AU747293B2 - Fibrinogen receptor antagonist prodrugs - Google Patents

Description

WO 98/34935 PCT/tJS98/01998 TITLE OF THE INVENTION FIBRINOGEN RECEPTOR ANTAGONIST PRODRUGS BACKGROUND OF THE INVENTION The invention relates generally to inhibiting the binding of fibrinogen and other proteins to blood platelets, and inhibiting the aggregation of blood platelets specifically to the gp IIb/IIIa fibrinogen receptor site. Fibrinogen is a glycoprotein present in blood plasma that participates in platelet aggregation and in fibrin formation. Platelets are cell-like anucleated fragments, found in the blood of all mammals, that also participate in blood coagulation. Interaction of fibrinogen with the IIb/IIIa receptor site is known to be essential for normal platelet function.

When a blood vessel is damaged by an injury or other causative factor, platelets adhere to the disrupted subendothethial surface. The adherent platelets subsequently release biologically active constituents and aggregate. Aggregation is initiated by the binding of agonists, such as thrombin, epinephrine, or ADP to specific platelet membrane receptors. Stimulation by agonists results in exposure of latent fibrinogen receptors on the platelet surface, and binding of fibrinogen to the glycoprotein IIb/IIIa receptor complex.

Attempts have been made to use natural products and synthetic peptides to determine the mechanism of adhesion and platelet aggregation. For example, Rouslahti and Pierschbacher in Science, 238, 491-497 (1987), describe adhesive proteins such as fibronectin, vitronectin, osteopontin, collagens, thrombospondin, fibrinogen, and von Willebrand factor that are present in extracellular matrices and in blood. The proteins contain the tripeptide arginine-glycine-aspartic acid (RGD) as their glycoprotein IIb/IIIa recognition site. These arginineglycine-aspartic acid containing tripeptides are recognized by at least one member of a family of structurally related receptors, integrins, which are heterodimeric proteins with two membrane-spanning subunits. The authors state that the conformation of the tripeptide sequence in the individual proteins may be critical to recognition specificity.

-1- WO 98/34935 PCT/US98/01998 Cheresh in Proc. Nat'l Acad. Sci. 84, 6471-6475, (1987), describes an Arg-Gly-Asp directed adhesion receptor expressed by human endothelial cells that is structurally similar to the IIb/IIIa complex on platelets but is antigenically and functionally distinct. This receptor is directly involved in endothelial cell attachment to fibrinogen, von Willebrand factor, and vitronectin.

Pierschbacher and Rouslahti, in J. of Biol. Chem., 262, (36), 17294-17298 (1987) hypothesized that the Arg-Gly-Asp sequence alone would be a sufficient signal for receptor recognition and binding and that, therefore, the conformation of the tri-peptide sequence would be determinative. Various synthetic peptides were produced and the authors concluded that the stereochemical conformation of Arg-Gly-Asp as influenced by enantiomeric substitutions or additions to this sequence significantly influenced receptor-ligand interaction. The authors further showed that cyclization of a decapeptide by forming a disulfide bridge between non-terminal residues Pen and Cys, rendered the peptide much less effective at inhibiting attachment to fibronectin.

In Proc. Nat'l Acad. Sci. 81, 5985-5988 (1984), the same authors describe tetrapeptide variants of the cell recognition site of fibronectin that retain attachment-promoting activity. Peptides having a tetrapeptide recognition site are described in U.S. Pat. Nos. 4,589,881 and 4,614,517. A number of large polypeptide fragments in the cell-binding domain of fibronectin have cell-attachment activity. For example, see U.S. Pat. Nos. 4,517,686, 4,661,111 and U.S. Pat. No. 4,578,079.

Ruggeri et al., Proc. Nat'l Acad. Sci. 83, 5708-5712 (1986) explore a series of synthetic peptides designed in lengths to 16 residues, that contain RGD and a valine attached to the aspartic acid residue of RGD that inhibit fibrinogen binding to platelets. See also Koczewiak et al., Biochem. 23, 1767-1774 (1984); Ginsberg et al., J. Biol. Chem. 260(7), 3931-3936 (1985); and Haverstick et al., Blood 66(4), 946-952 (1985). Other inhibitors are disclosed in Eur. Pat. App. Nos.

275,748 and 298,820.

A number of low molecular weight polypeptide factors have been isolated from snake venom. These factors apparently have high affinity for the gp IIb/IIIa complex. For example, Huang et al., J. Biol -2- WO 98/34935 PCT/US98/01998 Chem., 262, 16157-16163 (1987); Huang et al., Biochemistry, 28, 661-666 (1989) describe the primary structure of the venom trigramin which is a 72 amino acid polypeptide that contains the RGD subunit. Echistatin is another compound which has high affinity for the gp IIb/IIIa complex.

This polypeptide contains 49 amino acids and has the RGD subunit and various disulfide bridges. Gan et al., J. Biol. Chem., 263, 19827-19832 (1988). See also, Dennis et al., Proc. Nat'l Acad. Sci. USA, 87, 2471-2475 (1989). However, these snake venom factors also have high affinity for other members of the adhesive protein receptor family including the vitronectin and fibronectin receptors so are not selective for the gp IIb/IIIa complex.

While it is known that the tripeptide sequence Arg-Gly-Asp is present in certain polypeptides that can duplicate or inhibit the cell attachment-promoting effects of fibronectin and vitronectin, the tripeptide Arg-Gly-Asp has low activity. At present, there is little understanding of how other amino acids coupled to this sequence influence binding specificity. U.S. Pat. No 5,023,233 discloses small cyclic hexapeptides which contain the sequence Arg-Gly-Asp and are useful platelet aggregation inhibitors. U.S. Pat. No. 5,037,808 discloses the use of indolyl platelet-aggregation inhibitors which are believed to act by antagonizing interactions between fibrinogen and/or extracellular matrix proteins and the platelet gp IIb/IIIa receptor. U.S. Pat. No.

5,037,808 discloses guanidino peptide mimetic compounds that retain an Asp residue which inhibit platelet aggregation. W09014103 describes the use of antibody-poly-peptide conjugates wherein said polypeptides contain the Arg-Gly-Asp (RGD) sequence.

W09111458 discloses the use of large cyclic peptides containing RGD flanked by proline residues which are platelet aggregation inhibitors. W09101331 discloses small cyclic platelet aggregation inhibitors which are synthetic cyclic pentapeptides containing the tripeptide sequence Arg-Gly-Asp and a thioether linkage in the cycle. U.S. Patent No. 5,051,405 also discloses the use of peptides and pseudopeptides such as N-amidino-piperidine-3-carboxylglycyl-Laspartyl-L-valine that inhibit platelet aggregation and thrombus formation in mammalian blood. EP 445 796 discloses linear compounds -3- WO 98/34935 PCTIUS98/01998 which can include internal piperazinyl or piperidinyl derivatives. EP437 367 discloses linear polypeptide fibrinogen receptor antagonists. U.S.

Patent No. 5,256,812 discloses compounds of the R1-A-(W)a-X-(CH2)b- (Y)c-B-Z-COOR wherein R1 is a guandidino or amidino moiety and A and B are chosen from specific monosubstituted aryl or heterocyclic moieties.

While a multitude of compounds or peptide analogs believed to inhibit platelet aggregation by inhibiting binding to a blood platelet by fibrinogen are known, the present invention provides novel fibrinogen receptor antagonist prodrugs of antagonists that have significant binding activity and are, therefore, useful for the reasons stated herein.

SUMMARY OF THE INVENTION Fibrinogen receptor antagonist prodrugs having the structure, for example, of

HO,N

N

O

H

2 N X- N

COOR

4 R1 H /"R 2 R N R 3 more particularly, 0 N

COOCH

2

CH

3

H

2 N H NHSO 2

CH

3

NOH

Compounds of the invention, or pharmaceutically acceptable salts thereof, are useful in the manufacture of a medicament for inhibiting the aggregation of blood platelets, inhibiting angiogenesis, WO 98/34935 PTU9/19 PCT/US98/01998 inhibiting osteoclast mediated bone resorption, preventing platelet thrombosis, preventing thromboembolism or preventing reocciusion, in a mammal.

DETAILED DESCRIPTION OF THE INVENTION The invention relates to compounds having the formula HO,

N

H

2 N 0 0R or a pharmaceutically acceptable salt, wherein X is (CH2)q, (CH2)mO(CH2)p, (CH2)mNR 1 1 (CH2)p) (CH2)mC(O)NR11(CH2)p, (CH2)mNR 1 1 C(O)(CH2)p, (CH2)mC(O )(CH2)p, (CH2)mC(S)(CH2)p, (CH2)mSO2(CH2)p, (CH2)mS(CH2)p, (CH2)mSO(CH2)p, (CH2)mSO2NRl 1 1(CH2)p, (CH2)mC=C(CH2)p, or (CH2)mCH(OH)(CH2 )p, where m and p are integers independently chosen from 0-6, q is an integer chosen from 1-6, and R 1 1 is selected from the group consisting of hydrogen, WO 98/34935 PCTIUS98/01998 hydroxyl, C3-.8 cycloalkyl, aryl, aryl C1-.8alkyl-, amino, amino C1-8 alkyl-, C1-3 acylamino-, C1..3 acylamnino C1-8 alkyl-, C 1-6 alkylamino-, C1-6 alkylamino C1-8 alkyl-, C1-6 dialkylamino-, C1-6 dialkylamino C1..8 alkyl-, C 1-4 alkoxy, C1-4 alkoxy C1-6 alkyl-, carboxy, carboxy C1-6 alkyl-, C 1-3 alkoxycarbonyl-, C1-3 alkoxycarbonyl C 1-6 alkyl-, carboxyoxy-, carboxy C1-6 alkyloxy-, hydroxy C1-6 ailkyl-, C1-8 alkylcarbonyloxy C1-4 alkyloxycarbonyl-, and aryl C 1-8 alkylcarbonyloxy C 1-4 alkyloxycarbonyl-; Y is i)

R

E

where D and E are independently chosen from C, NH, N(CH3), N(CH2CH3), N(CI{CH2CH2), 0 and S, and R5 is independently selected from the group consisting of hydrogen, -6- WO 98/34935 WO 9834935PCTIUS98/01998 Ci..io alkyl, aryl, aryl C 1-8 alkyl-, oxo, thio, amino, amino Cl-8 alkyl-, CI-3 acylamino-, C1..3 acyllamino C1..8 alkyl-, Cl..6 alkylanino-, Cl..6 alkylannno C1-8 alkyl-, C 1-6 dialkylamino-, C1.6 chalkylamino C1-8 alkyl-, C1-4 alkoxy C1-4 alkoxy C1..6 alkyl-, carboxy, carboxy C1.6 alkyl-, C1..3 alkoxycarbonyl-, C 1..3 alkoxycarbonyl C 1-6 alkyl-, carboxyoxy-, carboxy C 1.6 alkyloxy-, hydroxy, and hydroxy C1..6 alkyl; WO 98/34935 PCT/US98/01998 ii) iii) S or iv)

AB,

wherein A and B, which form a fused ring system sharing adjacent carbon and nitrogen atoms, are defined as follows: A is a 5, 6 or 7 membered saturated, partially saturated, or unsaturated ring containing 1, 2 or 3 heteroatoms selected from O, S or N; B is a 5, 6 or 7 membered saturated, partially saturated, or unsaturated ring containing 1, 2 or 3 heteroatoms selected from O, S or N;

R

1 is hydrogen C1-6 alkyl, carboxy, carboxy C1-6 alkyl-, C1-6 alkylcarboxy C1-6 alkylcarboxy C1-6 alkyl-, oxo, C1-6 alkyloxy-, oxo C1-6 alkyl-, -8- WO 98/34935 WO 9834935PCTIUS98/01998 C1-6 alkyloxy C1-6 alkyl-, hydroxy, hydroxy 01.6 alkyl-, aryl, aryl C1-6 alkyl-, or halogen;

R

2 and R 3 are independently selected from the group consisting of hydrogen, fluoro, hydroxy C 1-6 alkyl-, carboxy, carboxy C1-6 alkyl-, hydroxyl, 01-6 alkyloxy-, aryl 0 1-6alkyloxy-, C3-8 cycloalkyl-, C1-8 alkyl, 2D aryl, aryl C1-6 alkyl-, 01-6 alkylcarbonyloxy-, amino, C1-6 alkylamino-, amino 01-6 alkyl-, 01-6 alkylamino 01-6 alkyl-, arylamino-, aryl 01-6 alkylamino-, arylamino 01-6 alkyl-, aryl 01-6 alkylamino 01-6 alkyl-, amino 01-6 alkyl-, 01-6 dialkylamino-, 01-6 dialkylamino 01-6 alkyl-, aminocarbonyloxy-, -9- WO 98/34935 PTU9/19 PCT/US98/01998 aminocarbonyloxy C1..6 alkyl-, C 1-6 alkylaminocarbonyloxy-, C1.6 alkylaminocarbonyloxy C1-6 alkyl-, aryl aminocarbonyloxy-, aryl aminocarbonyloxy C1-6 alkyl-, aryl Cl.6 alkylaminocarbonyloxy-, aryl C1.6 alkylaminocarbonyloxy Cl-6 alkyl-, C 1-8 alkylsulfonylammno-, C1-8 alkylsulfonylamino Cl-6 alikyl-, aryl sulfonylamino-, aryl sulfonylamino Cl.6 alkyl-, aryl C1-6 alkylsulfonylamino-, aryl C1-6 alkylsulfonylamino C1-6 alkyl-, C 1-8 alkyloxycarbonylamino-, C1-8 alkyloxycarbonylamino Cl-8 alkyl-, aryloxycarbonyl amino-, aryloxycarbonylamino Cl.8 ailkyl-, aryl C 1-8 alkyloxycarbonylamino-, aryl Cl.8 alkyloxycarbonylamino C1-8 alkyl-, C1.8 alkylcarbonylamino-, C1..8 alkylcarbonylamino C1-6 alkyl-, aryl carbonyl amino-, arylcarbonylamino C1-6 alkyl-, aryl Ci-8 alkylcarbonylamino-, aryl C1-8 alkylcarbonylamino C1-6 alkyl-, aminocarbonylamino-, aminocarbonylaniino Cl..6 alkyl-, C 1-8 alkylaminocarbonylamino-, C 1-8 alkylamninocarbonylamino C 1-6 alkyl-, arylaminocarbonylamino-, arylaininocarbonylamino C 1-6 alkyl-, aryl C 1-8 alkylaminocarbonylamino-, aryl C 1-8 alkylaminocarbonylamino C 1-6 alkyl-, amino sulfonylamino- 10 WO 98/34935 PTU9119 PCTIUS98/01998 aminosulfonylamino 01-6 alkyl-, C 1-8 alkylaminosulfonylamino-, 01-8 alkylaminosulfonylamino 01-6 alkyl-, arylaminosulfonylamino-, arylaminosulfonylamino 01-6 alkyl-, aryl 01-8 alkylaminosulfonylamino-, aryl 01-8 alkylaminosulfonylamino 01-6 alkyl-, 01-6 alkylsulfonyl-, Cl..6 alkylsulfonyl C1..6 alkyl-, aryl 01-6 alkylsulfonyl-, aryl C1..6 alkylsulfonyl C1-6 alkyl-, C 1-6 alkylcarbonyl-, 01-6 alkylcarbonyl C1..6 alkyl-, aryl 01-6 alkylcarbonyl-, aryl 01-6 alkylearbonyl 01-6 alkyl-, amino carbonyl-, aminocarbonyl C1.8 alkyl-, C1..8 alkylaminocarbonyl-, 01.8 alkylamninocarbonyl 01-8 alkyl-, 2D arylaminocarbonyl-, arylamninocarbonyl 01-8 alIkyl-, aryl C1..8 alkylaminocarbonyl-, aryl 01-8 alkylamninocarbonyl 01-8 alkyl-, aminosulfonyl-, aminosulfonyl Ci..8 alkyl-, C1.8 alkylaminosulfonyl-, C1.8 alkylaminosulfonyl 01-8 alkyl-, arylaminosulfonyl-, arylaminosulfonyl C1..8 alkyl-, aryl 01-8 alkylaminosulfonyl-, aryl 0 1-8 alkylamninosulfonyl C 1-8 alkyl-, 03-8 cycloalkylsulfonylamino-, 01-8 alkyloxyaryl sulfonylamino-, thiophenylsulfonylamino-, and 11 WO 98/34935 PrU9/19 PCT/US98/01998 -NHSO2- 0 ;and

R

4 is hydrogen, C1-8 alkyl, aryl, aryl C 1-6 alkyl-, C1-8 alkylcarbonyloxy C1..4 alkyl-, or aryl C1-8 alkylcarbonyloxy C1-4 alkyl-.

One class of compounds of the invention has the formula HO,

N

H

2 N 0--'CO H R 2 or a pharmaceutically acceptable salt, wherein Y is i) 9n H 12 WO 98/34935 WO 9834935PC'rIUS98O1998 where R 5 is independently selected from the group consisting of hydrogen, Ci-1o alkyl, aryl, aryl C1-8 alkyl-, oxo, thio, amino, amino C1-8 alkyl-, C1-3 acylamino-, C1-3 acylamino C1..8 alkyl-, C1-6 alkylamino-, C1-6 alkylamino C1..8 alkyl-, C1-6 dialkylamino-, C1-6 cialkylaniino C1-8 alkyl-, C1-4 alkoxy-.

C1-4 alkoxy C1-6 alkyl-, carboxy, carboxy C1-6 alkyl-, C 1-3 alkoxycarbonyl-, C 1-3 alkoxycarbonyl. C 1-6 alkyl-, carboxyoxy-, carboxy C1..6 alkyloxy-, hydroxy, and hydroxy C1..6 alkyl-; 13 WO 98/34935 PCTIUS980199

S

AB, where AB is selected from the group consisting of a) 0

V

2

N-.G

wherein V 1 and V 2 is N or CR 6 and G is CH 2

CH

2

-CH

2

CH

2

C(R

7 2

CH

2 or

H

2 C CH 2 (CH2)n.- (CH2)n

R

6 is H, branched or straight chain C1-4 substituted or unsubstituted alkyl, branched or straight chain lower alkenyl, C1-4 alkylaryl, substituted aryl, or 5 or 6 membered heteroaryl containing 1, 2, or 3 N, S, or 0 heteroatoms wherein substituted alkyl is hydroxysubstituted or C1-4 alkoxy-substituted alkyl, and wherein substituted aryl is substituted by one, two or three of the following groups: halogen, C1-4 alkoxy, hydroxy, or C1-4 alkyl; 14- WO 98/34935 PCTIUS98/01998

R

7 is H, branched or straight chain C1-4 substituted or unsubstituted alkyl, branched or straight chain lower alkenyl, C1-4 alkylaryl, substituted aryl, or 5 or 6 membered heteroaryl containing 1, 2, or 3 N, S, or 0 heteroatoms wherein substituted alkyl is hydroxysubstituted or C1-4 alkoxy-substituted alkyl, and wherein substituted aryl is substituted by one, two or three of the following groups: halogen, C1-4 alkoxy, hydroxy, or C1-4 alkyl; b) 0 S jN- wherein J N or CR, wherein R 8 CN, C(O)N(R)R 1 0 _N O or /-(CH 2 n

R

9 is is H, branched or straight chain C1-4 substituted or unsubstituted alkyl, branched or straight chain lower alkenyl, C1-4 alkylaryl, substituted aryl, or 5 or 6 membered heteroaryl containing 1, 2, or 3 N, S, or 0 heteroatoms wherein substituted alkyl is hydroxysubstituted or C1-4 alkoxy-substituted alkyl, and wherein substituted aryl is substituted by WO 98/34935 PTU9/19 PCTIUS98/01998 one, two or three of the following groups: halogen, C1-4 alkoxy, hydroxy, or C 1-4 alkyl;

R

10 is H, branched or straight chain C1-4 alkyl; wherein n and n' are 0-7; AlK Nk 16 WO 98/34935 PCT/US98/01998 i-I wherein n" is 0-3.

In a group of the class, the compounds have the formula

HO-

N 0 H2 r I N

COOR

4 X- H

NHSO

2 CH 3 or a pharmaceutically acceptable salt, wherein wherein Xis -CH2-, -CH2-O-, or

R

4 is -CH2CH3 or -C(CH3)3.

In a subgroup of the group, the compounds have the formula

H

2

N

SGcH or a pharmaceutically acceptable salt, wherein 17- WO 98/34935 PTU9119 PCTIUS98/01998 Y is 0

N

N-

N ,or

H

S

Specific exemplifications of this group are shown below: N N-N H NHS2 f..CH3

H

2 N

NOH

18 WO 98/34935 WO 9834935PCTIUS98/01998 H NHS0 2 j--CH 3 H 2

N~

HO

H

2

N

3-4 H2N' 2 N "-YC2t Bu H NHSOg 9 3-7 ,,COOC H 2

CH

3 HS0 2 -QCH3 NOH 0 19 WO 98/34935 PCT/US98/01998

.COOCH

2

CH

3

H

2 N

NHSO

2

CH

3 NOH

NOH

H

2 N 0 N COOC H2C H3 S- NH H NHSO2 CH3 H N2

H

2 N S H NHSO 2

-CH

3 NOH and pharmaceutically acceptable salts.

The prodrugs may be administered in low amounts relative to the amounts of antagonist that would ordinarily be administered. The prodrugs may be administered orally. The prodrugs retain structural integrity while passing though the gastrointestinal system, and are effectively delivered to cells. They are subjected to metabolic reactions to form the active acid which then interacts with the platelet receptor site.

A number of very serious diseases and disorders involve hyperthrombotic complications which lead to intravascular thrombi and emboli. Myocardial infarction, stroke, phlebitis and a number of other serious conditions create the need for novel and effective fibrinogen receptor antagonists.

One test which is used to evaluate fibrinogen receptor antagonist activity is based on evaluation of inhibition of ADP-stimulated WO 98/34935 PCTIUTS98/01998 platelets. Aggregation requires that fibrinogen bind to and occupy the platelet fibrinogen receptor site. Inhibitors of fibrinogen binding inhibit aggregation. In the ADP-stimulated platelet aggregation assay used to determine inhibition associated with the acids of the compounds claimed in the instant invention, human platelets are isolated from fresh blood, collected into acid citrate/dextrose by differential centrifugation followed by gel filtration on Sepharose 2B in divalent ionfree Tyrode's buffer (pH 7.4) containing 2% bovine serum albumin.

Platelet aggregation is measured at 370C in a Chronolog aggregometer. The reaction mixture contains gel-filtered human platelets (2 x 108 per ml), fibrinogen (100 micrograms per ml (ug/ml)), Ca 2 (1 mM), and the compound to be tested. The aggregation is initiated by adding 10 mM ADP 1 minute after the other components are added. The reaction is then allowed to proceed for at least 2 minutes.

The extent of inhibition of aggregation is expressed as the percentage of the rate of aggregation observed in the absence of inhibitor. The IC50 is the dose of a particular compound inhibiting aggregation by 50% relative to a control lacking the compound.

The active amidine-acids of these compounds have been evaluated in vitro and found to have an IC50 for inhibiting platelet aggregation of between about 1.0 nM and 10,000 nM.

Additionally, these compounds are useful for treating mammals suffering from a bone condition caused or mediated by increased bone resorption, who are in need of such therapy.

Pharmacologically effective amounts of the compounds, including pharamaceutically acceptable salts thereof, are administered to the mammal, to inhibit the activity of mammalian osteoclasts.

Additionally, these compounds are useful for treating angiogenesis (formation of new blood vessels). It has been postulated that the growth of tumors depends on an adequate blood supply, which in turn is dependent on the growth of new vessels into the tumor.

Inhibition of angiogenesis can cause tumor regression in animal models. (See, Harrison's Principles of Internal Medicine, 12th ed., 1991).

These compounds are therefore useful in the treatment of cancer for -21- WO 98/34935 PCT/US98/01998 inhibiting tumor growth. (See Brooks et al., Cell, 79:1157-1164 (1994)).

The term "pharmaceutically acceptable salts" shall mean non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote, palmitate, panthothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, valerate.

Compounds of the present invention may be chiral; included within the scope of the present invention are racemic mixtures and separated enantiomers of the general formula. Furthermore, all diastereomers, including E, Z isomers, of the general formula are included in the present scope. Furthermore, hydrates as well as anhydrous compositions and polymorphs of the general formula are within the present invention.

The term "pharmaceutically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician. The term "anti-coagulant" shall include heparin, and warfarin. The term "thrombolytic agent" shall include agents such as streptokinase and tissue plasminogen activator.

The term "platelet anti-aggregation agent" shall include agents such as aspirin and dipyridamole.

The term "alkyl" means straight or branched alkane containing 1 to about 10 carbon atoms, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexy, -22- WO 98/34935 PCT/US98/01998 octyl radicals and the like, straight or branched alkene containing 2 to about 10 carbon atoms, propylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2,2-methylbuten-l-yl, 3-methylbuten-l-yl, hexen-1-yl, hepten-1-yl, and octen-1-yl radicals and the like, or straight or branched alkyne containing 2 to about 10 carbon atoms, ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutyn-l-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-l-yl radicals and the like.

The term "aryl" means a 5- or 6-membered aromatic ring containing 0, 1, or 2 heteroatoms selected from 0, N, and S, e.g. phenyl, pyridine, pyrimidine, imidazole, thiophene, oxazole, isoxazole, thiazole, and amino- and halogen- substituted derivatives thereof.

The terms "alkyloxy" or "alkoxy" include an alkyl portion where alkyl is as defined above, methyloxy, propyloxy, and butyloxy.

The terms "arylalkyl" and "alkylaryl" include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above. The CO-n or Cl-n designation where n may be an integer from 1-10 or 2-10 respectively refers to the alkyl component of the arylalkyl or alkylaryl unit. Examples of arylalkyl include benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl. Examples of alkylaryl include toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine, butylpyridine, butenylpyridine, and pentenylpyridine.

The term "halogen" includes fluorine, chlorine, iodine and bromine.

The term "oxy" means an oxygen atom. The term "thio" means a sulfur atom. Under standard nonmenclature used throughout this disclosure, the terminal portion of the designated side chain is described first followed by the adjacent functionality toward the point of attachment. For example, a methylene substituted with ethylcarbonylamino is equivalent to -23- WO 98/34935 PCT/US98/01998

HO

I I I -CH2-N-C-CH2CH3 In the schemes and examples below, various reagent symbols have the following meanings:

BOC

(or Boc): Pd-C:

DMF:

DMSO:

CBZ:

CH2C12: CHC13: EtOH: MeOH: EtOAc: HOAc:

BOP:

EDC:

Oxone:

LDA:

PYCLU:

t-butyloxycarbonyl Palladium on activated carbon catalyst Dimethylformamide Dimethylsulfoxide Carbobenzyloxy Methylene chloride chloroform ethanol methanol ethyl acetate acetic acid Benzotriazol- 1-yloxytris(dimethylamino)phosphonium, hexafluorophosphate 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride potassium peroxymonosulfate Lithium diisopropylamide Chloro-N,N,N',N'-bis(pentamethylene)formamidinium hexafluorophosphate The compounds of the present invention can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, they may be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramusculsar form, all using forms well known to those of ordinary skill in the pharmaceutical -24- WO 98/34935 PCTIUS98/01998 arts. An effective but non-toxic amount of the compound desired can be employed as an anti-aggregation agent.

Compounds of the invention, or pharmaceutically acceptable salts thereof, are useful in the manufacture of a medicament for inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex IIb/IIIa receptor, preventing platelet thrombosis, thromboembolism and reocclusion during and after thrombolytic therapy or after angioplasty or coronary artery bypass procedures, and preventing myocardial infarction in a mammal.

Compounds of the invention may be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex IIb/IIIa receptor is desired. They are useful in surgery on peripheral arteries (arterial grafts, carotid endarterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption. The aggregated platelets may form thrombi and thromboemboli. Compounds of this invention may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.

Extracorporeal circulation is routinely used for cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit. Adhesion is dependent on the interaction between gp IIb/IIIa on the platelet membranes and fibrinogen adsorbed to the surface of the circuit. (Gluszko et al., Amer.

J. Physiol., 252(H), 615-621 (1987)). Platelets released from artificial surfaces show impaired hemostatic function. Compounds of the invention may be administered to prevent adhesion.

Other applications of these compounds include prevention of platelet thrombosis, thromboembolism and reocclusion during and after thrombolytic therapy and prevention of platelet thrombosis, thromboembolism and reocclusion after angioplasty or coronary artery bypass procedures. They may also be used to prevent myocardial infarction.

WO 98/34935 PCT/US98/01998 The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic fimunction of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day and preferably 0.01-100 mg/kg/day and most preferably 0.01-20 mg/kg/day. For example, a typical 90 kg patient would receive oral dosages ranging between about 0.9 mg/day and about 9 g/day, most preferably between about 0.9 mg/day and 1.8 g/day. Suitable pharmaceutical oral compositions such as tablets or capsules may contain, for example, mg, 100 mg, 200 mg and 500 mg. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion.

Advantageously, compounds of the present invention may be administered in divided doses of two, three, or four times daily.

Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, or course, be continuous rather that intermittent throughout the dosage regime.

In the methods of the present invention, the compounds herein described in detail are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, -26- WO 98/34935 PCTIUS98/01998 elixirs, syrups and the like, and consistent with convention pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the compound can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral prodrug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture.

Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.

Disintegrators include, without limitation, starch methyl cellulose, agar, bentonite, xanthan gum and the like.

Active drug can also be co-administered with the usual doses of suitable anticoagulation agents, such as heparin or warfarin (typically given in tablet doses between 1 and 20 mg daily during administration of the active drug), or thrombolytic agents such as tissue plasminogen activator (typically given in i.v. doses of between 20 and 150 mg over two hour period prior to or during administration of the active drug), to achieve beneficial effects in the treatment of various vascular pathologies. Such co-administration also includes administration if the active drug with doses of anticoagulant agents or thrombolyric agents less than the usual doses of those agents.

Compounds of the invention may prepared according to a number of methods familiar to persons skilled in the art.

-27- WO 98/34935 WO 9834935PCT/US98O1998 EXAMPLE 1

H

2 N

NS

2 aji 3 EtOH 1-1 HCI (i 1-2 HCI* H 2 N 11 2Et H NHS 2

Q-CH

3 OH EDC; HOBT; ~N-N NMM; DMF

HHNHS

2 Q-CH 3 IDMF; 500 0 rN ""y~CO 2 Et q HNHS2 00H 3 N C'

CS

2 00 3

NH

2

OH.HCI

H

2

N.

NOH

28 WO 98/34935 WO 9834935PCTIUS98/01998 1:2 3-Amino-2-(toluene-4-sulfonylamino)propionic acid ethyl ester, hydrochloride 1-2 3-Amino-2-(toluene-4-sulfonylmethyl) propionic acid (1-1; 23.2 mmol) was slurried in absolute EtOH and cooled to HCI was bubbled through until the solution is saturated. The resulting homogeneous reaction mixture was stirred at -15' for 15 minutes, then at room temperature for 16 hrs. The reaction mixture was concentrated and placed under high vacuum to give 1- as a white fluffy solid.

1 H NMR (400 MHz, CDCI 3 d 8.32 (bs, 2H); 7.85-7.83 2H); 7.52 1H); 7.25 2H); 4.50 (bt, 1H); 3.93-3.90 2H); 3.62 (bs, 2H); 2.38 3H); 1.0 1- .973 3H).

NC ~~JN H HNHS 2

CH

3 [5-(4-cyanobenzyl)-4-oxo-5,6,7,8-tetrahydro-4H-1 ,5 ,8atriazaazulene-2-carbonyl]-aminol -2-(toluene-4-sulfonylamino )propionic acid ethyl ester 1-4 5-(4-Cyano-benzyl )-4-oxo-5 ,6,7 ,8-tetrahydro-4H- 1,5 ,8a-triazaazulene-2-carboxylic acid, 1-3 (synthesis is described in WO 94/1898 1) 3.23 minol) and 1-1 are dissolved in DMF. HOBT (3.55 mmol; 543 mg), NEt 3 (6.78 mmol; 0.40 mL), and EDC (3.55 mniol; 680 mg.) was added and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc and H20, the layers were separated, and the organic layer was washed with 10% KHSO 4 Sat.

29 WO 98/34935 PCT/US98/01998 NaHCO 3 and brine, dried (MgSO 4 filtered and concentrated. This material was purified by flash chromatography, the product was eluted with EtOAc to give 1-4 as a white solid.

1 H NMR(400 MHz, CDC1 3 d 7.73-7.67 (dd, 4H); 7.48-7.46 2H); 7.29-7.26 4H); 7.19 (bt, 1H); 5.61-5.59 1H); 4.80 2H); 4.43-4.41 2H); 4.04- 4.02 3H); 3.83 1H); 3.76 1H); 3.37 (bs, 2H); 2.41 3H); 2.17 (bt, 2H); 1.26 3H).

0 N .CO2Et N N-N HNHSO2 a CH H2N

NOH

(R)-3-((5-[4-(N-hydroxycarbamimidoyl)benzyl]-4-oxo-5,6,7,8-tetrahydro- 4H-1,5,8a-triazaazulene-2-carbonyllamino)-2-(toluene-4-sulfonylamino) propionic acid ethyl ester 1-4 (1.3g, 2.1 mmol) was dissolved in DMF. Cs2CO3 (9.66 mmol; 3.1 g) and NH 2 OH (8 mmol; 543 mg.) was added and the heterogenous reaction mixture was stirred for 2 hours at 50°. H 2

NOH

(543 mg) was added and the reaction mixture was sturred at 500 for an additional 16 hours. The reaction mixture was filtered and the solids were washed with DMF. The filtrate was concentrated and the resulting solid is dissolved in 50/50 MeOH/EtOAc and loaded on a silica gel column. The product is eluted with 5% MeOH/EtOAc to give 1-5 as a white solid.

1H NMR 400 MHz, (DMSO-d 6 d 9.60 1H); 8.25-8.22 2H); 7.66-7.64 2H); 7.61-7.59 2H) 7.37-7.35 2H); 7.28-7.26 2H); 6.95 1H); 4.69 2H); 4.41-4.38 2H); 4.02-4.00 1H); 3.86-3.82 2H); 3.48-3.47 1H); 3.34-3.32 2H); 2.88 3H); 2.06-2.03 2H); 1.00-0.97 3H).

WO 98/34935 WO98/3935PCTIUS98/01998 EXAMPLE 2 HCI H 2 N H C2Et -NO.

HNHS2\/ CH 3 L-2

'OH

EDO; HOBT; NMM; DMF K I C0 2-2

I

NHSO

2

H

3 DMF; 500 0S 2 C0 3

NH

2

OH*HCI

NOH

N 1yOO 2 t H H NHSO

H

3 31 WO 98/34935 PCTIUS98/01998 NC NH S2 CH3 N- N 2-2 (R)-3-((5-[3-(N-hydroxycarbamimidoyl)benzyl]-4-oxo-5,6,7,8-tetrahydro- 4H-1,5,8a-triazaazulene-2-carbonyl)amino)-2-(toluene-4-sulfonvlamino) Dropionic acid ethyl ester 2-2 2-2 was prepared in a manner substantially the same as for 1-4. The synthesis for 5-(3-Cyano-benzyl)-4-oxo-5,6,7,8-tetrahydro-4H- 1,5,8a-triaza-azulene-2-carboxylic acid is disclosed in WO 94/18981.

1 H NMR (400 MHz CDC1 3 d 7.74-7.72 2H); 7.64-7.62 3H); 7.52-7.50 1H) 7.30 2H); 7.26 1H); 7.16(t, 1H); 5.56-5.55 2H); 4.77 2H); 4.43-4.41 2H); 4.13-4.00 3H) 3.9-3.82 1H); 3.78-3.70 1H); 3.37 2H); (2.41 s, 3H); 2.18-2.14 2H); 1.14-1.12 3H).

O

NOHH

NOH ON>(COEt

H

2 N N N 2 NHS2 a CH -O \2-3 {5-[3-(N-hydroxycarbamimidoyl)benzyl]-4-oxo-5,6,7,8-tetrahydro-4H- 1,5,8a-triazaazulene-2-carbonyl amino)-2-(toluene-4sulfonvlamino)propionic acid ethyl ester 2-3 2-3 was prepared in a manner substantially similiar to example 1H NMR (400 MHz, DMSO-d 6 d 9.61 1H); 8.24-8.23 2H); 7.68 1H); 7.62-7.60 3H); 7.36-7.37 2H); 7.28-7.26 2H); 6.96 1H); 5.80 (s, 2H); 4.70 2H); 4.39 2H); 4.0 1H); 3.84-3.82 2H); 3.49 1H); 3.33 3H); 2.311 3H); 2.02 2H); (.99-.96 3H).

32- WO 98/34935 PTU9/19 PCT/US98/01998 EXAMPLE 3 NC"a 2 HO aC2 NaH /DMSO 3-1 HCI -H 2

O

2 Et NHS0 2 1-2

OH

3 o CO 2

H

3-2 EDO HOBt i-Pr 2 NEt

NC,

N <CO 2 Et H 2

NOH

H N H S 2 N aC HOI CS 2 00 3 HO,

N

N CO 2 Et H N H SO 2 C 33 WO 98/34935 WO 9834935PCT/US98/01998 NC,,a o CO 2

H

0

CH

3 EDC /HOBt ""yCO 2 tBu H 2 NOH HOI CS 2 00 3 N H S 2 aH 1) 10% Pd/C

H

2 (g)

CH

3 0H HOAc 2) HOI (g)

OCH

3 N H 2 0

H

2 N N C2 0 NHS 0 2 -1 3-8 34 WO 98/34935 WO 9834935PCTIUS98/01998 NC, o CO 2

H

N H S 2 aH EDC /HOBt

NCI

H

2

N'

,dU 2 lt5U H 2 NOH HCI CS 2 00 3 S0 2 ACH3 1) 10% Pd/C

H

2 (g)

CH

3 0H HOAc yCO 2 tBu 2) HCI (g) N H S 2 N" aH 3-7

NH

2 2

H

N H S 2 C H 3 3-8 35 WO 98/34935 PCTIUS98/01998 NC CO 2

H

3-2 4-(4-Cvanophenoxv)benzoic acid 3-2 NaH (5.97 g, 149 mmol) was suspended in 100 mL DMSO under argon atmosphere and stirred for 30 min at rt. 4-Hydroxybenzoic acid 10.0 g, 72.4 mmol) was added portionwise, and the mixture was stirred for 30 min at rt and 1 h at 80 0 C. 4 Nitrobenzonitrile (10.7 g, 72.2 mmol) was added, and the mixture stirred at 80 0 C over 15 h. The resulting viscous suspension was diluted with H20 (50 mL) and acidified with cone. HC1 to pH 2. The resulting yellow precipitate was collected by vacuum filtration, recrystallized from EtOH, and washed with hexane to afford 3-2 as an orange solid. NMR (400 MHz, CDC13): d 8.15 J 8 Hz, 2H), 7.67 J 8 Hz, 2H), 7.20 4H).

NN C CO2Et H

NHSO

2 O "CH 3 3-3 (R)-3-[4-(4-Cyanophenoxy)benzoylamino]-2-(toluene -4-sulfonyl-amino)propionic acid ethyl ester 3-3 To a solution of 3-2 (0.73 g, 3.0 mmol) and amine 1-2 (1.00 g, 3.1 mmol) in 15 mL DMF was added diisopropylethylamine (0.50 mL, 2.9 mmol) followed by EDC (0.59 g, 3.1 mmol). The resultant mixture was stirred at rt over 36 h, then diluted with EtOAc, washed with H20, aq. KHSO4, sat'd NaHCO3, and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by chromatography on -36- WO 98/34935 PTU9119 PCT/US98/01998 SiO2 eluting with 60% EtOAc hexane to afford 3-3 as a white solid. Rf EtOAc hexane): 0.38. NMR (400 MHz, CDC13): d 7.86 J 8 Hz, 2H), 7.72 J 8 Hz, 2H), 7.64 J 8 Hz, 2H), 7.30 J =8 Hz, 2H), 7.10 (in, 4H), 6.76 (in, 1H), 5.59 (in, 1H), 4.0 (in, 4H), 3.61 (in, 1H), 2.42 (s, 3H), 1.16 J 7 Hz, 3H).

H 0, N 0

H

2 N N"-y 2E H NHS0 2 3-4

OH

3 3- {4-4-(Amino-hydroxyiminomethyl)phenoxylbenzoylaminol 4-sulfonvlalnino)projnionic acid ethyl ester 3-4 2-(toluene- Example 3- was prepared in a manner substantially the same as for example 1-5. Rf (EtOAc): 0.56. NMR (400 MHz, d-6 DMSO): d 9.59 1H), 8.43 (in, 1H), 8.27 1H), 7.77 J 9 Hz, 2H), 7.72 J 9 Hz, 2H), 7.62 J 8 Hz, 2 7.29 J 8 Hz, 2H), 7.05 (in, 4H), 5.80 (s, 2H), 4.06 (mn, 1H), 3.82 J 7 Hz, 2H), 3.49 (in, 1H), 3.35 (mn, 1H), 2.32 (s, 3H), 0.97 J 7 Hz, 3H).

37 WO 98/34935 WO 9834935PTIUS98/01998 N C"j N. I'yCO2tBu H. N H SO 2 a H 3 (R)-3-[4-(4-Cyanophenoxy)benzoylamaino]-2-(toluene-4 sulfonviamino)upropionic acid tert-butyl ester 3-6 A solution of 3- (0.57 g, 2.4 nixol), 3-5 (0.75 g, 2.4 mmol), and EDC (0.47 g, 2.4 mmol) in 10 mL DMF was stirred at rt over 15 h.

The mixture was then diluted with EtOAc, washed with H20, 10% aq.

KHSO4, sat'd NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by chromatography on SiO2 eluting with 60% EtOAc hexane to afford 3-6 as a white solid. Rf EtOAc hexane): 0.52. NMR (400 MHz, CDCl3): d 7.87 J 9 Hz, 2H), 7.73 J 8 Hz, 2H), 7.65 J 9 Hz, 2H), 7.30 J 8 Hz, 2H), 7.08 (in, 4H), 6.75 (mn, 1H), 5.54 (mn, 1H), 3.98 (mn, 1H), 3.89 (in, 1H), 3.54 (mn, 1H), 2.41 3H), 1.31 9H).

H

2 N N N N. H NHS0 2 N 3-7 OH 3 3- {4-[4-(Aminohydroxyiminomethyl) phenoxylbenzoylarmno 1-2- (toluene- 4-sulfonvlainnoropionic acid tert-butyl ester 3-7 2D Example 3- was prepared in a manner substantially the same as for example 38- SWO 98/34935 PCTIUS98/01998 Rf (80% EtOAc hexane): 0.40. NMR (400 MHz, d-6 DMSO): d 9.59 (s, 1H), 8.40 1H), 8.18 1H), 7.79 J 9 Hz, 2H), 7.72 J 9 Hz, 2H), 7.63 J 8 Hz, 2H), 7.30 J 8 Hz, 2H), 7.05 4H), 5.80 2H), 4.00 1H), 3.48 1H), 3.36 1H), 2.32 3H), 1.16 9H).

NH

2

H

2 N Z N C02H H NHSO 0& "CH3 3-8 3 (R)-3-{4-[4-(Aminoiminomethyl)phenoxy]benzoylamino)-2-(toluene- 4-sulfonylamino)propionic acid 3-8 To a suspension of 3-7 (0.618 g, 1.09 mmol) in 5 mL CH3OH and 5 drops HOAc was added 0.19 g (31% by weight) of 10% Pd/C, and the resulting mixture was stirred under H2 atmosphere at balloon pressure for 5 h. An additional 2 mL CH3OH and 0.5 mL HOAc were added, and the mixture stirred under H2 atmosphere over 15 h. An additional portion of 10% Pd/C (0.20 g, 32% by weight) was then added and the mixture stirred for 15 h. The reaction was filtered through a pad of Celite, eluting with CH30H, and concentrated in vacuo. The residue was azeotroped with CH2C12, concentrated, and suspended in 15 mL EtOAc and cooled to -78 0 C. The mixture was treated with HC1 for min, then allowed to warm to 0 OC and stir for 1 h. Concentration, azeotroping with CH2C12, and pumping at high vacuum afforded 3-8 as a white solid. NMR (400 MHz, D20 NaOD): d 7.67 J 9 Hz, 2H), 7.47 4H), 7.10 J 9 Hz, 2H), 7.02 J 9 Hz, 2H), 6.95 J 8 Hz, 2H), 3.57 2H), 3.09 (dd, J 9.5, 13 Hz), 2.07 3H).

-39- WO 98/34935 PTU9/19 PCTIUS98/01998 EXAMPLE 4 I Br

NC

4-1 HaCOOMe 4-2 NaH; DMF I O\/COOMe NC4 LiOH THF; H 2 0; MeOH

NC

O\/COOH

4-4

BOP/DMF/NMM

HCI

-HN*'

NHS0 2

CH

3 WO 98/34935 PTU9119 PCTfUS98/01998 N H'JHSO CH 3 0

NH

2 OH*HCI; CS 2 00 3 DMF I500

H

2 N I H NHS0(C

CH

3 NOH 0 NC COMe 4-3 4-(4-Cyanobenzvloxv)benzoic acid methyl ester 4-3 4-Methyl hydroxy benzoate(3.9 g; 5.5mmol) was dissolved in DMF. Cs 2

CO

3 (4.2 g; 12.8 mmol) was added and the slurry was stirred vigorously for 0.5 hr. Alpha-bromo-p- tolumitrile (5.0 g; 25.5 mmol) was added and the reaction was stirred for 16 hrs. The reaction mixture is diluted with EtOAc and washed with H 2 0 (2x) and brine. The organic layer was dried (MgSO 4 filtered and concentrated to yield 4-3 as a white solid.

1 H NMR (400 MHz; CDCl 3 d 8.02 2H); 7.70 2H); 7.56 2H); 5.18 2H); 3.89 3H).

41 WO 98/34935 PTU9/19 PCTIUS98/01998 NC- 4-.4 4-(4-Cvanobenzyvloxy)benzoic acid 4-4 (1.4 g; 5.2 minol) was slurried in THF/H0 eH.LO (1.09 g; 26 ramol) was added and the reaction was stirred for 20 hr. The resulting homogeneous reaction mixture was treated with EtOAc and

KHSO

4 The layers were separated, and the organic layer was washed with H 2 0 and brine, dried (MgSO 4 filtered and concentrated to yield 4-4 as a white solid.

N 0 N COOCHCH Ir N 2 NC 450 H NHS 2 -a CH 3 (R)-3-14-(4-Cyanobenzyloxy) benzoylamino]-2-(toluene-4-sulfonvlamino) propionic acid ethyl ester 4-4 (500 mg; 1.98 mmol) and 1-2 (630 mg; 1.98 nimol) are dissolved in DMF. BOP (875 mg; 1.98 minol) and NMM (0.44 mL; 3.96 mmol) are added and the reaction is stirred for 1.5 hrs. The reaction mixture is diluted with EtOAc, and washed with H 2 0 10 KHSO 4 sat NaHCO 3 and brine. The organic layer was dried, (MgSO 4 filtered, and concentrated to yield 4-5 as a white solid.

1H NMR (400 MIHz; CDCl 3 d 7.79-7.69 (in, 6H); 7.56-7.54 2H); 7.29-7.27 2H); 7.00 2H); 6.67-6.65 1H); 5.63-5.61 (di 11H); 5.18 2H); 4.09- 3.99 (mn, 4H); 3.64-3.60 (in, 1H); 2.41 3H); 1.17-1.15 3H).

42 WO 98/34935 PTU9119 PCT/US98/01998 .CO000H 2 C H 3

NOH

4-6 {4-[4-(N-hydroxycarbamimidoyl)benzyloxylbenzoylainol -2- (toluene-4-sulfonvlamino)p2rolionic acid ethyl ester 4-6 4-6 was prepared substantially the same as for example 1 H NMR (400 MHz; DMSO-d 6 d 10.90 (bs, 1H); 8.33 1H); 8.27-8.25 (d, 1H); 7.70-7.69 (in, 4H); 7.62-7.61 (mn, 4H); 7.29-7.27 2H); 7.05-7.07 (d, 2H); 5.27 2H); 4.05 (mn, 1H); 3.49 (mn, 1H); 3.45 (in, 1H); 2.3 3H); 0.96- 0.93 3H).

43 WO 98/34935 WO 9834935PCTIUS98/01998 EXAMPLE N CjBr 4-1 IO,. O NaH; DMF N C'

NC'

LiOH THF; H 2 0; MeOH BOP /DMF/INMM NHS0 2

-Q-CH

3 44 WO 98/34935 PTU9/19 PCTIUS98/01998 0 0 N 2 3 N" HNHS2 ~CH3 5-4

NH

2 0H -HCI CS 2

CO

3 DMF 500

COOCH

2

CH

3 NHS02-C

H

3 NOH -COOMe 4-(3-Cvanobenzvloxv) benzoic acid methyl ester 5-2 5-2 was prepared in a manner substantially similiar as for example 4-3 WO 98/34935P2TU9I98 PCTIUS98/01998 N 5-3 4-(3-Cvanobenzyloxv)benzoic acid 5-3 -3 was prepared in a manner substantially similiar as for example 4-4 0 0 -c y 0 H 2 H3 NC I HNHS0 2

()CH

3 (R)-3-[3-(4-Cyanobenzyloxy) benzoylamino]-2-(toluene-4-sulfonvlamino) propionic acid ethyl ester 5-4 5-4 was prepared in a manner substantially similiar as for example 1HNMR (400 MHz; CDC1 3 d 7.73-7.68 (in, 4H); 7.58-7.56 2H); 7.45 (s, 1H); 7.38-7.37 2H); 7.30-7.28 (d 2H); 7. 10 (in, 1H); 6.75 1H); 5.61 (d, 1H); 5.20 2H); 4.09-4.06 (mn, 4H1); 3.60 (mn, 1H); 2.41 3H1); 1.18-1.14 (t, 3H).

46 WO 98/34935 PTU9/19 PCTIUS98/01998 o H 'yCOOCH

CH,

H

2 N IH NHS 2 3 NOH {3-[4-(N-hydroxycarbamimidoyl)benzyloxylbenzoylamino)-2- (toluene-4-sulfonv lamino)nropionic acid ethyl ester 5-5 was prepared in a manner substantially similiar as for example 1H NMR (400 MHz; DMSO-d 6 d 10.95 (vbs, 1H); 8.49 1H); 8.30 1H); 7.73-7.71 1H); 7.64-7.62 (in, 2H); 7.39-7.35 (in, 3H); 7.18 1H); 5.25 (s, 2H); 4.07-4.05 (in, 1H); 3.83-3.8 1 2H); 3.45 (in, 1H); 3.25 (mn, 1H); 2.30 (s, 3H); 0.97-0.95 3H).

47 .WO 98/34935 PTU9/19 PCTIUS98/01998 EXAMPLE 6 N C B. Br

OCH

3 NaH

DMF

LiOH THF /H 2 0 /MeOH N C N 0

N

I

OCH

3

SN

6-3 H 0 BOP; NMM

DMF

HCI-Hle -*yCO~ NHS0 2

-CJCH

3 1 -2 48 WO 98/34935 PTU9119 PCTIUS98/01998 N~~>lCOOCH2CH3 IH 0 H NHS0 2 3

CS

2 00 3

NH

2

OH*HCI

DMF 5 0

NOH

H

H

2 N 0 O H2 3 IN NCH 2 H 3 6-6 HO H HO0~C HO- N

OCH

3

N

HO0 5-Hvdroxv-1H-indole-2-carboxvlic acid methyll ester 6-2 5-Hydroxy-2-indolecarboxylic acid (2.3 g; l3mmol) was dissolved in MeOH and cooled to 00. HCl was bubbled through until the solution was saturated. The reaction imixture was stirred for 2 days allowing the cooling bath to evaporate. The reaction mixture was concentrated to yield 6-2 as a tan solid.

1HNMIR (400 MHz; CDC13 d 8.82 (bs, 1H); 7.27-7.30 (in, 1H); 7.10-7.07 (dd, 2H); 6.95 1H); 4.69 1H); 3.95 3H).

49 WO 98/34935 PCT/US98/01998 5-(3-Cvanobenzvloxv)-lH-indole-2-carboxvlic acid methyl ester 6-3 6-2 was dissolved in DMF. NaH (9.5 mmol; 380mg of a dispersion on mineral oil) was added and the reaction mixtrure was stirred for 15 minutes. Alpha-bromo-meta-tolunitrile (9.5 mmol; 1.8 g) was added and the reaction mixture was stirred for 18 hours. The DMF was removed in vacuo to yield a brown viscous oil. Flash chromatography (10% EtOAc/Hexanes) yielded 6-3 as a white solid.

NC O

OH

NO

6-4 5-(3-Cvanobenzvloxv)-1H-indole-2-carboxvlic acid 6-4 6-3 (2.0 g; 6.5 mmol) was slurried in THF/H 2 0/MeOH mL/10 mL/lOmL), LiOH 19.5 mmol; 820 mg) was added and the reacion mixture was stirred for 18 hours. The homogeneous reaction mixture was neutralized to pH=8 and concentrated to yield 6-4 as a brown oil which will be used as is in the next step.

WO 98/34935 PTU9/19 PCT/US98/01998 N N SN H NHS0 2 3 H o 3- {15-(3-Cyanobenzyloxy)- 1H-indole-2-carbonyllaminol -2-(toluene-4sulfonylamino)]2ropionic acid ethyl ester 6-4 (1.6g; 5.4 mmol) and 1- (5.4 mmol; 1.7g) were dissolved in DMF. BOP (5.4 mmol; 2.4 g) and NMM (10.8 mmol; 1.18 mL) were added and the reaction mixture was stirred for 2 days. The reaction mixture was diluted with EtOAc and H 2 0. The layers were separated and the organic layer was washed with H 2 0 and brine, dried (MgSO 4 filtered and concentrated to yield a tan oil. Flash chromatography EtOAc/hexanes) yielded 6-5 as a white solid.

NOH

H

2 N OC2H H H NHS2- CH3 6-6 H 0 15-[13-(N-hydroxycarbamimidoyl)benzyloxy] H-indole-2-carbonyl) amino)-2-(toluene-4-sulfonylamino)propiom c acid ethyl ester 6-6 6-6 was prepared in a manner substantially similiar to example 1H NMR (400 MHz; DMSO-d 6 d 11.40 1H); 8.30 1H); 8.21 1H); 7.80 1H); 7.82-7.62 (in, 5H); 7.26 1H); 7.23 2H); 7.20 1H1); 6.95 1H); 6.93 1H); 5.15 2H); 4.05 (in, 1H); 3.81 (mn, 2H); 2.24 3H); 0.95 3H).

51 WO 98/34935 WO 9834935PCTIUS98/01998 EXAMPLE 7 HOOC> S>COOH 7-1 HOI MeOH oo_> RT S001 2

DMF

10000C NC NH 2 THF H 2 0 MeOH NC Q-N LiOH 0 0 NC -j-N

OH

EDC/HOBT/DMF HCI

H

2 N-y COOEt

NHS

2

-GCH

3 1-2 52 SWO 98/34935 PCTIS98/01998 H ~CCOOCH 3 JNC C NHSO 2 CH3 7-4 o o

NH

2 OH*HCI Cs 2

CO

3 DMF 50 0

C

N 2 >COOCH 2

CH

3 NC-N OCH 3 H I 7-2 5-(4-Cyanophenylcarbamoyl)thiophene-2-carboxylic acid methyl ester 7-2 A solution of 2,5 thiophenedicarboxylic acid 2.52 g, 14.6 mmol) in 100 mL CHO3H was cooled to 0 °C and treated with HC1 (g) for 5 min. The mixture was stirred for 4 h at rt, at which time HPLC analysis indicated an approximately 1:1 mixture of mono- and di-esters.

The precipitated solids were filtered off, and the filtrate concentrated and azeotroped with CH2C12 to afford a white solid consisting of mono-acid mono-ester, 33% diester, and 6% residual starting material.

A portion of this mixture (0.73 g, -4 mmol) suspended in 20 mL dichloroethane was treated with thionyl chloride (2.9 mL, 40 mmol) and -53- WO 98/34935 PCTIUS98/01998 1 drop DMF and heated at 100 OC for 30 min. After cooling to rt, the mixture was concentrated and azeotroped with dichloroethane and toluene. The residue was transferred with 10 mL CHC13 to a jacketed addition funnel cooled to 0°C, and added dropwise to a solution of 4 aminobenzonitrile (0.47 g, 4.0 mmol) and pyridine (0.9 mL, 10 mmol) in mL CHC13 at 0°C. The resulting mixture was stirred for 1 h at rt then concentrated in vacuo, and the residue purified by chromatography on SiO2 eluting with a gradient of 2% to 5% to 10% Et20 in CHC13 to afford 7-2 as a white solid. Rf(5% Et20 CHCl3): 0.11. NMR (400 MHz, d-6 DMSO-d 6 d 8.06 J 4 Hz, 1H), 7.93 J 8.6 Hz, 2H), 7.88 J 4 Hz, 1H), 7.82 J 8.6 Hz, 2H), 3.86 3H).

0 0 NC- N S i

OH

H O 7-3 5-(4-Cvano-phenvlcarbamovl)thiophene-2-carboxylic acid 7-3 7-2 (350 mg, 1.22 mmol) was slurried in LiOH (3.66 mmol; 154 mg.) was added and the reaction mixture was stirred at room temperature for 16 hours. The resulting homogeneous reaction mixture was then heated at 500 for four hours. After cooling, the reaction mixture was diltuted with EtOAc and 10% KHS04 The organic layer was washed with H20 and brine, dried (MgSO 4 filtered and concentrated to yield 7-3 as a white solid.

-54- WO 98/34935 PTU9/19 PCTIUS98/01998 IN 11 NHS 2

)-CH

3 0 .7-4 {[5-(4-Cyanophenylcarbamoyl )thiophene-2-carbonyl] -amino) 2-(toluene-4-sulfonvlamino)uropionic acid ethyl ester 7-4 7-3 (350 mg; 1.29 nunol) and j L- (1.29 mmol; 414 mg.) were dissolved in DMF. HOBT (1.29 mmoll; 197 mg) and EDC (1.29 mmol; 247 mg) were added and the reaction mixture was stirred for 2 days. The reaction mixture was then diluted with EtOAc andH 2 O. The layers were separated, and the organic layer was washed with H20,

KHSO

4 sat. NaHCO 3 and brine. The organic layer was then dried (MgSO 4 filtered and concentrated to yield a tan oil. Flash chromatography (60 EtOAc/Hexanes) yielded 7-4 as a white solid.

1 H NIVR (400 MHz, CDC1 3 d 8.14 1H); 7.8 2H); 7.73 2H); 7.68 (d, 2H); 7.64 1H); 7.60 1H); 7.32 2H); 7.01 1H); 6.70 1H); 4.09- 3.99 (in, 4H); 3.55 (in, 1H); 2.42 3H); 1.13 3H).

H 2 QNCOHH 3 H N S' 0 H 10NHS0J10 .CH3 NOH

Z_

[4-(N-hydroxycarbamimidoyl )phenylcarbamoyllthiophene- 2-carbonyl) amino)-2-(toluene-4-sulfonylamino)propionic acid ethyl ester was prepared in a manner substantially similiar to example 55 SWO 98/34935 PCT/US98/01998 1 H NMR (400 MHz, DMSO-d 6 d 10.9 (bs, 1H); 10.63 1H); 8.75 1H); 8.31 1H); 8.0 1H); 7.9 1H); 7.69-7.61 5H); 7.23 2H); 4.03 1H); 3.85 2H); 3.5 1H); 3.35 1H); 2.48 3H); 0.990 3H).

EXAMPLE 8 Tablet Preparation Tablets containing 25.0, 50.0, and 100.0 mg., respectively, of the compound (R)-3-((5-[4-(N-hydroxycarbamimidoyl)benzyl]-4-oxo- 5,6,7,8-tetrahydro-4H-1,5,8a-triazaazulene-2-carbonyl}amino)-2-(toluene- 4-sulfonylamino) propionic acid ethyl ester (Compound A) are prepared as illustrated below: TABLE FOR DOSES CONTAINING FROM 25-100MG OF COMPOUND A Amount-mg Compound A 25.0 50.0 100.0 Microcrystalline cellulose 37.25 100.0 200.0 Modified food corn starch 37.25 4.25 Magnesium stearate 0.50 0.75 All of the active compound, cellulose, and a portion of the corn starch are mixed and granulated to 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 25.0, 50.0, and 100.0 mg, respectively, of active ingredient per tablet.

-56- WO 98/34935 PCT/US98/01998 EXAMPLE 9 Intravenous formulations An intravenous dosage form of the above-indicated active compound is prepared as follows: Compound A Sodium Citrate Citric Acid Sodium Chloride Water for Injection (USP) 0.5-10.0mg 5-50mg 1-15mg 1-8mg q.s. to 1 L Utilizing the above quantities, the active compound is dissolved at room temperature in a previously prepared solution of sodium chloride, citric acid, and sodium citrate in Water for Injection (USP, see page 1636 of United States Pharmacopeia/National Formulary for 1995, published by United States Pharmacopeial Convention, Inc., Rockville, Maryland, copyright 1994.

-57-

Claims (21)

1. A compound having the formula HO, N H 2 N 0 J COOR 4 H2 RR or a pharmaceutically acceptable salt, wherein X is (CH2)q, (CH2)mO (CH2)p, (CH2)mNR 11 (CH2)p, (CH2)mC(O)NR11(CH2)p, (CH2)mNR 1 1 C(0)(CH2)p, (CH2)mC(O)(CH2)p, (CH2)mC(S)(CH2)p, (CH2)mSO2(CH2)p, (CH2)mS(CH2)p, (CH2)mSO(CH2)p, (CH2)mSO2NR11(CH2)p, (CH2)mC=C(CH2)p, or (CH2)mCH(OH)(CH2)p, where m and p are integers independently chosen from 0-6, q is an integer chosen from 1-6, and R 11 is selected from the group consisting of hydrogen, hydroxyl, Ci-jo alkyl, 58 WO 98/34935 PTIS8O19 PCT/US98/01998 C3-.8 cycloalkyl, aryl, aryl C1-.8 alkyl-, amino, amino C1..8 alkyl-, C1-3 acylamino-, C1..3 acylamino C1-8 alkyl-, C1-.6 alkylamino-, C1-.6 alkylamino C1-8 alkyl-, C1..6 dialkylamino-, C1..6 cialkylamino C1-8 alkyl-, C1-.4 alkoxy, C1-4 alkoxy C1..6 alkyl-, carboxy, carboxy C1..6 alkyl-, C 1-3 alkoxycarbonyl-, C1-3 alkoxycarbonyl C1-.6 alkyl-, carboxyoxy-, carboxy C1-6 alkyloxy-, hydroxy C1-6 alkyl-, C1-8 alkylcarbonyloxy C1-4 alkyloxycarbonyl-, and aryl C1..8 alkylcarbonyloxy C1..4 alkyloxycarbonyl-; Y is i) where D and E are independently chosen from C, NH, N(CH3), N(CH2CH3), N(CHCH2CH2), 0 and S, and R 5 is independently selected from the group consisting of hydrogen, 59 WO 98/34935 PTU9/19 PCTIUS98/01998 Ci-io alkyl, aryl, aryl 01.8 alkyl-, oxo, thio, amino, amino 01-8 alkyl-, 01-3 acylamino-, 01-3 acylamino 01-8 alkyl-, C1..6 alkylamino-, Cl-6 alkylamino 01.8 alkyl-, 01-6 dialkylamino-, 01-6 dialkylamino 01-8 alkyl-, 01-4 alkoxy 01-4 alkoxy 01-6 alkyl-, carboxy, carboxy C1..6 alkyl-, 01-3 alkoxycarbonyl-, 01..3 alkoxycarbonyl 01-6 alkyl-, 2D carboxyoxy-, carboxy 01-6 alkyloxy-, hydroxy, and hydroxy Oi..6 alkyl; ii) S ,or 60 WO 98/34935 PCTIUS98/01998 iv) AB, wherein A and B, which form a fused ring system sharing adjacent carbon and nitrogen atoms, are defined as follows: A is a 5, 6 or 7 membered saturated, partially saturated, or unsaturated ring containing 1, 2 or 3 heteroatoms selected from 0, S or N; B is a 5, 6 or 7 membered saturated, partially saturated, or unsaturated ring containing 1, 2 or 3 heteroatoms selected from 0, S or N; R 1 is hydrogen C1-6 alkyl, carboxy, carboxy C1-6 alkyl-, C1-6 alkylcarboxy C1-6 alkylcarboxy C1-6 alkyl-, oxo, C1-6 alkyloxy-, oxo C1-6 alkyl-, C1-6 alkyloxy C1-6 alkyl-, hydroxy, hydroxy C1-6 alkyl-, aryl, aryl C1-6 alkyl-, or halogen; R 2 and R 3 are independently selected from the group consisting of hydrogen, fluoro, hydroxy C1-6 alkyl-, -61- WO 98/34935PCUSIO19 PCTIUS98/01998 carboxy, carboxy 01-6 alkyl-, hydroxyl, 01..6 alkyloxy-, aryl 01..6alkyloxy-, C3-.8 cycloalkyl-, Cl.8 alkyl, aryl, aryl 01-6 alkyl-, 01-6 alkylcarbonyloxy-, amino, C1.6 alkylamino-, amino C1-6 alkyl-, 01-6 alkylamino 01-6 alkyl-, arylamino-, aryl 01..6 alkylaniino-, arylamino 01-6 alkyl-, aryl C1.6 alkylamino 01-6 alkyl-, amino Cl-6 alkyl-, 01-6 dialkylamino-, 01.6 dialkylamnino 01-6 alkyl-, aminocarbonyloxy-, amninocarbonyloxy C1..6 alkyl-, 01-6 alkylaminocarbonyloxy-, 01-6 alkylaminocarbonyloxy 01-6 alkyl-, aryl aminocarbonyloxy-, aryl aminocarbonyloxy 01-6 alkyl-, aryl 01-6 alkylaminocarbonyloxy-, aryl 01-6 alkylaminocarbonyloxy Ci-6 alkyl-, 01-8 alkylsulfonylamino-, 01-8 alkylsulfonylamino Cl-6 alkyl-, aryl sulfonyl amino-, aryl sulfonylamino 01-6 alkyl-, aryl C1..6 alkylsulfonylanuno-, aryl 01-6 alkyvlsulfonylamino C1-6 alkyl-, 62 WO 98/34935 PTU9/19 PCTIUS98/01998 C1..8 alkyloxycarbonylamino-, 01-8 alkyloxycarbonylamino 01-8 alkyl-, aryloxycarbonylamino-, aryloxycarbonylamino C 1-8 alkyl-, aryl C 1-8 alkyloxycarbonylarnino-, aryl C1-8 alkyloxycarbonylamino C1-8 alkyl-, 01-8 alkylearbonylainino-, C1-8 alkylcarbonylamino 01-6 alkyl-, arylcarbonylamino-, arylcarbonylamino 01-6 alkyl-, aryl C1-8 alkylcarbonylamino-, aryl Cl.8 alkylcarbonylamino C1-6 alkyl-, aminocarbonylamino-, aminocarbonylamino C1-6 alkyl-, 01-8 alkylaminocarbonylamino-, 01-8 alkylamninocarbonylamino 01-6 alkyl-, arylaminocarbonylamino-, arylaminocarbonylamino 01-6 alkyl-, aryl 01..8 alkylaminocarbonylamino-, aryl 01-8 alkylaminocarbonylamino 01-6 alkyl-, amino sulfonylamino-, aminosulfonylamino 01-6 alkyl-, 01-8 alkylaminosulfonylamino-, 01-8 alkylaminosulfonylamino 01-6 alkyl-, arylaminosulfonylamino-, arylaminosulfonylamino 01-6 alkyl-, aryl Ci-g alkylaminosulfonylamino-, aryl Ci-8 alkylaminosulfonylarnino C1-6 alkyl-, 01-6 alkylsulfonyl-, C1-6 alkylsuli'onyl 01-6 alkyl-, aryl 01-6 alkylsuflfonyl-, aryl C1-6 alkylsulfonyl C1-6 alkyl-, 01-6 alkylcarbonyl-, C1-6 alkylcarbonyl 01-6 alkyl-, 63 WO 98/34935 PTU9/19 PCT/US98/01998 aryl 01-6 alkylcarbonyl-, aryl 01-6 alkylcarbonyl 01-6 alkyl-, aminocarbonylb, aminocarbonyl 01-8 alkyl-, Cl..8 alkylaminocarbonyl-, 01-8 alkylaminocarbonyl 01--8 alkyl-, arylaminocarbonyl-, arylaininocarbonyl 01-8 alkyl-, aryl C 1.8 alkylaminocarbonyl-, aryl 01.8 alkylaminocarbonyl 01-8 alkyl-, aminosulfonyl-, aminosulfonyl 01-8 ailkyl-, 01-8 alkylaminosulfonyl-, Cl-8 alkylaminosulfonyl Cl-8 alkyl-, arylaminosulfonyl-, arylaminosulfony1 01-8 alkyl-, aryl C1-8 alkylaminosulfonyl-, aryl 01-8 alkylamninosulfonyl 01-8 alkyl-,

03-8 cycloalkylsulfonylamino-, C1-8 alkyloxyarylsulfonylarnino-, thiophenylsulfonylamino-, and -NHSO 2 0 ;and R 4 is hydrogen, 01-8 alkyl, aryl, aryl 0 1-6 alkyl-, 01-8 alkylcarbonyloxy 01-4 alkyl-, or aryl 01-8 alkylcarbonyloxy C1-4 alkyl-. 64 WO 98/34935 PTU9/19 PCT/US98/01998 2. A compound of Claim 1 having the formula HO, N H 2 N 0 '9 N>%7O H 2 or a pharmaceutically acceptable salt, wherein Y is i) N H where R5 is independently selected from the group consisting of hydrogen, Ci-1O alkyl, aryl, aryl C1-8 alkyl-, OXO, thio, amino, amino C1-8 alkyl-, C1-3 acylamino-, C 1-3 acylamino C1-8 alkyl-, C1-6 alkylamino-, C1-6 alkylamino C1-8 alkyl-, 65 WO 98/34935 PTU9119 PCTIUS98/01998 C1-6 dialkylamino-, C1-6 dialkylamino, C1-8 alkyl-, C1-4 alkoxy-. C 1-4 alkoxy C 1-6 alkyl-, carboxy, carboxy C1..6 alkyl-, C 1-3 alkoxycarbonyl-, C1-3 alkoxycarbonyl C1..6 alkyl-, carboxyoxy-, carboxy C 1.6 alkyloxy-, hydroxy, and hydroxy C1-6 alkyl-; ii) iii) S, iv) AB, where AB is selected from the group consisting of 66 WO 98/34935 PCTIS98/01998 a) 0 2V6 V2.N GN- wherein V 1 and V 2 is N or CR 6 and G is CH 2 CH 2 -CH 2 CH2C(RT) 2 CH 2 or H 2 C CH 2 (CH2)n. (CH2)n R 6 is H, branched or straight chain C1-4 substituted or unsubstituted alkyl, branched or straight chain lower alkenyl, C1-4 alkylaryl, substituted aryl, or 5 or 6 membered heteroaryl containing 1, 2, or 3 N, S, or 0 heteroatoms wherein substituted alkyl is hydroxy- substituted or C1-4 alkoxy-substituted alkyl, and wherein substituted aryl is substituted by one, two or three of the following groups: halogen, C1-4 alkoxy, hydroxy, or C1-4 alkyl; R 7 is H, branched or straight chain C1-4 substituted or unsubstituted alkyl, branched or straight chain lower alkenyl, C1-4 alkylaryl, substituted aryl, or 5 or 6 membered heteroaryl containing 1, 2, or 3 N, S, or O heteroatoms wherein substituted alkyl is hydroxy- substituted or C1-4 alkoxy-substituted alkyl, and wherein substituted aryl is substituted by -67- WO 98/34935 PCT/US98/01998 one, two or three of the following groups: halogen, C1-4 alkoxy, hydroxy, or C1-4 alkyl; b) O SL wherein J N or CR 8 wherein R 8 CN, C(O)N(R 9 )R 1 0 N 0 or 0 f[-(CH2 )n N R 9 is is H, branched or straight chain C1-4 substituted or unsubstituted alkyl, branched or straight chain lower alkenyl, C1-4 alkylaryl, substituted aryl, or 5 or 6 membered heteroaryl containing 1, 2, or 3 N, S, or 0 heteroatoms wherein substituted alkyl is hydroxy- substituted or C1-4 alkoxy-substituted alkyl, and wherein substituted aryl is substituted by one, two or three of the following groups: halogen, C1-4 alkoxy, hydroxy, or C1-4 alkyl; R 1 0 is H, branched or straight chain C1-4 alkyl; wherein n and n' are 0-7; -68- WO 98/34935 PTU9/19 PCTIUS98/01"8 S< N N (CH2in? 0 ~N 0 wherein n" is 0-3. 69 WO 98/34935 WO98/3935PCTIUS98/01998 3. A compound of Claim 2 having the formula or a pharmaceutically acceptable salt, wherein HO N -1 C O H 2 N )<'kOON NHS0 2 H 3 wherein X is R 4 is -CH2-, -CH2-0-, or -CH2CH3 or -C(CH3)3.

4. A compoun H 2 N d of Claim 3 having the formula H NHS0 2 OH 3 wherein 70 WO 98/34935 WO 9834935PCTIUS98/01998 Y is 0 UN-N S A compound of Claim 4 selected from the group consisting of N .%yCO 2 Et H HNHS0 CH 3 NOH 71 WO 98/34935 PTU9/19 PCTIUS98/01998 NOH 0- N/ H11 N N N H HNHO.CH 3 HO, N 0 H 2 N N 0E 0- NHS0 2 CH 3 HO, N 0 H 2 N -yotu N 0 NHS0 2 OH 3 I 01 C0CH2CH3 H 2 N- HOH HS0 2 aCH 3 72 CH 3 H II 0 o0 "H H N H 2 N 0 0 NOH NOH H 2 N 0 H 0 0 C H 3 OH 0. and pharmaceutically acceptable salts thereof. s 6. A fibrinogen receptor antagonist prodrug, substantially as hereinbefore described with reference to any one of the examples.

7. A composition comprising a compound of any one of claims 1 to 6, and a pharmaceutically acceptable carrier.

8. A composition of claim 7 further comprising one or more agents selected from a 10 thrombolytic agent, an anticoagulant agent, and an antiplatelet agent and a pharmaceutically acceptable carrier.

9. A method for inhibiting the binding of fibrinogen to blood platelets in a mammal, comprising treating the mammal with a compound of any one of claims 1 to 6 or of a composition of claim 7 or claim 8.

10. A compound of any one of claims 1 to 6 or of a composition of claim 7 or claim 8, when 000 used in inhibiting the binding of fibrinogen to blood platelets.

11. A compound of any one of claims 1 to 6 or of a composition of claim 7 or claim 8, for use in inhibiting the binding of fibrinogen to blood platelets.

12. Use of a compound of any one of claims 1 to 6, in the manufacture of a medicament for inhibiting the binding of fibrinogen to blood platelets.

13. A method for inhibiting the aggregation of blood platelets in a mammal, by blocking fibrinogen from acting at its receptor site, comprising treating the mammal with a compound of any one of claims 1 to 6 or of a composition of claim 7 or claim 8.

14. A compound of any one of claims 1 to 6 or of a composition of claim 7 or claim 8, when sed in inhibiting the aggregation of blood platelets. C07010 A compound of any one of claims 1 to 6 or of a composition of claim 7 or claim 8, for use in inhibiting the aggregation of blood platelets.

16. Use of a compound of any one of claims 1 to 6, in the manufacture of a medicament for inhibiting the aggregation of blood platelets.

17. A method for inhibiting osteoclast mediated bone resorption, comprising treating the mammal with a compound of any one of claims 1 to 6 or of a composition of claim 7.

18. A compound of any one of claims 1 to 6 or of a composition of claim 7, when used in inhibiting osteoclast mediated bone resorption.

19. A compound of any one of claims 1 to 6 or of a composition of claim 7, for use in inhibiting osteoclast mediated bone resorption. Use of a compound of any one of claims 1 to 6, in the manufacture of a medicament for inhibiting osteoclast mediated bone resorption.

21. A method for inhibiting angiogenesis in a mammal comprising treating the mammal with a compound of any one of claims 1 to 6 or of a composition of claim 7. 15 22. A compound of any one of claims 1 to 6 or of a composition of claim 7, when used in inhibiting angiogenesis.

23. A compound of any one of claims 1 to 6 or of a composition of claim 7, for use in inhibiting angiogenesis.

24. Use of a compound of any one of claims 1 to 6, in the manufacture of a medicament for 20 inhibiting angiogenesis. A method for inhibiting tumour growth in a mammal comprising treating the mammal with a compound of any one of claims 1 to 6 or of a composition of claim 7.

26. A compound of any one of claims 1 to 6 or of a composition of claim 7, when used in 6* 00 00 0 S S, S See. S 000 S inhibiting tumour growth. 25 27. A compound of any one of claims 1 to 6 or of a composition of claim 7, for use in inhibiting tumour growth.

28. Use of a compound of any one of claims 1 to 6, in the manufacture of a medicament for inhibiting tumour growth.

29. The use of a compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the aggregation of blood, platelets, inhibiting angiogenesis, inhibiting osteoclast mediated bone resorption, preventing platelet thrombosis, preventing thromboembolism or preventing reocclusion, in a mammal. A compound of any one of claims 1 to 6, for use in inhibiting the binding of fibrinogen to blood platelets, inhibiting the aggregation of blood platelets, treating thrombus formation or embolus formation, or preventing thrombus or embolus formation in a mammal. Dated 25 August 1999 MERCK CO., INC. SPatent Attorneys for the ApplicantlNominated Person SPRUSON FERGUSON C07010