Adhesion receptor antagonists

The invention relates to compounds of the formula I ##STR2## wherein X is O, S, NH or NA,
Y is ##STR3## R.sup.1 is ##STR4## R.sup.2 and R.sup.3 in each case independently of one another are H, A or benzyl,
A is alkyl having 1 to 6 C atoms,
B is H, A, benzyl or amidino,
D is amidino, aminomethyl, aminohydroxyiminomethyl, 5-oxo-1,2,4-oxadiazolin-3-yl, 5-methyl-1,2,4-oxadiazolin-3-yl or guanidinomethyl,
m, r and s in each case independently of one another are 0, 1, 2, 3 or 4 and
n is 2, 3 or 4, and to their physiologically acceptable salts.
Similar, but structurally different compounds are disclosed in EP-A1-0 381 033.
An object of the invention is to provide novel compounds having useful properties, in particular those which can be used for the production of 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 was found that the compounds of the formula I, and their solvates and salts, have useful pharmacological properties together with good tolerability. In particular, they inhibit the binding of fibrinogen, fibronectin and of the yon Willebrand factor to the fibrinogen receptor of blood platelets (glycoprotein IIb/IIIa) and also the binding thereof and of further adhesive proteins, such as vitronectin, collagen and laminin, to the corresponding receptors on the surface of various cell types. The compounds thus affect cell-cell and cell-matrix interactions. In particular, they prevent the formation of blood platelet thrombi and can therefore be used for the treatment of thromboses, osteoporoses, oncoses, apoplexy, cardiac infarct, ischaemias, inflammations, arteriosclerosis, osteolytic disorders and of acute kidney failure. The compounds also have an effect on tumor cells by inhibiting their metastasization. They can thus also be employed as antitumor agents.
There are indications that tumor cells pass into the vessels by means of microthrombi and are thus protected from detection by the cells of the immune system. Microthrombi also have a supportive effect on the binding of tumor cells to the vessel walls. Since the formation of the microthrombi is connected with the fibrinogen binding to the fibrinogen receptor (glycoprotein IIb/IIIa), fibrinogen binding inhibitors likewise count as metastasis inhibitors.
Also, since fibrinogen-binding inhibitors are ligands with fibrinogen receptor on platelets, they can be used as diagnostic 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 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 mechanisms 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 conjugate can then be employed in vitro as a research tool. By 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 additionally suitable as antimicrobial agents which can prevent infections, such as can be caused, for example, by bacteria, fungi or yeasts. The substances can therefore preferably be given as accompanying antimicrobial agents when operations on bodies are performed in which exogenous substances, such as biomaterials, implants, catheters or cardiac pacemakers, are employed. They act as antiseptics. Antimicrobial activities of the compounds can be demonstrated, for example, by the method of P. Valentin-Weigand et al., described in Infection and Immunity, 2851-2855 (1988).
Suitable preparations for using the compounds as antimicrobial agents are, for example, injection vials, ampoules, solutions and capsules. Carriers, excipients and further additives are mentioned in Examples A-H. The amount of the inventive compound in the antimicrobial agents is preferably about 0.05-500 mg/dosage unit.
The other properties of the compounds can be demonstrated by methods which are described in EP-A1-0 462 960. The inhibition of fibrinogen binding to the fibrinogen receptor can be demonstrated by the method which is indicated in EP-A1-0 381 033. The platelet aggregation-inhibiting action can be demonstrated in vitro by the method of Born (Nature 4832, 927-929, 1962).
The invention also relates to a process for the preparation of a compound of the formula I indicated, and of its salts, characterized in that
(a) a compound of the formula I is liberated from one of its functional derivatives by treating it with a solvolyzing or hydrogenolyzing agent, or in that
(b) a compound of the formula II ##STR5## wherein Z is Cl, Br, I or a reactive esterified OH group, and
R.sup.1 and X have the meanings indicated above, is reacted with a compound of the formula III
H--Y III,
wherein
Y has the meaning indicated, or in that
(c) a compound of the formula IV
R.sup.1 --NH--CH.sub.2 --CH(XH)--CH.sub.2 --Y IV,
wherein
R.sup.1, X and Y have the meanings indicated, is reacted with a reactive derivative of carbonic acid, or in that
(d) a compound of the formula V ##STR6## wherein X and Y have the meanings indicated, is reacted with a compound of the formula VI ##STR7## wherein B has the meaning indicated and
L is ##STR8## where Z' is Cl, Br, I, OA, OH or a reactive esterified OH group or easily nucleophilically substitutable leaving group, or in that
(e) (a) radical(s) R.sup.1 and/or Y is (are) converted into (an) other radical(s) R.sup.1 and/or Y, and/or in that
(f) a compound of the formula I is converted into one of its salts by treating with an acid or base.
The compounds of the formula I have 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.
Hereinbefore and hereinafter, the radicals or parameters A, B, L, X, Y, Z, Z', R.sup.1 to R.sup.3, m, n and r have the meanings indicated in the formulae I to VI if not expressly stated otherwise. If several groups designated as identical are present in the molecule, they can assume various definitions independently of one another.
In the above formulae, the group A has 1-6, preferably 1, 2, 3 or 4, C atoms. Specifically, A is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and 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.
R.sup.1 is preferably a 4-piperidyl, 1-amidino-4-piperidyl, 4-piperidylmethyl, 4-piperidylethyl, 1-methyl-4-piperidyl, 1-amidino-4-piperidylmethyl, 4-piperazinylethyl, 4-piperazinylpropyl, 4-piperazinylbutyl, 1-amidino-4-piperazinylethyl or a 1-amidino-4-piperazinylpropyl radical. Particularly preferably, however, R.sup.1 is 2-, 3- or 4-amidinophenyl, 4-(aminohydroxyiminomethyl)phenyl, 2-, 3- or 4-amino-methylphenyl, 2-, 3- or 4-guanidinomethylphenyl, 4-(5-oxo-1,2,4-oxadiazolin-3-yl)phenyl or 4-(5-methyl-1,2,4-oxadiazolin-3-yl)phenyl.
R.sup.2 and R.sup.3 in each case independently of one another are preferably hydrogen, methyl, ethyl or benzyl.
B is preferably amidino, while D is preferably amidino or aminomethyl.
X is preferably oxygen.
The parameter m is preferably 1or 2. The parameter n is preferably 2 or 3, and r is preferably 1, 2 or 3.
Among the compounds of the formula I, those are preferred in which at least one of the radicals, groups and/or parameters indicated has one of the preferred meanings indicated. Some groups of preferred compounds are those of the formulae Ia to Ih, which correspond to the formula I, but wherein
in Ia X is oxygen and R.sup.1 is 4-amidinophenyl;
in Ib X is oxygen and R.sup.1 is 1-amidino-4-piperidyl;
in Ic X is oxygen and R.sup.1 is 4-(aminohydroxyiminomethyl)phenyl or 4-(5-methyl-1,2,4-oxadiazolin-3-yl) phenyl;
in Id X is oxygen and R.sup.1 is 4-piperidylmethyl, -ethyl or -propyl;
in Ie X is oxygen and R.sup.1 is 1-amidino-4-piperidylmethyl, -ethyl or -propyl;
in If X is oxygen R.sup.1 is 4-amidinophenyl or 4-aminomethylphenyl
in Ig X is oxygen and R.sup.1 is 1-piperazinylethyl, 1-amidino-4-piperazinylethyl;
in Ih X is oxygen and R.sup.1 is 1-piperazinylpropyl or 1-amidino-4-piperazinylpropyl.
Compounds of the formulae Ii and Iai to Ihi are furthermore preferred, which correspond to the formulae I and Ia to Ih, but in which additionally
Y is 4-ethoxycarbonyl-4-ethoxycarbonylmethyl-piperidino, 4-(1,2-diethoxycarbonylethyl)piperazino, 4-(1,2-dibenzyloxycarbonylethyl)piperazino or 4-(1,2-dicarboxyethyl)piperazino.
The compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (e.g. in the standard works such as Houben-Weyl, Methoden der organischen Chemie, [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart; and also EP-A1-0 381 033, EP-A1-0 462 960), namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made in this case of variants which are known per se, but not mentioned here in greater detail.
The starting substances can also be formed in situ, if desired, such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.
The compounds of the formula I can be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis.
Preferred starting substances for the solvolysis is or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and/or hydroxyl groups contain corresponding protected amino and/or hydroxyl groups, preferably those which, instead of an H atom which is bonded to an N atom, carry an amino protective group, in particular those which, instead of an PIN group, carry an R'-N group wherein R' is an amino protective group, and/or those which, instead of the H atom of a hydroxyl group, carry a hydroxyl protective group, e.g. those which correspond to the formula I but instead of a group --COOH carry a group --COOR" wherein R" is a hydroxyl protective group.
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 are different from one another, they can be selectively removed in many cases.
The expression "amino protective group" is generally known and relates to groups which are suitable for protecting (for blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out in another position of the molecule. Typical groups of this type are, in particular, unsubstituted or substituted acyl, aryl (e.g. 2,4-dinitrophenyl (DNP)), aralkoxymethyl (e.g. benzyloxymethyl (BOM)) or aralkyl groups (e.g. benzyl, 4-nitrobenzyl, triphenylmethyl). Since the amino protective groups are removed after the desired reaction (or reaction sequence), their nature and size is otherwise not critical; but those having 1-20, in particular 1-8, C atoms are preferred. The expression "acyl group" is to be interpreted in the widest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and also, in particular, alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of acyl groups of this type are alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as phenoxyacetyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl (BOC), 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as benzyloxycarbonyl (CBZ), 4-methoxybenzyloxycarbonyl and 9-fluorenylmethoxycarbonyl (FMOC). Preferred amino protective groups are BOC, DNP and BOM, and also CBZ, benzyl and acetyl.
The expression "hydroxyl protective group" is likewise generally known and relates to groups which are suitable for protecting a hydroxyl group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out in another position of the molecule. Typical groups of this type are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, and 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, tert-butyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl and acetyl, benzyl and acetyl being particularly preferred.
The functional derivatives of the compounds of the formula I to be used as starting substances can be prepared by customary methods, such as are described, for example, in the standard works and patent applications mentioned, e.g. by reaction of compounds which correspond to the formulae II and III, but where at least one of these compounds contains a protective group instead of an H atom.
The liberation of the compounds of the formula I from their functional derivatives takes place--depending on the protective group used--using, for example, strong acids, expediently using trifluoroacetic acid or perchloric acid, but also 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-or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary.
Suitable inert solvents are preferably organic acids, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, sulfoxides such as dimethyl sulfoxide (DMSO), and also alcohols such as methanol, ethanol or isopropanol as well as water. Mixtures of the abovementioned solvents are also suitable. Trifluoroacetic acid is preferably used in an excess without addition of a further solvent; perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. The reaction temperatures for the cleavage are expediently between approximately 0.degree. and approximately 50.degree.; preferably the reaction is carried out between 15.degree. and 30.degree. (room temperature).
The BOC group can be removed, for example, preferably using 40% trifluoroacetic acid in dichloromethane or using approximately 3to 5N HCl in dioxane at 15.degree.-60.degree.; the FMOC group using an approximately 5-20% solution of dimethylamine, diethylamine or piperidine in DMF at 15.degree.-50.degree.. Removal of the group is carried out, for example, also using an approximately 3-10% solution of 2-mercaptoethanol in DMF/water at 15.degree.-30.degree..
Hydrogenolytically removable protective groups (e.g. BOM, CBZ or benzyl) can be removed, for example, by treating with hydrogen in the presence of a catalyst (e.g. of a noble metal catalyst such as palladium, expediently on a support such as carbon). Suitable solvents in this case are those indicated above, in particular, for example, alcohols such as methanol or ethanol or amides such as DMF. As a rule, the hydrogenolysis is carried out at temperatures between approximately 0.degree. and 100.degree. and pressures between approximately 1 and 200 bar, preferably at 20.degree.-30.degree. and 1-10 bar. A hydrogenolysis of the CBZ group readily takes place, for example, on 5-10% Pd--C in methanol at 20.degree.-30.degree..
Compounds of the formula I can preferably also be obtained by reaction of a compound of the formula II with an amine of the formula III. In this case, use is expediently made of the methods of N-alkylation which are known per se.
The leaving group Z is preferably Cl, Br, I, C.sub.1 -C.sub.6 -alkylsulfonyloxy such as methane- or ethanesulfonyloxy or C.sub.6 -C.sub.10 -arylsulfonyloxy such as benzene-, p-toluene- or 1- or 2-naphthalenesulfonyloxy.
The reaction preferably takes place 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, sodium, potassium or calcium carbonate, in an inert solvent, e.g. a halogenated hydrocarbon such as dichloromethane, an ether such as THF or dioxane, an amide such as DMF or dimethylacetamide, a nitrile such as acetonitrile, at temperatures between approximately -10 and 200, preferably between 0.degree. and 120.degree.. If the leaving group Z is different from I, an addition of an iodide such as potassium iodide is recommended. As a rule, the starting substances of the formula II are new. They can be prepared, for example, by reaction of a substituted phenyl, piperidine or piperazine derivative of the formula R.sup.1 --NH.sub.2 with a compound of the formula R.sup.5 CH.sub.2 --CHR.sup.6 --CH.sub.2 OH (wherein R.sup.5 is Z, R .sup.6 is XR.sup.7, R.sup.7 is a protective group and R.sup.5 and R.sup.6 together are also O) to give a compound of the formula R.sup.1 --NH--CH.sub.2 --CHR.sup.8 --CH.sub.2 OH (wherein R.sup.8 is XR.sup.7 or OH), if appropriate removal of the protective group R.sup.7 to give compounds of the formula R.sup.1 --NH--CH.sub.2 --CH(XH)--CH.sub.2 OH, reaction with a derivative of carbonic acid such as diethyl carbonate to give 3-R.sup.1 -5-hydroxymethyl-2-oxazolidinones and conversion of the hydroxymethyl group to a CH.sub.2 Z group, e.g. using SOCl.sub.2, SOBr.sub.2, methanesulfonyl chloride or p-toluenesulfonyl chloride. As a rule, the compounds of the formula H--Y (III) are known or can be prepared in analogy to known compounds.
Compounds of the formula I can also be obtained by reaction of a compound of the formula IV (or of a reactive derivative thereof) with a reactive derivative of carbonic acid.
Suitable carbonic acid derivatives are, in particular, dialkyl carbonates such as diethyl carbonate, and also alkyl chloroformates such as ethyl chloroformate. The carbonic acid derivative, which is expediently employed in an excess, is preferably also used as a solvent or suspending agent. However, one of the solvents indicated can also be present if it is inert in this reaction. The addition of a base is furthermore recommended, in particular of an alkali metal alkoxide such as potassium tert-butoxide. The reaction is expediently carried out at reaction temperatures between 0.degree. and 150.degree., preferably between 70.degree. and 120.degree..
As a rule, the starting substances of the formula IV are novel. They are obtainable, for example, by functionalization of the abovementioned compounds of the formula R.sup.1 --NH--CH.sub.2 --CH(XH)--CH.sub.2 OH to give compounds of the formula R.sup.1 --NH--CH.sub.2 --CH(XH)--CH.sub.2 --E and reaction with compounds of the formula H--Y (III).
For the preparation of compounds of the formula I wherein R.sup.1 is a 1-amidinopiperidinyl or -piperazinyl group, a corresponding piperidine or piperazine compound can be treated with an amidinating agent. The preferred amidinating agent is 1-amidino-3,5-dimethylpyrazole, which is employed, in particular, in the form of its nitrate. The reaction is expediently carried out with addition of a base such as triethylamine or ethyldiisopropylamine in an inert solvent or solvent mixture, e.g. water/dioxane at temperatures between 0.degree. and 120.degree., preferably 60 and 120.degree..
A compound of the formula I can also be prepared by reacting a compound of the formula V with a piperidine or piperazine derivative of the formula VI.
Compounds of the formula V can be obtained by reaction of a compound of the formula H.sub.2 N--CH.sub.2 --CH(XH)--CH.sub.2 --Y, wherein X and Y have the meanings already indicated, with a reactive carbonic acid derivative. The reaction conditions and the suitable carbonic acid derivatives correspond to the details given previously.
As a rule, the compounds of the formula VI are known or can be obtained by methods known per se, those where B.noteq.H, for example, by functionalization of corresponding piperidine or piperazine derivatives of the formula VI (B=H).
The reactions can expediently be carried out by the methods for the N-alkylation of amines, in particular of cyclic amines, known per se, as were previously described for the compounds II and III.
It is furthermore possible to convert one or both of the radicals R.sup.1 and/or Y into (a) other radical(s) R.sup.1 and/or Y in a compound of the formula I.
For example, a 4--(5-oxo-1,2,4-oxadiazolin-3-yl)phenyl, a 4-(5-methyl-1,2,4-oxadiazolin-3-yl)phenyl or a 4-(aminohydroxyiminomethyl) group can be converted into a 4-amidinophenyl group by hydrogenation, e.g. with Raney Nickel.
In particular, carboxyl groups can be esterified, ester groups cleaved, benzyl groups removed hydrogenolytically or amino groups treated with an amidinating agent. Conventional amino or hydroxyl protective groups can also be introduced or removed.
For the esterification, an acid of the formula I (R.sup.3 =H) can be treated with an excess of an alcohol of the formula R.sup.3 --OH (R.sup.3 =A or benzyl), expediently in the presence of a strong acid such as hydrochloric acid or sulfuric acid at temperatures between 0.degree. and 100.degree., preferably 20.degree. and 50.degree..
Conversely, an ester of the formula I (R.sup.3 =A or benzyl) can be converted into the corresponding acid of the formula I (R.sup.3 =H), expediently by solvolysis according to one of the methods indicated above, e.g. using NaOH or KOH in water/dioxane at temperatures between 0.degree. and 40.degree., preferably 10.degree. and 30.degree..
A base of the formula I can be converted into the associated acid addition salt using an acid. For this reaction, suitable acids are in particular those which yield physiologically acceptable salts. Inorganic acids can thus be used, e.g. sulfuric acid, nitric acid, halohydric acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- 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, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids, and laurylsulfuric acid. Salts with physiologically unacceptable acids, e.g. picrates, can be used for the isolation and/or purification of the compounds of the formula I.
If desired, the free bases of the formula I can be liberated from their salts by treatment 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 (R.sup.3 =H) into their metal or ammonium salts, e.g. their sodium, potassium or calcium salts, by reaction with appropriate bases.
The compounds of the formula I contain one or more chiral centers and can therefore exist in racemic or in optically active form. Racemates which are obtained can be separated into the enantiomers mechanically or chemically by methods known per se. Preferably, diastereomers are formed from the racemic mixture by reaction with an optically active resolving agent. Suitable resolving agents are, for example, optically active acids, such as the D- and L-forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as .beta.-camphorsulfonic acid. Resolution of the enantiomers with the aid of a column packed with an optically active resolving agent (e.g. dinitrobenzoylphenylglycine) is also advantageous; a suitable eluent is, for example, a hexane/isopropanol/acetonitrile mixture, e.g. in the volume ratio 82:15:3.
Of course, it is also possible to obtain optically active compounds of the formula I according to the methods described above by using starting substances (e.g. those of the formula II) which are already optically active.
The novel compounds of the formula I and their physiologically acceptable salts can be used for the production of pharmaceutical preparations by bringing them into a suitable dosage form together with at least one excipient or auxiliary and, if desired, together with one or more further active compounds. The preparations thus obtained can be employed as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (e.g. oral or rectal) or parenteral administration or for administration in the form of an inhalation spray and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatine, soya lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc or cellulose. For oral administration, tablets, coated tablets, capsules, syrups, juices or drops are used in particular; coated tablets and capsules having enteric coatings or capsule shells are especially of interest. For rectal administration, suppositories are used and for parenteral administration solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants.
For administration as an inhalation spray, sprays can be used which contain the active compound either dissolved or suspended in a propellant mixture. The active compound is expediently used in this case in micronized form, it being possible for one or more additional physiologically tolerable solvents to be present, e.g. ethanol. Inhalation solutions can be administered with the aid of customary inhalers. The novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. The preparations indicated can be sterilized and/or contain auxiliaries such as preservatives, stabilizers and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colorants and/or aromatic substances. If desired, they can also contain one or more further active compounds, e.g. one or more vitamins.
As a rule, the substances according to the invention are administered in analogy to other known, commercially available pharmaceuticals, but in particular in analogy to the compounds described in EP-A-459 256, preferably in doses of about 5 mg-1 g, particularly about 50-500 mg per dose unit. The daily dose is preferably about 0.1-20 mg/kg, particularly about 1-10 mg/kg, of body weight. The specific dose for each particular/individual patient depends, however, on all sorts of factors, for example, on the activity of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and route of administration, on the excretion rate, pharmaceutical substance combination and severity of the particular disorder to which the therapy applies. Oral administration is preferred.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight.
The entire disclosure of all applications, patents and publications, cited above and below, and of corresponding German application P 195 04 954.3, filed Feb. 15, 1995, are hereby incorporated by reference.

EXAMPLES
Hereinbefore and hereinafter all temperatures are indicated in .degree.C. In the following examples "customary working up" means: water is added, if necessary, the mixture is adjusted, depending on the constitution of the final product, to a pH of between 2 and 8 and filtered through an ion exchanger, separated off, extracted with, for example, ethyl acetate, dried over sodium sulfate, evaporated, lyophilized if appropriate, and the product is purified by chromatography on silica gel and/or crystallization.
Example 1
3.0 g of 3-[4-(5-oxo-1,2,4-oxadiazolin-3-yl)phenyl]-5-methanesulfonyloxymethyloxazolidin-2-one [obtainable by reaction of 4-(5-oxo-1,2,4-oxadiazolin-3-yl)aniline with 2,3-epoxypropan-1-ol to give N-[4-(5-oxo-1,2,4-oxadiazolin-3-yl)phenyl]-2,3-dihydroxypropylamine, reaction with diethyl carbonate in the presence of K tert-butoxide to give 3-[4-(5-oxo-1,2,4-oxadiazolin-3-yl)phenyl]-5-hydroxymethyloxazolidin-2-one and subsequent esterification with methanesulfonyl chloride], dissolved in 10 ml of DMF, is added to a solution of 1.2 g of 4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidine ("A") in 20 ml of DMF and the mixture is stirred for 60 min at room temperature. After removal of the solvent and customary working up, 3-[4-(5-oxo-1,2,4-oxadiazolin-3-yl)phenyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one is obtained.
Analogously, the following are obtained by reaction of "A"
with 3-(1-methyl-4-piperidyl)-5-methanesulfonyloxymethyloxazolidin-2-one 3-(1-methyl-4-piperidyl)-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-(1-N-BOC-amidino-4-piperidyl)-5-methanesulfonyloxymethyloxazolidin-2-one 3-(1-N-BOC-amidino-4-piperidyl)-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-(1-benzyl-4-piperidylmethyl)-5-methanesulfonyloxymethyloxazolidin-2-one 3-(1-benzyl-4-piperidylmethyl)-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-(1-N-BOC-amidino-4-piperidylmethyl)-5-methanesulfonyloxymethyloxazolidin-2-one 3-(1-N-BOC-amidino-4-piperidylmethyl)-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-[2-(1-benzyl-4-piperidyl)ethyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[2-(1-benzyl-4-piperidyl)ethyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl) oxazolidin-2-one;
with 3-[2-(1-N-BOC-amidino-4-piperidyl)ethyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[2-(1-N-BOC-amidino-4-piperidyl)ethyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl) oxazolidin-2-one;
with 3-[3-(1-benzyl-4-piperidyl)propyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[3-(1-benzyl-4-piperidyl)propyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-[3-(1-N-BOC-amidino-4-piperidyl)propyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[3-(1-N-BOC-amidino-4-piperidyl)propyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-[4-(1-benzyl-4-piperidyl)butyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[4-(1-benzyl-4-piperidyl)butyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-[4-(1-N-BOC-amidino-4-piperidyl)butyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[4-(1-N-BOC-amidino-4-piperidyl)butyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-[2-(1-benzyl-4-piperazinyl)ethyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[2-(1-benzyl-4-piperazinyl)ethyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-[2-(1-N-BOC-amidino-4-piperazinyl)ethyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[2-(1-N-BOC-amidino-4-piperazinyl)ethyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-[3-(1-benzyl-4-piperazinyl)propyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[3-(1-benzyl-4-piperazinyl)propyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-[3-(1-N-BOC-amidino-4-piperazinyl)propyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[3-(1-N-BOC-amidino-4-piperazinyl)propyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-[4-(1-benzyl-4-piperazinyl)butyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[4-(1-benzyl-4-piperazinyl)butyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-[4-(1-N-BOC-amidino-4-piperazinyl)butyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[4-(1-N-BOC-amidino-4-piperazinyl)butyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-(1-methyl-4-piperidyl)-5-methanesulfonyloxymethyloxazolidin-2-one 3-(1-methyl-4-piperidyl)-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-(1-isopropyl-4-piperidyl)-5-methanesulfonyloxymethyloxazolidin-2-one 3-(1-isopropyl-4-piperidyl)-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-(1-tert-butyl-4-piperidylmethyl)-5-methanesulfonyloxymethyloxazolidin-2-one 3-(1-tert-butyl-4-piperidylmethyl)-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-(1-ethyl-4-piperidylmethyl)-5-methanesulfonyloxymethyloxazolidin-2-one 3-(1-ethyl-4-piperidylmethyl)-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-[2-(1-isopropyl-4-piperidyl)ethyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[2-(1-isopropyl-4-piperidyl)ethyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-[2-(1-methyl-4-piperazinyl)ethyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3[2-(1-methyl-4-piperazinyl)ethyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-[3-(1-ethyl-4-piperazinyl)propyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[3-(1-ethyl-4-piperazinyl)propyl]-5-(4-ethoxycarbony 1-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-[3-(1-isopropyl-4-piperazinyl)propyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[3-(1-isopropyl-4-piperazinyl)propyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one;
with 3-[4-(1-propyl-4-piperazinyl)butyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[4-(1-propyl-4-piperazinyl)butyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one.
Example 2
Analogously to Example 1, by reaction of 0.9 g of 1-(1,2-diethoxycarbonylethyl)piperazine ("B") with one equivalent of 3-[4-(5-oxo-1,2,4-oxadiazolin-yl) phenyl]-5-methanesulfonyloxymethyloxazolidin-2-one [obtainable as described in Ex. 1] after removal of the solvent and customary working up, 3-[4-(5-oxo-1,2,4-oxadiazolin-3-yl)phenyl]-5-[4-(1,2-diethoxy-carbonylethyl)piperazinomethyl]oxazolidin-2-one is obtained.
Analogously, the following are obtained by reaction of "B"
with 3-(1-methyl-4-piperidyl)-5-methanesulfonyloxymethyloxazolidin-2-one 3-(1-methyl-4-piperidyl)-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-(1-N-BOC-amidino-4-piperidyl)-5-methanesulfonyloxymethyloxazolidin-2-one 3-(1-N-BOC-amidino-4-piperidyl)-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-(1-benzyl-4-piperidylmethyl)-5-methanesulfonyloxymethyloxazolidin-2-one 3-(1-benzyl-4-piperidylmethyl)-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-(1-N-BOC-amidino-4-piperidylmethyl)-5-methanesulfonyloxymethyloxazolidin-2-one 3-(1-N-BOC-amidino-4-piperidylmethyl)-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-[2-(1-benzyl-4-piperidyl)ethyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[2-(1-benzyl-4-piperidyl)ethyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-[2-(1-N-BOC-amidino-4-piperidyl)ethyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[2-(1-N-BOC-amidino-4-piperidyl)ethyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-[3-(1-benzyl-4-piperidyl)propyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[3-(1-benzyl-4-piperidyl)propyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-[3-(1-N-BOC-amidino-4-piperidyl)propyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[3-(1-N-BOC-amidino-4-piperidyl)propyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-[4-(1-benzyl-4-piperidyl)butyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[4-(1-benzyl-4-piperidyl)butyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-[4-(1-N-BOC-amidino-4-piperidyl)butyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[4-(1-N-BOC-amidino-4-piperidyl)butyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-[2-(1-benzyl-4-piperazinyl)ethyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[2-(1-benzyl-4-piperazinyl)ethyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-[2-(1-N-BOC-amidino-4-piperazinyl)ethyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[2-(1-N-BOC-amidino-4-piperazinyl)ethyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-[3-(1-benzyl-4-piperazinyl)propyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[3-(1-benzyl-4-piperazinyl)propyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-[3-(1-N-BOC-amidino-4-piperazinyl)propyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[3-(1-N-BOC-amidino-4-piperazinyl)propyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-[4-(1-benzyl-4-piperazinyl)butyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[4-(1-benzyl-4-piperazinyl)butyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-[4-(1-N-BOC-amidino-4-piperazinyl)butyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[4-(1-N-BOC-amidino-4-piperazinyl)butyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-(1-methyl-4-piperidyl)-5-methanesulfonyloxymethyloxazolidin-2-one 3-(1-methyl-4-piperidyl)-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-(1-isopropyl-4-piperidyl)-5-methanesulfonyloxymethyloxazolidin-2-one 3-(1-isopropyl-4-piperidyl)-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-(1-tert-butyl-4-piperidylmethyl)-5-methanesulfonyloxymethyloxazolidin-2-one 3-(1-tert-butyl-4-piperidylmethyl)-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-(1-ethyl-4-piperidylmethyl)-5-methanesulfonyloxymethyloxazolidin-2-one 3-(1-ethyl-4-piperidylmethyl)-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-[2-(1-isopropyl-4-piperidyl)ethyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[2-(1-isopropyl-4-piperidyl)ethyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-[2-(1-methyl-4-piperazinyl)ethyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[2-(1-methyl-4-piperazinyl)ethyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-[3-(1-ethyl-4-piperazinyl)propyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[3-(1-ethyl-4-piperazinyl)propyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-[3-(1-isopropyl-4-piperazinyl)propyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[3-(1-isopropyl-4-piperazinyl)propyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-[4-(1-propyl-4-piperazinyl)butyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[4-(1-propyl-4-piperazinyl)butyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one.
Example 3
Analogously to Example 1, starting from 1.6 g of 1-(1,2-diethoxycarbonylethyl)piperazine ("B") by reaction with one equivalent of 3-[4-(5-methyl1,2,4-oxadiazol-3-yl)phenyl]-5-methanesulfonyl-oxymethyloxazolidin-2-one [obtainable by reaction of 4-(5-methyl-1,2,4-oxadiazol-3-yl)aniline with 2,3-epoxypropan-1-ol to give N-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,3-dihydroxypropylamine, reaction with diethyl carbonate in the presence of K tert-butoxide to give 3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-5-hydroxymethyloxazolidin-2-one and subsequent esterification with methanesulfonyl chloride], after customary working up, 3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-5-[4-(1,2-dibenzyloxycarbonylethyl)piperazinomethyl)oxazolidin-2-one, m.p. 119.degree., is obtained.
Example 4
1.3 g of 3-(4-cyanophenyl)-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl)oxazolidin-2-one [obtainable by reaction of 4-cyanoaniline with 2,3-epoxypropan-1-ol to give N-[4-cyanophenyl]-2,3-dihydroxypropylamine, reaction with diethyl carbonate in the presence of K tert-butoxide to give 3-(4-cyano-phenyl)-5-hydroxymethyloxazolidin-2-one, subsequent esterification with methanesulfonyl chloride and reaction with "B"] and 1.1 g of hydroxylamine hydrochloride are boiled for 2 hours in 125 ml of ethanol in the presence of 2.24 g of sodium ethoxide. The reaction mixture is then filtered and concentrated in vacuo. The residue is dissolved in water, the solution is adjusted to pH 3 using 2N hydrochloric acid and the resulting precipitate is filtered off with suction. After recrystallizing from water/glacial acetic acid, 3-[4-amino(hydroxyimino)methylphenyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one, m.p. 186.degree., is obtained.
Example 5
Analogously to Example 1, starting from 1-(1,2dibenzyloxycarbonylethyl)piperazine ("C") by reaction
with 3-(4-N-BOC-aminomethylphenyl)-5(R)-methanesulfonyloxymethyloxazolidin-2-one [obtainable by reaction of 4-N-BOC-aminomethyianiline with 2,3-epoxypropan-1-ol to give N-(4-N-BOC-aminomethylphenyl)-2,3-dihydroxypropylamine, reaction with diethyl carbonate in the presence of K tert-butoxide to give (4-N-BOC-aminomethylphenyl)-5-hydroxymethyl-oxazolidin-2-one and subsequent esterification with methanesulfonyl chloride], after customary working up, 3-(4-N-BOC-aminomethylphenyl)-5(R)-[4-(1,2-dibenzyloxycarbonylethyl)piperazinomethyl]oxazolidin-2-one is obtained.
Analogously, the following are obtained by reaction of "C"
with 3-(1-N-BOC-amidino-4-piperidyl)-5-methanesulfonyloxymethyloxazolidin-2-one 3-(1-N-BOC-amidino-4-piperidyl)-5-[4-(1,2-dibenzyloxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-(1-benzyl-4-piperidylmethyl)-5-methanesulfonyloxymethyloxazolidin-2-one 3-(1-benzyl-4-piperidylmethyl)-5-[4-(1,2-dibenzyloxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-(1-N-BOC-amidino-4-piperidylmethyl)-5-methanesulfonyloxymethyloxazolidin-2-one 3-(1-N-BOC-amidino-4-piperidylmethyl)-5-[4-(1,2-dibenzyloxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-[2-(1-N-BOC-amidino-4-piperazinyl)ethyl]-5-methanesulfonyloxymethyloxazolidin-2-one 3-[2-(1-N-BOC-amidino-4-piperazinyl)ethyl]-5-[4-(1,2-dibenzyloxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
with 3-[3-(1-benzyl-4-piperazinyl)propyl]-5-methanesulfonyloxymethyloxazolidin-2-one3-[3-(1-benzyl-4-piperazinyl)propyl]-5-[4-(1,2-dibenzyloxycarbonylethyl)piperazinomethyl]oxazolidin-2-one.
Example 6
0.9 g of 3-(1-N-BOC-amidino-4-piperidyl)-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)oxazolidin-2-one[obtainable according to Ex. 1] are suspended in 40 ml of 2N HCl solution based on dioxane and stirred at room temperature for 3 hours. After removal of the solvent and customary working up, 3-(1-amidino-4-piperidyl)-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one, hydrochloride is obtained.
Analogously, the following are obtained after removal of the BOC protective group of the products from Example 1.
3-(1-amidino-4-piperidylmethyl)-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one, hydrochloride;
3-[2-(1-amidino-4-piperidyl)ethyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one, hydrochloride;
3-[3-(1-amidino-4-piperidyl)propyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one, hydrochloride;
3-[4-(1-amidino-4-piperidyl)butyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one, hydrochloride;
3-[2-(1-amidino-4-piperazinyl)ethyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one, hydrochloride;
3-[3-(1-amidino-4-piperazinyl)propyl]-5-(4ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one, hydrochloride;
3-[4-(1-amidino-4-piperazinyl)butyl]-5-(4ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one, hydrochloride.
Example 7
Analogously to Example 6, starting from the compounds of Example 2 by removal of the BOC protective groups, the following compounds are obtained in the form of their hydrochlorides:
3-(1-amidino-4-piperidyl)-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
3-(1-amidino-4-piperidylmethyl)-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
3-[2-(1-amidino-4-piperidyl)ethyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
3-[3-(1-amidino-4-piperidyl)propyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
3-[4-(1-amidino-4-piperidyl)butyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
3-[2-(1-amidino-4-piperazinyl)ethyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
3-[3-(1-amidino-4-piperazinyl)propyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
3-[4-(1-N-BOC-amidino-4-piperazinyl)butyl]-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one.
Analogously to Example 6, starting from the compounds of Example 5 by removal of the BOC protective groups, the following compounds are obtained:
3-(4-aminomethylphenyl)-5(R)-[4-(1,2-dibenzyloxycarbonylethyl)piperazinomethyl]oxazolidin-2-one, trihydrochloride hydrate, m.p. 187.degree.;
3-(1-amidino-4-piperidyl)-5-[4-(1,2-dibenzyloxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
3-(1-amidino-4-piperidylmethyl)-5-[4-(1,2-dibenzyloxycarbonylethyl)piperazinomethyl]oxazolidin-2-one;
3-[2-(1-amidino-4-piperazinyl)ethyl]-5-[4-(1,2-dibenzyloxycarbonylethyl)piperazinomethyl]oxazolidin-2-one.
Example 8
1.1 g of 3-(4-chloromethylphenyl)-5(R)-[4-(1,2di-benzyloxycarbonylethyl)piperazinomethyl]oxazolidin-2-one [obtainable by reaction of 4-chloromethylaniline with 2,3-epoxypropan-1-ol to give N-(4-chloro-methylphenyl)-2,3-dihydroxypropylamine, reaction with diethyl carbonate in the presence of K tert-butoxide to give 3-(4-chloromethylphenyl)-5-hydroxymethyl-oxazolidin-2-one, subsequent esterification with methanesulfonyl chloride and reaction with 1-(1,2-dibenzyloxycarbonylethyl)piperazine], dissolved in 30 ml of DMF, are treated at room temperature with 0.9 g of freshly prepared guanidine, dissolved in 10 ml of DMF, and the mixture is stirred for two hours. After removal of the solvent and customary working up, 3-(4-guanidinylmethylphenyl)-5(R)-[4-(1,2-dibenzyloxycarbonylethyl)piperazinomethyl]oxazolidin-2-one is obtained.
Example 9
1.1 g of 3-(4-aminomethylphenyl)-5(R)-[4-(1,2dibenzyloxycarbonylethyl)piperazino-methyl]oxazolidin-2-one (hydrochloride trihydrate, m.p. 187.degree.) are dissolved in 30 ml of toluene and treated at room temperature for one hour with hydrogen gas (p=1 atm) with catalytic action of 150 mg of Pd--C (Pd content 1%). The reaction mixture is then filtered and, after customary working up, 3-(4-aminome thylphenyl)-5(R)-[4-(1,2-dicarboxyethyl)piperazino-methyl]-oxazolidin-2-one, trihydrochloride hydrate, m.p. 200.degree., is obtained.
Analogously, by removal of the benzyl groups from 3-(4-guanidinylmethylphenyl)-5(R)-[4-(1,2-dibenzyloxycarbonylethyl)piperazinomethyl]oxazolidin-2-one 3-(4-guanidinylmethylphenyl)-5(R)-[4-(1,2-dicarboxyethyl)piperazinomethyl]oxazolidin-2-one, m.p. 262.degree., is obtained.
Example 10
1.3 g of 3-[4-(5-oxo-1,2,4-oxadiazolin-3-yl)phenyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one [obtainable according to Ex. 1] are dissolved in 50 ml of methanol and hydrogenated on Raney nickel. The reaction mixture is then filtered and the filtrate is concentrated in vacuo. The product obtained is treated with 20 ml of ethyl acetate in the presence of heat and filtered off with suction after cooling. 3-(4-Amidinophenyl)-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one, hydroiodide, m.p. 123.degree., is obtained.
Example 11
Analogously to Example 9, by reductive cleavage of the 5-oxo-1,2,4-oxadiazoline group, starting from 3-[4-(5-oxo-1,2,4-oxadiazolin-3-yl)phenyl]5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl)oxazolidin-2-one, after customary working up, 3-(4-amidinophenyl)-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one, acetate, m.p. 179.degree., is obtained.
Example 12
20 ml of 20% NaOH solution are added to a solution of 0.3 g of 3-(4-amidinophenyl)-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)-oxazolidin-2-one in 20 ml of THF and the mixture is stirred at room temperature for 24 hours. After removal of the solvent and freeze-drying, 3-(4-amidino-phenyl)-5-(4-carboxy-4-carboxymethylpiperidinomethyl)-oxazolidin-2-one Na salt, m.p.>330.degree., is obtained.
Analogously, from 3-(4-amidinophenyl)-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one 3-(4-amidinophenyl)-5-[4-(1,2-dicarboxyethyl)piperazinomethyl]oxazolidin-2-one Na salt, dihydrate, m.p. >300.degree., is obtained.
Example 13
0.8 g of 3-(4-amidinophenyl)-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)-oxazolidin-2-one [obtainable accord to Ex. 9] are suspended in 60 ml of methanol, treated with 10 ml of 2N of NaOH solution and stirred at room temperature for 4 hours. After removal of the solvent, the residue is taken up in water, the pH is adjusted to 3 by addition of dilute HCl and the reaction mixture is filtered through an ion exchanger. After extraction with ethyl acetate the filtrate is dried over MgSO.sub.4. After removal of the solvent and subsequent freeze-drying, 3-(4-amidinophenyl)-5-(4-carboxy-4-carboxymethylpiperidinomethyl)oxazolidin-2-one is obtained.
Analogously, the following are obtained by hydrolysis
of 3-(4-amidinophenyl)-5-[4-(1,2-diethoxycarbonylethyl)piperazinomethyl]oxazolidin-2-one 3-(4-amidinophenyl)-5-[4-(1,2-dicarboxy-ethyl)piperazinomethyl]oxazolidin-2-one acetate, m.p. 145.degree.;
of 3-(1-methyl-4-piperidyl)-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one 3-(1-methyl-4-piperidyl)-5-(4-carboxy-4-carboxymethylpiperidinomethyl)oxazolidin-2-one;
of 3-(1-benzyl-4-piperidylmethyl)-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one 3-(1-benzyl-4-piperidylmethyl)-5-(4-carboxy-4-carboxymethylpiperidinomethyl)oxazolidin-2-one;
of 3-[2-(1-benzyl-4-piperidyl)ethyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one 3-[2-[(1-benzyl-4-piperidyl)ethyl]-5-(4-carboxy-4-carboxymethylpiperidinomethyl)oxazolidin-2-one;
of 3-[3-(1-benzyl-4-piperidyl)propyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one 3-[3-(1-benzyl-4-piperidyl)propyl]-5-(4-carboxy-4-carboxymethylpiperidinomethyl)oxazolidin-2-one;
of 3-[4-(1-benzyl-4-piperidyl)butyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one 3-[4-(1-benzyl-4-piperidyl)butyl]-5-(4-carboxy-4-carboxymethylpiperidinomethyl)oxazolidin-2-one;
of 3-[2-(1-benzyl-4-piperazinyl)ethyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one 3-[2-(1-benzyl-4-piperazinyl)ethyl]-5-(4-carboxy-4-carboxymethylpiperidinomethyl)oxazolidin-2-one;
of 3-[3-(1-benzyl-4-piperazinyl)propyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one 3-[3-(1-benzyl-4-piperazinyl)propyl]-5-(4-carboxy-4-carboxymethylpiperidinomethyl)oxazolidin-2-one;
of 3-[4-(1-benzyl-4-piperazinyl)butyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one 3-[4-(1-benzyl-4-piperazinyl)butyl]-5-(4-carboxy-4-carboxymethylpiperidinomethyl)oxazolidin-2-one;
of 3-(1-methyl-4-piperidyl)-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one 3-(1-methyl-4-piperidyl)-5-(4-carboxy-4-carboxymethylpiperidinomethyl)oxazolidin-2-one;
of 3-(1-isopropyl-4-piperidyl)-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one 3-(1-isopropyl-4-piperidyl)-5-(4-carboxy-4-carboxymethylpiperidinomethyl)oxazolidin-2-one;
of 3-(1-tert-butyl-4-piperidylmethyl)-5-(4-ethoxycarbonyl-4ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one 3-(1-tert-butyl-4-piperidylmethyl)-5-(4-carboxy-4-carboxymethylpiperidinomethyl)oxazolidin-2-one;
of 3-(1-ethyl-4-piperidylmethyl)-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one 3-(1ethyl-4-piperidylmethyl)-5-(4-carboxy-4-carboxymethylpiperidinomethyl)oxazolidin-2-one;
of 3-[2-(1-isopropyl-4-piperidyl)ethyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one 3-[2-(1-isopropyl-4-piperidyl)ethyl]-5-(4-carboxy-4-carboxymethylpiperidinomethyl)oxazolidin-2-one;
of 3-[2-(1-methyl-4-piperazinyl)ethyl]-5-(4-ethoxy-carbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one 3-[2-(1-methyl-4-piperazinyl)ethyl]-5-(4-carboxy-4-carboxymethylpiperidinomethyl)oxazolidin-2-one;
of 3-[3-(1-ethyl-4-piperazinyl)propyl]-5-(4-ethoxy-carbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one 3-[3-(1-ethyl-4-piperazinyl)propyl]-5-(4-carboxy-4-carboxymethylpiperidinomethyl)oxazolidin-2-one;
of 3-[3-(1-isopropyl-4-piperazinyl)propyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one 3-[3-(1-isopropyl-4-piperazinyl)propyl]-5-(4-carboxy-4-carboxymethylpiperidinomethyl)oxazolidin-2-one;
of 3-[4-(1-propyl-4-piperazinyl)butyl]-5-(4-ethoxycarbonyl-4-ethoxycarbonylmethylpiperidinomethyl)oxazolidin-2-one 3-[4-(1-propyl-4-piperazinyl)butyl]-5-(4-carboxy-4-carboxymethylpiperidinomethyl)oxazolidin-2-one.
Example 14
Analogously to Example 1, by reaction of 1,3 g 1-(1,2-diethoxycarbonylethyl)piperazine ("B") with one equivalent of 3-[4-(methyl-1,2,4-oxadiazolin-3-yl)phenyl]-5-methanesulfonyloxymethyloxazolidin-2-one [obtainable by reaction of 4-cyanoaniline with 2,3-epoxypropan-1-ol to give N-[4-cyano-phenyl]-2,3-dihydroxypropylamine, reaction with diethyl carbonate in the presence of K tert-butoxide to give 3-(4-cyano-phenyl)-5-hydroxymethyl-oxazolidin-2-one, reaction of the nitrile with hydroxylamine and subsequently with acetyl chloride to give 3-[4-(5-methyl-1,2,4-oxadiazolin-3-yl)phenyl]-5-hydroxymethyl-oxazolidin-2-one and subsequent esterification with methanesulfonyl chloride] after removal of the solvent and customary working up 3-[4-(5-methyl-1,2,4-oxadiazolin-3-yl)phenyl]-5-[4-(1,2-di-ethoxycarbonyl-ethyl)-piperazinomethyl]-oxazolidin- 2-one is obtained, m.p. 126.degree.-127.degree..
Analogously the following are obtained by reaction of "B"
with 3-[4-(5-phenyl-1,2,4-oxadiazolin-3-yl)phenyl]-5-methanesulfonyloxymethyl-oxazolidin-2-one 3-[4-(5-phenyl-1,2,4-oxadiazolin-3-yl)phenyl]-5-[4-(1,2-di-ethoxycarbonyl-ethyl)-piperazinomethyl]-oxazolidin-2-one.
Example 15
1,3 g 3-[4-(5-phenyl-1,2,4-oxadiazolin-3-yl)phenyl]-5-[4-(1,2-diethoxycarbonyl-ethyl)-piperazinomethyl]-oxazolidin-2-one [obtainable as described in Ex. 14] are dissolved in 50 ml methanol and hydrogenated on Raney nickel. The reaction mixture is then filtered and the filtrate is concentrated in vacuo. The product obtained is treated with 20 ml of ethyl acetate in the presence of heat and filtered off with suction after cooling. 3-[4-(N-benzoylamidino)-phenyl]-5-[4-(1,2-diethoxycarbonylethyl)-piperazinomethyl]-oxazolidin-2-one, m.p. 136.degree., is obtained.
The following examples relate to pharmaceutical preparations:
Example A: Injection Vials
A solution of 100 g of an active compound of
The following examples relate to pharmaceutical preparations:
Example A: Injection Vials
A solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate are adjusted to pH 6.5 in 31 of double-distilled water using 2N hydrochloric acid, sterile-filtered, filled into injection vials, lyophilized under sterile conditions and sealed aseptically. Each injection vial contains 5 mg of active compound.
Example B: Suppositories
A mixture of 20 g of an active compound of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allowed to cool. Each suppository contains 20 mg of active compound.
Example C: Solution
A solution is prepared from 1 g of an active compound of the formula I, 9.38 g of NaH.sub.2 PO.sub.4 .multidot.2H.sub.2 O, 28.48 g of Na2HPO4.multidot.2H2O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. The solution is adjusted to pH 6.8, made up to 11 and sterilized by irradiation. This solution can be used in the form of eye drops.
Example D: Ointment
500 mg of an active compound of the formula I is mixed with 99.5 g of petroleum jelly under aseptic conditions.
Example E: Tablets
A mixture of 1 kg of active compound of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in a customary manner to give tablets such that each tablet contains 10 mg of active compound.
Example F: Coated tablets
Analogously to Example E, tablets are pressed which are then coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
Example G: Capsules
2 kg of active compound of the formula I are filled into hard gelatin capsules in a customary manner such that each capsule contains 20 mg of the active compound.
Example H: Ampoules
A solution of 1 kg of active compound of the formula I in 60 1 of double-distilled water is sterile-filtered, filled into ampoules, lyophilized under sterile conditions and sealed aseptically. Each ampoule contains 10 mg of active compound.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Number	Name	Date
3856962	Alphin et al.	Dec 1974
4970217	Pr ucher et al.	Nov 1990
5053393	Tjoeng et al.	Oct 1991
5256812	Alig et al.	Oct 1993
5399585	Alig et al.	Mar 1995
5532255	Raddatz et al.	Jul 1996

Number	Date	Country
7736191	Dec 1991	AUX
2008311	Jul 1990	CAX
2036586	Aug 1991	CAX
2122571	Nov 1994	CAX
0294307	Dec 1988	EPX
0381033	Aug 1990	EPX
0459256	Dec 1991	EPX
0462960	Dec 1991	EPX

Adhesion receptor antagonists

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Nierodzick, M. L. et al. Thrombosis and Haemostasis, 1995 (Jul), 74(1), pp. 282-290.
Valentin-Weigand et al., Infection and Immunity, 56(11):2851-2855 (Nov. 1988) Born, Nature, 194(4832):927-929 (Jun. 9, 1962).