United States Patent [19]
`Juraszyk et al.
`
`US005614535A
`[ii] Patent Number:
`[45] Date of Patent:
`
`5,614,535
`Mar. 25, 1997
`
`[54] ADHESION RECEPTOR ANTAGONISTS
`
`[75]
`
`Inventors: Horst Juraszyk; Joachim Gante;
`Hanns Wurziger; Sabine
`Bernotat-Danielowski; Guido Melzer,
`all of Darmstadt, Germany
`
`0462960 12/1991 European Pat. Off. .
`0459256 12/1991 European Pat. Off. .
`0645376
`3/1995 European Pat. Off. .
`4405633 11/1994 Germany .
`
`OTHER PUBLICATIONS
`
`[73] Assignee: Merck Patent Gesellschaft Mit
`Beschrankter Haftung, Darmstadt,
`Germany
`
`[21] Appl. No.: 516,937
`Aug. 18, 1995
`[22] Filed:
`Foreign Application Priority Data
`
`[30]
`
`Aug. 19, 1994
`[51] Int. CI.6
`
`44 29 461.1
`[DE] Germany
`A61K 31/445; A61K 31/42;
`C07D 263/24; C07D 413/12
`514/326; 514/212;
`[52] U.S. CI.
`514/255;
`514/364; 514/374; 540/603; 544/369; 546/208;
`548/134; 548/135; 548/230
`[58] Field of Search
`540/603; 544/369;
`546/208; 548/134, 135, 230; 514/212, 255,
`326, 364, 374
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3/1948 Homeyer et al
`2,437,388
`9/1989 Schnettler et al
`4,866,182
`5,356,918 10/1994 Ishihara et al
`
`548/230
`548/230
`514/376
`
`FOREIGN PATENT DOCUMENTS
`
`0381033
`
`8/1990 European Pat. Off. .
`
`chro­
`liquid
`high performance
`
`Vajta et al. "Reversed-phase
`matographic separation of 14C-labeled toloxatone and tis
`metabolites" CA 102:5518 1984.
`Bom, Nature, 4832:927-929
`(1962).
`Smith et al., J. Biol. Chem., 265:12267-12271 (1990).
`
`Primary Examiner—Ceila Chang
`Attorney, Agent, or Firm—Millen, White, Zelano, & Brani-
`gan, RC.
`
`[57]
`
`ABSTRACT
`
`Compounds of the formula I
`
`o
`
`X
`
`I
`
`v.'
`y
`
`R1'
`
`o
`in which R1 and X have the meanings herein defined, their
`salts
`and/or
`physiologically unobjectionable
`the binding of fibrinogen to the corresponding receptor and
`can be employed for
`the
`treatment of
`thromboses,
`osteoporosis,
`tumoral
`diseases,
`apoplexy,
`cardiac
`inflammations, arteriosclerosis and osteolytic disorders.
`
`solvates
`
`infarction,
`
`20 Claims, No Drawings
`
`MYLAN - EXHIBIT 1020
`
`

`
`1
`ADHESION RECEPTOR ANTAGONISTS
`
`SUMMARY OF THE INVENTION
`
`5,614,535
`
`2
`
`n is 1, 2, 3 or 4,
`p is 0, 1 or 2,
`q is 0 or 1,
`r is 1 or 2,
`A is alkyl of 1 to 6 carbon atoms,
`—alk— is alkylene of 1 to 6 carbon atoms,
`Ar is phenyl or benzyl, and
`Ph is phenylene,
`and their physiologically unobjectionable salts and/or
`solvates.
`Compounds having a similar activity profile are known
`from EP-A1-0 381 033.
`An object of the invention is to provide novel compounds
`15 having valuable properties, in particular those compounds
`which can be used for preparing medicaments.
`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 are achieved by the invention. It has been
`found that the compounds of the formula I and their solvates
`and salts possess valuable pharmacological properties while
`being well tolerated. In particular, they inhibit the binding of
`fibrinogen, fibronectin
`and the yon Willebrand factor to the
`fibrinogen receptor of blood platelets (glycoprotein Eb/IIIa),
`25 as well as the binding of these proteins and of 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
`30 blood-platelet thrombi in particular, and can therefore be
`used for the treatment of thromboses, apoplexy, cardiac
`infarction, inflammations and arteriosclerosis. In addition,
`the compounds have an effect on tumor cells, by preventing
`them from forming metastases. Consequently, they can also
`35 be used as antitumor agents.
`There is evidence that tumor cells spreading from a solid
`tumor into the vasculature are carried by microthrombi, i.e.,
`microaggregates of tumor cells and platelets. As a result, the
`tumor cells in the microthrombi are protected from being
`40 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 to the fibrinogen
`receptor
`(glycoprotein Ilb/IIIa) on activated platelets, fibrinogen-
`45 binding inhibitors are expected to be effective as antimeta-
`statics.
`inhibitors are ligands with
`Also, since fibrinogen-binding
`fibrinogen receptor on platelets, they can be used as diag­
`nostic tools for detection and localization of thrombi in the
`50 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
`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
`nisms of the fibrinogen receptor. For example, as described
`60 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
`binding the conjugate to fibrinogen receptors, it is possible
`|_0 rnonitor and study the metabolism of platelets, as well as
`the activation states and signalling mechanisms of the
`fibrinogen receptors.
`
`The invention relates to oxazolidinonecarboxylic acid 5
`derivatives of the formula I
`
`O
`
`x
`
`I
`
`R1'
`
`o
`
`!
`0
`
`10
`
`wherein
`,
`R1
`is N02, NR6R7, CN, CONR6R7, CSNR6R7
`C(=NH)SA,
`C(=NH)OA,
`C(=NH)SAr.
`7'
`C(=)NR6R7,
`C(=NH)NHOH,
`CH2NR6R ,
`NHC(=NH)NR6R7,
`CH2NHC(=NH)NR6R7,
`CH2NHCO—alk—NR6R7,
`CH2NHCO—Ph—E,
`CH2NHCONH— 20
`CH2NHCO—Ph—CH2NR6R7,
`Ph—E or D,
`X is OH, OA, AS, AS—AS',
`
`Y \
`
`N—R3 or — N—(CH2)» ,
`
`R4
`
`—N
`
`D is
`
`\
`
`N Y
`
`R2
`
`E is —CN, —C(=NH)OA, —CSNH2, —C(=NH)SA or
`—C(=NH)NH2,
`Y is CH2, CHOR5 or C=0,
`R2 is H, A, Ar, OH, OA, CF3, CCI3, NR6R7, —alk—
`NR6R7, —alk(CH2Ar)NR6R7, or
`
`O
`\\
`
`-CH2-N
`
`0
`
`R3 is — (CH2)m—COOR5,
`R4 is — (CH2)p—COOR5 or — (CH2)9—O—(CH2) —
`COOR5,
`AS or AS' is in each case, independent of the other, an
`amino-acid residue selected from Ala, (5-Ala, Arg, Asn,
`Asp, Gin, Glu, Gly, Leu, Lys, Om, Phe, Pro, Sar, Ser,
`Thr, Tyr, Tyr (OMe), Val, C-allyl-Gly, C-propargyl-Gly,
`N-benzyl-Gly, N-phenethyl-Gly, N-benzyl-p-Ala,
`N-methyl-P-Ala and N-phenethyl-P-Ala, it being pos­
`sible for free amino or carboxyl groups also to be
`provided with conventional protective groups which
`are known per se.
`R5, R6 and R7 are each, independent of one another, H or 55
`A,
`m is 1, 2 or 3,
`
`

`
`5,614,535
`
`3
`Furthermore, the compounds are suitable for the prophy­
`laxis and treatment of osteolytic disorders, especially
`osteoporosis and restenosis following angioplasty. In addi­
`tion, they have antiangiogenetic properties.
`Moreover, the compounds display an antimicrobial action s
`and can be employed in treatments and interventions in
`which it is necessary to prevent microbial infection. Anti­
`microbial activity of the compounds can be demonstrated by
`the procedure described by P. Valentin-Weigan et al., Infec­
`tion and Immunity, 2851-2855 (1988).
`The properties of the compounds can be demonstrated by
`methods which are described in EP-A1-0 462 960. The
`inhibition of the binding of fibrinogen
`to the fibrinogen
`receptor can be demonstrated by the method indicated in
`EP-A1-0 381 033. The inhibitory effect on blood-platelet
`aggregation can be demonstrated in vitro by the method of 15
`Bora (Nature, 4832:927-929 (1962)). The inhibition of the
`interactions of (^-integrin receptors with suitable ligands
`can be demonstrated by the method of J. W. Smith et al., J.
`Biol. Chem., 265:12267-12271 (1990).
`The invention relates to compounds of the indicated 20
`formula I, to their salts and solvates, and to a process for the
`preparation of these compounds, characterized in that
`(a) a compound of the formula I is liberated from one of
`its functional derivatives by treatment with a solvolyzing or
`hydrogenolyzing agent, or in that
`(b) a compound of the formula II
`
`25
`
`R1.
`
`O
`11
`
`L
`
`v»
`y °
`
`0
`
`II
`
`in which
`R1 has the meaning given and
`L is CI, Br, OH or a reactive esterified OH group or a
`leaving group which is readily capable of undergoing
`nucleophilic substitution,
`is reacted with a compound of the formula III
`
`H—X'
`
`HI,
`
`in which
`X' is AS, AS—AS',
`r Y
`\
`\
`/
`
`—N
`
`R4
`
`N—R3 or —N—(CHiJn .
`
`30
`
`35
`
`40
`
`45
`
`50
`
`where Y, R3, R4 and n have the meanings given, or in
`that
`c) a radical X is converted into a different radical X by 55
`hydrolyzing an ester of the formula I or esterifying a
`carboxylic acid of the formula I, or in that
`d) a radical R1 is converted into a different radical R1 by
`catalytically hydrogenating a NO2 and/or CN group, or
`converting a nitrile group by reaction with ammonia 60
`into a C(=NH)—NH2 group, or
`converting a nitrile group into a thiocarbamoyl group.
`or
`converting a thiocarbamoyl group into an alkyl-
`sulfimido group, or
`converting a carbamoyl group into an alkylimido
`group, or
`
`65
`
`4
`convening a methylsulfimido group into an amidine
`group, or
`converting a nitrile group by reaction with NH2OH into
`a C(=NH)—NHOH group, or
`converting a NH2 group into a guanidinyl group, or
`converting a C(—NH)—NHOH group into an amidine
`group, or
`converting a CH2NH2 group into an alkanoylaminom-
`ethyl, CH2NHC(=NH)NR6R7, CH2NHCO—Ph—
`C(=NH)NH2, CH2NHCO—Ph—CH2NR6R7 or a
`CH2NHC0NH—Ph—E group, or
`converting a 1,2,4-oxadiazole or 1,2,4-oxadiazolinone
`group into an amidine group,
`e) or in that a compound of the formula IV
`
`NH-CH2-CHOH-COX,
`
`IV
`
`R1'
`in which
`R1 and X have the given meanings, is reacted with a
`reactive derivative of carbonic acid, and/or in that
`f) a compound of the formula V
`
`/ \
`
`v
`
`OH
`
`HO—N
`w
`H2N
`OH
`is reacted with 2 equivalents of a reactive carbonic acid
`derivative and then oxidized, or in that
`g) a compound of the formula I is converted by treatment
`with an acid or a base into one of its salts.
`The abbreviations given above and below for amino-acid
`residues are the residues of the following amino acids:
`
`Ala
`P-Ala
`Arg
`Asn
`Asp
`Asp(0 But)
`Gin
`Glu
`Gly
`Leu
`Lys
`Om
`Phe
`Pro
`Sar
`Ser
`Thr
`Tyr
`Tyr(OMc)
`Val
`
`alanine
`p-alaninc
`arginine
`asparaginc
`aspartic acid
`aspartic acid P-butyl eslcr
`glutaminc
`glutamic acid
`glycine
`leucine
`lysine
`ornithine
`phenylalanine
`proline
`sarcosine (N-mcthylglycine)
`serine
`threonine
`tyrosine
`2-ainino-3-p-mcthoxyphenylpropionic acid
`valine.
`
`Further abbreviations used below arc:
`
`BOC
`CBZ
`DCCI
`DMF
`EDCI
`
`Et
`Me
`OMe
`OEt
`TEA
`
`tert-butoxycarbonyl
`benzyloxycarbonyl
`dicyclohexylcarbodiimide
`dimethylform amide
`N-ethyl-N'-(3-dimethylaminopropyl)-
`carbodiimide hydrochloride
`ethyl
`methyl
`methyl ester
`ethyl ester
`trifluoroacetic acid
`
`Above and below, the radicals R1 and X have the mean­
`ings given for the formula I. Where a compound of the
`
`

`
`5,614,535
`
`10
`
`5
`6
`formula I possesses a chiral center, it may occur in a
`methods which are known per se, as described in the
`plurality of enantiomeric forms. All of these forms and
`literature (e.g., in the standard works such as Houben-Weyl,
`mixtures thereof, especially racemates, are included by the
`Methoden der organischen Chemie [Methods for Organic
`invention.
`Chemistry], Georg-Thieme-Verlag, Stuttgart; and also J.
`In the formula above and below, the group A has 1-6, 5 March, Adv. Org. Chem., 3rd Ed. (1985), J. Wiley & Sons),
`preferably 1, 2, 3 or 4, carbon atoms. Specifically, A is
`specifically under reaction conditions which are known and
`preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
`suitable for the stated reactions. In this context, use can also
`sec-butyl or tert-butyl, and also pentyl, 1-, 2- or 3-methyl-
`be made of variants which are known per se which are not
`butyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl,
`mentioned here in more detail.
`or 1-, 2- or 3-methylpentyl.
`^ desired, the starting compounds can also be formed in
`f w
`nrH
`n n-T TH
`OH
`Y
`•
`fu' such th/ they 316 no}
`1 from ^ re1action
`4-carb1oSxyPp?peeriadinyo, 4-carboxyalkylpiperidino, 4-carboxy3-
`alkoxypiperidino and the corresponding alkyl ester groups
`but> msteJad' ?? rf cted1
`^mediately to give the
`compounds of the formula I.
`of the radicals mentioned, 4-alkoxycarbonylpiperidino,
`4-carboxymethylpiperazino, 4-carboxyethylpiperazino or,
`compounds of the formula I can be obtained by
`particularly preferably, is an amino-acid residue or a dipep- 15
`liberating them from their functional derivatives by solvoly-
`tide residue which is attached to the carbonyl group via an
`s's> i11 particular hydrolysis, or by hydrogenolysis.
`amide bond. If X is an amino-acid residue or dipeptide
`Preferred starting compounds for the solvolysis or hydro-
`residue, the following are particularly preferred: Ala, p-Ala,
`genolysis are those which, while otherwise corresponding to
`the formula I, contain corresponding protected amino and/or
`Gly, Arg and P-Ala-Asp, Phe, N-phenethylglycine, N-phen-
`20 hydroxyl groups in place of one or more free amino and/or
`ethyl-P-alanine or Sar.
`The C-terminal amino-acid residue can in this case like­
`hydroxyl groups, preferably those which carry an amino-
`wise be attached to a conventional protective group. An
`protective group in place of a hydrogen atom which is linked
`esterification is particularly suitable.
`to a nitrogen atom, in particular those which carry, in place
`The group R1 is preferably —NH2, —C(=NH)—NH2,
`of an HN group, a group R'—N in which R' is an amino-
`—CH2—NH2, —CH2—NH—CO—alk—NH2, —CH2—
`25 protective group, and/or those which carry, instead of the
`NH—CO—Ph—C(=NH)—NH2, —CH2—NH—CO—
`hydrogen atom of a hydroxyl group, a hydroxy-protective
`alk—C(=NH)—NH2, —CH2—NH—CO—Ph—CH2—
`group, for example those which correspond to the formula I
`NH2, N02 or CN. In addition, R1 is also preferably
`but, instead of a —COOH group, carry a group —COOR"
`—C(=NH)—S—A, —CSNH2, —C(=NH)—NHOH or
`in which R" is a hydroxy-protective group.
`It is also possible for two or more—identical or differ­
`ent—protected amino and/or hydroxyl groups to be present
`in the molecule of the starting compound. If the protective
`groups present are different from one another, 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
`The radical Ar is unsubstituted benzyl or phenyl.
`blocking) an amino group from chemical reactions but
`The parameters m and n are preferably 1, but also, in
`which are readily removable once the desired chemical
`addition, preferably 2 or 3. The variable p is preferably 0 or
`reaction has been carried out at another site of the molecule.
`1, whereas q and r are preferably 1.
`40 Typical groups of this kind are, in particular, unsubstituted
`Among the compounds of the formula I, preference is
`or substituted acyl, aryl (e.g., 2,4-dinitrophenyl (DNP)),
`given to those in which at least one of the indicated radicals,
`aralkoxymethyl (e.g., benzyloxymethyl (BOM)) or aralkyl
`groups and/or parameters has one of the preferred meanings
`groups (e.g., benzyl, 4-nitrobenzyl or triphenylmethyl).
`given. Some groups of preferred compounds are those of the
`Since the amino-protective groups are removed after the
`formulae la to If, which correspond to the formula I except 45 desired reaction (or sequence of reactions), their nature and
`that
`size is otherwise not critical; however, preference is given to
`in la R1 is C(=NH)NH2 and X is OH or OA;
`those having 1-20, especially 1-8 carbon atoms. In connec­
`tion with the present process, the expression "acyl group"
`in lb R1 is C(=NH)NH2 and X is 4-carboxypiperidino,
`should be interpreted in the broadest sense. It embraces acyl
`4-carboxylalkylpiperidino or 4-carboxyalkoxypiperi-
`50 groups derived from aliphatic, araliphatic, aromatic or het­
`dino;
`erocyclic carboxylic acids or sulfonic acids and also, in
`in Ic R1 is C(=NH)NH2 and X is (5-Ala, Asp, Tyr,
`particular, alkoxycarbonyl, aryloxycarbonyl and, especially,
`Tyr(OMe), N-phcnethyl-fi-Ala or Phe, and the corre­
`aralkoxycarbonyl groups. Examples of such acyl groups are
`sponding esterified derivatives;
`alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such
`in Id R1 is C(=NH)NH2 and X is 4-alkoxycarbonylpip-
`55 as phenylacetyl; aroyl such as benzoyl or tolyl; aryloxyal-
`eridino, 4-alkoxycarbonylpiperazino, 4-alkoxycarbo-
`kanoyl such as phenoxyacetyl; alkoxycarbonyl such as
`nylalkylpiperidino, 4-alkoxycarbonylalkoxypiperazino
`methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxy-
`or 4-alkoxycarbonylalkoxypiperidino;
`carbonyl, isopropoxycarbonyl, tert-butoxycarbonyl (BOC)
`in le R1 is C(=NH)NH2 and X is 4-carboxypiperazino or
`and 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as ben-
`4-carboxyalkylpiperazino;
`60 zyloxycarbonyl (CBZ), 4-methoxybenzyloxycarbonyl and
`9-fluorenylmethoxycarbonyl (FMOC). Preferred amino-
`in If R1 is C(=NH)NHOH and X is one of the radicals
`protective groups are BOC, DNP and BOM, and also CBZ,
`mentioned under la to le.
`benzyl and acetyl.
`Furthermore, the invention includes all those compounds
`The expression "hydroxy-protective group" is likewise
`which have a NH2 group within which this NH2 group is
`65 well known and relates to groups which are suitable for
`provided with a protective group which is known per se.
`protecting a hydroxyl group against chemical reactions, but
`The compounds of the formula I, and also the starting
`which are readily removable once the desired chemical
`compounds for their preparation, are otherwise prepared by
`
`R2
`
`N
`
`.
`
`30
`
`35
`
`

`
`5,614,535
`
`7
`8
`reaction has been carried out at another site of the molecule.
`with a compound of the formula III. In this case use is
`Typical groups of this kind are the abovementioned unsub-
`advantageously made of the methods which are known per
`stituted or substituted aryl, aralkyl or acyl groups, and also
`se of nucleophilic substitution and/or of the N-alkylation of
`alkyl groups. The nature and size of the hydroxy-protective
`amines or the reactions for amide formation.
`groups is not critical, since after the desired chemical 5
`The leaving group L in the formula II is preferably CI, Br
`reaction or sequence of reactions they are removed again;
`or OH, or a group which can be derived therefrom, for
`preference is given to groups having 1-20, especially 1-10,
`example the trifluoromethanesulfonyloxy, toluenesulfony-
`carbon atoms. Examples of hydroxy-protective groups
`loxy or methanesulfonyloxy group.
`include tert-butyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl
`The reaction is preferably carried out in the presence of an
`and acetyl, with particular preference being given to benzyl
`additional base, for example an alkali metal or alkaline-earth
`and acetyl.
`metal hydroxide or carbonate, such as sodium hydroxide,
`The functional derivatives of the compounds of the for-
`potassium hydroxide or calcium hydroxide, sodium carbon-
`mula I, which derivatives are to be used as starting com-
`ate, potassium carbonate or calcium carbonate, in an inert
`pounds, can be prepared by conventional methods as
`solvent, for example a halogenatcd hydrocarbon such as
`described, for example, in the standard works and Patent
`dichloromethane, an ether such as THF or dioxane, an amide
`Applications mentioned, for example by reaction of com- 15 such as DMF or dimethylacetamide, or a nitrile such as
`pounds which correspond to the formulae II and III but in
`acetonitrile, at temperatures of between about -10° and
`which at least one of these compounds contains a protective
`200°, preferably between 0° and 120°. The addition of an
`group instead of a hydrogen atom.
`iodide such as potassium iodide may favor the progress of
`The liberation of the compounds of the formula I from
`the reaction.
`their functional derivatives is achieved—depending on the 20
`The starting compounds of the formula II are in general
`protective group used—by employing, for example, strong
`known or can be prepared in an analogy to known com­
`acids, advantageously using trifluoroacetic or perchloric
`pounds. Their preparation is described, for example, in DE
`acid, but also with other strong inorganic acids such as
`37 23 797 (EP 300 272). They can be prepared, for example,
`hydrochloric acid or sulfuric acid, strong organic carboxylic
`by reacting an appropriately substituted aniline with allyl
`acids such as trichloroacetic acid or sulfonic acids such as 25 chloride, subsequently converting the double bond into a
`benzene- or p-toluenesulfonic acid. The presence of an
`diol, reacting this diol with a reactive derivative of carbonic
`additional inert solvent is possible, but not always necessary.
`acid, for example phosgene, N-N-carbonyldiimidazole, a
`Suitable inert solvents are preferably organic, for example
`dialkyl carbonate or diphosgene, oxidizing the product to
`carboxylic, acids such as acetic acid, ethers such as tetrahy-
`5-oxazolidinonecarboxylic acid and, if desired, carrying out
`drofuran (THF) or dioxane, amides such as dimethylforma- 30 further activation by derivatizing the acid group,
`mide (DMF), halogenated hydrocarbons such as dichlo­
`In a compound of the formula II it is possible to convert
`romethane, and also alcohols such as methanol, ethanol or
`a radical L into a different radical L by, for example, reacting
`isopropanol, and water. Also suitable are mixtures of the
`an OH group (Y=OH) with SOCl2, SOBr2, methanesulfo-
`abovementioned solvents. Trifluoroacetic acid is preferably
`nylchloride or p-toluenesulfonyl chloride.
`used in excess without the addition of a further solvent, 35
`The compounds of the formula III are, in general, known
`perchloric acid in the form of mixture of acetic acid and 70%
`and commercially available
`perchloric acid in a ratio of 9:1. The reaction temperatures
`The reaction of the oxazolidinones of the formula II with
`for the cleavage are advantageously between about 0° and
`the compounds of the formula III is carried out in a manner
`about 50°; it is preferably carried out at between 15° and 30°
`known per se, preferably in a protic or aprotic polar inert
`(room temperature).
`40 solvent at temperatures of between 20° and the boiling point
`The BOC group may, for example, preferably be elimi­
`of the solvent. The reaction times are from 10 min to 24 h,
`nated using 40% trifluoroacetic acid in dichloromethane or
`preferably from 2 h to 10 h.
`with from about 3 to 5N HC1 in dioxane at 15°-60°, and the
`Suitable solvents include, in particular, alcohols such as
`FMOC group removed using an approximately 5-20% solu-
`methanol, ethanol, isopropanol, n-butanol and tert-butanol;
`tion of dimethylamine, diethylamine or piperidine in DMF 45 ethers such as diethyl ether, diisopropyl ether, tetrahydro-
`at 15°-50o. Elimination of the DNP group is also achieved,
`fiiran (THF) and dioxane; glycol ethers such as ethylene
`for example, with an approximately 3-10% solution of
`glycol monomethyl and monoethyl ether (methyl glycol or
`2-mercaptoethanol in DMF/water at 15°-30°.
`ethyl glycol), and ethylene glycol dimethyl ether (diglyme);
`Protective groups which can be removed by hydrogenoly-
`ketones such as acetone and butanone; nitriles such as
`sis (e.g., BOM, CBZ or benzyl) may, for example, be 50 acetonitrile; nitro compounds such as nitromethane and
`eliminated by treatment with hydrogen in the presence of a
`nitrobenzene; esters such as ethyl acetate and hexameth-
`catalyst (e.g., a noble metal catalyst such as palladium,
`ylphosphoric triamide; sulfoxides such as dimethyl sulfox-
`advantageously on a support such as charcoal). In this case
`ide (DMSO); chlorinated hydrocarbons such as dichlo-
`suitable solvents are those indicated above, particular
`romethane,
`chloroform,
`trichloroethylene,
`1,2-
`examples being alcohols such as methanol or ethanol, or 55 dichloroethane and carbon tetrachloride; and hydrocarbons
`amides such as DMF. The hydrogenolysis is generally
`such as benzene, toluene and xylene. Also suitable are
`carried out at temperatures of between 0° and 100° and at
`mixtures of these solvents with one another. N-methylpyr-
`pressures of between 1 and 200 bar, preferably 20°-30o and
`rolidone is particularly suitable.
`1-10 bar. Hydrogenolysis of the CBZ group is readily
`Derivatives having a free primary or secondary amino
`achieved, for example, over 5-10% Pd-C in methanol at 60 group are advantageously converted into a protected form.
`20°-30°.
`Suitable protective groups are those mentioned above.
`It is also possible, for example, to perform a hydro-
`It is also possible to obtain a compound of the formula I
`genolytic conversion of a l,2,4-oxadiazolin-5-on-3-yl or a
`by converting a radical X into a different radical X. For
`5-alkyl-l,2,4-oxadiazol-3-yl group into amidine group by
`example, a free acid group (X=OH) can be esterified
`catalytic hydrogenation.
`65 (X=OA) or linked by a peptide bond to an amino acid or a
`Compounds of the formula I can also be obtained, pref­
`dipeptide. Furthermore, it is also possible, for example, to
`erably, by reaction of an oxazolidinone of the formula II
`convert an acid into an amide.
`
`

`
`5,614,535
`
`10
`9
`In addition, it is possible to obtain a compound of the
`indicated to be present, provided it is inert in this reaction.
`formula I by converting a radical R1 in a compound of the
`Furthermore, the addition of a base is advisable, especially
`formula I into a different radical R1.
`an alkali metal alcoholate such as potassium tert-butylate.
`In particular, cyano groups can be reduced to aminom-
`The reaction is advantageously carried out at a temperature
`of between 0° and 150°, preferably between 70° and 120°.
`ethyl groups or converted into amidino groups, benzyl 5
`The starting compounds of the formula IV are, in general,
`groups can be removed by hydrogenolysis, aminomethyl
`groups can be converted into guanidinomethyl groups, or
`novel. They are obtainable, for example, by reacting a
`ring-substituted aniline with an a-hydroxy-P-halocarboxylic
`nitrile groups can be converted into thiocarbamoyl groups.
`A reduction of cyano groups to aminomethyl groups is
`acid.
`carried out advantageously by catalytic hydrogenation, for 10
`It is possible, moreover, to obtain a compound of the
`example over Raney-Nickel at temperatures between 0° and
`formula I by reacting a diol of the formula V with an excess
`100°, preferably 10° and 30°, and at pressures between 1 and
`of a reactive carbonic acid derivative, a reaction which is
`200 bar, preferably at atmospheric pressure, in an inert
`preferably carried out under the abovementioned conditions.
`solvent, for example a lower alcohol such as methanol or
`While the carbonic acid derivatives are commercially avail-
`ethanol, advantageously in the presence of ammonia. If the 15 able, the compounds of the formula V can be obtained, for
`operation is carried out, for example, at about 20° and 1 bar,
`example, by reacting allyl chloride with p-aminobenzoni-
`then benzyl ester groups or N-benzyl groups present in the
`trile, converting the double bond into a dihydroxy grouping,
`starting material are retained. If it is desired to cleave these
`and reacting the resulting compound with hydroxylamine.
`by hydrogenolysis, then use is advantageously made of a
`A base of the formula I can be converted with an acid into
`noble metal catalyst, preferably Pd/charcoal, in which case 20
`the corresponding acid addition salt. Acids suitable for this
`it is possible to add to the solution an acid such as acetic
`reaction are in particular those which give physiologically
`acid, and also water.
`unobjectionable salts. For instance, it is possible to use
`In order to prepare compounds of the formula I in which
`inorganic acids, for example sulfuric acid, nitric acid, hydro-
`R1 is a guanidinophenyl group, a corresponding aminophe-
`halic acids such as hydrochloric acid or hydrobromic acid,
`nyl compound can be treated with an amidinating agent. A 25 phosphoric acids such as orthophosphoric acid, sulfamic
`preferred amidinating agent is l-amidino-3,5-dimethylpyra-
`acid, and also organic acids, especially aliphatic, alicyclic,
`zole, which is employed in particular in the form of its
`araliphatic, aromatic or heterocyclic mono- or polybasic
`nitrate. The operation is advantageously carried out with the
`carboxylic, sulfonic or sulfuric acids, for example formic
`addition of a base, such as triethylamine or ethyldiisopro-
`acid, acetic acid, trifluoroacetic acid, propionic acid, pivalic
`pylamine, in an inert solvent or solvent mixture, for example 30 acid, diethylacetic acid, malonic acid, succinic acid, pimelic
`water/dioxane, at temperatures of between 0° and 120°,
`acid, fumaric acid, maleic acid, lactic acid, tartaric acid.
`preferably between 60° and 120°.
`malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic
`In order to prepare an amidine of the formula I, ammonia
`acid, isonicotinic acid, methane- or ethanesulfonic acid,
`ethanedisulfonic acid, 2-hydroxyethanesulfomc acid, benze-
`can be added on to a nitrile of the formula I. The addition is
`preferably accomplished over two or more stages in a 35 nesulfonic acid, p-toluenesulfonic acid, naphthalenemono-
`and -disulfonic acids, and lauryl sulfuric acid.
`manner known per se by a) converting the nitrile with H2S
`The free bases of the formula I may, if desired, be
`into a thioamide which is converted with an alkylating agent,
`for example CH3I, into the corresponding S-alkyl-imidothio
`liberated from their salts by treatment with strong bases such
`as sodium hydroxide or potassium hydroxide, sodium car-
`ester, which in turn is reacted with NH3 to give the amidine,
`b) converting the nitrile with an alcohol, for example etha- 40 bonate or potassium carbonate,
`nol, in the presence of HC1 into the corresponding imido
`It is also possible to convert carboxylic acids of the
`formula I, by reaction with corresponding bases, into their
`ester and treating the latter with ,ammonia, or c) reacting the
`nitrile with lithium bis(trimethylsilyl)amide and then hydro-
`metal or ammonium salts, for example their sodium, potas­
`lyzing the product.
`sium or calcium salts.
`Analogously, the corresponding N-hydroxy amidines of 45
`The compounds of the formula I may contain one or more
`the formula I are obtainable from the nitriles by working in
`chiral centers and may therefore be present in racemic or in
`accordance with a) or b) but using hydroxylamine instead of
`optically active form. Racemates which are obtained can be
`ammonia.
`separated by methods which are known per se, mechanically
`Furthermore, N-hydroxyamidines can be converted, by
`or chemically, into the enantiomers.
`Preferably, diastereomers are formed from the racemic
`reaction with aliphatic carbonyl chlorides, into 1,2,4-oxa- 50
`mixture by reaction with an optically active resolving agent.
`diazoles or 1,2,4-oxadiazolinones, which can then be con­
`Examples of suitable resolving agents are optically active
`verted, by catalytic hydrogenation over, for example, Raney-
`acids, such as the D and L forms of tartaric acid, diacetyl-
`Ni, Pd/C or Pt02, preferably in MeOH, dioxane, glacial
`tartaric acid, dibenzoyltartaric acid, mandelic acid, malic
`acetic acid, glacial acetic acid/acetic anhydride or DMF, into
`55 acid, lactic acid or the various optically active camphorsul-
`amidines.
`fonic acids such as (3-camphorsulfonic acid.
`Furthermore, a compound of the formula I can be
`Also advantageous is an enantiomeric resolution using a
`obtained by reacting a compound of the formula IV with a
`column packed with an optically active resolving agent (e.g.,
`reactive derivative of carbonic acid. Reactive derivatives of
`dinitrobenzoylphenylglycine); a suitable eluent is, for
`carbonic acid may, for example, be those mentioned above,
`with particular preference being given to phosgene and 60 example, a hexane/isopropanol/acetonitrile mixture,
`It is of course also possible to obtain optically active
`diphosgene and to N,N-carbonyldiimidazole. Further suit­
`compounds of the formula I in accordance with the methods
`able carbonic acid derivatives are, in particular, dialkyl
`described above by using starting compounds (e.g., those of