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-
`butyl, and, additionally, also pentyl, 1-, 2- or 3-methylbutyl,
`1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl or 1-,
`2-, 3- or 4-methylpentyl.
`X is preferably 0, or else S, NH or NA, e.g., N-CH3.
`Y is preferably 3-(R300C)-azetidino, 3-(R300C-
`CH2-O-)-azetidino, (cid:9)
`2-(R300C-)-pyrrolidino,
`3-(R300C-)-pyrrolidino, (cid:9)
`2-(R300C-)-piperidino,
`3-(R300C-)-piperidino, (cid:9)
`4-(R300C-)-piperidino,
`2-(R300C-CH2-)-piperidino, 3-(R300C-CH2-)-pip-
`eridino, 4-(R300C-CH2-)-piperidino, 4-(R300C-
`CH2CH2-)-piperidino, 4-hydroxy-4-(R300C)-piperidino,
`4-hydroxy-4-(R300C-CH2-)-piperidino, 4-amino-4-
`(R300C)-piperidino, 4-amino-4-(R300C-CH2-)piperi-
`dino, 3-oxo-4-(R300C-CH2-)-piperidino, 2-(R300C-
`3-(R300C-CH2-0-)-
`CH2-O-)-piperidino, (cid:9)
`piperidino, 4-(R300C-CH2-0-)-piperidino, 1-oxa-2-
`oxo-8-azaspiro[4.5]dec-8-yl, 2-, 3- or 4-(R300C)-
`hexahydroazepino, (cid:9)
`4-(R300C-CH2-)-piperazino,
`4-(R300C-CH2CH2)-piperazino, 2-(R300C)-piper-
`azino, 3-(R300C)-piperazino, or 4-benzy1-3-(R300C)-pip-
`erazino.
`Z is preferably H, more preferably A such as methyl or
`ethyl, phenyl, benzyl, acetyl or benzoyl.
`R1 is preferably a phenyl radical, which is substituted, as
`indicated, in the 4 position, or else in the 2 or 3 position,
`those which are specifically preferred being 2-, 3- or (in
`particular) 4-cyanophenyl, 2-, 3- or (in particular)
`4-aminomethylphenyl, 2-, 3- or (in particular) 4-dim-
`ethylaminomethylphenyl, 2-, 3- or (in particular)
`4-amidinophenyl, 2-, 3- or 4-guanidinophenyl or 2-, 3-
`or 4-guanidinomethylphenyl, 2-, 3- or (in particular)
`4-hydroxyamidinophenyl.
`R2 is preferably -COORS, -CH2COOR3 or
`-O-CH2COOR3.
`R3 is preferably H, methyl, ethyl, tert-butyl or benzyl.
`
`4
`R4 is preferably H, methyl, ethyl, benzyl or
`-CH2COOR3.
`Ac is preferably alkanoyl having 1-6 carbon atoms, such
`as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl or
`caproyl, and also benzoyl, tolyl, 1- or 2-naphthoyl or phe-
`nylacetyl.
`The parameters k and m are preferably 0 or 1. The
`parameter n is preferably 0. The parameter p is preferably 1.
`Those compounds of the formula I are preferred in which
`10 at least one of the indicated radicals, groups and/or param-
`eters has one of the indicated preferred meanings. Some
`groups of preferred compounds are those of the formulae Ia
`to Id which correspond to the formula I where, however,
`in Ia X is 0;
`in Ib X is 0, and
`R' is cyanophenyl;
`in Ic X is 0, and
`R1 is aminomethylphenyl;
`in Id X is 0, and
`R1 is amidinophenyl.
`Furthermore, compounds are preferred which are of the
`formulae Ie, as well as Iae, Ibe, Ice and Ide, which corre-
`spond to the formulae I, Ia, Ib, Ic and Id where, however in
`addition,
`Y is 3-R2-azetidino, 2-R2-pyrrolidino, 2-R2-piperidino,
`3-R2-piperidino, 4-R2-piperidino, 4-R2-piperazino or
`3-R2-4-R4-piperazino,
`R2 is -COORS, -CH2COOR3 or -OCH2COOR3, and
`R4 is -CH2COOR3.
`Smaller, selected, groups of compounds are those of the
`formulae If and Ig. They correspond to the formula I where,
`however, in If
`X is 0,
`Y is 3-(R300C-CH2-0-)-azetidino, 2-(R300C-)-
`pyrrolidino, 2-, 3- or 4-(R300C-)-piperidino,
`4-(R300C-CH2-)-piperidino, 3- or 4-(12300C-
`CH2-0-)-piperidino, 4-(R300C-CH2)-piperazino
`or 3-(R300C-)-4-1e-piperazino,
`R1 is 4-cyanophenyl, 4-aminomethylphenyl, 4-amidi-
`nophenyl, or 4-guanidinomethylphenyl,
`R3 is H, C1--C4-alkyl or benzyl and
`R4 is H or benzyl, and
`in Ig X is 0,
`Y is 4-(R300C-)-piperidino or 4-(R300C-CH20-)-
`piperidino,
`R1 is 4-cyanophenyl, 4-aminomethylphenyl or 4-amidi-
`nophenyl, and
`R3 is H, C1--C4-alkyl or benzyl.
`The compounds of the formula I, and also the starting
`compounds for their preparation, are otherwise prepared by
`methods which are known per se, as described in the
`literature (e.g., in the standard works, such as Houben-Weyl,
`Methoden der organischen Chemie (Methods of Organic
`55 Chemistry), Georg-Thieme Verlag, Stuttgart; additionally
`EP-A1-0381033 and EP-A1-0462960), specifically under
`reaction conditions which are known, and suitable, for the
`reactions. In this context, use can also be made of variants
`which are known per se but which are not mentioned here in
`60 detail.
`If desired, the starting compounds can also be formed in
`situ, such that they are not isolated from the reaction mixture
`but, instead, immediately further reacted to give the com-
`pounds of the formula I.
`The compounds of the formula I can be obtained by
`liberating them from their functional derivatives by solvoly-
`sis, in particular hydrolysis, or by hydrogenolysis.
`
`25 (cid:9)
`
`30 (cid:9)
`
`35 (cid:9)
`
`40 (cid:9)
`
`45 (cid:9)
`
`50 (cid:9)
`
`65 (cid:9)
`
`

`
`5,532,255
`
`5
`Preferred starting compounds for the solvolysis or hydro-
`genolysis are those which, while otherwise corresponding to
`the formula I, contain corresponding protected amino and/or
`hydroxyl groups in place of one or more free amino and/or
`hydroxyl groups, preferably those which carry an amino 5
`protective group in place of an H atom which is linked to an
`N atom, in particular those which carry an R'—N— group,
`where R' is an amino protective group, in place of an HN
`group, and/or those which carry a hydroxyl protective group
`in place of the H atom of a hydroxyl group, e.g., those which to
`correspond to the formula I but carry a —COOR" group,
`where R" is a hydroxyl protective group, in place of a
`—COOH group.
`Several—identical or different—protected amino and/or
`hydroxyl groups may also be present in the molecule of the 15
`starting compouund. If the protective groups which are
`present differ from each other, they can in many cases be
`eliminated selectively.
`The expression "amino protective group" is well known
`and relates to groups which are suitable for protecting (for 20
`blocking) an amino group from chemical reactions but
`which are readily removable once the desired chemical
`reaction at another site in the molecule has been carried out.
`Typical groups of this nature are, in particular, unsubstituted
`or substituted acyl, aryl (e.g., 2,4-dinitrophenyl (DNP)), 25
`aralkoxymethyl (e.g., benzyloxymethyl (BOM)) or aralkyl
`(e.g., benzyl, 4-nitrobenzyl or triphenylmethyl) groups.
`Since the amino protective groups are removed following
`the desired reaction (or sequence of reactions), their nature
`and size is otherwise not critical; however, those are pre- 30
`ferred which have 1-20, in particular 1-8, C atoms. In
`connection with the present process, the expression "acyl
`group" is to be interpreted in the widest sense. It embraces
`acyl groups derived from aliphatic, araliphatic, aromatic or
`heterocyclic carboxylic acids or sulfonic acids, such as, in 35
`particular, alkoxycarbonyl, aryloxycarbonyl and, above all,
`aralkoxycarbonyl groups. Examples of acyl groups of this
`nature are alkanoyl, such as acetyl, propionyl or butyryl;
`aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl or
`tolyl; aryloxyalkanoyl, such as phenoxyacetyl; alkoxycar- 40
`bonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2,-
`trichloroethoxycarbonyl, isopropoxycarbonyl, tert-butoxy-
`carbonyl (cid:9)
`(BOC) (cid:9)
`or (cid:9)
`2-iodoethoxycarbonyl;
`aralkyloxycarbonyl, such as benzyloxycarbonyl (CBZ),
`4-methoxybenzyloxycarbonyl or 9-fluorenylmethoxycarbo- 45
`nyl (FMOC). Those amino protective groups which are
`preferred are BOC, DNP and BOM, and, additionally, CBZ,
`benzyl and acetyl.
`The expression "hydroxyl protective group" is likewise
`well known and relates to groups which are suitable for 50
`protecting a hydroxyl group from chemical reactions but
`which are readily removable once the desired chemical
`reaction has been carried out at another site in the molecule.
`Typical groups of this nature are the abovementioned unsub-
`stituted or substituted aryl, aralkyl or acyl groups, and 55
`additionally, alkyl groups. The nature and size of the
`hydroxyl protective groups is not critical, since they are
`removed once more following the desired chemical reaction
`or sequence of reactions; groups having 1-20, in particular
`1-10, C atoms are preferred. Examples of hydroxyl protec- 60
`tive groups are, inter alia, tert-butyl, benzyl, p-nitrobenzoyl,
`p-toluenesulfonyl and acetyl, with benzyl and acetyl being
`particularly preferred.
`The functional derivatives of the compounds of the for-
`mula Ito be used as starting compounds can be prepared by 65
`customary methods, such as are described, for example, in
`said standard works and patent applications, e.g., by the
`
`6
`reaction of compounds which correspond to the formulae II
`and III, with, however, at least one of these compounds
`containing a protective group in place of a H atom.
`The liberation of the compounds of the formula I from
`their functional derivatives is achieved—in dependence on
`the protective group used—e.g., using strong acids, expe-
`diently using trifluoroacetic acid or perchloric acid, or else
`using 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-
`sulfonic acid or p-toluenesulfonic acid. It is possible, but not
`always necessary, for an additional inert solvent to be
`present.
`Suitable inert solvents are, preferably, organic, for
`example carboxylic, acids, such as acetic acid, ethers, such
`as tetrahydrofuran or dioxane, amides, such as dimethylfor-
`mamide (DMF), halogenated hydrocarbons, such as dichlo-
`romethane, sulfoxides such as dimethyl sulfoxide (DMSO),
`and, in addition, alcohols, such as methanol, ethanol or
`isopropanol, as well as water. Additionally mixtures of the
`abovementioned solvents are suitable. Trifluoroacetic acid is
`preferably used in excess without addition of any further
`solvent; perchloric acid is used in the form of a mixture
`consisting of acetic acid and 70% perchloric acid in the ratio
`9:1. The reaction temperatures for the cleavage are expedi-
`ently about 0°-50°; preferably 15°-30° (room temperature).
`The BOC group can, for example, preferably be elimi-
`nated using 40% trifluoroacetic acid in dichloromethane, or
`using about 3 to 5N HC1 in dioxane, at preferably about
`15°-60°, and the FMOC group using an approximately
`5-20% solution of dimethylamine, diethylamine or piperi-
`dine in DMF at preferably about 15°-50°. Elimination of the
`DNP group is also achieved, for example, using an approxi-
`mately 3-10% solution of 2-mercaptoethanol in DMF/water
`at preferably about 15°-30°.
`Protective groups (e.g., BOM, CBZ or benzyl) which are
`removable by hydrogenolysis can be eliminated, for
`example, by treating with hydrogen in the presence of a
`catalyst (e.g., a precious metal catalyst such as palladium,
`expediently on a carrier such as carbon). In this context,
`suitable solvents are those given above, in particular, for
`example, alcohols, such as methanol or ethanol or amides,
`such as DMF. The hydrogenolysis is carried out, as a rule,
`at temperatures of preferably about 0°-100° and pressures of
`preferably about 1-200 bar, especially at 20°-30° and 1-10
`bar. Hydrogenolysis of the CBZ group is achieved satisfac-
`torily, for example, on 5-10% Pd-C in methanol at prefer-
`ably about 20°-30°.
`Compounds of the formula I can preferably also be
`obtained by reacting a compound of the formula II with a
`base of the formula III. The known methods of N-alkylation
`are then expediently utilized.
`The leaving group E is preferably Cl, Br, I, CI—Cc
`alkylsulfonyloxy, such as methanesulfonyloxy or ethane-
`sulfonyloxy, or C5—C10-arylsulfonyloxy, such as benzene-
`sulfonyloxy, (cid:9)
`p-toluenesulfonyloxy (cid:9)
`or (cid:9)
`1- (cid:9)
`or
`2-naphthalenesulfonyloxy.
`The reaction is preferably effected in the presence of an
`additional base, e.g., of an alkali metal or alkaline earth
`metal hydroxide or carbonate, such as sodium, potassium or
`calcium hydroxide, or sodium, potassium or calcium car-
`bonate, in an inert solvent, e.g., a halogenated hydrocarbon,
`such as dichloromethane, an ether, such as THE or dioxane,
`an amide, such as DMF or dimethylacetamide, or a nitrile,
`such as acetonitrile, at temperatures of preferably about
`—10°-200°, especially 0°-120°. If the leaving group E of I
`is different, the addition of an iodide, such as potassium
`iodide, is advisable.
`
`

`
`5,532,255
`
`20
`
`7
`The starting compounds of the formula II are novel, as a
`rule. They can be prepared, for example, by reacting a
`substituted aniline of the formula R1—NH2 with a com-
`pound of the formula R5CH2—CHR6—CH2OH (where R5
`is E, R6 is XR7, R7 is a protective group, or R5 and R6 5
`together are also 0) to give a compound of the formula
`RI —NH—Cf12—CHR8—CH,OH (where R8 is XR7 or
`OH), where appropriate eliminating the protective group R7
`to give compounds of the formula R1—NH—C1-12—
`CH(XH)—CH,OH, reacting with a derivative of carbonic 10
`acid, such as diethyl carbonate, to give 3-R'-5-hydroxym-
`ethyl-2-oxazolidinones, and converting the hydroxymethyl
`group into a CH2E group, e.g., using SOC12, SOBr2, meth-
`anesulfonyl chloride or p-toluenesulfonyl chloride. The
`compounds of the formula H—Y (III) are known, as a rule, 15
`or can be prepared in analogy with known compounds.
`In addition, compounds of the formula I can be obtained
`by reacting a compound of the formula IV (or a reactive
`derivative thereof) with a reactive derivative of carbonic
`acid. (cid:9)
`Suitable carbonic acid derivatives are, in particular,
`dialkyl carbonates, such as diethyl carbonate, and, addition-
`ally, alkyl esters of chloroformic acid, such as ethyl chlo-
`roformate. Preferably, the carbonic acid derivative, which is
`expediently employed in excess, also serves as a solvent or 25
`suspending agent. One of the given solvents can be present
`as well, provided it is inert in this reaction. Furthermore, the
`addition of a base is advisable, in particular of an alkali
`metal alcoholate, such as potassium tert-butylate. Reaction
`temperatures of preferably about 0°-150°, especially 30
`70°-120°, are expediently employed.
`The starting compounds of the formula IV are novel, as a
`rule. They can be obtained, for example, by functionalizing
`the abovementioned compounds of the formula 1V—NH—
`CH,—CH(XH)—CH,OH to give compounds of the for- 35
`mula R1—NH—CH„--CH(XH)—CH2—E and reacting
`with compounds of the formula H—Y (III).
`In order to prepare compounds of the formula I, in which
`R' is a guanidinophenyl group, a corresponding aminophe-
`nyl compound can be treated with an amidinating agent. 40
`1-Amidino-3,5-dimethylpyrazol which is, in particular,
`employed in the form of its nitrate, is preferred as an
`amidinating agent. The reaction is expediently carried out in
`the presence of a base, such as triethylamine or ethyl
`diisopropylamine, in an inert solvent or solvent mixture, 45
`e.g., water/dioxane, at temperatures of preferably about
`0°-120°, especially 60°-120°.
`It is furthermore possible, in a compound of the formula
`I, to convert one or both of the radicals R' and/or Y into (an)
`other radical(s) R1 and/or Y. (cid:9)
`In particular, cyano groups can be reduced to aminom-
`ethyl groups, or converted into amidino groups or hydroxya-
`midino groups, carboxyl groups esterified, ester groups
`cleaved, benzyl groups removed hydrogenolytically, and
`aminomethyl groups converted into guanidinomethyl 55
`groups.
`Reduction of cyano groups to aminomethyl groups is
`expediently effected by catalytic hydrogenation, e.g., on
`Raney nickel at temperatures of preferably about 0°-100°,
`especially 10°-30°, and pressures of preferably about 1-200 60
`bar, especially at atmospheric pressure, in an inert solvent,
`e.g., a lower alcohol, such as methanol or ethanol, expedi-
`ently in the presence of ammonia. If the reaction is carried
`out, for example, at about 20° and 1 bar, benzyl ester groups
`or N-benzyl groups present in the starting material are then 65
`preserved. If it is desired to cleave these groups hydro-
`genolytically, a precious metal catalyst, preferably Pd-car-
`
`50
`
`8
`bon, is then expediently used, it being possible to add an
`acid, such as acetic acid, and water as well, to the solution.
`In order to prepare an amidine of the formula I (R'=
`amidinophenyl), ammonia can be added onto a nitrile of the
`formula I (R1=cyanopheny1). The addition is preferably
`effected in several steps, by, in a manner known per se, a)
`transforming the nitrile with H2S into a thioamide, which is
`converted with an alkylating agent, e.g., CH3I, into the
`corresponding S-alkyl imidothio ester, which latter reacts
`with NH3 to give the amidine, b) transforming the nitrile
`with an alcohol, e.g., ethanol, in the presence of HC1 into the
`corresponding imido ester, and treating the latter with
`ammonia, or c) reacting the nitrile with lithium bis(trimeth-
`ylsilyl)amide and subsequently hydrolyzing the product.
`The corresponding N-hydroxyamidines of the formula I
`(R'=phenyl substituted by HO—NH—C(=NH)) can be
`obtained from the nitriles in an analogous manner if the
`work is carried out according to a) orb) but using hydroxy-
`lamine in place of ammonia.
`For the esterification, an acid of the formula I (R3=H)
`can be treated with an excess of alcohol of the formula
`R3—OH (R3=--A or benzyl), expediently in the presence of
`a strong acid, such as hydrochloric acid or sulfuric acid, at
`temperatures of preferably about 0°-100°, especially
`20°-50°.
`Conversely, an ester of the formula I (R3=A or benzyl)
`can be converted into the corresponding acid of the formula
`I (R3=H), expediently by solvolysis in accordance with one
`of the abovementioned methods, e.g. with NaOH or KOH in
`water/dioxane at temperatures of preferably about 0°-40°,
`especially 10°-30°.
`A base of the formula I can be converted with an acid into
`the associated acid addition salt. Those acids, in particular,
`are suitable for this reaction which yield physiologically
`harmless salts. Thus, inorganic acids, e.g., sulfuric acid,
`nitric acid, hydrohalic acids, such as hydrochloric acid or
`hydrobromic acid, phosphoric acids, such as orthophospho-
`ric acid, and sulfamic acid, and, in addition, organic acids,
`in particular aliphatic, alicyclic, araliphatic, aromatic or
`heterocyclic monobasic or polybasic carboxylic, sulfonic or
`sulfuric acids, e.g., formic acid, acetic acid, trifluoroacetic
`acid, propionic acid, pivalic acid, diethylacetic acid, malonic
`acid, succinic acid, pimelic acid, fumaric acid, maleic acid,
`lactic acid, tartaric acid, malic acid, citric acid, gluconic
`acid, ascorbic acid, nicotinic acid, isonicotinic acid, meth-
`anesulfonic acid or ethanesulfonic acid, ethanedisulfonic
`acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
`p-toluenesulfonic acid, naphthalenemonosulfonic and naph-
`thalenedisulfonic acids, and laurylsulfuric acid, can be used.
`Salts with acids which are not physiologically harmless, e.g.,
`picrates, may be used for isolating and/or purifying the
`compounds of the formula I.
`The free bases of the formula I can, if desired, be liberated
`from their salts by treating with strong bases, such as sodium
`or potassium hydroxide, or sodium or potassium carbonate.
`It is also possible to convert carboxylic acids of the
`formula I (R3=H) into their metal or ammonium salts, e.g.,
`their sodium, potassium or calcium salts, by reaction with
`corresponding bases.
`The compounds of the formula I contain one or more
`chiral centers and can therefore be present in racemic or in
`optically active form. Racemates which are obtained can be
`resolved mechanically or chemically into the enantiomers in
`accordance with methods which are known per se. Prefer-
`ably, diastereomers are formed from the racemic mixture by
`reaction with an optically active resolving agent. Suitable
`resolving agents are, for example, optically active acids,
`
`

`
`5,532,255
`
`5 (cid:9)
`
`35
`
`EXAMPLES
`
`Example 1
`
`9
`10
`such as the D and L forms of tartaric acid, diacetyltartaric
`solutions, and capsules. Carriers, excipients, and further
`acid, dibenzoyltartaric acid, mandelic acid, malic acid or
`additive are mentioned in Examples A—E. The amount of the
`lactic acid, or the various optically active camphorsulfonic
`inventive compound in the antimicrobial agents is preferably
`acids, such as 13-camphorsulfonic acid. Enantiomeric reso-
`about 0.05-500 mg per dosage unit.
`lution using a column filled with an optically active resolv-
`In the above and that which follows, all temperatures are
`ing agent (e.g., dinitrobenzoylphenylglycine) is also advan-
`given in °C. in the examples below, "customary working-
`tageous; a mixture of hexane/isopropanol/acetonitrile, e.g.,
`up" means: if necessary, water is added, pH values are
`in the volume ratio of 82:15:3, is an example of a suitable
`adjusted to between 2 and 8 depending on the constitution of
`eluent.
`the end product, extraction takes place with ethyl acetate or
`Naturally, it is also possible to obtain optically active
`to dichloromethane, the phases are separated, the organic phase
`compounds of the formula I in accordance with the above-
`is dried over sodium sulfate and evaporated, and purification
`described methods by using starting compounds (e.g., those
`is then effected by chromatography on silica gel and/or by
`of the formula II) which are already optically active.
`crystallization. FAB=(M++1) peak in the mass spectrum,
`The novel compounds of the formula I, and their physi-
`obtained by the "fastatom bombardment" method.
`ologically harmless salts, may be used for producing phar-
`15 (cid:9) Without further elaboration, it is believed that one skilled
`maceutical preparations by bringing them into a suitable
`in the art can, using the preceding description, utilize the
`dosage form together with at least one excipient or auxiliary
`present invention to its fullest extent. The following pre-
`agent, and, if desired, together with one or more additional
`ferred specific embodiments are, therefore, to be construed
`active compound(s). The formulations thus obtained can be
`as merely illustrative, and not limitative of the remainder of
`employed as pharmaceuticals in human or veterinary medi-
`cine. Those organic or inorganic compounds can be used as 2
`0 the disclosure in any way whatsoever.
`carrier substances which are suitable for enteral (e.g., oral or
`In the foregoing and in the following examples, all
`rectal) or parenteral administration, or for administration in
`temperatures are set forth uncorrected in degrees Celsius and
`the form of an inhalation spray, and do not react with the
`unless otherwise indicated, all parts and percentages are by
`novel compounds, for example water, vegetable oils, benzyl
`weight.
`alcohols