AU719495B2 - Fibrinogen receptor antagonists - Google Patents

Description

,WO 98/25601 PCT/US97/22622 -1- TITLE OF THE INVENTION FIBRINOGEN RECEPTOR ANTAGONISTS BACKGROUND OF THE INVENTION The invention relates generally to inhibition of the binding of fibrinogen and other proteins to blood platelets, and inhibiting the aggregation of blood platelets specifically to the gp IIb/IHa 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 arginine-glycineaspartic 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.

WO 98/25601 PCT/US97/22622 -2- Cheresh in Proc. Nat'lAcad. 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 WO 98/25601 PCT/US97/22622 -3affinity for the gp IIb/IIa complex. For example, Huang et al., J. Biol 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. Patent No 5,023,233 discloses small cyclic hexapeptides which contain the sequence Arg-Gly-Asp and are useful platelet aggregation inhibitors. U.S. Patent 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. Patent 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-L- WO 98/25601 PCT/US97/22622 -4aspartyl-L-valine that inhibit platelet aggregation and thrombus formation in mammalian blood. EP 445 796 discloses linear compounds which can include internal piperazinyl or piperidinyl derivatives. EP 437 367 discloses linear polypeptide fibrinogen receptor antagonists. U.S. Patent No. 5,256,812 discloses compounds of the R I B-Z-COOR wherein RI is a guanidino or amidino moiety and A and B are chosen from specific monosubstituted aryl or heterocyclic moieties.

W09412181 describes fibrinogen receptor antagonists such as biphenylcarboxamides.

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 antagonists that have significant binding activity and are, therefore, useful for the reasons stated herein. 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.

SUMMARY OF THE INVENTION Compounds of this invention have the formula: R HN Aryl'-Z-Aryl 2

-A-B

and pharmaceutically acceptable salts, e.g.

0. 0 HN N N CO2PH

NH

2 H NHS0 2 Ph WO 98/25601 PCT/US97/22622 Compounds of the invention are useful for inhibiting the binding of fibrinogen to blood platelets and for inhibiting the aggregation of blood platelets. The above-mentioned compounds can be used in a method of acting upon a fibrinogen receptor which comprises administering a therapeutically effective amount of such compound to a mammal, preferably a human. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, dispersed therein, an effective amount of such compound is another feature of this invention. The use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the binding of fibrinogen to blood platelets and for inhibiting the aggregation of blood platelets in a mammal.

DETAILED DESCRIPTION OF THE INVENTION The invention relates to a compound of the formula Aryl'-Z-Ary l2

-A-B

R

5

HN

and pharmaceutically acceptable salts thereof, wherein Aryll and Aryl 2 are independently selected from a 6-membered monocyclic aromatic ring system containing 0, 1, 2, 3, or 4 nitrogen or sulfur atoms, wherein the carbon atoms of the Aryl I ring system are either unsubstituted or substituted with R2a, and wherein the carbon atoms of the Aryl 2 ring system are either unsubstituted or substituted with R2b; R2a and R2b are independently selected from hydrogen C1-6 alkyl, carboxy, carboxy C1-6 alkyl-, 1. WO 98/25601 WO 9825601PCTIUS97/22622 -6- C 1-6 alkylcarboxy C 1-6 alkylcarboxy Cl1-6 alkyl-, oxo, Cl1-6 alkyloxy-, oxo C 1-6 alkyl-, CI1-6 alkyloxy C 1-6 alkyl-, hydroxy, hydroxy C 1-6 alkyl-, aryl, aryl CI1-6 alkyl-, or halogen; RI and R 5 are independently selected from the group consisting of hydrogen, hydroxyl, C 1-10 alkyl, C3-8 cycloalkyl, aryl, aryl Ci1 -8 alkyl-, amino, amino C 1-8 alkyl-, C 1-3 acylammno-, CI-3 acylamino CI-g alkyl-, C 1-6 alkylamino-, CI1-6 alkylammno C 1 alkyl-, C 1-6 dialkylamino-, CL1-6 dialkylamnino C 1-8 alkyl-, C 1-4 alkoxy-, C 1-4 alkoxy CI1-6 alkyl-, carboxy, carboxy Ci1 -6 alkyl-, Ci 1 3 alkoxycarbonyl-, C 1-3 alkoxycarbonyl Ci1 -6 alkyl-, carboxy C 1-6 alkyloxy-, 1. WO 98/25601 W098/5601PCTIUS97/22622 -7hydroxy C 1-6 alkyl-, C 1-8 alkylcarbonyloxy C1-4 alkyloxycarbonyl-, and aryl Cl1-8 alkylcarbonyloxy CI1-4 alkyloxycarbonyl-; Z and A are independently chosen from (CH2)p, (CH2)mO(CH2)n, (CH2)mNR 3 (CH2)n, (CH2)mC(O)NR 3 (CH2)n, (CH2)mNR 3 C(O)(CH2)n, (CH2)mC(O)(CH2)n, (CH2)mC(S)(CH2)n, (CH2)mSO2(CH2)n, (CH2)mS(CH2)n, (CH2)mSO(CH2)n, (CH2)mSO2NR 3 (CH2)n, (CH2)mC=C(CH2)n, and (CH2)mCH(OH)(CH2)n, where m and n are integers independently chosen from 0-6, p is, an integer chosen from 1-6, and R 3 is selected from the group consisting of hydrogen, hydroxyl, CI-1O alkyl, C3-8 cycloalkyl, aryl, aryl C 1 -8 alkyl-, amino, amino C I-S alkyl-, C 1 -3 acylamino-, C 1.-3 acylamino C 1 alkyl- C 1-6 alkylamino-, WO 98/25601 WO 9825601PCTIUS97/22622 -8- C 1-6 alkylamino C 1 alkyl-, C 1-6 dialkylammno-, C 1-6 dialkylamnino C 1 -8 alkyl-, C 1-4 alkoxy, C 1-4 alkoxy C 1-6 alkyl-, carboxy, carboxy C 1-6 alkyl-, Ci1 -3 alkoxycarbonyl-, Ci 1 3 alkoxycarbonyl Ci1 -6 alkyl-, carboxyoxy-, carboxy C 1-6 alkyloxy-, hydroxy C 1-6 alkyl-, Cl-8 alkylcarbonyloxy C1-4 alkyloxycarbonyl-, and aryl C 1 -8 alkylcarbonyloxy Ci1 -4 alkyloxycarbonyl-; B is 0 11R8

R

CR

8

R

9 0 orx (CH 2 01

C-R

1 0 R 6

R

6

R

7 wherein R6, R7, R9, and R9 are independently chosen from: hydrogen, fluoro, hydroxy C 1-6 alkyl-, carboxy, carboxy C 1 -6 alkyl, hydroxyl, C 1 -6 alkyloxy-, aryl CI -6alkyloxy-, WO 98/25601 WO 9825601PCTIUS97/22622 -9- C3-8 cycloalkyl-, C 1-9 alkyl, aryl, aryl Cl1-6 alkyl-, CI1-6 alkyicarbonyloxy-, amino, Ci1 -6 alkylamino-, amino C 1 6 alkyl-, Cl1-6 alkylamino CI1-6 alkyl-, arylamino-, aryl CL1-6 alkylamino-, arylamino C 1-6 alkyl-, aryl C 1-6 alkylamino Cl1-6 alkylamino C 1-6 alkyl-, Ci1 -6 dialkylamino-, Cl1-6 dialkylamino CI1-6 alkyl-, aminocarbonyloxy-, amninocarbonyloxy Ci1 -6 alkyl-, Ci1 -6 alkylaminocarbonyloxy-, C 1 -6 alkylamninocarbonyloxy Ci1 -6 alkyl-, aryl aminocarbonyloxy-, aryl aminocarbonyloxy CI1-6 alkyl-, aryl C 1 -6 alkylaminocarbonyloxy-, aryl CL1-6 alkylaminocarbonylox y C 1-6 alkyl-, C 1 -g alkylsulfonylamino-, Ci1-9 alkylsulfonylamino Ci1 -6 alkyl-, aryl sulfonylamino-, aryl sulfonylamnino, C1-6 alkyl-, aryl C 1 -6 alkylsulfonylamino-, aryl C 1 -6 alkylsulfonylamino C 1 -6 alkyl-, C 1 -8 atkyloxycarbonylamnino-, C I-g alkyloxycarbonylamino C 1-8 alkyl-, aryloxycarbonylamino-, aryloxycarbonylamino C 1-8 alkyl-, WO 98/25601 WO 9825601PCT/US97/22622 aryl C 1 -8 alkyloxycarbonylamnino-, aryl C 1 -8 alkyloxycarbonylamino C I -8 alkyl-, C I -8 alkylcarbonylamino-, Ci1 -8 alkylcarbonylamino C 1 -6 alkyl-, arylcarbonylamino-, arylcarbonylamino C 1-6 alkyl-, aryl C 1 -8 alkylcarbonylamino-, aryl C I -8 alkylcarbonylamino C 1 -6 alkyl-, ammnocarbonylamino-, aminocarbonylamino C 1-6 alkyl-, C I -8 alkylaminocarbonylamino-, CI -g alkylaminocarbonylamino C 1-6 alkyl-, arylaminocarbonylamino-, arylaminocarbonylamino C 1-6 alkyl-, aryl C 1-8 alkylaminocarbonylamino-, aryl C 1-g alkylaminocarbonylamino C 1 -6 alkyl-, aminosulfonylamino-, aminosulfonylamino C 1 -6 alkyl-, C I -8 alkylaminosulfonylamino-, C I alkylaminosulfonylamino C1 -6 alkyl-, arylaminosulfonylamino-, arylaminosulfonylamino Ci1 -6 alkyl-, aryl C 1 -8 alkylaminosulfonylamrino-, aryl C 1 alkylaminosulfonylamino C 1-6 alkyl-, C 1-6i alkylsulfonyl-, C 1 -6 alkylsulfonyl C 1 -6 alkyl1-, aryl C 1-6 alkylsulfonyl-, aryl C1-6 alkylsulfonyl C1-6 alkyl-, C 1 -6 alkylcarbonyl-, CI1-6 alkylcarbonyl C 1-6 alkyl-, aryl C 1-6 alkylcarbonyl-, aryl C 1-6 alkylcarbonyl C 1 -6 alkyl-, aminocarbonyl-, aminocarbonyl C1I-g alkyl-, 11 WO 98/25601 WO 9825601PCT/US97/22622 -11 I- Ci1 -8 alkylamninocarbony I-, C 1-9 alkylamninocarbonyl Ci1 -8 alkyl-, arylaminocarbonyl arylaminocarbonyl C 1-8 -alkyl-, aryl C 1 -8 alkylaminocarbonyl-, aryl Ci1 -8 alkylaminocarbonyl C I -8 alkyl-, aminosulfonyl-, aminosulfonyl C 1-8 alkyl-, Ci 1-8 alkylaminosulfonyl-, C1I-g alkylamninosulfonyl C I -8 alkyl-, arylaminosulfonyl-, arylaminosulfonyl C I -8 alkyl-, aryl C 1-8 alkylammnosulfonyl-, aryl Ci1 -8 alkylamninosulfonyl Ci1 -8 alkyl-, C3-8 cycloalkylsulfonylamino-, thienylsulfonylamino-, and

-NHSO

2 0 wherein groups may be unsubstituted or substituted with one or more substituents selected from RI and R2a; and RiO0 is chosen from hydroxy, C I alkyloxy-, aryloxy-, aryl Ci1 -6 alkyloxy-, C 1-8 alkylcarbonyloxy CI1.-4 alkyloxy-, aryl C I-g alkylcarbonyloxy CI..-4 alkyloxy-.

WO 98/25601 WO 9825601PCTIUS97/22622 12 In one class of compounds of the invention, the compounds have the formula 0 0 R N N

N-B

3 RI 2 b F 3 b and pharmaceutically acceptable salts thereof, wherein R2a and R2b are independently selected from the group consisting of hydrogen C 1-6 alkyl, carboxy, Ci1 -6 alkylcarboxy-, carboxy C 1-6 alkyl-, C 1 -6 alkylcarboxy Ci1 -6 alkyl-, oxo C 1-6 alkyl-, Ci1 -6 alkyloxy-, Ci1 -6 alkyloxy Ci1 -6 alkyl-, hydroxy-, hydroxy CL1-6 alkyl-, aryl,or aryl C 1-6 alkyl-, or halogen; R I, R 5

R

3 a and R3b are independently selected from the group consisting of hydrogen, hydroxyl, C I- 10 alkyl, C3-8 cycloalkyl, aryl, aryl C 1-8 alkyl-, 1. WO 98/25601 WO 9825601PCT/US97/22622 -13 amino, amino C I-g alkyl-, CI1-3 acylamino-, C 1-3 acylamino CI -g alkyl- C 1-6 alkylamino-, CI1-6 alkylamino C 1-8 alkyl-, Ci1 -6 dialkylamino-, Ci1 -6 dialkylamino C I -8 alkyl-, C 1-4 alkoxy-, C 1-4 alkoxy C 1-6 alkyl-, carboxy, carboxy CI1-6 alkyl-, C 1 -3 alkoxycarbonyl-, Cl1-3 alkoxycarbonyl C 1-6 alkyl-, carboxyoxy-, carboxy C 1-6 alkyloxy-, hydroxy Cl1-6 alkyl-, C I-g alkylcarbonyloxy C 1 4 alkyloxycarbonyl-, and aryl C I-g alkylcarbonyloxy CI -4 alkyloxycarbonyl-; B is

R

8

R

9 0 X

OH

RH

6 R 7 In a group of this class of compounds of the invention, the compounds have the formula WO 98/25601 WO 9825601PCTIUS97/22622 -14- H N,

COOH

H

2

N

and pharmaceutically acceptable salts thereof, wherein

R

7 is arylsulfonylamino-, aryl C1-6 alkylsulfonylamino-, arylsulfonylamino C1-6 alkyl-, aryl C1-6 alkylsulfonylamino CI-6 alkyl-, C1-8 alkylsulfonylamino-, Cl-8 alkylsulfonylamino CI-.6 alkyl-, C3-.8 cycloalkylsulfonylamino-, thienyl sulfonylamino-, or -NHSO'2 In a subgroup of this group of compounds of the invention, the compounds have the formula HN 0 COOH

N'N

H

2 H HI and pharmaceutically acceptable salts thereof, wherein

R

7 is arylsulfonylamino-, C3-8 cycloalkylsulfonylamino-, thienylsulfonylamino-, or WO 98/25601 WO 9825601PCTIUS97122622 15 -N HSO .0 In a family of this subgroup of compounds of the invention, the compounds have the formula HN 0 N 0W' COGH NH 0 H NH02- HN 0& 0- COOH N HNH

.COOH

NH

2 0i= 0 HN N

NH

2

H

NHSO'2 WO 98/25601 PCT/US97/22622 -16and pharmaceutically acceptable salts thereof.

A specific example of the family of compounds is compound 1-8, which is 0 D HN N CO2H NH H NHSO 2 Ph and pharmaceutically acceptable salts thereof.

One test which is used to evaluate fibrinogen receptor antagonist activity is based on evaluation of inhibition of ADP-stimulated 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 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 ion-free Tyrode's buffer (pH 7.4) containing 2% bovine serum albumin.

Platelet aggregation is measured at 37 0 C in a Chronolog aggregometer. The reaction mixture contains gel-filtered human platelets (2 x 108 per ml), fibrinogen (100 micrograms per 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.

Compound 1-8 was tested and found to have an IC50 of less than 50 nM.

WO 98/25601 PCT/US97/22622 -17- 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 are 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.

Prodrugs, such as ester derivatives of described compounds, are compound derivatives which, when absorbed into the bloodstream of a warm-blooded animal, cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.

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.

WO 98/25601 PCTIUS97/22622 18- 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, octyl radicals and the like, straight or branched alkene containing 2 to.

about 10 carbon atoms, propylenyl, buten-l-yl, isobutenyl, pentenylen- -yl, 2,2-methylbuten- 1-yl, 3-methylbuten-l-yl, hexen- -yl, hepten- -yl, and octen- -yl radicals and the like, or straight or branched alkyne containing 2 to about 10 carbon atoms, ethynyl, propynyl, butyn- -yl, butyn-2-yl, pentyn- -yl, pentyn-2-yl, 3-methylbutyn- -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 O, N, and S, phenyl, pyridine, pyrimidine, imidazole, thiophene, oxazole, isoxazole, and thiazole.

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 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 nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described WO 98/25601 PCT/US97/22622 -19first followed by the adjacent functionality toward the point of attachment. For example, a methylene group substituted with benzenesulfonylamino is equivalent to

-CH

2

NHSO

2 In the schemes and examples below, various reagent symbols have the following meanings:

BOC

(or Boc): t-butyloxycarbonyl Pd-C: Palladium on activated carbon catalyst DMF: Dimethylformamide DMSO: Dimethylsulfoxide CBZ: Carbobenzyloxy CH2C12: Methylene chloride CHC13: chloroform BOP: Benzotriazol-1 -vloxvtris(dimethvlamino)hosnhoniu m

EDC:

Oxone:

LDA:

J hexafluorophosphate 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Potassium peroxymonosulfate Lithium diisopropylamide 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 arts. An effective but nontoxic amount of the compound desired can be employed as an antiaggregation agent.

Compounds of the invention may be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the WO 98/25601 PCT/US97/22622 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/IIa 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.

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 function 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 WO 98/25601 PCT/US97/22622 -21 0.01-100 mg/kg/day and most preferably 0.01-20 mg/kg/day. Typically, oral dosages for an adult patient are, for example, 1 mg, 10 mg or 100 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 can form the active ingredient, and 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, 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 active drug component can be combined with an oral, nontoxic, 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 drug 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, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, 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, WO 98/25601 PCT/US97/22622 -22sodium chloride and the like. Disintegrators include, without limitation, starch methyl cellulose, agar, bentonite, xanthan gum and the like.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention 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.

The compounds of the present invention can also be coadministered with suitable anticoagulation agents or thrombolytic agents such as plasminogen activators or streptokinase in the treatment of various vascular pathologies. They may also be combined with heparin, aspirin, or warfarin. Coadministration includes administration together or separately in order to achieve beneficial thrombosis prevention or thrombolysis.

Compounds of the invention may be prepared according to the following synthetic procedure. A derivatized 4aminophenyliminomethyl compound having the structure R N R HN

-NHR

3a

R

2 a WO 98/25601 PCT/US97/22622 -23is condensed with methyl terephthalic acid to form

R

5

HN

-I-Y R 3 a

R

2 a which is hydrolized to form

R

5

HN

The acid is treated with NH(R3b)-B, prepared according to the procedure outlined in in WO 94/12181, scheme 19) to form

R

3 b

R

5

HN

b 0 R2b which is deprotected under acidic conditions to form the finished product.

The novel compounds of the present invention were prepared according to general procedures illustrated by the following.

WO 98/25601 PCT/US97/22622 -24- EXAMPLE 1 HN

NH

2

BOCNH

1-2 [(4-aminophenvl)iminomethvllcarbamic acid tert-butyl ester 1-2 A slurry of 4-aminobenzamidine dihydrochloride (Aldrich, 46g, 221 mmol) in THF/Dioxane (180 mL/420 mL) was treated with enough of a 1 N NaOH solution (less than 2 equivalents (442 mL)) to bring the pH of the solution to 12. A solution of di-tert-butyl dicarbonate (BOC20, Aldrich, 72.3g, 331 mmol) in CHC13 (100 mL) was added dropwise and the pH of the reaction monitored closely with a pH meter.

Additional 1 N NaOH was added as needed to maintain the pH of the solution >12 throughout the addition of the BOC20. After addition was complete TLC showed starting material remaining. An additional equivalents (110 mmol, 24g) of BOC20 was added, again maintaining the pH of the solution >12. HPLC indicated the disappearance of starting material. The reaction was acidified to pH 3.5 with 10% KHSO4, transferred to a separatory funnel and the layers separated. The organic layer was diluted with Et20 and back extracted with 10% KHSO4. The aqueous layers were combined and carefully basified with 50% NaOH to pH 11. A solid formed and was collected by filtration, washed with water and dried on the pump overnight to give a first crop of The mother liquor was extracted with CHC13 until all product had been extracted and the resulting organic layers were concentrated to give a second crop of 1-2 as a white solid.

MeOH/CHCI3 saturated with NH3) 0.45 1H NMR (400 MHz, DMSO-d6) d 9.0-8.5 (br, 1H), 7.70 2H), 6.53 2H), 5.75 2H), 1.4 9H).

WO 98/25601 PCT/US97/22622 HN O-O B NOCH 3 BOCNH

H

N-[4-(tert-butoxycarbonylaminoiminomethyl)phenyl]terephthalamic acid methyl ester A slurry of methyl terephthalic acid (Aldrich, 15g, 83.3 mmol) in CH2C12 (400 mL) was treated with oxalyl chloride (14.5 mL, 167 mmol) and five drops of DMF and stirred at room temperature. After 1 hour the mixture became homogeneous. After a total of 1.5 hours the solution was concentrated and evaporated to give an oil that was evaporated twice more from CH2C12 to give the acid chloride 1-4 as a white solid. The acid chloride was dissolved in CHC13 (100 mL), cooled to 0°C in a jacketed addition funnel, then added dropwise to a 0°C slurry of 1-2 (19.6g, 83.3 mmol), and pyridine (29 mL, 250 mmol) in CHC13 (500 mL). The resulting slurry was stirred for one hour, then treated with 1 L of 10% KHSO4. The resulting precipitate was collected by filtration, then re-suspended in H20, refiltered and washed with water and dried under vacuum to give 1-5 as a white solid.

MeOH/CHC13 saturated with NH3) 0.65.

1 H NMR (400 MHz, DMSO-d6) d 10.82 1H), 9.0 (br, 2H), 8.10 (s, 4H), 8.00 2H), 7.87 2H), 3.90 3H), 1.42 9H).

WO 98/25601 PCT/US97/22622 -26- 0 0 HN BOCNH

H

1-6 N-[4-(tert-butoxycarbonylaminoiminomethyl)phenyl]terephthalamic acid 1-6 A suspension of 1-5 (9.78g, 2.12 mmol) in MeOH (110 mL) and THF (250 mL) was treated with 1 N NaOH solution (42.4 mL, 8.48 mmol) to give a yellow suspension that was stirred at room temperature overnight. The pH of the solution was adjusted to -7 and the MeOH and THF carefully removed under vacuum. The resulting aqueous slurry was diluted with H20 and acidified with 10% KHSO4. A white solid precipitated and was collected by filtration, washed with water and Ethyl Acetate and dried under vacuum at 50C to give 1-6 as a white solid.

1 H NMR (400 MHz, DMSO-d6) d 11.8 (br, 1H),10.82 1H), 10.0 (br, 1H), 9.23 1H), 8.82 1H), 8.2 4H), 7.95 2H), 7.86 2H), 1.51 9H).

0 0 HN N CO2tBu BOCN HH H NHSO 2 Ph 1-7 2(S)-benzenesulfonylamino-3- 4 -(tert-butoxycarbonylaminoiminomethyl)phenylcarbamoyl]benzoylamino }-propionic acid tert-butyl ester 1-7 A solution of 1-6 (5.0 g, 13 mmol) and 2-1 (prepared as described in WO 94/12181, scheme 19, 3.9g, 13 mmol) in DMF (65 mL) was treated with NMM (1.44 mL, 31 mmol) and HOBT (1.8g, 13mmol), WO 98/25601 PCT/US97/22622 -27followed by EDC (2.5 g, 13 mmol) to give a slurry. The reaction was stirred for 1 hour. The solution was diluted with EtOAc and washed with H20. 10% KHSO4 was then added, resulting in a heterogeneous solution. Clear aqueous layer was collected. The remaining organic and aqueous layers were filtered and the solids washed w/ 10% KHSO4 and ether. The solids were collected and dried overnight to yield 1-7 as a white solid.

MeOH/EtOAc)0.21 1 H NMR (400 MHz, DMSO-d6) d 10.56 1H), 9.0 (br, 2H), 8.67 (t, 1H), 8.2 (br, 1H), 8.03-7.87 8H), 7.7 2H), 7.5 3H), 4.05 (t, 1H), 3.5 1H), 3.4 1.5 9H), 1.1(s, 9H).

HN CO2H

NH

2 H NHSO 2 Ph 1-8 2(S)-benzenesulfonylamino-3-[4-(4-carbamimidoylphenylcarbamoyl)benzoylaminol-propionic acid 1-8 A slurry of 1-7 (1.2g, 1.8 mmol) in EtOAc 15 mL is cooled to -78 0 C and saturated with HCL gas, warmed to 0 C for 1 hour, then to room temperature for a total of 6 hours. The reaction was concentrated to give a tan solid that was purified by preparative HPLC to give 1-8 as the zwitterion containing 0.3 mole equivalents of TFA.

Rf (10/1/1 EtOH/NH40H/H20) 0.15 1 H NMR (400 MHz, DMSO-d6) d 10.7 IH), 9.4 (bs, 2H), 9.05 (bs, 2H), 8.7 (bs, 8.0 4H), 7.93 2H), 7,8 4H), 7.6-7.45 4H), 3.6 (bs, 1H), 3.5 1H), 3.4 1H).

Additional examples of compounds within the scope of the invention include those shown below: WO 98/25601 WO 9825601PCTfUS97/22622 28 Table 1

HN

NH

2

H

,-COOH

H _,NHSO 2 Ph

COOH

H NHSO 2 tBu

~COOH

H CH 2

NHSO

2 Ph-

COOH

HNHSO

2

CH

2 Ph WO 98/25601 WO 9825601PCTIUS97/22622 29

~COOH

H4 NHS 2

-(J

,,,COOH/\

H NHSO 2

S

xCOOH 4 -NHSO 2 0H 3

~COOH

NH NHS0 WO 98/25601 WO 9825601PCTIUS97/22622 Table 2 R 3 b 000H

R

5

HN

H' Rj R 3 b

H

-OH -OH 3

-OH

2 -0

-OH

3

H

H

-CH

2

CH

3

H

Another example of a compound of the invention is Nr

>COOH

0Y NHS0 2 WO 98/25601 PCT/US97/22622 -31 EXAMPLE 2 Tablet Preparation Tablets containing 25.0, 50.0, and 100.0 mg., respectively, of the active compound 2(S)-benzenesulfonylamino-3-[4-(4carbamimidoylphenylcarbamoyl)benzoylamino]-propionic acid are prepared as illustrated below: TABLE FOR DOSES CONTAINING FROM 25-100MG OF THE ACTIVE COMPOUND Amount-mg Active Compound 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.

WO 98/25601 PCT/US97/22622 -32- EXAMPLE 3 Intravenous formulations An intravenous dosage form of the above-indicated active compound is prepared as follows: 0.5-10.0mg Active Compound Sodium Citrate 5-50mg Citric Acid 1-15mg Sodium Chloride 1-8mg Water for Injection (USP) 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.

WO 98/25601 PCT/US97/22622 -33- EXAMPLE 4 Intravenous formulation A pharmaceutical composition was prepared at room temperature using 2(S)-benzenesulfonylamino-3-[4-(4carbamimidoylphenylcarbamoyl)benzoylamino]-propionic acid, a citrate buffer, and.sodium chloride, to obtain a concentration of 0.25 mg/ml.

800 grams of water was introduced into a standard pharmaceutical mixing vessel. 0.25 grams of (3(R)-[(2-Amino-4pyridyl)ethyl]-2-piperidon-1-yl)acetic-p-alanine was dissolved in the water. 2.7 grams sodium citrate and 0.16 grams citric acid were added to obtain a finished citrate concentration of 10 mM. 8 grams of sodium chloride was added. 200 grams of water was then added to achieve the desired final concentrations of ingredients. The resulting aqueous formulation had the following concentrations: Ingredient Amount 2(S)-benzenesulfonylamino-3-[4-(4carbamimidoylphenylcarbamoyl)benzoylamino]propionic acid 0.25 mg/ml citrate buffer 10 mM sodium chloride 8 mg/ml The finished concentrated formulation is stored in a standard USP Type I borosilicate glass container at 30-40 degrees C. Prior to compound administration, the concentrated formulation is diluted in a 4:1 ratio resulting in a finished concentration of 0.05 mg/ml and transferred to an infusion bag.

WO 98/25601 PCT/US97/22622 -34- EXAMPLE In a procedure for determining potency of fibrinogen receptor antagonist following oral administration to a patient, compound 1-8 was orally administered to a dog. Blood samples were drawn at various intervals over a 6 hour period and subjected to the ADPstimulated platelet aggregation assay.

Compound 1-8 was shown to have a profound oral profile with regard to platelet aggregation over time. According to the ADP extent measurement of percent inhibition of platelet aggregation, a dose of 0.2 mg/kg p.o. provided 100% inhibition over a period of 6 hours.

Therapeutic Treatment Compounds of the invention may be administered to patients where inhibition of human or mammalian platelet aggregation or adhesion is desired.

Compounds of the invention are useful in inhibiting platelet aggregation and thus, they may find utility in surgery on peripheral arteries (arterial grafts, carotid endaterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interation of platelets with artificial surfaces, leads to platelet aggregation and consumption. The aggregated platelets may form thrombi and thromboemboli. Compounds of the invention may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.

Claims (27)

1. A compound of the formula RN Aryl'-Z-Aryi 2 -A-B and pharmaceutically acceptable salts thereof, wherein Aryll and Aryl 2 are independently selected from a 6-membered monocyclic aromatic ring system containing 0, 1, 2, 3, or 4 nitrogen or sulfur atoms, wherein the carbon atoms of the Aryll ring system are either unsubstituted or substituted with R2a, and wherein the carbon atoms of the Aryl 2 ring system are either unsubstituted or substituted with R2b; R2a and R2b are independently selected from hydrogen C1-6 alkyl, carboxy, carboxy C 1-6 alkyl-, C1-6 alkylcarboxy C1-6 alkylcarboxy C1-6 alkyl-, oxo, C 1-6 alkyloxy-, oxo Cl-6 alkyl-, C1-6 alkyloxy Cl-6 alkyl-, hydroxy, hydroxy C1-6 alkyl-, aryl, aryl C1-6 alkyl-, or halogen; R 1 and R5 are independently selected from the group consisting of WO 98/25601 WO 9825601PCT/US97/22622 36 hydrogen, hydroxyl, C 1- 10 alkyl, C3-8 cycloalkyl, aryl, aryl C I-g alkyl-, amino, amino CI -g alkyl-, Ci1 -3 acylamino-, CI1-3 acylamino C1I-g alkyl-, CI1-6 alkylamino-, C 1-6 alkylamino C 1 alkyl-, C 1-6 dialkylamnino-, C 1-6 dialkylamnino Ci1-9 alkyl-, C 1-4 alkoxy-, C 1-4 alkoxy C 1-6 alkyl-, carboxy, carboxy C 1-6 alkyl-, Ci1 -3 alkoxycarbonyl-, C 1-3 alkoxycarbonyl C 1-6 alkyl, carboxy Ci1 -6 alkyloxy-, hydroxy CI1-6 alkyl-, Cl1 -8 alkylcarbonyloxy Cl1 -4 alkyloxycarbonyl-, and aryl C1-8 alkylcarbonyloxy Cl-4 alkyloxycarbonyl-; Z and A are independently chosen from (CH2)p, (CH2)mO(CH2)n, (CH2)mNR 3 (CH2)n, (CH2)mC(O)NR 3 (CH2)n, (CH2)mNR 3 C(O)(CH2)n, (CH2)mC(O)(CH2)n, (CH2)mC(S)(CH2)n, WO 98/25601 WO 9825601PCTIUS97/22622 37 (CH2)mSO2(CH2)n, (CH2)mS(CH2)n, (CH2)mSO(CH2)n, (CH2)mSO2NR 3 (CH2)n, (CH2)mC=C(CH2)n, and (CH2)mCH(OH)(CH2)n, where m and n are integers independently chosen from 0-6, p is an integer chosen from 1-6, and R 3 is selected from the group consisting of hydrogen, hydroxyl, C 1-10 alkyl, C3-8 cycloalkyl, aryl, aryl C 1 -g alkyl-, amino, amino C 1-8 ailkyl-, C 1-3 acylamino-, C 1-3 acylammno C1I-S alkyl-, C 1-6 alkylamino-, C 1-6 alkylamino C I -8 alkyl-, Ci1 -6 dialkylamnino-, CI1-6 dialkylammno C1I-g alkyl, C 1-4 alkoxy, C1-4 alkoxy C 1-6 alkyl-, carboxy, carboxy C 1-6 alkyl-, C 1 -3 alkoxycarbonyl-, C 1 -3 alkoxycarbonyl Ci1 -6 alkyl-, carboxyoxy-, carboxy Ci1 -6 alkyloxy-, hydroxy C 1-6 alkyl-, C I alkylcarbonyloxy C 1 -4 alkyloxycarbonyl-, and WO 98/25601 WO 9825601PCTIUS97/22622 -38- aryl C 1 -g alkylcarbonyloxy C 1 -4 alkyloxycarbonyl-; B is 0 11R' R CR 8 R 9 0 or it or (CH 2 0 1 C-Rl 0 R 6 R 7 R 6 R 7 wherein R6, R7, R8, and R9 are independently chosen from: hydrogen, fluoro, hydroxy C 1-6 alkyl-, carboxy, carboxy C 1-6 alkyl-, hydroxyl, Ci1 -6 alkyloxy-, aryl C1I-6alkyloxy-, C3-8 cycloalkyl-, C 1 alkyl, aryl, aryl C1-6 alkyl-, C 1 -6 alkylcarbonyloxy-, amino, Ci1 -6 alkylamino-, amino C 1-6 alkyl-, C 1-6 alkylamino CI1-6 alkyl-, arylamino-, aryl Ci1 -6 alkylamino-, arylammno C 1-6 alkyl-, aryl C 1-6 alkylamino C 1-6 alkyl, amino C 1-6 alkyl-, WO 98/25601 WO 9825601PCTIUS97/22622 39 C 1 -6 dialkylamino-, C 1-6 dialkylamino CL1 -6 alkyl-, aminocarbonyloxy-, aminocarbonyloxy Ci1 -6 alkyl-, Ci1 -6 alkylaminocarbonyloxy-, Ci1 -6 alkylaminocarbonyloxy C 1 -6 alkyl-, aryl aminocarbonyloxy-, aryl aminocarbonyloxy CI1-6 alkyl-, aryl C 1 -6 alkylaminocarbonyloxy-, aryl Ci1 -6 alkylaminocarbonyloxy C 1-6 alkyl-, C I -8 alkyisulfonylamino-, C I -8 alkylsulfonylamino Ci1 -6 alkyl-, aryl sulfonylamnino-, aryl sulfonylamino CI-6 alkyl-, aryl Ci1 -6 alkylsulfonylamino-, aryl C 1 -6 alkylsulfonylamino Ci 1-6 alkyl-, C I -8 alkyloxycarbonylamino-, C I -8 alkyloxycarbonylamino C 1 -8 alkyl-, aryloxycarbonylamino-, aryloxycarbonylamino Ci I alkyl-, aryl Ci1 -8 alkyloxycarbonylamino-, aryl C I -8 alkyloxycarbonylamino C 1 -8 alkyl-, Ci1 -8 aikylcarbonylamino-, Ci1 -8 atkylcarbonylamino C 1-6 alkyl-, arylcarbonylamino-, arylcarbonylamino C 1-6 alkyl-, aryl Ci1 -8 alkylcarbonylamino-, aryl Ci1 -8 aikylcarbonylamino Ci 1-6 alkyl-, aminocarbonylamino-, aminocarbonylamino Ci1 -6 alkyl- Ci1 -8 alkylammnocarbonylammno-, Cl1 -8 alkylaminocarbonylamino Ci1 -6 alkyl-, arylaminocarbonylamino-, arylaminocarbonylamino C 1-6 alkyl-, WO 98/25601 WO 9825601PCTIUS97/22622 aryl Ci1 -8 alkylaminocarbonylamino-, aryl C 1-8 alkylaminocarbonylamino C 1.-6 alkyl-, aminosulfonylamino-, ammnosulfonylamino Ci1 -6 alkyl-, C1I-g alkylaminosulfonylamnino-, C1-8 atkylaminosuifonylarnino CI-6 alkyl-, arylaminosulfonylamnmo-, arylaminosulfonylamino Ci1 -6 alkyl-, aryl CI1-8 alkylaminosulfonylamino-, aryl CI -g alkylaminosulfonylamino CI1-6 alkyl-, Ci1 -6 alkylsulfonyl-, C 1-6 alkylsulfonyl CI1-6 alkyl-, aryl C 1-6 alkylsulfonyl-, aryl C 1-6 alkyisulfonyl C 1-6 alkyl-, CI1-6 alkylcarbonyl-, Ci1 -6 alkylcarbonyl C 1 -6 alkyl-, aryl C 1-6 alkylcarbonyl-, arylI Ci1 -6 alkylcarbonyl C 1 -6 alkyl-, ammnocarbonyl-, aminocarbonyl Ci -8 alkyl-, C 1 -8 alkylaminocarbonyl-, C 1-8 alkylaminocarbonyl C1I-g alkyl-, arylaminocarbonyl-, arylami-nocarbonyl C 1-8 alkyl-, aryl C I -8 alkylaminocarbonyl-, aryl Ci1 -8 alkylammnocarbonyl C 1-8 alkyl-, aminosulfonyl-, aminosulfonyl CI -g alkyl-, C I -8g alkylaminosulfonyl-, C I-g alkylaminosulfonyl C I-g alkyl-, arylaminosulfonyl-, arylaminosulfonyl Ci1-8 alkyl-, aryl C 1 -8 alkylaminosulfonyl-, aryl Ci1 -8 alkylaminosulfonyl C 1 -8 alkyl-, WO 98/25601 WO 9825601PCT/US97/22622 -41- C3-8 cycloalkyl sulfonylamino-, thienylsulfonylamino-, and -NHSO 2 0 wherein groups may be unsubstituted or substituted with one or more substituents selected from R 1 and R2a; and R 10 is chosen from hydroxy, Ci- alkyloxy-, aryloxy-, aryl Ci -6 alkyloxy-, C1I8- alkylcarbonyloxy CI1-4 alkyloxy-, aryl C I -g alkylcarbonyloxy Ci 1 -4 alkyloxy-.

2. A compound of claim I having the formula 0 0 N N- R 5 HN I I Ra 2 b 3 b and pharmaceutically acceptable salts thereof, wherein R2a and R2b are independently selected from the group consisting of hydrogen C 1-6 alkyl, carboxy, Ci1 -6 alkylcarboxy-, WO 98/25601 WO 9825601PCTIUS97/22622 42 carboxy C 1-6 alkyl-, C 1-6 alkylcarboxy CI1-6 alkyl-, oxo C 1-6 alkyl-, Ci1 -6 alkyloxy-, C 1-6 alkyloxy C 1-6 alkyl-, hydroxy-, hydroxy C 1-6 alkyl-, aryl, or aryl C 1-6 alkyl-, or halogen; R 1 R 5 R 3 a and R3b are independently selected from the group consisting of hydrogen, hydroxyl, C3-9 cycloalkyl, aryl, aryl C 1-8 alkyl-, amino, amino Ci1-8 alkyl-, C 1-3 acylamino-, C 1-3 acylamino C 1 alkyl, C 1-6 alkylammno-, CI1.-6 alkylamino C I-g alkyl-, C 1-6 dialkylamino-, C 1-6 dialkylamino, Ci1-g alkyl-, Ci1 -4 alkoxy-, C 1-4 alkoxy C 1-6 alkyl-, carboxy, carboxy CI-6 alkyl-, C 1 -3 alkoxycarbonyl-, C 1-3 alkoxycarbonyl CI1-6 alkyl-, carboxyoxy-, WO 98/25601 WO 9825601PCTIUS97/22622 43 carboxy Cl1-6 alkyloxy-, hydroxy C1-6 alkyl-, C I -g alkylcarbonyloxy Ci1 -4 alkyloxycarbonyl and aryl C I-g alkylcarbonyloxy Ci1 -4 alkyloxycarbonyl-; B is R 8 R OH R 6 R 7

3. A compound of claim 2 having the formula HN -0 COOH H 2 N H' H and pharmaceutically acceptable salts thereof, wherein R 7 is arylsulfonylamino-, aryl CI-6 alkylsulfonylammno-, arylsulfonylamino C 1-6 alkyl-, aryl Cl1-6 alkylsulfonylamino Cl1-6 alkyl-, C1- alkylsulfonylamino-, CI -g alkylsulfonylamnino C 1-6 alkyl-, C3-9 cycloalkylsulfonylamnino-, thienylsulfonylainino-, or -NHSO 2 4 WO 98/25601 WO 98/560 1PCTIUS97/22622 -44-

4. A compound of claim 3 having the formula o0 H N COOH H 2 N R/ 7 H H and pharmaceutically acceptable salts thereof, wherein R 7 is arylsulfonylamino-, C3-9 cycloalkylsulfonylamino-, thienylsulfonylamino-, or -NHSO 2 0 A compound of claim 4 having the formula HN NH 2 N 00'y~ 2 H H NHSO 2 Ph WO 98/25601 WO 9825601PCTIUS97/22622 HN 0 0' COOH N H NH NHS 2 -D O, OOH NHS 2 4 I ~COOH NHSO 2 /OCH 3 NH 2 NH 2 and pharmaceutically acceptable salts thereof.

6. A compound of claim 5 having the formula 0 0 HN _a N N ->(,C2H N H 2 H H H NHSO 2 Ph and pharmaceutically acceptable sats thereof. 46

7. A compound of claim 6 having the formula 0 0 HN QN N 0 H 2 N H H OH O0

8. A carbamimidoylaryl fibrinogen receptor antagonist derivative, substantially as hereinbefore described with reference to any one of the examples.

9. A pharmaceutical composition including or consisting of an effective amount of at least one compound of any one of claims 1 to 8, together with a pharmaceutically acceptable carrier, diluent or adjuvant therefor. A composition of claim 9, further comprising an effective amount of a thrombolytic agent.

11. A composition of claim 9 or claim 10, further comprising an effective amount of an S 10 anticoagulant agent. oo°: 12. A method for inhibiting the binding of fibrinogen to blood platelets in a mammal, which method includes or consists of administering to said mammal an effective amount of at least one o: compound of any one of claims 1 to 8, alone or in combination with a thrombolytic agent and/or an anticoagulant agent, or of a composition of any one of claims 9 to 11.

13. A compound of any one of claims 1 to 8, alone or in combination with a thrombolytic agent and/or an anticoagulant agent, or a composition of any one of claims 9 to 11 when used in inhibiting the binding of fibrinogen to blood platelets.

14. A compound of any one of claims 1 to 8, alone or in combination with a thrombolytic agent and/or an anticoagulant agent, or a composition of any one of claims 9 to 11 for use in inhibiting S 20 the binding of fibrinogen to blood platelets.

15. The use of a compound of any one of claims 1 to 8, alone or in combination with a thrombolytic agent and/or an anticoagulant agent, for the manufacture of a medicament for inhibiting the binding of fibrinogen to blood platelets.

16. A method for inhibiting the aggregation of blood platelets in a mammal, which method 25 includes or consists of administering to said mammal an effective amount of at least one compound of any one of claims 1 to 8, alone or in combination with a thrombolytic agent and/or an anticoagulant agent, or of a composition of any one of claims 9 to 11.

17. A compound of any one of claims 1 to 8, alone or in combination with a thrombolytic agent and/or an anticoagulant agent, or a composition of any one of claims 9 to 11 when used in inhibiting the aggregation of blood platelets.

18. A compound of any one of claims 1 to 8, alone or in combination with a thrombolytic agent and/or an anticoagulant agent, or a composition of any one of claims 9 to 11 for use in inhibiting c the aggregation of blood platelets. C06797

19. The use of a compound of any one of claims 1 to 8, alone or in combination with a thrombolytic agent and/or an anticoagulant agent, for the manufacture of a medicament for inhibiting the aggregation of blood platelets. A method for inhibiting the aggregation of blood platelets in a mammal, by blocking fibrinogen from acting at its receptor site, which method includes or consists of administering to said mammal an effective amount of at least one compound of any one of claims 1 to 8, alone or in combination with a thrombolytic agent and/or an anticoagulant agent, or of a composition of any one of claims 9 to 11.

21. A compound of any one of claims 1 to 8, alone or in combination with a thrombolytic agent and/or an anticoagulant agent, or a composition of any one of claims 9 to 11 when used in inhibiting the aggregation of blood platelets by blocking fibrinogen from acting at its receptor site.

22. A compound of any one of claims 1 to 8, alone or in combination with a thrombolytic agent and/or an anticoagulant agent, or a composition of any one of claims 9 to 11 for use in inhibiting the aggregation of blood platelets by blocking fibrinogen from acting at its receptor site. Ss s 15 23. The use of a compound of any one of claims 1 to 8, alone or in combination with a thrombolytic agent and/or an anticoagulant agent, for the manufacture of a medicament for inhibiting the aggregation of blood platelets by blocking fibrinogen from acting at its receptor site.

24. A method for treating thrombus formation or embolus formation in a mammal, which method includes or consists of administering to said mammal an effective amount of at least one compound of any one of claims 1 to 8, alone or in combination with a thrombolytic agent and/or an anticoagulant agent, or of a composition of any one of claims 9 to 11. A compound of any one of claims 1 to 8, alone or in combination with a thrombolytic agent and/or an anticoagulant agent, or a composition of any one of claims 9 to 11 when used in treating thrombus formation or embolus formation.

26. A compound of any one of claims 1 to 8, alone or in combination with a thrombolytic agent and/or an anticoagulant agent, or a composition of any one of claims 9 to 11 for use in treating thrombus formation or embolus formation.

27. The use of a compound of any one of claims 1 to 8, alone or in combination with a S thrombolytic agent and/or an anticoagulant agent, for the manufacture of a medicament for treating 30 thrombus formation or embolus formation.

28. A method for preventing thrombus formation or embolus formation in a mammal, which method includes or consists of administering to said mammal an effective amount of at least one compound of any one of claims 1 to 8, alone or in combination with a thrombolytic agent and/or an anticoagulant agent, or of a composition of any one of claims 9 to 11.

29. A compound of any one of claims 1 to 8, alone or in combination with a thrombolytic agent and/or an anticoagulant agent, or a composition of any one of claims 9 to 11 when used in preventing thrombus formation or embolus formation. A compound of any one of claims 1 to 8, alone or in combination with a thrombolytic agent and/or an anticoagulant agent, or a composition of any one of claims 9 to 11 for use in 4 preventing thrombus formation or embolus formation. C06797

31. The use of a compound of any one of claims 1 to 8, alone or in combination with a thrombolytic agent and/or an anticoagulant agent, for the manufacture of a medicament for preventing thrombus formation or embolus formation.

32. A composition for inhibiting the binding of fibrinogen to blood platelets in a mammal, comprising an antifibrinogenic binding effective amount of a compound of any one of claims 1 to 8, and a pharmaceutically acceptable carrier.

33. A composition for inhibiting the aggregation of blood platelets in a mammal, by blocking fibrinogen from acting at its receptor site, comprising an antifibrinogenic binding effective amount of a compound of any one of claims 1 to 8, in combination with a thrombolytic agent and a pharmaceutically acceptable carrier.

34. A composition for inhibiting the aggregation of blood platelets in a mammal, by blocking fibrinogen from acting at its receptor site, comprising an antifibrinogenic binding effective amount of a compound of any one of claims 1 to 8, in combination with an anticoagulant agent and pharmaceutically acceptable carrier. S 15 35. A process for the preparation of a carbamimidoylaryl fibrinogen receptor antagonist derivative, said process being substantially as hereinbefore described with reference to any one of the examples. Dated 9 July 1999 MERCK CO., INC. Patent Attorneys for the ApplicantlNominated Person SPRUSON FERGUSON *S. C g C06797