Background of the Invention One process for coupling amino-substituted benzopyrans and benzoyl derivatives is described in U. S. Patent 5,731,324 at pages 147 and 148 (Examples E and F).

However, that process of coupling a carbonyl nitrile derivative to the amino-substituted benzopyran and converting the cyano group to an aminoiminomethyl group (amidino group) has an overall yield of 36% which may not be desirable for commercial production.

Further, if the bicyclic starting material is a resolved single enantiomer, the loss of 64% of the enantiomer in the coupling step is very expensive. The carbonyl nitrile derivative may be substituted by various groups as described in U. S. Patent 5,731,324, such as halogen, see for example, Scheme 17 on pages 77-78, wherein 2-fluoro-4-cyano benzoic acid is coupled with a tetralone compound.

Summary of the Invention In one aspect, there are provided novel processes for producing amino substituted bicyclic compounds such as racemic, (6-amino-chroman-2-yl) acetic acid esters, and resolving such bicyclic compounds into either the R or S enantiomer. There are also provided novel processes for producing amidino-substituted benzoyl compounds, wherein the phenyl ring may be substituted with lower (Cl-C6) alkyl, lower (Cl-C,) alkoxy,, halo (Cl, F, Br, I), and the like, which are intermediates for coupling with bicyclic compounds to produce therapeutic agents, or are themselves therapeutic agents, for disease states in mammals that have disorders caused by or impacted by platelet dependent narrowing of the blood supply. There is also provided a coupling process for coupling a benzoyl derivative salt with an amine salt of a bicyclic compound to form such therapeutic agents.

The compounds produced by the coupling reactions, whether racemic mixtures, materials comprised primarily of one of the R and S enantiomers, or materials comprised of one of the R and S enantiomers which is substantially free of the other of said enantiomers, are all effective therapeutic agents for inhibition of platelet aggregation. It has surprisingly been found, however, that the S enantiomer form, an example of which is shown below, generally has greater activity than the R enantiomer form.

2-{(2S)-6-[(4-amidino-2-fluorophenyl) carbonylamino] chroman-2-yl} acetic acid In accordance with a preferred embodiment, there is provided a compound or a pharmaceutical acceptable salt or solvate thereof, selected from: wherein R is hydrogen or halogen, and R, is hydrogen or alkyl ; wherein said compound is present in pure, substantially pure or enriched form. In a preferred embodiment, R is fluorine and R, is ethyl. In another embodiment, there is provided a pharmaceutical formulation comprising one of the compounds above and a pharmaceutical acceptable carrier, excipient or diluent. Other embodiments involve using the above compounds or pharmaceutical formulations to inhibit platelet aggregation or to treat a mammal suffering from any of a variety of conditions characterized by platelet aggregation or thrombosis formation.

In accordance with another embodiment, there is provided a process for making a compound selected from the following formulae : wherein R is an alkyl group. The process comprises reactions (a) through (d) below : (a) reacting an alkyl ester of racemic (6-aminochroman-2-yl) acetic acid with pyridine and an acyl halide in a suitable organic solvent or solvent system to form the alkyl ester of racemic (6-alkylamidochroman-2-yl) acetic acid as follows :

where R'is an alkyl group; (b) converting the alkyl ester of racemic (6-alkylamidochroman-2-yl) acetic acid to the free acid such as by addition of a strong base such as aqueous sodium hydroxide, followed by treatment with acid, such as hydrochloric acid, to form the acid as follows :

(c) reacting the racemic (6-alkylamidochroman-2-yl) acetic acid with (L) or (D) alaninol in a suitable solvent to form a diastereomeric salt, wherein the (L) alaninol is added if the alkyl ester of (2R)- (6-aminochroman-2-yl) acetic acid is the desired product and the (D) alaninol is added if the alkyl ester of (2S)- (6-aminochroman-2-yf) acetic acid is the desired product; and (d) refluxing the diastereomeric salt in an alcoholic acid solution, followed by adding a base such as sodium hydrogen carbonate in a suitable organic solvent, and adding an ethereal acid solution to precipitate either the (2R) or (2S) alkyl ester of (6- aminochroman-2-yl) acetic acid at an enantiomeric excess of at least 70% as follows :

In accordance with another embodiment, there is provided a process for making a compound according to the formula: wherein R is hydrogen or halogen. The process comprises (a) and (b) as follows :

(a) reacting 4-cyano-2-R-benzoic acid with lithium bis (trimethylsilyl) amide in a suitable solvent such as anhydrous THF to form 4-amidino-2-R-benzoic acid as follows : (b) reacting the 4-amidino-2-R-benzoic acid from step (a) with hydrochloric acid in a suitable solvent such as dimethylformamide to form the product as follows : In accordance with another embodiment, there is provided a process for making a bicyclic compound based on the ring system AB, having optional unsaturated bonds, according to the formula wherein R is hydrogen or halogen ; R'is alkyl ; z is a number from 1 to 6; B1, B2, B3, and B4 are carbon, nitrogen or oxygen; Ro and Rio are independently selected from the group consisting of C110 alkyl, C110 halosubstituted alkyl, C210 alkenyl, C210 alkynyl, C110 alkoxy, halo, and =O, with the proviso that if Ro is =O, then only one of B,, B2, B3, and B4 may be nitrogen; m is a number from 0 to 3; and n is a number from 0 to 3. The method comprises (a) through (c) below : (a) preparing a suspension of a salt of a 4-amidino-2-R-benzoyl halide : in acetonitrile with heating, wherein X is a halogen ; (b) preparing a suspension of a salt of a bicyclic intermediate compound according to the formula : in acetonitrile and pyridine, wherein R3 is (CH2) C (O) OR' ; and (c) adding the suspension from step (b) to the heated suspension from step (a) to couple the compounds as follows :

In preferred embodiments, the salt of the 4-amidino-2-benzoyl halide and the salt of the bicyclic intermediate compound are as follows : such that the bicyclic compound formed is:

Minor alterations, including, but not limited to use of salts other than HCI salts and use of acyl halides other than acyl chlorides may be made to the reactions shown herein.

Such minor alterations are within the scope of the disclosure herein. Although the esters shown are primarily ethyl esters, other esters may be made, either by use of different solvents and/or reagents in the initial formation reactions or by transesterification.

Detailed Description of the Preferred Embodiments Processes for Producing The Bicydic Ring Portion for Coupling In view of the processes known in the art, there is a need for improved coupling processes for producing aminoiminomethylbenzoyl compound coupled via an amide bond to bicyclic intermediates for producing platelet aggregation inhibitors. Also, there is a need for improved intermediates of bicyclic compounds such as benzopyrans substituted by an amino group or a protected amino group and carbonyl derivatives (or salts thereof) which are useful as intermediates for coupling with an carbonyl group to produce a carboxamide link and result in compounds that are useful platelet aggregation inhibitors or are intermediates for forming platelet aggregation inhibitors. Also needed is a process to produce relatively inexpensively large quantities of such intermediates that are useful for producing substantially pure compositions of a single enantiomer (R or S enantiomer) of the platelet aggregation inhibitor compounds. One or more of the foregoing needs may be met using the processes described herein and the compounds and intermediates made thereby.

For the purposes of the disclosure herein, any amino substituted bicyclic compound useful for making platelet aggregation inhibitor compounds may be utilized for the coupling reaction step, examples of such bicyclic compounds can be found at pages 5-6 of U. S. patent 5,731,324, the entire disclosure of which is hereby incorporated by reference. For exemplification purposes, in the paragraph bridging pages 147 and 148 of that patent there is described a bicyclic free amino-substituted acetic acid ester compound (described as a dark oil) having the following formula: If desired, one or both of the amino group and the ester group of the acetic acid side chain can be modified with a group which can be utilized to resolve the R and S enantiomers.

For example, the ester group can be reacted resolved with a conventional camphor sulfonic acid derivative, a dibenzoyl tartaric acid derivative, (L) or (D) alaninol, and the like, for example) to produce a desired enantiomer. The amino group can be protected by converting the it to an acetamido group, as follows : 0 0 Pyridine and 0 0 Acetyl Chloride t t H2N (Toluene/CH30H 0 /"0 O In a preferred embodiment, the racemic ethyl (6-acetamidochroman-2-yl) acetate is converted to the free acid by reaction with a base such as sodium hydroxide and neutralized with an acid such as hydrochloric acid. Preferably, the free acid is then

reacted with a slight excess of 1/2 mole of (L) or (D) alaninol per mole of'racemate in the presence of methanol. One of the enantiomers will preferentially react with the alaninol and crystallize out (depending upon whether (L) or (D) alaninol is used as the reactant).

The crystalline salt can be rinsed by an appropriate solvent such as isopropyl alcohol and may be further purified by recrystallization in an appropriate solvent such as methanol or a mixture of isopropanol and ethanol, and the like. This procedures and the optional recrystallization result in an enriched, essentially pure, or pure crystalline composition of the alaninol salt of either the (R) or (S) enantiomer.

Both the alaninol and the amino protecting group can be removed from the crystalline alaninol salt by heating the salt in an appropriate solvent in the presence of an acid. Preferably, the acid is sulfuric acid and the solvent is absolute ethanol. Upon concentration of the reaction mixture by evaporation of the solvent, the mixture is neutralized with an appropriate base (such as sodium hydrogen carbonate and the like) in the presence of an appropriate solvent (such as toluene and the like). The aqueous layer can be separated from the organic layer and the aqueous layer extracted with toluene.

After pooling of the organic layers, an acid halide can be added to precipitate the amino halide salt from the toluene solvent as follows : IO :,,.. o O I O alanino I H2S04/Ethanol o ,, y0 HNa ninol Toluene/NaH (C03) H N" \ 0-_ then HCI/Toluene2 . HCI The halide salt can optionally be recrystallized in an appropriate solvent such ethanol, ethyl acetate, ethanol/isopropyl alcohol, and the like to produce a higher enantiomeric purity. Preferably, the crude enantiomer is heated in absolute alcohol or denatured absolute alcohol (no methanol) or the like, and recrystallized. If the preferred enantiomer remains in the solvent, the solvent can be evaporated to yield the more pure form of the single enantiomer halide salt.

In the above description, an alcoholic sulfuric acid solution followed by an alcoholic HCI solution are utilized for the esterification and to cause the amino group to form a hydrochloride salt, but other esters such as the methyl or propyl ester may likewise be envisioned. The purity of the enantiomer my be optionally improved by recrystallization, HPLC or the like. The preferred solvent for recrystallization is methanol or isopropyl alcohol or a mixture. In either event, after resolving the desired (2S or 2R)-enantiomer and obtaining the 2-carboxylic acid form of the molecule, the acidic alcoholic solutions may be added to the free acid R or S enantiomer compound to form the 2-carboxylic acid ethyl ester (or another ester) and an excess of HCI is then utilized to produce the hydrochloride salt of the amino group.

The amino halide salt of the bicyclic compound thus produced can be utilized in a coupling reaction with a carbonyl compound or a halide salt of a carbonyl compound to provide a carboxamide coupled compound, as described in greater detail below.

Processes for Producing The Carbonyl Substituted Ring Portion for Coupling For the purposes of the present disclosure any basic substituted carbonyl group useful for making platelet aggregation inhibitor compounds may be utilized for the coupling reaction step. Examples of preferred carbonyl derivative compounds are those in U. S. patent 5,731,324, particularly at pages 17-20, and more preferably, are the substituted or unsubstituted amidino-benzoyl or amidino thiophenoyl derivatives. Even more preferably, the carbonyl derivative is an amidino benzoyl derivative, which is optionally substituted by a halogen atom. Such compounds include those selected from the group consisting of 4- amidinobenzoic acid, 4-amidino-2-fluorobenzoicacid, 4-amidino-2-bromobenzoic acid, 4- amidino-2-iodobenzoic acid and 4-amidino-2-chlorobenzoic acid. For exemplification purposes, on page 20, at formula IV, is shown coupled 4-amidino-2-fluorobenzoic acid, which is readily obtained from the nitrile shown in Scheme 17, pages 77-78, by converting the cyano group to a carbamidoyl group using procedures described in the patent 5,731,324. Alternatively, the acid halide of the coupled 4-carbamidoyl-2-halobenzoic acid can be made as follows : vOH C R R lithium bis (trimethylsilylj amide and THF 4-cyano-2-R- -- ' JL-rLJ benzoicacid OH HN R Cone.HCI NH2 DMF 4-amidino-2-R- benzoic acid He.ci HN<R NH2 where R is H or halogen. 4-amidino-2-R-benzoyl chloride hydrochloride Preferably, the acid halide for coupling is 4-amidino-2-fluorobenzoyl chloride or 4- amidinobenzoyl halide.

Processes, for Coupling the Amine Salt and the Acyl Halide Salt to Form a Carboxamide For the purposes of the present disclosure any salt of an aminobicyclic compound and any basic substituted carbonyl group that are useful for coupling to make platelet aggregation inhibitor compounds may be utilized for the coupling reaction step. However,

for purposes of illustration only, the above described ethyl (R or S) (6-aminochroman-2- yl) acetate hydrochloride and 4-amidino-2-fluorobenzoyl chloride, will be utilized. The acyl chloride is suspended in anhydrous acetonitrile and stirred. A suspension of the bicyclic amino hydrochloride salt in pyridine and anhydrous acetonitrile is added rapidly with stirring at about 10 to about 40 degrees centigrade (preferably at about 20°C) and stirring is continued for about 10-30 minutes (preferably for about 15 minutes) to result in coupling. This coupling step may be illustrated as follows : HUI CI form acetonitrile suspensions separately then add bicyclic suspension to benzoic acid /R suspension NH2 PO 4-amidino-2-R-benzoyl chloridehydrochlorid 0 Stirredacetonitrile suspension in H N I/O anhydrous toluene 2N \. HCI ethyl (2R) or (2S) (6-aminochroman-2-yl) acetate hydrochloride \ Stirred acetonitrile suspension to which pyridine has been slowly added rapid addition of bicyclic suspension from 28-30°C to 38-42°C with stirring undernitrogen ON s O HN 4d .HCI \ HN HN+R NH2

The solid obtained from the coupling step illustrated above can be filtered, washed with anhydrous acetonitrile and dried at about 40 °C to about 60 °C (preferably at about 50°C) under reduced pressure. Optionally, the solid can be further purified by recrystallized in an appropriate solvent The recrystallization solvent may be water or a lower alcohol such as ethanol, propanol, isopropanol. Alternatively, a mixed alcohol solve nvanti-solve nt can be used as the recrystallization solvent, an example would be ethanol/isopropanol in a ratio of about 1: 1 to about 1: 6, preferably about 1: 5, which may be optimized by simple testing.

The (S) and (R) enantiomers of ethyl (6- (4-amidino-2-fluorobenzoyl) amino- chroman-2-yl) acetate (and other compounds produced by the above methods but utilizing the different carbonyl and bicyclic structures set forth in U. S. patent 5,731,324) may be

used as potent therapeutic agents therapeutic agents for disease states in mammals which have disorders that are due to platelet dependent narrowing of the blood supply, such as atherosclerosis and arteriosclerosis, acute myocardial infarction, chronic stable angina, unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis following angioplasty, carotid endarterectomy, anastomosis of vascular grafts, and etc. These conditions represent a variety of disorders thought to be initiated by platelet activation on vessel walls.

Therefore, in accordance with one preferred embodiment such (S) and (R) enantiomers are provided in pure, substantially pure or enriched form as therapeutic agents for treating such disorders, and pharmaceutical compositions comprising an effective amount of such compounds.

Also, in accordance with preferred embodiments there is provided a method comprising administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of either the (S) and (R) enantiomers of ethyl (6- (4- amidino-2-fluorobenzoyl) amino-chroman-2-yl) acetate, the free acid, or other esters and salts thereof.

Uses of the Compounds, Compositions and Formulations As mentioned above, the compounds disclosed herein find utility as intermediates for producing therapeutic agents or as therapeutic agents for disease states in mammals which have disorders that are due to platelet dependent narrowing of the blood supply, such as atherosclerosis and arteriosclerosis, acute myocardial infarction, chronic stable angina, unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis following angioplasty, carotid endarterectomy, anastomosis of vascular grafts, and etc. These conditions represent a variety of disorders thought to be initiated by platelet activation on vessel walls.

Platelet adhesion and aggregation is believed to be an important part of thrombus formation. This activity is mediated by a number of platelet adhesive glycoproteins. The binding sites for fibrinogen, fibronectin and other clotting factors have been located on the platelet membrane glycoprotein complex llb/lila. When a platelet is activated by an agonist such as thrombin the GP llb/lila binding site becomes available to fibrinogen, eventually resulting in platelet aggregation and clot formation. Thus, intermediate compounds for producing compounds that effective in the inhibition of platelet aggregation and reduction of the incidence of clot formation are useful intermediate compounds.

The compounds produced according to the methods disclosed herein may used as intermediates for producing therapeutic compounds or as compounds that may be administered in combination or in concert with other therapeutic or diagnostic agents. In certain preferred embodiments, the compounds produced by the intermediates according to the disclosure herein may be co-administered along with other compounds typically prescribed for these conditions according to generally accepted medical practice such as

anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or. warfarin. The compounds produced from the intermediates according to preferred embodiments may act in a synergistic fashion to prevent reocclusion following a successful thrombolytic therapy and/or reduce the time to reperfusion. Such compounds may also allow for reduced doses of the thrombolytic agents to be used and therefore minimize potential hemorrhagic side-effects. Such compounds can be utilized in vivo, ordinarily in mammals such as primates, (e. g. humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.

The starting materials used in above processes are commercially available from chemical vendors such as Aldrich, Sigma, Nova Biochemicals, Bachem Biosciences, and the like, or may be readily synthesized by known procedures, for example, by using procedures such as indicated above.

Reactions are carried out in standard laboratory glassware and reaction vessels under reaction conditions of standard temperature and pressure, except where otherwise indicated, or is well-know in literature available in the art. Further, the above procedures of the processes described herein may be carried out on a commercial scale by utilizing reactors and standard scale-up equipment available in the art for producing large amounts of compounds in the commercial environment. Such equipment and scale-up procedures are well-know to the ordinary practitioner in the field of commercial chemical production.

During the synthesis of these compounds, amino or acid functional groups may be protected by blocking groups to prevent undesired reactions with the amino group during certain procedures. Examples of suitable blocking groups are well known in the art.

Further, removal of amino or acid blocking groups by procedures such as acidification or hydrogenation are well-know in the art.

Preferred Compositions and Formulations The compounds according to preferred embodiments may be isolated as the free acid or base or converted to salts of various inorganic and organic acids and bases. Such salts are within the scope of this disclosure and are presently contemplated. Non-toxic and physiologically compatible salts are particularly useful although other less desirable salts may have use in the processes of isolation and purification.

A number of methods are useful for the preparation of the salts described above and are known to those skilled in the art. For example, reaction of the free acid or free base form of a compound of the structures recited above with one or more molar equivalents of the desired acid or base in a solvent or solvent mixture in which the salt is insoluble, or in a solvent like water after which the solvent is removed by evaporation, distillation or freeze drying. Alternatively, the free acid or base form of the product may be passed over an ion exchange resin to form the desired salt or one salt form of the product may be converted to another using the same general process.

Diagnostic applications of compounds according to preferred embodiments disclosed herein will typically utilize formulations such as solution or suspension. In the

management of thrombotic disorders preferred compounds according to the present disclosure may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories, sterile solutions or suspensions for injectable or parenteral administration, and the like, or incorporated into shaped articles. Subjects in need of treatment (typically mammalian) using the compounds according to the present disclosure can be administered dosages that will provide optimal efficacy. The dose and method of administration will vary from subject to subject and be dependent upon such factors as the type of mammal being treated, its sex, weight, diet, concurrent medication, overall clinical condition, the particular compounds employed, the specific use for which these compounds are employed, and other factors which those skilled in the medical arts will recognize.

Formulations of the compounds disclosed herein are prepared for storage or administration by mixing the compound, or a pharmaceutical acceptable salt, solvate or prodrug thereof, having a desired degree of purity with physiologically acceptable carriers, excipients, stabilizers etc., and may be provided in sustained release or timed release formulations. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A. R. Gennaro edit. 1985). Such materials are nontoxic to the recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate and other organic acid salts, antioxidants such as ascorbic acid, low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidinone, amino acids such as glycine, glutamic acid, aspartic acid, or arginine, monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins, cheating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counter ions such as sodium and/or nonionic surfactants such as Tween, Pluronics or polyethyleneglycol.

Dosage formulations of the present compounds to be used for parenteral administration are preferably sterile. Sterility is readily accomplished by filtration through sterile membranes such as 0.2 micron membranes, or by other conventional methods known to those skilled in the art. Formulations are preferably stored in lyophilized form or as an aqueous solution. The pH of the preparations are preferably between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of cyclic polypeptide salts. While the preferred route of administration is by injection, other methods of administration are also anticipated such as intravenously (bolus and/or infusion), subcutaneously, intramuscularly, colonically, rectally, nasally or intraperitoneally, employing a variety of dosage forms such as suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches. The compounds according to the present disclosure are desirably incorporated into shaped articles such as implants which may employ inert

materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers commercially available.

The compounds according to the present disclosure may also be administered in the form of liposom delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of lipids, such as cholesterol, stearylamine or phosphatidylcholines.

The compounds according to the present disclosure may also be delivered by the use of antibodies, antibody fragments, growth factors, hormones, or other targeting moieties, to which the compound molecules are coupled. The compounds may also be coupled with suitable polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidinone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the platelet aggregation inhibitors disclosed herein may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels. Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like.

Therapeutic compound liquid formulations generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by hypodermic injection needle.

Therapeutically effective dosages may be determined by either in vitro or in vivo methods. For each particular compound presently disclosed, individual determinations may be made to determine the optimal dosage required. The range of therapeutical effective dosages will naturally be influenced by the route of administration, the therapeutic objectives, and the condition of the patient. For injection by hypodermic needle, it may be assumed the dosage is delivered into the body's fluids. For other routes of administration, the absorption efficiency must be individually determined for each inhibitor by methods well known in pharmacology. Accordingly, it may be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect. The determination of effective dosage levels, that is, the dosage levels necessary to achieve the desired result, will be within the ambit of one skilled in the art. Typically, applications of compound are commenced at lower dosage levels, with dosage levels being increased until the desired effect is achieved.

A typical dosage might range from about 0.001 mg/kg to about 1000 mg/kg, preferably from about 0.01 mg/kg to about 100 mg/kg, and more preferably from about 0.10 mg/kg to about 20 mg/kg. Advantageously, the compounds disclosed herein may be administered several times daily, and other dosage regimens may also be useful.

Typically, about 0.5 to 500 mg of a compound or mixture of compounds, as the free acid or base form or as a pharmaceutically acceptable salt, is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, dye,

flavor etc., as called for by accepted pharmaceutical practice. The amount of active ingredient in these compositions is such that a suitable dosage in the range indicated is obtained.

Typical adjuvants which may be incorporated into tablets, capsules and the like are a binder such as acacia, corn starch or gelatin, and excipient such as microcrystalline cellulose, a disintegrating agent like corn starch or alginic acid, a lubricant such as magnesium stearate, a sweetening agent such as sucrose or lactose, or a flavoring agent.

When a dosage form is a capsule, in addition to the above materials it may also contain a liquid carrier such as water, saline, a fatty oil. Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice. For example, dissolution or suspension of the active compound in a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate, or into a liposom may be desired. Buffers, preservatives, antioxidants and the like can be incorporated according to accepted pharmaceutical practice.

In practicing the methods disclosed herein, the compounds may be used alone or in combination, or in combination with other therapeutic or diagnostic agents. In certain preferred embodiments, the compounds disclosed herein may be coadministered along with other compounds typically prescribed for these conditions according to generally accepted medical practice, such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin. The compounds disclosed herein can be utilized in vivo, ordinarily in mammals such as primates, such as humans, sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.

The preferred compounds disclosed herein are characterized by their ability to inhibit thrombus formation with acceptable effects on classical measures of coagulation parameters, platelets and platelet function, and acceptable levels of bleeding complications associated with their use. Conditions characterized by undesired thrombosis would include those involving the arterial and venous vasculature.

With respect to the coronary arterial vasculature, abnormal thrombus formation characterizes the rupture of an established atherosclerotic plaque which is the major cause of acute myocardial infarction and unstable angina, as well as also characterizing the occlusive coronary thrombus formation resulting from either thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTCA).

With respect to the venous vasculature, abnormal thrombus formation characterizes the condition observed in patients undergoing major surgery in the lower extremities or the abdominal area who often suffer from thrombus formation in the venous vasculature resulting in reduced blood flow to the affected extremity and a predisposition to pulmonary embolism. Abnormal thrombus formation further characterizes disseminated intravascular coagulopathy commonly occurs within both vascular systems during septic shock, certain viral infections and cancer, a condition wherein there is rapid consumption of coagulation factors and systemic coagulation which results in the formation of life-

threatening thrombi occurring throughout the microvasculature leading to widespread organ failure.

The compounds disclosed herein, selected and used as disclosed herein, are believed to be useful for preventing or treating a condition characterized by undesired thrombosis, such as (a) the treatment or prevention of any thrombotically mediated acute coronary syndrome including myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring post-thrombolytic therapy or post-coronary angioplasty, (b) the treatment or prevention of any thrombotically mediated cerebrovascular syndrome including embolic stroke, thrombotic stroke or transient ischemic attacks, (c) the treatment or prevention of any thrombotic syndrome occurring in the venous system including deep venous thrombosis or pulmonary embolus occurring either spontaneously or in the setting of malignancy, surgery or trauma, (d) the treatment or prevention of any coagulopathy including disseminated intravascular coagulation (including the setting of septic shock or other infection, surgery, pregnancy, trauma or malignancy and whether associated with multi-organ failure or not), thrombotic thrombocytopenic purpura, thromboanginitis obliterans, or thrombotic disease associated with heparin induced thrombocytopenia, (e) the treatment or prevention of thrombotic complications associated with extracorporeal circulation (e. g. renal dialysis, cardiopulmonary bypass or other oxygenation procedure, plasmapheresis), (f) the treatment or prevention of thrombotic complications associated with instrumentation (e. g. cardiac or other intravascular catheterization, intra-aortic balloon pump, coronary stent or cardiac valve), and (g) those involved with the fitting of prosthetic devices.

Anticoagulant therapy is also useful to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage. Thus the compounds disclosed herein can be added to or contacted with any medium containing or suspected to contain factor llb/lila, and the like, in which it is desired that blood coagulation be inhibited, e. g., when contacting the mammal's blood with material such as vascular grafts, stents, orthopedic prostheses, cardiac stents, valves and prostheses, extra corporeal circulation systems and the like.

Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the disclosed and claimed compounds and practice the disclosed and claimed methods.

The following working examples therefore, specifically point out preferred embodiments, and are not to be construed as limiting in any way the remainder of the disclosure.

EXAMPLES Examples 1-2 Example 1 Production of 4-amidino-2-fluoro-benzoic acid A suspension of 3.39 Kg of 4-cyano-2-fluoro-benzoic acid in 21.1 Kg of anhydrous tetrahydrofuran was cooled to 12°C and 40.59 Kg of lithium bis (trimethylsilyl) amide 1 M in tetrohydrofuran (45.66 moles) was added drop-wise. At the end of the addition, the mixture was heated to room temperature and stirred for 1 hour at 20 °C. The solution was then cooled to 8 °C and 61 L of water was slowly added while maintaining the temperature below 30 °C. After stirring for at least 10 minutes at room temperature, the mixture was allowed to decant and the organic layer was separated. 4.2 L of concentrated HCI was slowly added to the aqueous layer until there was a sudden increase in pH between 4.0 to 6.0. The reaction mixture was stirred for 1 hour at room temperature, filtered and rinsed 3 times with 60 L of water. The product was dried under vacuum at 40 °C for at least 16 hours to afford 3.19 Kg of 4-amidino-2-fluoro-benzoic acid. (Yield = 85%).

Example 2 Production of 4-amidino-2-fluorobenzoyl chloride hydrochloride To a suspension of 3.17 Kg of 4-amidino-2-fluoro-benzoic acid (17.39 moles) in 45 Kg of DMF was added 2 L of concentrated hydrochloric acid. The solution was stirred for at least 30 minutes until complete dissolution occurs. Precipitation of the 4-amidino-2- fluoro-benzoyl chloride hydrochloride occurs during the addition of up to 143 L of acetone at room temperature. The reaction mixture was then stirred for 60 minutes at the same temperature. The product was filtered and rinsed twice with 13 L of acetone. The wet crystals were suspended in 48 L of acetone and stirred again at room temperature for 1hour. The crystals were then filtered with 6 L of acetone and dried under reduced pressure at 35°C for a minimum of 16 hours to obtain 3.06 Kg of 4-amidino-2-fluoro- benzoyl chloride hydrochloride. (Yield > 80%).

Example 3 Example 3

Production of ethyl (6-acetamido-chroman-2-yl) acetate methanolltoluene solution 8.80 Kg (34.80 moles) of ethyl (6-aminochroman-2-yl) acetate (described in U. S.

Patent at the paragraph bridging pages 147 and 48 as a dark oil) was added to 80 L of toluene and the mixture was heated with stirring to 40°C under reduced pressure to effect dissolution of the oil. The solution was cooled to about-5°C and 4.40 Kg of pyridine was added. To this solution was added 3.70 Kg of acetyl chloride (47.13 moles) over 1 hour (-5°C < T < 5°C). The reaction mixture was then stirred for at least 30 minutes after which 47 Kg of water was added. The solution was warmed up to room temperature and stirred for at least 15 minutes before decantation. The organic layer was separated and distilled off under reduced pressure (T < 55°C) until most of the solvent was eliminated. The residue was cooled down to about 15°C, 19.77 Kg of methyl alcohol was added and the distillation was continued until the volume of the residue was about 25 L (ethyl (6- acetamidochroman-2-yl) acetate in a mixture of methyl alcohol and toluene).

'H-NMR (250 MHz, CDCI3) 7.34 (d (br), J = 2.5 Hz, 1H), 7.13 (s, 1H), 7.05 (dd, J = 8.9 Hz, 2.5Hz, 1H), 6.74 (d, J=8. 9Hz, 1H), 4.46 (qd, J = 7. 5 Hz, 1.2Hz, 1H), 4.23 (q, J = 7.2 Hz, 2H), 2.84 (ddd, J = 16.5 Hz, 5.2 Hz, 4.1 Hz, 1H), 2.60 (dd, J, = 15.4 Hz, 6.1 Hz, 1H), 2.6 (s, 3H), 1.2 (m, 1H), 1.77 (m, 1H), 1.31 (t, J = 7.2 Hz, 3H) 13C-NMR (62.9 MHz, CDCI3) 170.7,168.2,151.4,130.5,121.9,121.8,119.9, 117.0,72,. 4,60.7,40.6,28.4,26.9,24.5,24.4,14.2 Example 4 Production of (6-acetamido-chroman-2-yl)-acetic acid To the 25 L of ethyl (6-acetamido-chroman-2-yl) acetate in a mixture of methyl alcohol and toluene (from Example 3) was added 27.2 Kg of methyl alcohol followed by 57.40 Kg of 1 N aqueous sodium hydroxide (55.19 moles) while maintaining a T < 30°C.

The solution was stirred for at least one hour at room temperature. The solvents were distilled off under reduced pressure (at T < 35°C), until the volume of the residue was about 65 L. The mixture was cooled down to room temperature and 40.65 Kg of toluene was added. The mixture was stirred for about 15 minutes. The organic phase was separated and the aqueous layer was extracted with 19.9 kg of toluene. The pH of the aqueous phase was reduced to 2 < pH < 3 by slow addition of the 25.3 Kg of 2 N aqueous hydrochloric acid. The suspension was stirred for at least 1 hour at room temperature. The crystals were filtered, rinsed with 28 Kg of water and dried under reduced pressure (45°C zu T < 50°C) for about 16 hours to yield 7.81 Kg of (6-acetamido- chroman-2-yl) acetic acid (31.33 mole). Yield 90 % from combined Examples 3 and 4.

'H-NMR (250 MHz, DMSO-d6), 12.32 (s (br), 1H), 9.68 (s, 1H), 7.31 (dd, J = 2.5 Hz, 1H), 7.18 (dd, J = 8.9 Hz, 2.5 Hz, 1H), 6.62 (d, J = 8.9 Hz, 1H), 4.31 (qd, J = 7.5 Hz, 1.2 Hz, 2H), 2.80 (m, 1H), 2.78 (m, 1H), 2.75 (m, 1H), 2.60 (m, 1H), 1.98 (m, 4H), 1.68 (m, 1H)

13C-NMR (62.9 MHz, DMSO-d6), 171.9,167.7,150.0,132.1,121.6,120.4,118.7, 116.2,72.4,40.1,26.5,24.1,23.8 Example 5 Production of ethyl (6-acetamido-chroman-2-yl)-acetate methanol/toluene solution 660 g (about 2.6 moles) of ethyl (6-amino-chroman-2-yl) acetate (described in U. S.

Patent at the paragraph bridging pages 147 and 48 as a dark oil) was added to 6 L of toluene and the mixture was heated with stirring to 40°C under reduced pressure to effect dissolution of the oil. The solution was cooled to about-5°C in a sodium chloride-ice bath and 293 g of anhydrous pyridine was added in one portion, followed by dropwise addition of 246 g (3.2 moles) of acetyl chloride with good agitation to maintain the temperature in the range of from about-5°C to about 5°C.). The reaction mixture was stirred for 30 minutes after addition, after which TLC analysis indicated that the reaction was not yet complete. An additional 50 g (0.6 mole) of pyridine and 50 g (0.45 mole) of acetyl chloride were added and the reaction stirred for 30 more minutes before it was quenched by the addition of 4 L of water. After stirring for 15 minutes, the organic layer was separated.

The aqueous layer was extracted with 1 L of toluene and the combined toluene extracts were washed with 2 L of water. After removal of most of the toluene by distillation under reduced pressure (T < 55°C) until most of the solvent was eliminated. The residue was cooled down to about 15°C, 2.5 L of methyl alcohol was added and the distillation was continued until the volume of the residue was about 1.5 L (ethyl (6-acetamido-chroman-2- yl)-acetate in a mixture of methyl alcohol and toluene).

'H-NMR (250 MHz, CDCI3) 7.34 (d (br), J = 2.5 Hz, 1H), 7.13 (s, 1H), 7.05 (dd, J = 8.9 Hz, 2.5 Hz, 1 H), 6.74 (d, J=8. 9Hz, 1H), 4.46 (qd, J = 7. 5 Hz, 1.2 Hz, 1 H), 4.23 (q, J = 7.2 Hz, 2H), 2.84 (ddd, J = 16.5 Hz, 5.2 Hz, 4.1 Hz, 1H), 2.60 (dd, J, = 15.4 Hz, 6.1 Hz, 1H), 2.6 (s, 3H), 1.2 (m, 1H), 1.77 (m, 1H), 1.31 (t, J = 7.2 Hz, 3H) 13C-NMR (62.9 MHz, CDCI3) 170.7,168.2,151.4,130.5,121.9,121.8,119.9, 117.0,72,. 4,60.7,40.6,28.4,26.9,24.5,24.4,14.2 Example 6 Production of (6-acefamido-chroman-2-yl)-acetic acid To the 1.5 L of ethyl (6-acetamido-chroman-2-yl) acetate in a mixture of methyl alcohol and toluene (from Example 5) was added 3.5 L of methyl alcohol followed by 3.5 L of 1 N aqueous sodium hydroxide while maintaining a temperature < 30°C. The solution was stirred for at least one hour at room temperature. The solvents were distilled off under reduced pressure (at T < 35°C), until the volume of the residue was about 5 L.

The mixture was cooled down to room temperature and 6 L of toluene was added. The mixture was stirred for about 15 minutes. The organic phase was separated and the aqueous layer was extracted with 2 x 2 L of toluene. The pH of the aqueous phase was reduced to 2 : pH < 3 by slow addition of about 2.75 L of 2 N aqueous hydrochloric acid.

The suspension was stirred for at least 1 hour at room temperature. The crystals were

filtered, rinsed with 10 L of water and dried under reduced pressure (45°C < T < 50°C) for about 16 hours to yield 598 g of 6-acetamido-2 [2H] chromane acetic acid (2.4 mole). Yield from combined Examples 5 and 6 = 92%.

'H-NMR (250 MHz, DMSO-d6), 12.32 (s (br), 1H), 9.68 (s, 1H), 7.31 (dd, J = 2.5 Hz, 1H), 7.18 (dd, J = 8.9 Hz, 2.5 Hz, 1H), 6.62 (d, J = 8.9 Hz, 1H), 4.31 (qd, J = 7.5 Hz, 1.2 Hz, 2H), 2.80 (m, 1H), 2.78 (m, 1H), 2.75 (m, 1H), 2.60 (m, 1H), 1.98 (m, 4H), 1.68 (m, 1H) '3C-NMR (62.9 MHz, DMSO-d6), 171.9,167.7,150.0,132.1,121.6,120.4,118.7, 116.2,72.4,40.1,26.5,24.1,23.8 Example 7 Production of D-alaninol Salt of (6-acetamido-chroman-2-yl)-acetic acid 477.42 g (1.92 mole) of racemic (6-acetamido-chroman-2-yl)-acetic acid (from Example 4 or 6, above was suspended in 2.86 L of methanol (1 g/6 mL) at 20°C. During addition of D-alaninol (80.53 g = 0.55 equivalents with respect to the chroman racemate) the whole mixture dissolved completely. This solution was heated to reflux.

Crystallization may start at reflux, but the solution was maintained at reflux for about 45 minutes and then the temperature was decreased gradually to 20°C over a period of 60 minutes. The crystalline suspension was then stirred for an additional 3.5 hours. After filtration, the crystals were washed with 150 mL of isopropanol, dried overnight at 45°C under reduced pressure to yield 260 g of enriched diastereomeric n-salt (D-alaninol N-salt of (6-acetamido-chroman-2-yl)-acetic acid). Yield for crude S enantiomer salt = 42%. The optical density at 20°C = + 64.0° (c = 2, H20) : calculated composition 95.1/4.9 (S>R) = 90.2% ee. Chiral HPLC: composition 95/5 (S>R) = 90% ee (enantiomeric excess).

To purify the enriched S enantiomer even further the enriched diasteromer (about 90% ee) was suspended in 4.8 L of methanol. The mixture was heated at reflux for 16 hours. The suspension was cooled down to room temperature and stirred for 1 hour.

After filtration, the crystals were washed with 480 mL of methyl alcohol and dried overnight at 50°C under reduced pressure to give 211 g of optically pure n-salt. Yield for this step was 82.1% with an overall resolution yield and purification of 34.5%. (Assuming a 50/50 mixture of the chromane racemate, this was a 69% isolation yield of the amount of (S) enantiomer which was present in the racemate.) The optical density at 20°C = + 71.3° (c = 2, H2O) ; calculated composition 99.7/0.3 (S>R) = 99.4% ee, and the (R) enantiomer was no longer detectable by chiral HPLC.

Example 8 Larger-Scale Production of D-alaninol Salt of (6-acetamido-chroman-2-yl)-acetic acid 7.71 Kg (30.91 mole) of racemic (6-acetamido-chroman-2-yl)-acetic acid (from Example 5, above) was processed essentially as set forth in Example 7, except that in the purification step the solution was only heated to reflux and maintained with stirring for 8 hours to provide 3.41 Kg of optically pure n-salt (10.5 moles). The overall yield for the

production of the crude and then further purified (S) enantiomer was 34%. The optical density at 20°C = +71. 75° (c = 2, H20) ; and chiral HPLC shows a composition of 98.95/1.85 (S>R) = 97. 9% ee. mp 218. 4°C (capillary) 'H-NMR (400 MHz, DMSO-d6), 9.75 (s, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.19 (dd, J = 8.9 Hz, 2.5 Hz, 1H), 6.62 (d, J = 8.9 Hz, 1H), 4.29 (qd, J = 7.5 Hz, 1.2 Hz, 1H), 3.25 9dd, J = 11.3 Hz, 4.3 Hz, 1H), 3.39 (dd, J = 11.3 Hz, 6.7 Hz, 1H), 3.15 (m, 1H), 2.80 (ddd, J = 16.5 Hz, 10.4 Hz, 5.2 Hz, 1H), 266 (dm, J = 16.5 Hz, 1H), 2.53 (m, 2H), 1.98 (m, 4H), 1.64 (m, 1H), 1.13 (d, J = 6. 6 Hz, 3H) 13C-NMR (100 MHz, DMSO-d6), 173.3,167.6,150.4,131.7,121.6,120.3,118.6, 116.1,73.7,64.6,48.4,40.1,26.8,24.4,23.8,16.8 IR (KBr) 3316,3029,2974,2925,1570,1494,1408 cm-' Example 9-13 Production of L-alaninol salt of (6-acetamido-chroman-2-yl)-acetic acid and isolation of enriched L-alaninol salt of (R) enantiomer.

Examples 4-8 were repeated with essentially the same results except that L- alaninol was reacted with the racemic chromane acetic acid and the (R) enantiomer was obtained in enriched form with essentially the same yields.

Examples 14-16

Example 14 Production of ethyl (2S)- (6-amino-chroman-2-yl)-acetate hydrochloride salt 257 g of the (S) enantiomer enriched as set forth in Examples 7-8 (about 92% ee with respect to the (S) enantiomer) was refluxed for 16 h under nitrogen in 2.7 L of 3N sulfuric acid solution in absolute ethyl alcohol. The reaction mixture was then concentrated under reduced pressure (rotory evaporator) to a whole mass of 1.03 Kg.

Then 5 L of toluene and 430 g of sodium hydrogen carbonate in 1 L of water were added successively (at neutralization the reaction mixture becomes pink). After 10 minutes under stirring, the toluene was separated from the aqueous layer. The aqueous layer was then extracted successively 4 times with 1 L of toluene until completion of extraction (monitoring by HPLC to follow extraction process). The pooled toluenic phase was dried on magnesium sulfate and after filtration concentrated to 4 L. 430 mL of a hydrochloric acid 3.6 N ethereal solution was then added to precipitate the crude hydrochloride salt.

After 1 hour stirring at 20°C the hydrochloride salt was filtrated and rinsed with 500 mL of toluene. This material was dried under reduced pressure at 45°C to give 199 g of crude ethyl (2S)- (6-amino-chroman-2-yl) acetate. Yield 92%. OD at 20°C = + 90.3° (c = 0.2, EtOH) ; estimated composition 96/4 (S>R) = 92% ee.

This crude ester was further purified by suspending the 199 g of crude product in 980 mL ethanol (ratio of about 1 g/4.5 mL of ethanol) and kept at reflux for 1 hour (digestion). The suspension was cooled to 20°C and stirred for an additional 4 hours.

After filtration and washing with a little volume of ethyl alcohol, the white crystals were dried for 24 hours at 42°C under reduced pressure to yield 177 g of purified ethyl (2S)- (6- amino-chroman-2-yl) acetate. Yield 88. 5% from the crude ester and overall 81.4% from the n-salt starting material. OD at 20°C = + 94.6° (c = 0.2, EtOH) ; estimated composition 98.5/1.5 (S>R) = 97% ee.

Example 15 Larger-scale production of ethyl (2S)- (6-amino-chroman-2-yl) acetate hydrochloride salt 2.88 Kg (8.87 moles) of the (S) enantiomer enriched as set forth in Examples 7-8 (about 98% ee with respect to the (S) enantiomer) was added to 21 Kg of absolute ethyl alcohol under stirring at room temperature. 2.42 L of concentrated sulfuric acid were slowly added to the solution and the mixture was refluxed under stirring for at least 16 h under nitrogen. The solution was cooled to room temperature and slowly added to a mixture of 26.6 L of 10% aqueous sodium hydrogen carbonate and 29 L of dichloromethane while maintaining the temperature at about 5°C. The stirring was continued for at least 15 minutes at the same temperature before decantation (pH of the solution was over 7). The organic layer was separated and washed again with 36.7 L of 2% aqueous sodium hydrogen carbonate while maintaining the temperature at about 5 °C.

The organic phase was concentrated to minimum stirrable volume under reduced pressure while keeping the temperature below 40°C 29 L of toluene was added under vacuum and distillation was continued until the volume was about 12 L, while maintaining

the temperature below 50°C. The reaction mixture was then cooled to about 19°C and 1.45 L of 6.2 M hydrochloric acid in ethyl alcohol was slowly added in order to maintain the temperature between 10 and 20°C. The crystals were maturated under stirring for at least 16 h at the same temperature, filtered and washed with 6 L of toluene. The product was dried for at least 16 hours under reduced pressure while maintaining the temperature between 45 and 50°C to afford 2.16 Kg (7.96 mole) of ethyl (2S)- (6-amino-chroman-2-yl) acetate hydrochloride. Yield 89.85 based on the starting material.

OD at 20°C = + 98.0° (c = 0.2, EtOH) ; estimated composition 99/1 (S>R) = 98% ee.

'H-NMR (250 MHz, DMSO-d6), 9.97 (s (br), 3H), 7.05 (m, 2H), 6.80 (m, 1H), 4.42 (qd, J = 75 Hz, 1.2 Hz, 1H), 4.14 (q, J = 6.7 Hz, 2H), 2.88 (ddd, J = 16.5 Hz, 10.4 Hz, 5.2 Hz, 1H), 2.8 (dd, J = 11.3 Hz, 4.3 Hz, 1H), 2.76 (m, 1H), 2.74 (dd, J = 11.3 Hz, 6.7 Hz, 1 H), 2.05 (m, 1 H), 1.70 (m, 4H), 1.22 (t, J = 6.7 Hz, 3H) '3C-NMR (62.9 MHz, DMSO-d6), 170. 2,153.4,123.9,123.1,121.9,117.3,72.6, 60.1,39.7,25.9,23.7,14.1 IR (KBr) 2907,2632,1733,1504,1201 cm- Example 16 Production of an acetonitrile suspension of N-hydrochloride 4-amidino-2-fluorobenzoyl chloride salt and coupling with ethyl (2S)- (6-aminochroman-2-yl) acetate hydrochloride salt (97% ee) (a) Production of an acetonitrile suspension of N-hydrochloride 4-amidino-2-fluoro- benzoyl chloride salt A clean and dry reaction vessel was obtained, which was purged with nitrogen and all reactions in this vessel were conducted under nitrogen. Add to the reaction vessel 377 g (1.73 moles) of fluoroamidino benzoic acid produced as in Example 1 which has been sifted through a 200 micron screen (non-copper) and 7.5 L of anhydrous toluene. Agitate the suspension for 15-30 minutes. Add 329 g (228 mL; 2.58 moles) of oxalyl chloride.

Add slowly 21.7 g (23 mL; 0.3 moles) of anhydrous dimethylformamide to control the rate of gas evolution during the formation of the Vilsmeir reagent (a typical addition rate was about 4-10 minutes per kilogram). Continue stirring at ambient temperature for an additional 10 minutes after all of the dimethylformamide has been added. Heat the reaction mixture to 50°C and maintain this temperature for 2 hours with good stirring.

Discontinue the stirring and the heat and allow the solids to settle (or a pressure filter may be used in a manner to avoid contact with moisture). Siphon out the supernatant carefully since the temperature is about 40 to 50°C. Wash the yellow solids two times with 1 L and once with 0.5 L of anhydrous acetonitrile stirring the mixture for about 5-10 minutes and siphoning out the supernatant each time to yield a white solid (keep under nitrogen to avoid moisture). Add 5.5 L of anhydrous acetonitrile to the solid acid chloride and heat to 30°C with stirring to produce the N-hydrochloride 4-amidino-2-fluoro-benzoyl chloride salt acetonitrile suspension for coupling with the bicyclic amine hydrochloride.

(b) Production of an ethyl (2S)- (6-amino-chroman-2-yl)-acetate hydrochloride salt (97% ee) and pyridine mixture in an acetonitrile suspension A second clean and dry reaction vessel was obtained, which was purged with nitrogen and all reactions in this vessel were conducted under nitrogen. Add to the reaction vessel 408 g (1.5 moles) of ethyl (2S)- (6-amino-chroman-2-yl)-acetate hydrochloride salt (97% ee) produced as in Examples 14 or 15,249.4 g (3.1 moles of pyridine, and 2.0 L of anhydrous acetonitrile. Stir to effect a homogeneous suspension for coupling, keep under nitrogen and transfer to a transfer vessel for adding to the reaction vessel of (a) above containing the preheated acetonitrile suspension of the benzoic acid chloride salt (may also be transferred by conduit from the second reaction vessel to the first while avoid moisture contact).

(c) Coupling the acetonitrile suspensions of (a) and (b) to yield ethyl (2S)- (6- (4- amidino-2-fluorobenzoyl) amino-chroman-2-yl)-acetate To the preheated (30°C) acetonitrile suspension of (a) with stirring add the acetonitrile suspension of (b) at a fast rate (less than 15 minutes) to keep the typically noted exotherm from raising the reaction temperature by more than about 10°C (usually about 28-32°C to about 38-42°C). Cooling of the reaction vessel may optionally be utilized to keep the reaction from exceeding 40-45°C during this step. The heating was discontinued and the reaction was allowed to cool to ambient temperature.

The yellow product was filtered and the crude product was washed with 1.0 L of anhydrous acetonitrile. The product was dried under vacuum at 50°C until a constant weight was obtained (about 10 hours). The weight of the crude product was 590 g (about 90% crude yield).

The 590 g of crude product was dissolved in 3 L of absolute ethanol at reflux. The solution was cooled to from about 70 to about 80°C and passed through a polishing filter to remove any particulates. The solution was concentrated by removing 1790 g of ethanol under reduced pressure, and 3.7 L of preheated isopropyl alcohol (preheated to 60°C) was added to the reaction mixture to provide a recrystallization ratio of about 1.5 mL of ethanol and 7.5 mL isopropyl alcohol per gram of crude product. The solution was cooled to ambient temperature and filtered. The product was washed with 1.0 L of isopropanol and dried to a constant weight at 50°C under vacuum to provide 507.5 g of product, which was sifted through a 125 micron screen to ensure uniformity of particle size. Yield 77.6% based on the amount of the (2S) bicyclic ester starting material of (b), above. mp 207.5°C (DSC); OD at 20°C = + 73.3 (c = 1, EtOH/AcOH; 9/1, v/v) 'H-NMR (400 MHz, DMSO-d6), 10.49 (s, 1H), 9.66 (s (br), 2H), 9.48 (s (b), 2H), 7.89 (t, J = 7.9 Hz, 1H), 7.87 (dd, J = 10.3 Hz, 1.2 Hz, 1H), 7.79 (dd, J = 7.9 Hz, 1.2 Hz, 1H) 7.49 (d, J = 2.4 Hz, 1H), 7.3 (dd, J = 8.8 Hz, 2.4 Hz, 2H), 6.71 (d, J = 8.8 Hz, 1H), 4.38 (qm, J = 7.5 Hz, 1H), 4.13 (q, J = 6.4 Hz, 2H), 2.86 (ddd, j = 11.3 Hz, 6.7 Hz, 1H), 2.74 (m, 1 H), 2.04 (m, 1 H), 1.75 (m, 4H), 1.22 (t, J = 6.7 Hz, 3H) '3C-NMR (62.9 MHz, DMSO-d6), 170.2,163.9 (d, J = 2 Hz), 161.0 (d, J = 3 Hz), 158.5, (d, J = 258 Hz), 150.6,131.2 (d, J = 9 Hz), 131.1,130.4 129.6 (d, J = 10 Hz), 124.4,121.7,121.1,119.4,116.3 (d, J = 26 Hz), 116.3,72.3,60.0,40.0,26.3,23.9,14.1

IR (KBr) 3077,1733,1668,1549,1497 cm-1 Example 17 Larger-scale production of ethyl (2S)-(6-(4-amidino-2-fluorobenzoyl) amino-chroman-2-yl)- acetate by coupling an acetonitrile suspension of N-hydrochloride 4-amidino-2-fluoro- benzoyl chloride salt with ethyl (2S)- (6-amino-chroman-2-yl)-acetate hydrochloride salt) A clean and dry reaction vessel was obtained, which was purged with nitrogen and all reactions in this vessel were conducted under nitrogen. Add to the reaction vessel 1.94 Kg (8. 89 moles) of fluoroamidino benzoic acid produced as in Example 1 which has been sifted through a 200 micron screen (non-copper) and 39.0 L of anhydrous toluene. The suspension was stirred for 10 minutes, and then 1.17 L (1.69 Kg, 13.34 moles, 1.5 eq) of oxalyl chloride was added at ambient temperature. Upon addition of 140 mL (130 g, 1.7 moles, 0.2 eq) of anhydrous DMF, gases released from the reaction. It was stirred for 10 minutes at room temperature and then the reaction was heated at 50°C for 2 hours with good agitation. The stirrer was turned off and the yellow solid was allowed to precipitate down for 10 minutes. The supernatant was carefully decanted at 50°C. The yellow solid was washed with 15 L (6 L x 2,3 L) of anhydrous acetonitrile three times. For each wash, the acetonitrile suspension was stirred for 5 minutes before acetonitrile was sucked out under nitrogen. After washing was completed, a white solid was obtained to which was added 20 L of anhydrous acetonitrile. The suspension was slowly heated up to 32°C.

To the heated (32°C) acetonitrile mixture of the white N-hydrochloride 4- carbamidoyl-2-flurobenzoic acid chloride salt product from the first step, was quickly added in three portions with stirring a mixture of 2.1 Kg (7.73 moles, 0.88 eq with respect to the benzoic acid salt) of ethyl (2S)- (6-amino-chroman-2-yl)-acetate hydrochloride salt (> 97 ee produced as in Examples 14 or 15) and 1.28 K g (16.23 moles) of anhydrous pyridine in 20 L of anhydrous acetonitrile. The reaction mixture raises to 42°C within 5 minutes after the addition. The reaction was cooled back to room temperature and the yellow product was filtered off, washed with 10 L of acetonitrile, and dried at 50°C under vacuum for 10 hours to provide 3.25 Kg of crude product.

The 3.25 Kg of crude product was dissolved in 20 L of absolute ethanol with refluxing and then the insolubles were removed by filtration. The filtrate was concentrated to 4.5 L of ethanol and 22 L of hot isopropyl alcohol (about 60°C) was added. The resultant solution was slowly cooled to room temperature with stirring.

The product was filtered off, washed with 3.0 L of isopropyl alcohol and dried at 50°C under vacuum to give 2.75 Kg of pure of product, which was sifted to ensure uniformity of particle size of less that 125 microns. Yield 85% of >97% pure ethyl (2S)- (6- (4-amidino-2-fluorobenzoyl) aminochroman-2-yl)-acetate based on the amount of the (2S) bicyclic ester starting material.

Example 18

Production of ethyl (2R)- (6- (4-amidino-2-fluorobenzoyl) aminochroman-2-yl) acetate by coupling an acetonitrile suspension of N-hydrochloride 4-amidino-2-fluoro-benzoyl chloride salt with ethyl (2R)- (6-amino-chroman-2-yl) acetate hydrochloride salt) The procedures of Example 17 were followed substantially except that ethyl (2R)- (6-aminochroman-2-yl) acetate hydrochloride salt (> 97 ee produced as in Examples 14 or 15, but using the (2R) materials) was utilized Yield 75.9% of >97% pure ethyl (2R)- (6- (4- amidino-2-fluorobenzoyl) aminochroman-2-yl) acetate based on the amount of the (2R) bicyclic ester starting material.

Example 19 Potency comparison of (2S)-6- (4-amidino-2-fluorobenzoyl) aminochroman-2-yl) acetic acid, (2R>2S, 97. 5%l2. 5%)- (6-amino-chroman-2-yl) acetic acid and the racemate (2S/2R)-(6- amino-chroman-2-yl) acetic acid The three compositions were compared in vitro with respect to their antagonist of fibrinogen binding to GP llb-lila in a solid phase plate ELISA (enzyme-linked immunoadsorbent assay) utilizing immobilized GP llb-lila and biotinylated fibrinogen as the ligand. The (2S) enantiomer was greater than 15 times more active than the (2R>2S, 97.5%/2.5%) enantiomer. Further the (2S) enantiomer was 200% more active than the racemate. The corresponding esters, such as the ethyl ester, were found to be substantially less active than the free acid forms.

In vivo plasma studies with orally dosed corresponding ethyl ester forms for each of the enantiomers and the racemate show that the ester forms are converted in vivo into the active free acid forms of the drug that were utilized in the fibrinogen binding assay in the above paragraph. Thus, the ester forms are good prodrug forms of the free acids.

In view of the above description it is believed that one of ordinary skill can practice the invention. The examples given above are non-limiting in that one of ordinary skill in view of the above will readily envision other obvious permutations and variations without departing from the principal concepts embodied therein. Such permutations and variations are also within the scope of the disclosure.