WO1997033576A1

WO1997033576A1 - Carbamyl guanidine and amidine prodrugs

Info

Publication number: WO1997033576A1
Application number: PCT/US1997/003640
Authority: WO
Inventors: Ping Chen; S. David Kimball
Original assignee: Bristol-Myers Squibb Company
Priority date: 1996-03-12
Filing date: 1997-03-07
Publication date: 1997-09-18
Also published as: AU1990197A

Abstract

Carbamyl guanidine, thioguanidine and amidine compounds are provided which have the structure (I) wherein Z is a substructure which when linked to (II) forms a prodrug of compounds with pharmaceutically active properties. In preferred embodiments, Z is a thrombin inhibitor substructure containing residues binding at the distal and proximal sites. Ax and A'x may be the same or different and are independently selected from carbamyl, H or alkyl, at least one of Ax and A'x being carbamyl; and including all stereoisomers thereof, and pharmaceutically acceptable salts thereof.

Description

CARBAMYL GUANIDINE AND AMIDINE PRODRUGS

Field of the Invention

The present invention relates to prodrugs of guanidine, thioguanidine or amidine containing compounds which are pharmaceutically active and, for example, are useful in inhibiting formation of thrombin, or in inhibiting platelet aggregation, or as fibrinogen receptor antagonists, and the like.

Background of the Invention U.S. application Serial No. 443,940, filed May 18, 1995, discloses acylguanidine and amidine prodrugs having the structure A

A

wherein Z is a substructure which when linked to the moiety

forms a prodrug of compounds with pharmaceutically active properties; with the proviso that Z does not contain boron or a boron-containing moiety.

Z is preferably a thrombin inhibitor substructure containing residues binding at the distal and proximal sites;

Ax and

may be the same or different and are independently selected from Acyl, H or alkyl, at least one of Ax and

being Acyl, wherein Acyl includes the moiety

wherein

is linked to a nitrogen atom in formula A; and

including all stereoisomers thereof, and pharmaceutically acceptable salts thereof.

The term "Acyl" as employed in formula A more preferably refers to a moiety of the structure

In the above groups (1), (2), (3) and (4),

R¹ is H, alkyl, cycloalkyl, heterocycloalkyl, hetero-aryl, aryl, substituted alkyl or substituted aryl;

R¹' is alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, substituted alkyl or substituted aryl;

Q^I is alkyl, cycloalkyl, aryl, heterocycloalkyl, substituted alkyl, substituted aryl or heteroaryl;

Het or Het ' is independently O, NH, N-lower alkyl or S.

Examples of the Z thrombin inhibitor substructure include substructures Z(l) to Z(6) as set out below:

wherein G is an amido moiety which is

Substituted carbamyl groups, represented by alkanoyl-, aroyl- or arylalkanoyl-oxyalkoxycarbonyl (AOAC) groups, wherein a single carbon atom

separates the two oxygen atoms of the oxyalkoxy moiety (i.e., the oxyalkoxy moiety is a diacylated acetal or ketal) are known as prodrugs for amine- containing drugs [1a] to [1d]. The application of this type of masking group has recently been extended to highly basic guanidine-containing molecules (such as anti-thrombotics, antitumor, antibiotics, and thrombin active site inhibitors) [2a] to [2c]. The mechanism of bioactivation of the AOACs involves the initial hydrolysis of a terminal ester by an esterase, followed by

decomposition to liberate an aldehyde or ketone, carbon dioxide and the amine and/or guanidine- containing drug, as shown in the following scheme drawn for the case where an acetal is liberated to release an aldehyde.

The syntheses of alkanoyl-, arylalkanoyl- and aroyl oxyalkoxycarbonyl (AOAC) amine and/or guanidine-containing molecules or prodrugs are described by Alexander [1a], Lund [3] and more recently, Saulnier [2a]. In addition, the

preparation of simple carbamates, typically Boc or Cbz, protected 1H-pyrazole-1-carboxamidine has been reported by Bernatowicz [4] and Lebl [5]. Also, Real and Kronenthal [6] described the preparation of mono-acyl guanidine-containing prodrugs.

Reference:

[1] a) J. Alexander, R. Cargill, S.R.

Michelson and H. Schwam, J. Med. Chem, 1988, 31(2), 318-322 and references cited therein.

b) U.S. Gogate, A.J. Repta and J.

Alexander, International Journal of Pharmaceutics, 1987, 40, 235-248.

c) U.S. Gogate and A.J. Repta,

International Journal of Pharmaceutics, 1987, 40, 249-255.

d) J. Alexander, U.S. Patent Application, 1984, 507316.

[2] a) M.G. Saulnier, D.B. Frennesson, M.S. Deshpande, S.B. Hansel and D.M. Vyas, Bioorganic & Medicinal Chem. Lett., 1994, 4(16), 1985-1990. b) J. Das et al, U.S. Patent Application Serial No. 443,940, filed May 18, 1995.

c) For the AOAC prodrug of benzamidine, see: F.D. Himmelsbach, V.D. Weisenberger and T.D. Mueller, European Patent, 1993, EP 0567966A (Filing date: April 26, 1993; Publication date: Nov. 3, 1993).

[3] M. Folkmann and F.J. Lund, Synthesis, 1990, 1159.

[4] a) M.S. Bernatowicz, Y. Wu and G.R.

Matsueda, J. Org. Chem. 1992, 57, 2497-2502.

b) Y. Wu, G.R. Matsueda and M.

Bernatowicz, Synthetic Communications, 23(21), 3055-3060.

[5] B. Drake, M. Patek and M. Lebl, Synthesis, 1994, 579-582.

[6] Real and Kronenthal, U.S. Patent

Application Serial No. 08/443,960, filed May 18, 1995. Description of the Invention

In accordance with the present invention, compounds having the structure I

I

wherein Z is a substructure which when linked to the guanidino or amidino moiety

forms a prodrug of compounds with pharmaceutically active properties; with the proviso that Z

preferably does not contain boron or a boron- containing moiety. Thus, the Z substructure when linked to

forms a prodrug of a thrombin inhibitor, a platelet aggregation

inhibitor, or a fibrinogen receptor antagonist, a GPIIb/IIIa receptor blocker, an antihypertensive, an antidepressant, an antibiotic, a viricide, an immunostimulant, an anti-inflammatory agent, a peptide hydrolase inhibitor, a Factor Xa inhibitor, an antianaphylactic, an antiulcer agent or can have other pharmaceutical activity as defined

hereinafter.

Z is preferably a thrombin inhibitor substructure containing residues binding at the distal and proximal sites (which sites are

described by Banner and Hadvary, J. Biol. Chem.

(1991), 266, 20085-20093);

Ax and A'x may be the same or different and are independently selected from H or alkyl and at least one of Ax and A'x forms a Carbamyl group with a nitrogen of the guanidino or amidino; and

The term "Cambamyl" as employed in formula I more preferably includes a moiety of the

following structure attached to a nitrogen of the guanidino or amidino

In the above Cambamyl group IA, R^I is alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, substituted alkyl or substituted aryl;

Q^I is alkyl of at least 2, preferably 2, 3 or 4 carbons in the chain, cycloalkyl, aryl, heterocycloalkyl, substituted alkyl of at least 2, preferably 2, 3 or 4 carbons in the chain,

substituted aryl or heteroaryl;

Het is O, NH, N-lower alkyl or S;

Het¹ is a bond, O, NH, N-lower alkyl or S; where in the definition of R^I and/or Q^I, substituted alkyl refers to alkyl, by itself or as part of another group, which includes linear or branched alkyl, substituted with from 1 to 4 substituents, which substituents include the following: OH, NH₂, SH, OR^II, NHR^II, NR^IIR^III, SR^II, SSR^II, CHO, COR^II, alkyl, arylalkyl,

heteroaryl, cycloalkyl, halogen and/or aryl; and substituted aryl refers to aryl, by itself or as part of another group, substituted with from 1 to 5 substituents which substituents include the following: OH, NH₂, SH, OR^II, NHR^II, NR^IIR^III, SR^II, SSR^II, CHO, COR^II, alkyl, cycloalkyl, halogen and/or aryl;

R^II and R^III are the same or different and are independently selected from H, alkyl,

cycloalkyl, aryl, substituted alkyl or substituted aryl; and

the term "heterocyclyl" may include 1 to 3 rings and may be heteroaryl or cycloheteroalkyl.

In the Carbamyl moiety, it is preferred that Het is oxygen.

The preferred Carbamyl moiety will be where Het is 0, Het¹ is a bond, and R^I is alkyl, aryl or heteroaryl, and Q^I is alkyl of 2 or 3 carbons in the chain, or cycloalkyl.

Thus, preferred are compounds where Carbamyl includes the moiety

where Q^I is alkyl or cycloalkyl, and R^IV is alkyl, aryl or heteroaryl. More preferred are compounds where Carbamyl includes the moiety

where R^II and R^III are lower alkyl such as CH₃ or n-propyl, where R^IV is alkyl such as CH₃ or t- butyl, aryl such as phenyl, or heteroaryl such as pyridyl.

In formula I, Carbamyl is exclusive of groups of the structures

The carbamyl prodrugs of the invention are distinguished from the above-described prior art prodrugs in terms of structure and mechanism of bioactivation. It is theorized that the mechanism of action of the prodrugs of the invention is as follows. For example, where Het is oxygen and Het¹ is a bond as shown, following esterase hydrolysis, the alkoxide intermediate cyclizes to form a unstable tetrahedral intermediate, which decomposes to liberate the amidine or guanidine-containing drug and a cyclic carbonate, as shown in the following scheme.

In accordance with the present invention, the prodrugs of the guanidine, thioguanidine or amidine containing compounds of formula I of the invention have enhanced absorption and improved bioavailability properties.

The compounds of the invention include prodrugs of sulfonamido heterocyclic thrombin inhibitors having the Z substructure and which include a guanidine, thioguanidine or amidine moiety, and have the structure Ix

wherein

is an amido moiety which is

including all stereoisomers thereof; and including all pharmaceutically acceptable salts thereof;

wherein

R is hydrogen, hydroxyalkyl, aminoalkyl, airtidoalkyl, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkenyl, alkynyl, arylalkoxyalkyl, or an amino acid side chain, either protected or unprotected;

R¹ and R² are independently hydrogen, lower alkyl, cycloalkyl, aryl, hydroxy, alkoxy, oxo, thioxo, thioketal, thioalkyl, thioaryl, amino or alkylamino; or R¹ and R² together with the carbons to which they are attached form a cycloalkyl, aryl, or heteroaryl ring; and R³ is alkyl, aryl, arylalkyl, heteroaryl, quinolinyl, tetrahydroquinolinyl, 10-camphoryl, pentamethyIchromanyl, pentaalkylphenyl, pentahalophenyl, trialkylphenyl, 3-carboxyphenyl,

3-trifluoromethylphenyl or 4-carboxyphenyl;

n is 0, 1 or 2;

m is 0, 1, 2 or 3 ;

Y is NH or S;

p is 0, 1 or 2 ;

Q is a single bond or

Y_l is a bond or -NH-;

A is aryl or cycloalkyl, or an

azacycloalkyl ring A of 4 to 8 ring members, or an azacycloalkenyl ring A of 5 to 9 ring members, or an azaheterocyclo-alkyl ring A of 6 to 8 ring members,

A

where X is CH₂, -CH=CH-, O, S or NH;

if A is an azacycloalkyl, azacycloalkenyl, or azaheterocycloalkyl ring A, then Y₁ is a bond and the acylamidine group

is attached to the nitrogen atom in the ring as indicated below

q is 0, 1, 2, 3 or 4 if X is CH₂ or -CH=CH-; q is 2, 3 or 4 if X is 0, S or NH;

Y¹ and Y² are independently H, lower alkyl, oxo or halo;

provided that where X is a hetero atom (that is, A is azaheterocycloalkyl), then there must be at least a 2-carbon chain between X and any N atom in the ring A or outside ring A.

Examples of the A ring (azacycloalkyl, azacycloalkenyl or azaheterocycloalkyl) which may be employed herein include

and the like. Preferred are compounds of formula I_x

w

wherein Q is a single bond and A is an

azacycloalkyl ring

where q is 0 or 1; p is 1 or 2;

R³ is lower alkyl or arylalkyl;

R is arylalkyl or hydroxyalkyl;

R¹ and R² are each H;

n is 0 or 1; and

Ax or A'x is

wherein Q¹ is alkyl or cycloalkyl;

Het is O, Het¹ is a bond, and R¹ is alkyl or arylalkyl, and the other is H.

A more preferred embodiment of the

heterocyclic thrombin inhibitors of the invention has the structure IxA

IxA

where R is arylalkyl (preferably benzyl), aryl (preferably phenyl), substituted alkyl (preferably cyclohexylmethyl) or arylalkoxyalkyl (preferably benzyloxymethyl) and R³ is preferably methyl, ethyl, trifluoroethyl or benzyl, and the preferred Ax and A'x are as set out above, including all stereoisomers thereof.

The compounds of the invention also include prodrugs of guanidinyl- or amidinyl-substituted heterocyclic thrombin inhibitors having the Z substructure and include a guanidine or amidine moiety, and have the structure 1.

1.

including all stereoisomers thereof, wherein n is 0, 1 or 2;

Xa is S, SO, SO₂ or O;

R_a is -A¹-R^3a, where A¹ is an alkyl, alkenyl, or alkynyl chain, with the proviso that there is at least one carbon between any S or 0 and an alkenyl or alkynyl moiety, each of the A¹ radicals having from 2 to 6 carbon atoms, and R^3a is

R_a is - (CH₂)_P-A²-R²' where A² is an

azacycloalkyl ring A of 4 to 8 ring members, or a azacycloalkenyl ring A of 5 to 9 ring members, or an azaheterocycloalkyl ring A of 6 to 8 ring members,

where X is CH₂, -CH=CH-, O, S or NH; p is 0, 1 or 2; the group is attached to the nitrogen atom in the ring as indicated below

q is 0, 1, 2, 3 or 4 if X is CH₂ or -CH=CH- ; q is 2, 3 or 4 if X is 0, S or NH; Y¹ and Y² are independently H, lower alkyl, oxo or halo;

provided that where X is a hetero atom

(that is, A is azaheterocycloalkyl), then there must be at least a 2-carbon chain between X and any heteroatom atom in the ring A or outside ring A; and R² ' is

and A³ is aryl or cycloalkyl;

R, R¹ and R² are as defined hereinbefore; and

R^6' is hydrogen,

-SO₂R³ or -CO₂R⁷ (wherein R⁷ is lower alkyl, aryl, arylalkyl, cycloheteroalkyl or heteroaryl; and R³ is alkyl, arylalkyl, aryl, heteroaryl, quinolinyl,

tetrahydro-quinolinyl, 10-camphoryl,

pentamethylchromanyl, pentaalkylphenyl,

pentahalophenyl, trialkylphenyl, 3-carboxyphenyl, 3-trifluoromethylphenyl or 4-carboxyphenyl);

including pharmaceutically acceptable salts thereof, and all stereoisomers thereof.

Preferred are compounds of formula 1. wherein Xa is S or SO₂, n is 0, R_a is - (CH₂)_p-A²R²' or -CH₂(CH₂)_Z-R^3a, z is 1, 2, 3 or 4;

Ax or A'x is

wherein Q^I is alkyl or cycloalkyl,

Het is 0, Het¹ is a bond, and R^I is alkyl or arylalkyl, and the other is H; more preferably

q is 1 or 2, p is 1 or 2, R¹ and R² are each H, R is H or -CH₂OH, Xa is S, and R^6' is

-

and Ax and A'x are as set out above.

The compounds of the invention also include prodrugs of guanidinyl- or amidinyl-substituted methylamino heterocyclic thrombin inhibitors having the Z substructure and include a guanidine or amidine moiety, and have the structure Iq

including all stereoisomers thereof

wherein n is 0, 1 or 2;

R_b is -A¹-R^3a, -CO-A¹-R^3a or -SO₂-A¹-R^3a;

wherein R^3a is

and A¹ is an alkyl, alkenyl or alkynyl chain, each of the A¹ radicals preferably having 2 to 6 carbons, with the proviso that there is at least one carbon between any NH, S or 0 and an alkenyl or alkynyl moiety; or

R_b is -(CH₂)_P-A²-R²' or - (CH₂)_p-CO-A²-R² ' or (CH₂)_p-SO₂-A²-R²' where p is 0, 1 or 2, R² ' is

and A² is an azacycloalkyl ring A of 4 to 8 ring members, or an azacycloalkenyl ring

A of 5 to 9 ring members, or an azaheterocycloalkyl ring A of 6 to 8 ring members),

where X is CH₂, O, -CH=CH-, S or NH; and the is attached to the nitrogen atom in the ring as indicated below

q is 0, 1, 2, 3 or 4 if X is CH₂ or -CH=CH-; q is 2, 3 or 4 if X is O, S, NH;

Y¹, Y² are independently H, lower alkyl, oxo or hale;

provided that where X is a hetero atom (that is, A is azaheterocycloalkyl), then there must be at least a 2-carbon chain between X and any N atom in the ring A or outside ring A or

R_b is -(CH₂)_P-A³-R⁴, - (CH₂)_p-CO-A³-R⁴, or

-(CH₂)_P-SO₂-A³-R⁴,

wherein R⁴ is N X

A³ is aryl or cycloalkyl, and p is as defined above;

R, R¹ and R² are as defined hereinbefore; R⁶ is hydrogen,

-SO₂R³ or -CO₂R⁷

(wherein R⁷ is lower alkyl, aryl, arylalkyl, cycloheteroalkyl or heteroaryl; and R³ is alkyl, arylalkyl, aryl, heteroaryl, quinolinyl,

tetrahydro-quinolinyl, 10-camphoryl,

pentamethylchromanyl, pentaalkylphenyl,

including pharmaceutically acceptable salts thereof.

Preferred are compounds of formula Iq wherein n is 0, R_b is

and q is 3 , 4 or 5; and compounds of formula Iq

wherein R_b is

A³ is phenyl and compounds of formula Iq wherein R_b is

p is 0 or 1, A² is azacycloalkyl or

azacycloalkenyl;

R¹ and R² are each H, R is hydroxymethyl, -CH₂COOalkyl, or benzyl and R⁶ is

H, BOC or CBZ;

Ax or A'x is

wherein Q^I is alkyl or cycloalkyl;

Het is 0, Het¹ is a bond, and R^I is alkyl or arylalkyl, and the other is H.

Most preferred are compounds of formula Iq wherein n is 0, R_b is

wherein p is 0 or 1, A² is

R¹ and R² are each H, R is hydroxymethyl,

-CH₂COOCH₃, or benzyl, and R⁶ is

H, BOC or CBZ; and

Ax and A'x are as set out above.

The compounds of the invention also include prodrugs of heterocyclic thrombin inhibitors of the invention having the Z substructure and include a guanidine or amidine moiety, and have the structure

including all stereoisomers thereof, and including all pharmaceutically acceptable salts thereof;

wherein n is 0, 1 or 2;

p is 0, 1 or 2; Q is a single bond or

A is aryl or cycloalkyl (in which case R⁴ is either of the acylguanidine or acylamidine group set out above), or an azacycloalkyl ring A of 4 to

8 ring members; or an azacycloalkenyl ring A of 5 to 9 ring members, or an azaheterocycloalkyl ring A of 6 to 8 ring members,

A

where X is CH₂ , -CH=CH- , O, S or NH;

if A is an azacycloalkyl, azacycloalkenyl, or azaheterocycloalkyl ring A, then R⁴ is the acylamidine group

which is attached to the nitrogen atom in the ring as indicated below

Y¹ and Y² are independently H, lower alkyl, oxo or halo;

provided that where X is a hetero atom (that is, A is azaheterocycloalkyl), then there must be at least a 2-carbon chain between X and any N atom in the ring A or outside ring A. R, R¹ and R² are as defined hereinbefore; and

R⁸ is hydrogen, or -CO₂R⁷ (wherein R⁷

is lower alkyl, aryl, arylalkyl, cycloheteroalkyl or heteroaryl);

with the provisos that where A is aryl or cycloalkyl, R⁴ includes guanidine or amidine;

where A is azacycloalkyl, azacycloalkenyl or azaheterocycloalkyl, R⁴ includes amidine.

Preferred are compounds of formula A. wherein

n is 0 or 1,

R⁸ is H; R is aralkyl or hydroxyalkyl, R¹ and R² are each H, p is 0 or 1,

Q is a single bond, A is an azacycloalkyl ring

where q is 1 or 2 ; R⁴ includes amidine ; and

Ax or A'x is

wherein Q^I is alkyl or cycloalkyl,

Het is 0, Het¹ is a bond, and R^I is alkyl or arylalkyl, and the other is H.

Most preferred are compounds of formula A. wherein R⁸ is H, n is 0, R¹ and R² are each H,

R is arylalkyl such as benzyl,

p is 1, Q is a single bond, AR⁴ is

Ax and A'x are as set out above.

The compounds of the invention also include prodrugs of tripeptide thrombin inhibitors having the Z substructure and include a guanidine

functionalized sidechain, and have the structure ly

including all stereoisomers thereof, wherein Ax and A'x are as defined above, m' is 2, 3, 4 or 5 ; n is 0, 1 or 2; p is 0, 1 or 2 ;

R^x is cycloalkyl, heteroaryl, CO₂H, CONR^sR^t

(where R^s and R^t are independently selected from H, alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl), or aryl optionally substituted with NO₂, OH, alkoxy, acyloxy, -

halogen, alkyl, aryl, CO₂alkyl, CONHalkyl, alkylthio, arylthio,

NHalkyl or NHcycloalkyl;

R^y is an amino acid sidechain (either protected or unprotected);

R^z is H, alkyl, aryl, cycloalkyl,

cyclohetero-alkyl or heteroaryl;

R^v is H, alkyl, CO₂R^u or CONR^sR^t;

wherein R^u is H or alkyl;

including pharmaceutically acceptable salts thereof; The term "amino acid side chain" refers to any known alpha-amino acid, such as arginine, histidine, alanine, glycine, lysine, proline, leucine, valine, serine, threonine, allothreonine, homoserine, cyclohexylalanine, t-butylglycine, asparagine, glutamine, isoleucine, phenylalanine and the like.

Preferred are compounds of formula ly wherein m' is 3 , 4 or 5; n is 0, 1 or 2; p is 0 or 1; R^x is optionally substituted phenyl; R^y is alkyl, hydroxyalkyl or aminocarbonylalkyl; R^z is cycloalkyl, phenyl or H; and R^v is alkoxycarbonyl or alkyl; and

Ax or A'x is

wherein Q^I is alkyl or cycloalkyl,

Het is O, Het¹ is a bond, and R^I is alkyl or arylalkyl, and the other is H.

Most preferred are compounds of formula ly wherein m' is 3; n is 1; and p is 1;

R^x is p-NO₂C₆H₅, -o-FC₆H₅, or C₆H₅ ;

R^y is

CH₃

R^z is C₆H₅, or

R^v is HOCH₂- or alkyl; Ax and A'x are as set out above.

The compounds of the invention also include prodrugs of disubstituted heterocyclic inhibitors having the Z substructure and include a guanidine, thioguanidine or amidine moiety, and have the structure

wherein

is an amido moiety which is

including all stereoisomers thereof; and including all pharmaceutically acceptable salts thereof; wherein

R, R¹ and R² are as defined hereinbefore; R⁹ is lower alkyl, cycloalkyl, aryl, or arylalkyl; or R⁹ and R² together with the carbons to which they are attached form a cycloalkyl, aryl or heteroaryl ring;

R¹⁰ is hydrogen, lower alkyl, aryl, arylalkyl,

or -CO₂R^7' wherein R^7' is lower alkyl, aryl, arylalkyl, cycloheteroalkyl, heteroaryl, quinolinyl or tetrahydroquinolinyl; and R³ is alkyl,

arylalkyl, aryl, heteroaryl, quinolinyl,

tetrahydroquinolinyl, 10-camphoryl,

pentamethylchromanyl, pentaalkylphenyl,

pentahalophenyl, trialkylphenyl, 3-carboxyphenyl, 3-trifluoromethylphenyl or 4-carboxyphenyl;

n is 0, 1 or 2;

m is 0, 1, 2 or 3;

Z_q is NR¹¹ or 0 (where R¹¹ is H, lower alkyl, aryl or arylalkyl);

Y is NH or S;

p is 0, 1 or 2;

Q is a s

ingle bond or

Y₁ is a bond or -NH-;

A is aryl or cycloalkyl, or an

azacycloalkyl ring A of 4 to 8 ring members , or an azacycloalkenyl ring A of 5 to 9 ring members, or an azaheterocycloalkyl ring A of 6 to 8 ring members,

where X is CH₂, -CH=CH- , O, S or NH;

is _attached to the nitrogen atom in the ring as indicated below

q is 0, 1, 2, 3 or 4 if X is CH₂ or -CH=CH- ; q is 2, 3 or 4 if X is O, S or NH;

Y¹ and Y² are independently H, lower alkyl, oxo or halo;

provided that where X is a hetero atom (that is, A is azaheteroalkyl), then there must be at least a 2-carbon chain between X and any N atom in the ring A or outside ring A.

Preferred are compounds of formula Iz

wherein

is

wherein R is H, p is 1, Q is a single bond, A is an azacycloalkyl ring ; Y₁ is a bond;

where q is 0 or 1; and

R⁹ is arylalkyl such as benzyl, or alkyl;

R² and R¹ are independently H and/or alkyl;

R¹⁰ is benzyloxycarbonyl, alkylsulfonyl, such as methylsulfonyl, or alkyl such as ethyl;

Z_q is NH;

n is 0 or 1; and

Ax or A'x is

wherein Q^I is alkyl or cycloalkyl,

Het is 0, Het¹ is a bond, and R^I' is alkyl or arylalkyl, and the other is H.

Another preferred embodiment of the heterocyclic thrombin inhibitors of the invention

of formula Iz wherein

λ

where R¹⁰ is benzyloxycarbonyl, or alkylsulfonyl such as methyl sulfonyl, Z_q is NH, R is H, R⁹ is arylalkyl such as benzyl, R² and R¹ are independently H and/or alkyl, m is 2 and Y is NH; and

Ax or A'x is

wherein Q^I is alkyl or cycloalkyl,

Het is 0, Het¹ is a bond, and R^I is alkyl or arylalkyl, and the other is H.

It will be appreciated that the formula I structure includes all tautomers thereof, for example,

As seen above, examples of the Z thrombin inhibitor substructure include substructures Z(1) to Z(6) as set out below:

wherein G is an amido moiety which is

The thrombin inhibitor substructures Z(l) through Z ( 6 ) and methods for preparing same are disclosed in pending U.S. patent applications and published European applications as follows. The Z(l) substructure is disclosed in U.S. application Serial No. 146,714, filed November 10, 1993, and application Serial No. 373,334, filed January 17, 1995, and published European

Application 0601459.

The Z(2) substructure is disclosed in U.S. application Serial No. 373,334, filed January 17, 1995, and published European application 0623595.

The Z(3) thrombin inhibitor substructure is disclosed in U.S. application Serial No. 373,334, filed January 17, 1995, and published European Application 0623596.

The Z(4) thrombin inhibitor substructure is disclosed in U.S. application Serial No. 373,334, filed January 17, 1995, and published European Application 0648780.

The Z(5) thrombin inhibitor substructure is disclosed in U.S. application Serial No. 396,320, filed February 28, 1995, which is incorporated herein by reference.

The Z(6) thrombin inhibitor substructure is disclosed in U.S. application Serial No. 215,433, filed March 21, 1994, which is incorporated herein by reference.

Compounds of the invention of formula I which include the moiety

any of the A, A¹ or A³ moieties which are aryl or cycloalkyl, may be prepared employing the methods for preparing the Z substructures set out in the above-mentioned applications employing commercially available arylamines (such as aniline) and

cycloalkylamines as starting materials. In addition to the guanidine, thioguanidine or amidine-containing thrombin inhibitors (ZH) set out above employed to form the prodrugs of the invention of formula I, other guanidine,

thioguanidine or amidine-containing compounds (ZH) which may be employed to form the prodrugs of formula I of the invention include, but are not limited to, the following:

N²-arylsulfonyl-L-argininamides as disclosed in U.S. Patent Nos. 4,069,323; 4,066,758;

4,073,914; 4,055,651; 4,066,773; 4,117,127;

4,258,192; all to Okamoto et al;

ester derivatives of N^α-(arylsulfonyl) L- arginine as disclosed in Okamoto et al, J. Med. Chem. 1980, 23, No. 8, 827-830;

amide derivatives of N^α-substituted-L- arginine as disclosed in Kikumoto et al, J. Med. Chem. 1989, 23, No. 8, 830-836;

carboxyl-containing amide derivatives of N^α-substituted L-arginine as disclosed in Kikumoto et al, J. Med. Chem. 1980, 23, No. 12, 1293-1299;

(2R,4R)-4-methyl-1-[N²-[(3-methyl-1,2,3,4- tetrahydro-8-quinolinyl)sulfonyl]-L-arginyl)]-2- piperidinecarboxylic acid as disclosed in Kikumoto et al, Biochemistry 1984, 23, No. 1, 85-90;

N-arylsulphonyl-L-argininamide derivatives as disclosed in DE2655636-C2;

trisubstituted-2, 3,4, 5-tetrahydrobenzazepine derivatives as disclosed in Japanese Patent No. 2193971A;

derivatives of N^α-substituted N^α- arylsulfonylaminoacyl p-amidinophenylalaninamides as disclosed in published European Patent

Application 0236163A1;

derivatives of N^α-arylsulfonylaminoacyl p- amidinophenylalaninamides as disclosed in European Patent Application 0236164A1; glycopeptide derivatives as disclosed in published European Patent Application 558961A2;

amidinophenylalanine derivatives as

disclosed in DE4115468A1 and published European Patent Application 508220A1;

2-[3-(4-amidinophenyl)]-propanoic acid derivatives as disclosed in DE4121947A1;

L- and D-phenylalanine derivatives as disclosed in WO92/08709;

piperazides of substituted phenyl

derivatives as disclosed in W094/18185-A1;

para-substituted phenylalanine derivatives as disclosed in W092/16549;

cyclotheonamides A and B as disclosed in Maryanoff et al, Proc. Nat'l Acad. Sci. USA, Vol. 90, 8048-8052, September 1993, Biochemistry, and Maryanoff et al, J. Am. Chem. Soc. Vol. 117, No. 4, 1995, 1225-1239;

derivatives of the dipeptide of L- azetidine-2-carboxylic acid and L-arginine aldehyde as disclosed in U.S. Patent No. 5,252,566 to

Shuman;

derivatives of the dipeptide L-proline-L- arginine aldehyde as disclosed in published

European Patent Application 0479489A2;

polyfluorinated alkyl derivatives of tripeptides as disclosed in published European Patent Application 0504064A1;

peptide aldehydes as disclosed in

W094/17817 and W093/15756;

guanidine derivatives as disclosed in W094/08941 and guanidine derivatives as disclosed in published European Patent Application 84/118280;

guanidine derivatives as disclosed in published European Patent Application 0530167A1;

peptide aldehydes as disclosed in published European Patent Application 93/526877 and Balasubramanian et al, J. Med. Chem. (1993), 36, 300-303;

tripeptides as disclosed in published European Patent Application 0479489A2 or European Patent Application 0643073A1;

arginine aldehydes as disclosed in

published European Patent Application 0526877A2;

guanidine derivatives as disclosed in WO93/18060A1;

tripeptides such as Boc-D-Phe-Pro-Arg-H, as disclosed in Shuman et al, J. Med. Chem., 1993, 36, 314-319;

tripeptides such as D-Phe-Pro-Arg-H as disclosed in Bajusz et al, J. Med. Chem., 1990, 33, 1729-1735;

agmatine derivatives as disclosed in U.S. Patent No. 4,346,078 to Bajusz et al;

peptidyl-arginine aldehyde derivatives as disclosed in U.S. Patent No. 4,316,889 to Bajusz et al;

peptide aldehydes as disclosed in U.S. Patent No. 4,703,036 to Bajusz et al;

guanidine derivatives as disclosed in WO 94/29335;

guanidine derivatives as disclosed in WO 93/11152A1;

isosteric peptides as disclosed in

published European Patent Application 0530167A1;

peptide derivatives as disclosed in WO93/18060;

guanidine derivatives as disclosed in W094/29336;

azetidinone derivatives as disclosed in U.S. Patent No. 5,326,863 to Han;

azetidin-2-one derivatives as disclosed in

U.S. Patent No. 5,175,283 to Han; arginine α-keto-amide derivatives as disclosed in WO94/08941A1;

N-aminopiperidinyl or N-amidino-1,4- oxazinyl substituted sulphonamide derivatives as disclosed in published European Patent Application 559046A1;

guanidine derivatives as disclosed in U.S. Patent Nos. 5,260,307, and 5,393,760 both to

Ackermann et al;

guanidine derivatives as disclosed in published European Patent Application 0468231A2;

1-amidino piperidine and 4-amidino

morpholine derivatives as disclosed in published European Patent Application 0641779A1;

fibrinogen and/or GPIIb/IIIa receptor antagonists and/or antiaggregants including, but not limited to, tetrapeptides as disclosed in Alig et al, J. Med. Chem. 1992, 35, 4393-4407, GR144053 and published European Application 542363;

substituted benzodiazepinediones as disclosed in WO93/08174 and W094/14776;

BIBU-52 as disclosed in published European Application 93/567967;

SC-47643 as disclosed in U.S. Patent No. 4,879,313;

SDZ GPI 562 as disclosed in published European Patent Application 93/560730;

RO43-5054 as disclosed in published European Patent Application 91/445796A2;

RO44-9883 (LAMIFIBAN) as disclosed in published European Patent Application 92/505868 and U.S. Patent No. 5,378,712;

SKF107260 as disclosed in published European Patent Application 91/425212;

aromatic azacyclic compounds as disclosed in WO94//33051; DMP-728 (Arg-Gly-Asp-Ser), disclosed in FASEB J. 1992, 6(4), Abs. 3827 and J. Org. Chem. (1995) 60, 946-952;

cyclic peptide derivatives as disclosed in W094/26779;

SC-52012 and SC-57101 as disclosed in Nicholson et al, 67th Scientific Sessions of Amer. Heart Assn., Nov. 14-17, 1994, Poster, 0975 and J. Med. Chem. (1993) 36, 1811-1819;

SC54684 and SC54701 as disclosed in Drugs

Fut., 1994, 19(5) 467 and WO93/07867, U.S. Patent No. 5,344,957 and U.S. Patent No. 5,239,113;

SC58053 and SC58052 disclosed in 1st Winter Confr. on Med. and Bioorg. Chem., Steamboat

Springs, Co., 29 Jan-2 Feb. 1995, Poster 1 (Searle) and WO94/333038;

R043-8857 as disclosed in U.S. Patent No. 5,084,466 and U.S. Patent No. 5,256,812;

GR144053 as disclosed in published European Patent Application 542363A2 and in Thrombosis and Haemostasis (1993) 69, Abstracts 64, 1884, 1885, 1886;

antihypertensives and antidepressants related to guanethidine (as disclosed in U.S.

Patent No. 2,928,829) and related to guanoxyfen (as disclosed in BE612362);

antibiotics and viricides related to amidinomycin (as disclosed in JP 21,418); stallimycin (as disclosed in DE 1,039,198); Arphamenine B (as disclosed in published

European Patent Application 85/133550A2);

chitinovorin-A (as disclosed in published European Patent Application 85/150, 378A2 and U.S. Patent No., 4,723,004);

streptomycin (as disclosed in U.S. Patent No. 2,868,779); SB-59 (as disclosed in Justus Liebigs, Ann. Chem. (1973) 7, 1112-1140);

TAN-1057-A (as disclosed in U.S. Patent No. 4,971,965);

streptoniazid (as disclosed in J. Am. Chem.

Soc. (1953) 75, 2261);

immunostimulants related to

ST-789 (as disclosed in published European Patent Application 88/260588);

peptide hydrolase inhibitors related to nafamastat (as disclosed in U.S. Patent No. 4,454,338);

gabexate (as disclosed in U.S. Patent No. 3,751,447);

sepimostat (as disclosed in U.S. Patent

Nos. 4,777,182 and 4,820,730);

Factor Xa inhibitors related to

DX-9065a (as disclosed in published European Patent Application 92/0540051);

anti-inflammatory agents related to paranyline as disclosed in U.S. Patent No.

2,877,269;

peptidyl aldehydes (as disclosed in W094/13693);

antianaphylactics related to GMCHA-TBP

(Batebulast) (as disclosed in U.S. Patent No.

4,465,851);

anti-ulcer agents related to

benexate (as disclosed in U.S. Patent No. 4,348,410);

deoxyspergualin (as disclosed in U.S. Patent Nos. 4,518,532, 4,658,058 and 4,983,328); and arginine.

The compounds of formula I of the invention may be prepared as shown in the following reaction schemes and as described below. It will be appreciated that the term

"guanidine prodrugs" as employed in conjunction with the Reaction Schemes I and II encompasses guanidine prodrugs and thioguanidine prodrugs.

Reaction Scheme I

Reaction Schemes I and II depict the synthesis of monocarbamyl (la) or biscarbamyl (lb) guanidine prodrugs from an amino-containing substructure ZH wherein Z may be any of the Z substructures Z(1), Z(2), Z(3), Z(4), Z(5) and Z(6) as defined herein or any of the Z substructures set out in the various patent and literature references set out hereinbefore.

In the following schemes, -C(=O)OR* is used as the carbamyl precursor to Ax and A'x for illustrative purposes. In these equations,

-C(=O)OR* may be replaced by -C (=O) -Q^I-Het-C (=O)- Het¹-R^I, where Q^I, Het, Het¹ and R^I are as defined herein.

Reaction Scheme I

Synthesis of monocarbamyl (la) or biscarbamyl (lb) guanidine prodrugs from an amino-containing thrombin inhibitor substructure ZH

ZH is an amino-containing thrombin inhibitor substructure

Z-C=(NH)NH₂ is a guanidine-containing thrombin inhibitor

Referring to Scheme I, 1H-pyrazole-1- carboxamidine hydrochloride 1 is allowed to react, in the presence of a base, such as diisopropyl- ethylamine, or N,N-dimethylaminopyridine, with a 4- nitrophenylcarbonate, such as R*OC (=O) OPh(4-NO₂), or with a chloroformate, such as R*OC(=O)Cl, or an N-hydroxysuccinimide carbonate, such as

R*OC(=O)OSu, in a solvent such as DMF or THF or dichloromethane to give an N-monocarbamyl pyrazole carboxamidine 2. A'x is a portion of a carbamyl group as defined previously, that is, A'x has the structure of -C(=O)OR*, where R* is -Q^I-Het-C (=O) - Het¹-R^I.

The N-N'-biscarbamyl pyrazole carboxamidine 3 is prepared by reaction of N-monocarbamyl pyrazole carboxamidine 2 with a 4-nitrophenyl- carbonate, such as R*OC(=O)OPh(4-NO₂), or with a chloroformate, such as R*OC(=O)Cl, or an N-hydroxy- succinimide carbonate, such as R*OC(=O)OSu, in the presence of a base, such as sodium hydride, potassium hydride, lithium hydride, or lithium hexamethyldisilazide, or potassium t-butoxide, in a solvent such as THF or DMF. A'x is a portion of a carbamyl group as defined previously, that is, A'x has the structure of -C(=O)OR*, where A'x may or may not equal Ax.

Biscarbamyl guanidine prodrugs lb are prepared by reacting an amino-containing thrombin inhibitor substructure ZH with N-N' -biscarbamyl pyrazole carboxamidine 3, in a solvent such as THF or DMF and in the presence of a base such as diisopropylethyl amine or N,N-dimethylamino- pyridine.

Monocarbamyl guanidine prodrugs la are prepared by reacting an N-protected monocarbamyl pyrazole carboxamidine 4 (typically P.G. = Boc or Cbz), obtained by treatment of 1H-pyrazole-1- carboxamidine hydrochloride 1 with a 4-nitrophenyl carbonate, such as R*OC (=O)OPh(4-NO₂), or with a chloroformate, such as R*OC(=O)Cl or an N-hydroxy- succinimide carbonate, such as R*OC(=O)OSu in the presence of a base, such as sodium hydride, potassium hydride, lithium hydride, lithium hexamethyldisil-azide, or potassium t-butoxide, in a solvent such as THF or DMF, to give an unsymmetrical biscarbamyl pyrazole carboxamidine 5. Alternatively, 5 may be obtained from reacting N-monocarbamyl pyrazole carboxamidine 2 with di-t- butyldicarbonate, or Boc-ON (for P.G. = Boc) or Cbz-Cl (for P.G. = Cbz) in the presence of a base, such as sodium hydride, potassium hydride, lithium hydride, lithium hexamethyldisil-azide, or

potassium t-butoxide, in a solvent such as THF or DMF. Reaction of 5 with an amino-containing thrombin inhibitor substructure ZH, in the

presence of a base such as diisopropylethyl amine and in a solvent such as THF provides 6, which upon removal of protecting group under acidic (for P.G. = Boc) or hydrogenolytic (for P.G. = Cbz) conditions, give the monocarbamyl guanidine

prodrugs la.

Alternatively, la can be prepared directly by reacting the N-monocarbamyl pyrazole

carboxamidine 2 with an amino-containing thrombin inhibitor substructure ZH, in the presence of a base such as 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), in a solvent such as THF or acetonitrile.

In carrying out the reactions set out in Reaction Scheme I, the (a) carbonate, (b)

chloroformate or ester, or (c) succinimide ester, is employed in a molar ratio to the 1H-pyrazole-1- carboxamidine hydrochloride 1 within the range from about 10:1 to about 1:1, preferably from about 3:1 to about 1:1.

The reaction to form the N-monocarbamyl pyrazole carboxamidine 2 is carried out at a temperature within the range from about -40 to about 100°C, preferably from about -20 to about 50°C, in the presence of a base, preferably diisopropylethylamine, as well as triethylamine, N- methylmorpholine or DBU, in an inert organic solvent such as chloroform and acetonitrile and preferably DMF (dimethylformamide) or

tetrahydrofuran (THF).

The N-monocarbamyl pyrazole carboxamidine 2 is reacted with (a) carbonate, (b) chloroformate or (c) succinimide ester (in the presence of a base such as sodium hydride in THF, potassium hydride, lithium-hexamethyldisilazide (LHMDS) or potassium t-butoxide) in a molar ratio to the carboxamidine 2 of within the range from about 3:1 to about 1:1, preferably from about 2:1 to about 1:1, and the reaction will be carried out at a temperature within the range from about -40 to about 60°C, preferably from about -20 to about 30°C.

The N-biscarbamyl pyrazole carboxamidine 3 is reacted with substructure ZH employing a molar ratio of 3:ZH within the range from about 5:1 to about 1:2, preferably from about 2:1 to about 1:1, in the presence of an inert organic solvent preferably acetonitrile, dichloromethane,

dimethyIformamide or tetrahydrofuran, and a base such as DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), preferably diisopropylethylamine, at a temperature within the range from about -40 to about 100°C, preferably from about -20 to about 50°C, to form lb.

In the method for preparing monocarbamyl la, the carbonate (a), chloroformate (b) or succinimide ester (c), will be employed in a molar ratio to the protected pyrazole carboxamide 4 within the range from about 3:1 to about 1:1, preferably from about 2:1 to about 1:1, and the reaction thereof will be carried out at a

temperature within the range from about -40 to about 60°C, preferably from about -20 to about 30°C.

Alternatively, la can be prepared by protecting the N-monocarbamyl pyrazole carboxamidine 2 with a protecting group (PG) such as BOC or CBZ which is then reacted with a base such as sodium hydride, lithium hexamethyldisilazide, or potassium t-butoxide, preferably sodium hydride, in a solvent such as THF or DMF, to give the protected carboxamidine 5.

The protected monocarbamyl carboxamidine 5 will be employed in a molar ratio to ZH within the range from about 3:1 to about 1:2, preferably from about 1.5:1 to about 1:1, and the reaction is carried out at a temperature within the range from about -40 to about 60°C, preferably from about -20 to about 40°C.

Compound 6 is deprotected using methods known in the art to give monocarbamyl compounds of formula la; for example, trifluoroacetic acid is empoyed where P.G. =BOC .

In preparing the bisacyl compounds of the invention lb, the carbonate (a), chloroformate (b) or succinimide ester (c) is employed in a molar ratio to monocarbamyl carboxamidine 2 within the range from about 4:1 to about 1:1, preferably from about 2:1 to about 1:1, and the reaction is carried out at a temperature within the range from about -40 to about 50°C, preferably from about -10 to about 30°C, to form the N,N'-biscarbamyl pyrazole carboxamidine 3.

Reaction Scheme II

Synthesis of monocarbamyl (la) or

biscarbamyl (lb) guanidine prodrugs from an amidine or guanidine-containing thrombin inhibitor

ZC(=NH)NH2 is an amidine or guanidine-containing thrombin inhibitor

Referring to Reaction Scheme II, an amidine or guanidine-containing thrombin inhibitor 7 is allowed to react, in the presence of a base, such as diisopropylethylamine or N,N-dimethylamino- pyridine, with a 4-nitrophenylcarbonate, such as (a) R*OC(=O)OPh(4-NO₂), or with a chloroformate, such as (b) R*OC(=O)Cl, or an N-hydroxysuccinimide carbonate, such as (c) R*OC(=O)OSu, in a solvent such as DMF or THF or dichloromethane to provide an N-monocarbamyl thrombin inhibitor prodrug of formula la.

Alternatively, la can be prepared by protecting an amidine or guanidine-containing thrombin inhibitor 7 with a protecting group such as Boc or Cbz to give the N-protected guanidine 8, and then acylating with a 4-nitrophenylcarbonate, such as (a) R*OC(=O)OPh(4-NO₂), or with a

chloroformate, such as (b) R*OC(=O)Cl or an N- hydroxysuccinimide carbonate, such as (c)

R*OC(=O)OSu, in the presence of a base, such as sodium hydride, potassium hydride, or lithium hydride, lithium hexamethyldisilazide, or

potassium t-butoxide, in a solvent such as THF or DMF, to give compound 9. Removal of the

protecting group under acidic (for P.G. = Boc) or hydrogenolytic (for P.G. = Cbz) conditions provides the monocarbamyl amidine or guanidine prodrug la. A'x is a carbamyl group as defined previously, that is, A'x has the structure -C(=O)OR*, where R* is -Q^I-Het-C(=O-Het¹-R^I.

The N, N' -biscarbamyl amidine or guanidine- containing prodrugs lb can be prepared by

acylation of N-monocarbamyl amidine or guanidine- containing prodrugs la with a 4-nitrophenyl- carbonate, such as (a) R*OC (=O) OPh(4-NO₂), or with a chloroformate, such as (b) R*OC(=O)Cl, or an N- hydroxysuccinimide carbonate, such as (c)

R*OC(=O)OSu, in the presence of a base, such as sodium hydride, potassium hydride, lithium hydride, lithium hexamethyldisilazide, or potassium t- butoxide, in a solvent such as THF or DMF. A'x is a carbamyl group as defined previously, that is, A'x has the structure of -C(=O)OR*, where A'x may or may not equal to Ax.

In carrying out the reactions set out in

Reaction Scheme II, the (a) carbonate, (b) chloroformate or (c) succinimide ester, is employed in a molar ratio to the amidine-containing compound (such as thrombin inhibitor) 7 within the range from about 3:1 to about 1:1, preferably from about 2:1 to about 1:1. The reaction to form monocarbamyl amidine la is carried out at a temperature within the range from about -20 to about 50°C, preferably from about 0 to about 30°C, in the presence of a base, preferably diisopropylethylamine, as well as N- methylmorpholine, potassium carbonate or DBU in an inert organic solvent such as acetonitrile,

chloroform and tetrahydrofuran, in addition to DMF (dimethylformamide) or dichloromethane (which are preferred).

In the preparation of the protected amidine 9, the carbonate (a), chloroformate (b),

succinimide ester (c), is employed in a molar ratio to the protected amidine-containing compound (such as thrombin inhibitor) 8 within the range from about 4:1 to about 1:1, preferably from about 2:1 to about 1:1, and the reaction thereof will be carried out at a temperature within the range from about -40 to about 60°C, preferably from about -20 to about 30°C.

In preparing the biscarbamyl compounds of the invention lb, carbonate (a), chloroformate (b) and the succinimide ester (c), is employed in a molar ratio to monocarbamy amidine la within the range from about 3:1 to about 1:1, preferably from about 2:1 to about 1:1, and the reaction is carried out at a temperature within the range from about

-40 to about 60°C, preferably from about -10 to about 30°C.

The starting materials ZH and

may be prepared as described in the aforementioned U.S. applications and published European and WO applications as well as in any of the

aforementioned patent and/or literature references. In General

The term "prodrug (s)" as used herein refers to a class of drugs the pharmacologic action of which results from conversion by processes within the body (biotransformation).

The phrase "pharmaceutically active properties" as employed herein in describing the compounds of the invention is used interchangeably with the phrase "pharmacologically active

properties".

The term "lower alkyl" or "alkyl" as employed herein by itself or as part of another group includes both straight and branched chain radicals of up to 18 carbons, preferably 1 to 8 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4- trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups including 1, 2 or 3 halo substituents (for example, to form CF₃ or CF₃CH₂) and/or 1 or 2 of the following

substituents: an aryl substituent (for example, to form benzyl or phenethyl), a heteroaryl

substituent, an alkyl-aryl substituent, a haloaryl substituent, a cycloalkyl substituent, an

alkylcycloalkyl substituent, an alkenyl

substituent, an alkynyl substituent, hydroxy or a carboxy substituent. It will be appreciated that the same "alkyl" group may be substituted with one or more of any of the above substituents.

The term "cycloalkyl" by itself or as part of another group includes saturated cyclic

hydrocarbon groups containing 3 to 12 carbons, preferably 3 to 8 carbons, which include

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, any of which groups may be

substituted with substituents such as halogen, lower alkyl, alkoxy, and/or hydroxy groups.

The term "aryl" or "Ar" as employed herein by itself or as part of another group refers to mono-cyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, or naphthyl. Aryl (or Ar), phenyl or naphthyl may include substituted aryl, substituted phenyl or substituted naphthyl, which may include 1, 2, 3, 4 or 5 substituents on either the Ar, phenyl or naphthyl such as lower alkyl, cyano, amino, alkylamino, dialkylamino, nitro, carboxy, alkoxycarbonyl, trifluoromethyl, halogen (Cl, Br, I or F), lower alkoxy, arylalkoxy, hydroxy,

alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl and/or arylsulfonyl.

In a separate embodiment of the invention, where R³ in formula I is phenyl, the phenyl group may include 3, 4 or 5 substituents such as alkyl, for example, pentamethyl and 2,4,6-tri-isopropyl, and halo, for example, pentafluoro.

The term "aralkyl", "aryl-alkyl" or "aryl- lower alkyl" as used herein by itself or as part of another group refers to lower alkyl groups as discussed above having an aryl substituent, such as benzyl.

The term "lower alkoxy", "alkoxy" or aralkoxy" includes any of the above lower alkyl, alkyl or aralkyl groups linked to an oxygen atom.

The term "halogen" or "halo" as used herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine with chlorine being preferred.

The term "lower alkenyl" or "alkenyl" as employed herein by itself or as part of another group includes a carbon chain of up to 16 carbons, preferably 3 to 10 carbons, containing one double bond which will be separated from "N" by at least one saturated carbon moiety such as -(CH₂)_q- where q can be 1 to 14, such as 2-propenyl, 2-butenyl, 3- butenyl, 2-pentenyl, 4-pentenyl and the like, and may include a halogen substituent such as I, Cl, or F.

The term "lower alkynyl" or "alkynyl" as employed herein by itself or as part of another group includes a carbon chain of up to 16 carbons, preferably 3 to 10 carbons, containing one triple bond which will be separated from "N" by at least one saturated carbon moiety such as -(CH2)_q'- where q' can be 1 to 14, such as 2-propynyl, 2-butynyl, 3-butynyl and the like.

The term "heteroaryl" or heteroaromatic by itself or as part of another group refers to a 5- to 10-membered monocyclic or bicyclic aromatic ring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur, such as

and the like. The heteroaryl rings may optionally be fused to aryl rings defined previously. The heteroaryl rings may optionally include 1 or 2 substituents such as halogen (Cl, Br, F or CF₃), lower alkyl, lower alkoxy, carboxy, amino, lower alkylamino and/or dilower alkylamino.

The term "cycloheteroalkyl" or

"heterocycloalkyl" as used herein refers to a 5-, 6- or 7-membered saturated ring which includes 1 or 2 hetero atoms such as nitrogen, oxygen and/or sulfur, which may optionally include 1 to 4 substituents such as halo, alkyl or oxo, such as

and the like.

The term "azacycloalkenyl" as used herein refers to a 4- to 8-membered ring which includes a double bond, such as

The term "amino acid side chain" refers to any of the known alpha-amino acids such as

arginine, histidine, alanine, glycine, lysine, glutamine, cyclohexylalanine, t-butylglycine, leucine, valine, serine, homoserine, allothreonine, naphthylalanine, isoleucine, phenylalanine and the like.

The compounds of formulae I, l., la, A., Ix, Iq, ly and Iz of the invention can be obtained as pharmaceutically acceptable acid addition salts by reacting a free base with an acid, such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, fumaric, citric, maleic, succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic, ethanesulfonic,

benzenesulfonic, p-toluenesulfonic acid or the like.

The prodrug compounds of formula I of the invention will have the same utility as the Z substructure employed therein linked to

Thus, if the Z substructure linked to

is a thrombin inhibitor, the prodrug of formula I will be useful as a thrombin inhibitor in dosages and dosage forms as described in the references set out above; if the Z substructure linked to

is an inhibitor of platelet aggregation, the prodrug of formula I will be useful as an inhibitor of platelet aggregation in dosages and dosage forms as described in the references set out above (and so on).

Depending on the Z substructure, the compounds of the present invention may be serine protease inhibitors, and in particular may inhibit thrombin, Factor Xa, and/or trypsin. Such

compounds of the present invention are useful for the treatment or prophylaxis of those processes which involve the production and/or action of thrombin. This includes a number of thrombotic and prothrombotic states in which the coagulation cascade is activated which include, but are not limited to, deep vein thrombosis (DVT),

disseminated intravascular coagulopathy (DIC), Kasabach-Merritt syndrome, pulmonary embolism, myocardial infarction, stroke, thromboembolic complications of surgery (such as hip replacement and endarterectomy) and peripheral arterial

occlusion. In addition to its effects on the coagulation process, thrombin has been shown to activate a large number of cells (such as

neutrophils, fibroblasts, endothelial cells, smooth muscle cells). Therefore, the compounds of the present invention may also be useful for the treatment or prophylaxis of adult respiratory distress syndrome, septic shock, septicemia, inflammatory responses which include, but are not limited to, edema, acute or chronic

atherosclerosis, and reperfusion damage.

The compounds of the invention (as serine protease inhibitors) may also be useful in treating neoplasia/metastasis (in particular those which utilize fibrin) and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In addition, the compounds of the present invention may be useful to prevent restenosis following arterial injury induced by endogenous (rupture of an atherosclerotic plague) or exogenous (invasive cardiological procedure) events.

The compounds of the present invention as thrombin inhibitors, inhibitors of platelet aggregation and/or fibrinogen receptor antagonists may also be used as an anticoagulant in

extracorpeal blood circuits, such as those

necessary in dialysis and surgery (such as coronary artery bypass surgery).

The compounds of the present invention as thrombin inhibitors, platelet aggregation

inhibitors or fibrinogen receptor antagonists may also be used in combination with thrombolytic agents, such as tissue plasminogen activator

(natural or recombinant), streptokinse, urokinase, prourokinase, anisolated streptokinase plasminogen activator complex (ASPAC), animal salivary gland plasminogen activators, and the like. The

compounds of the present invention as thrombin inhibitors, platelet aggregation inhibitors or fibrinogen receptor antagonists may act in a synergistic fashion to prevent reocclusion

following a successful thrombolytic therapy and/or reduce the time to reperfusion. The compounds of the present invention as thrombin inhibitors, platelet aggregation inhibitors or fibrinogen receptor antagonists may also allow for reduced doses of the thrombolytic agent to be used and therefore minimize potential hemorrhagic side- effects.

inhibitors or fibrinogen receptor antagonists may also be used in combination with other

antithrombotic or anticoagulant drugs such as thromboxane receptor antagonists, prostacyclin mimetics, phosphodiesterase inhibitors, fibrinogen antagonists, aspirin and the like.

Compounds of the present invention that inhibit trypsin may also be useful for the

treatment of pancreatitis.

The compounds of the invention can be administered orally or parenterally such

subcutaneously or intravenously, as well as by nasal application, rectally or sublingually to various mammalian species known to be subject to such maladies, e.g., humans, cats, dogs and the like in an effective amount within the dosage range of about 0.1 to about 100 mg/kg, preferably about 0.2 to about 50 mg/kg and more preferably about 0.5 to about 25 mg/kg (or from about 1 to about 2500 mg, preferably from about 5 to about 2000 mg) on a regimen in single or 2 to 4 divided daily doses.

The active substance can be utilized in a composition such as tablet, capsule, solution or suspension or in other type carrier materials such as transdermal devices, iontophoretic devices, rectal suppositories, inhalant devices and the like. The composition or carrier will contain about 5 to about 500 mg per unit of dosage of a compound or mixture of compounds of formula I, l., la, Ix, Iq, ly and Iz. They may be compounded in conventional matter with a physiologically

acceptable vehicle or carrier, excipient, binder, preservative, stabilizer, flavor, etc., as called for by accepted pharmaceutical practice.

The following working Examples represent preferred embodiments of the present invention. Example 1

N-[[1-[[[[2-(Acetyloxy)-1,1-dimethylethoxy]- carbonyl]amino]iminomethyl]-4-piperidinyl]methyl]- 1-[N-(methylsulfonyl)-D-phenylalanyl]-L- prolinamide, trifluoroacetate

A. 2-Methyl-1 , 2-propanediol-1-acetate

A mixture of isobutylene oxide (14.42 g, 0.2 mol), sodium acetate (131.2 g, 1.6 mol) in 400 ml of dry DMF containing 22.9 ml of glacial acetic acid (0.4 mol) was heated at 80°C for three days. The mixture was poured into a 1:1 mixture of EtOAc (1.0 L) and water. The aqueous layer was extracted with EtOAc (1.0 L x2) and the combined organic extracts were washed with water, saturated NaHCO₃, brine and dried over anhydrous Na₂SO₄. EtOAc (ca. 4.0 L) was removed by distillation. Short-path distillation afforded required title tertiary alcohol (bp: 153-175°C, contaminated with DMF) as a colorless liquid. The material was used

immediately in next reaction.

B. Carbonic acid, 2-(acetyloxy)-1,1- dimethylethyl 4-nitrophenyl ester

To a mixture of Part A alcohol (5.54 g, contaminated with DMF) in 55 ml of dry CH₂Cl₂ containing 11 ml of dry pyridine cooled at 0°C was added a solution of 4-nitrophenol chloroformate (7.62 g, 37.8 mmol) in 55 ml of dry CH₂Cl₂. The mixture was stirred for 1.0 hr at 0°C and then overnight at room temperature. The reaction mixture was partitioned between a 1:1 mixture of EtOAc and water (500 ml). The aqueous layer was extracted once with EtOAc (250 ml). The combined organic extracts were washed with sat'd NaHCO₃, brine and dried over anhydrous Na₂SO₄.

Concentration in vacuo followed by flash

chromatography (hexane-CH₂Cl₂ : 2:1 to 100% CH₂Cl₂) on silica gel afforded 7.80 g (70%) of title para- nitrophenol carbonate as a light yelow oil.

C. [[[(1,1-Dimethylethoxy)carbonyl]imino]- (1H-pyrazol-1-yl)methyl]carbamic acid, 2- (acetyloxy)-1,1-dimethylethyl ester

To a suspension of 95% sodium hydride (316 mg, 12.5 mmol) in 10.5 ml of dry THF cooled at 0°C was added a solution of mono-Boc guanylpyrazole (1.05 g, 5.0 mmol) in 4.5 ml of dry THF, dropwise via a syringe, while maintaining the internal temperature below 2°C. The mixture was stirred for 10 min at 0°C and a solution of Part B 4- nitrophenyl carbonate (1.93 g, 6.5 mmol) in 4.0 ml of dry THF was added over 10 min. The ice bath was removed and the mixture was stirred overnight at room temperature. The resulting thick yellow paste was poured into an ice-cold mixture of EtOAc-sat'd NH₄CI . The aqueous layer was extracted once with EtOAc. The combined organic extracts were washed with water, sat'd NaHC0₃ and brine, dried over anhydrous Na₂S0₄- Concentration in vacuo followed by flash chromatography (hexane-EtOAc : 5:1) on silica gel afforded 1.54 g of title guanylpyrazole bis-carbamate as a yellow oil.

D. N-[[1-[[[[2-(Acetyloxy)-1,1-dimethyl- ethoxy]carbonyl]amino]iminomethyl]-4- piperidinyl]methyl]-1-[N-(methylsulfonyl)- D-phenylalanyl]-L-prolinamide, trifluoroacetate

To a solution of Part C bis-carbamate (0.98 g, 1.582 mmol, contaminated with some para- nitrophenol) in 5 ml of dry THF was added a solution of [4-[piperidinyl]methyl]-1-[N-

(methylsulfonyl)-D-phenylalanyl]-L-prolinamide (827 mg, 1.50 mmol) in 5 ml of dry THF, followed by addition of i-Pr₂NEt (0.965 ml, 5.54 mmol). The mixture was stirred overnight at room temperature. Concentration in vacuo followed by flash

chromatography (CH₂Cl₂-MeOH: 99:1 to 96:4) on silica gel afforded 1.01 g of coupling product as a yellow foam. To the solution of above product (1.01 g, 1.37 mmol) in 5.0 ml of dry CH₂Cl₂ cooled at 0°C was added 5.0 ml of TFA. The mixture was stirred at 0°C for 15 min and room temperature for 2.0 hrs. Concentration in vacuo followed by trituration with CH₂CH₂-ether-hexane afforded 0.734 g (84%) of TFA salt of N-[[1-[[[[2-(acetyloxy)-1,1- dimethylethoxy]carbonyl]amino]iminomethyl]-4- piperidinyl]methyl]-1-[N-(methylsulfonyl)-D- phenylalanyl]-L-prolinamide as a white solid. mp: 112-114°C. [α]_D = -56.4° (c 1.21, MeOH).

Anal.: Calcd. for C₂₉H₄₄N₆O₈S· 1.10 TFA:

C, 48.41; H, 6.04; N, 10.86; S, 4.14;

F, 8.10

Found: C, 48.41; H, 6.06; N, 10.76; S, 4.16;

F, 8.30.

Using the above procedure, the following compounds were prepared.

Example 2

N-[[1-[Amino[[[2-(benzoyloxy)-2-methylpropoxy]- carbonyl]imino]methyl]-4-piperidinyl]methyl]-1-[N- (methylsulfonyl)-D-phenylalanyl]-L-prolinamide, trifluoroacetate

mp: 116-118°C. [α]_D = -51.0° (c 0.73, MeOH) .

Anal.: Calcd. for C₃₄H₄₆N₆O₈S· 1.03 TFA- 0.89 H₂O:

C, 54.23; H, 6.64; N, 9.40; S, 3.58; F, 6.56

Found: C, 54.23; H, 6.47; N, 9.60; S, 3.37;

F, 6.55. Example 3

cis-N-[[1-[[Amino[[[[2-(benzoyloxy)cyclohexyl]oxy]- carbonyl]imino]methyl]-4-piperidinyl]methyl]-1-[N- (methylsulfonyl)-D-phenylalanyl]-L-prolinamide, trifluoroacetate (1:1)

mp: 129-131°C. [α]_D = -47.4° (c 0.86, MeOH).

Anal.: Calcd. for C₃₆H₄₈N₆O₈S ·1.0 TFA·1.2 H₂O:

C, 53.04; H, 6.02; N, 9.77; S, 3.73; F, 6.62

Found: C, 53.04; H, 6.06; N, 9.68; S, 3.86;

F, 6.49.

Example 4

(1R,2R)-N-[[1-[Amino[[[2-(benzoyloxy)-1-methylpro- poxy]carbonyl]imino]methyl]-4-piperidinyl]methyl]- 1-[N-(methylsulfonyl)-D-phenylalanyl]-L- prolinamide, trifluoroacetate

mp: 126-128°C. [α]_D = -70.9° (c 0.83, MeOH) .

Anal. : Calcd. for C₃₄H₄₆N₆O₈S · 1.06 TFA· 0.87 H₂O: C, 51.93; H, 5.89; N, 10.06; S, 3.84;

F, 7.23

Found: C, 51.93; H, 5.79; N, 10.00; S, 3.85;

F, 7.25.

Example 5

N-[[1-[Amino[[[[2-(benzoyloxy)-1,1-dimethylethoxy]- carbonyl]amino]imino]methyl]-4-piperidinyl]methyl]- 1-[N-(methylsulfonyl)-D-phenylalanyl]-L- prolinamide, trifluoroacetate

mp: 108-110°C. [α]_D = -54.3° (c 0.69, MeOH).

Anal.: Calcd. for C₃₄H₄₆N₆O₈S· 0.86 TFA·1.33 H₂O:

C, 52.27; H, 6.08; N, 10.24; S, 3.91; F, 5.97;

Found: C, 52.27; H, 5.92; N, 10.16; S, 3.86;

F, 5.92.

Example 6

2-Methylpropanoic acid, 2-[[[[Amino[4-[[[1-[N- (methylsulfonyl)-D-phenylalanyl]-L-prolyl]amino]- methyl]-1-piperidinyl]methyl]imino]carbonyl]oxy]-2- methylpropylester, trifluoroacetate

mp: 108-110°C. [α]_D = -53.7° (c 0.97, MeOH). Anal.: Calcd. for C₃₁H₄₈N₆O₈S · 1.50 TFA· 0.34 H₂O:

C, 48.50; H, 6.01; N, 9.98; S, 3.81;

F, 10.15

Found: C, 48.50; H, 6.15; N, 9.73; S, 3.75;

F, 9.92.

Example 7

2-Methylpropanoic acid, 2-[[[amino[4-[[1-[N- (methylsulfonyl)-D-phenylalanyl]-L-prolyl]- amino]methyl]-1-piperidinyl]methyl]imino]- carbonyl]oxy]-1,1-dimethylethyl ester,

trifluoroacetate

mp: 74-76°C. [α]_D = -52.6° (c 1.37, MeOH).

Anal.: Calcd. for C₃₁H₄₈N₆O₈S· 1.21 TFA· 1.02 H₂O:

C, 48.88; H, 6.29; N, 10.23; S, 3.90;

F, 8.40

Found: C, 48.88; H, 6.21; N, 10.11; S, 4.09;

F, 8.40. Example 8

2,2-Dimethylpropanoic acid, 2-[[[amino[4-[[1-[N-

(methylsulfonyl)-D-phenylalanyl]-L-prolyl]amino] methyl]-1-piperidinyl]methyl]imino]carbonyl]oxy]

1,1-dimethylethyl ester, trifluoroacetate

mp: 92-94°C. [α]_D = -51.6° (c 1.20, MeOH).

Anal.: Calcd. for C₃₂H₅₀N₆O₈S · 1.04 TFA· 1.06 H₂O:

C, 50.13; H, 6.56; N, 10.29; S, 3.93;

F, 7.26

Found: C, 50.13; H, 6.43; N, 9.99; S, 3.85;

F, 7.23

Example 9

3-Pyridinecarboxylic acid, 2-[[[amino[4-[[1-[N- (methylsulfonyl)-D-phenylalanyl]-L-prolyl]amino]- methyl]-1-piperidinyl]methyl]imino]carbonyl]oxy]-2- methylpropyl ester, trifluoroacetate

mp: 90-94°C. [α]_D = -49.4° (c 1.44, MeOH).

Anal.: Calcd. for C₃₃H₄₅N₇O₈S· 1.62 TFA- 1.08 H₂O:

C, 48.15; H, 5.44; N, 10.85; S, 3.55; F, 10.21

Found: C, 48.15; H, 5.24; N, 10.70; S, 3.69;

F, 10.23. Example 10

N-[[1-[[[[2-(Acetyloxy)-1,1-dimethylethoxy]- carbonyl]amino][[[2-(acetyloxy)-1,1-dimethyl- ethoxy]carbonyl]imino]methyl]-4-piperidinyl]- methyl]-1-[N-(methylsulfonyl)-D-phenylalanyl]- L-prolinamide

A. [Imino (1H-pyrazol-1-yl)methyl]carbamic acid, 2-(acetyloxy)-1,1-dimethylethyl ester

To a solution of Example 1 Part B 4- nitrophenol carbonate in 5.0 ml of dry DMF cooled at 0°C was added i-Pr₂NEt (1.12 ml, 6.4 mmol), followed by solid guanylpyrazole HCl salt (375 mg, 2.56 mmol) in one portion. The mixture was stirred for 15 min at 0°C, then overnight at room

temperature. The reaction mixture was partitioned between a 1:1 mixture of EtOAc and water (100 ml). The aqueous layer was extracted once with EtOAc (50 ml). The combined organic extracts were washed with water, saturated NaHC0₃ , brine and dried over anhydrous Na₂SO₄. Concentration in vacuo followed by flash chromatography (hexane-EtOAc: 4:1) on silica gel afforded 891 mg of title compound, as a colorless oil. B. [[[[2-(Acetyloxy)-1,1-dimethylethoxy]- carbonyl]imino](1H-pyrazol-1-yl)methyl]- carbamic acid, 2-(acetyloxy)-1,1-dimethyl- ethyl ester

To a suspension of 95% sodium hydride (210 mg, 8.30 mmol) in 7.0 ml of dry THF cooled at 0°C was added a solution of Part A compound (891 mg, 3.32 mmol) in 3.0 ml of dry THF, dropwise via a syringe, while maintaining the internal temperature below 2°C. The mixture was stirred for 10 min at 0°C and a solution of Example 1 Part B 4- nitrophenol carbonate (1.48 g, 5.0 mmol) in 3.0 ml of dry THF was added over 10 min. The ice bath was removed and the mixture was stirred overnight at room temperature. The resulting thick yellow paste was poured into an ice-cold mixture of EtOAc- saturatedd NH₄CI. The aqueous layer was extracted once with EtOAc. The combined organic extracts were washed with water, saturated NaHCO₃ and brine, dried over anhydrous Na₂SO₄. Concentration in vacuo followed by flash chromatography (hexane- EtOAc: 4:1 to 2:1) on silica gel afforded 710 mg (50%) of title compound, as a light yellow oil.

C. N-[[1-[[[[2-(Acetyloxy)-1,1-dimethyl- ethoxy]carbonyl]amino][[[2-(acetyloxy)-1,1- dimethylethoxy]carbonyl]imino]methyl]-4- piperidinyl]methyl]-1-[N-(methylsulfonyl)- D-phenylalanyl]-L-prolinamide

To the solution of Part B compound (0.63 g, 1.48 mmol) in 5 ml of dry THF was added a solution of TFA salt of [4-[piperidinyl]methyl]-1-[N-

(methylsulfonyl)-D-phenylalanyl]-L-prolinamide (773 mg, 1.40 mmol) in 5 ml of dry THF, followed by addition of i-Pr₂NEt (0.643 ml, 3.69 mmol). The mixture was stirred overnight at room temperature. Concentration in vacuo followed by flash

chromatography (CH₂Cl₂-MeOH: 99:1 to 98:2) on silica gel afforded 821 mg (74%) of title compound as a white solid. mp: 82-85°C. [α]_D = -54.7° (c 0.69, MeOH).

Anal.: Calcd. for C₃₆H₅₄N₆O₁₂S· 0.63 H₂O·0.25 hexane:

C, 54.51; H, 7.15; N, 10.15; S, 3.87 Found: C, 54.51; H, 7.17; N, 10.17; S, 3.88. Using the above procedure the following examples were prepared.

Example 11

N-[[1-[[[[2-(Acetyloxy)ethoxy]carbonyl]amino][[[2- (acetyloxy)ethoxy]carbonyl]-imino]methyl]-4-piper- idinyl]methyl]-1-[N-methyl-N-(methylsulfonyl)-D- phenyl-alanyl]-N-methyl-L-prolinamide

mp: 77-80°C. [α]_D = -60.5° (c 0.41, MeOH).

Anal.: Calcd. for C₃₂H₄₆N₆O₁₂S· 0.57 H₂O:

C, 50.79; H, 6.29; N, 11.06; S, 4.22 Found: C, 50.79; H, 6.20; N, 10.94; S, 4.20.

Example 12

N-[[1-[[[[1,1-Dimethyl-2-(2-methyl-1-oxopropoxy)- ethoxy]carbonyl]amino] [[[1,1-dimethyl-2-(2-methyl- 1-oxopropoxy)ethoxy]carbonyl] imino]methyl]-4- piper-idinyl]methyl]-1-[N-(methylsulfonyl)-D- phenvlalanvll-L-prolinamide

mp: 78-81°C. MS (Electrospray): 851⁺ (M+H)⁺.

1H-NMR (400 MHz, CDCl₃): δ 1.18 (d, J = 6.84, 12H),

1.22-1.40 (m, 4H), 1.49 (s, 12H), 1.54-1.90 (m, 8H), 2.18 (m, 1H), 2.60 (m, 2H), 2.70 (m, 1H), 2.82 (m, 3H), 2.83-3.09 (m, 5H) , 3.21 (m, 1H), 3.60 (m, 1H), 4.18-4.33 (m, 6H), 4.42 (m, 1H), 5.62 (bs, 1H), 6.70 (m, 1H), 7.20-7.36 (m, 5H). ¹³H-NMR (400 MHz, CDCl₃) : 5 19.0, 23.6, 24.1, 28.6, 29.1, 29.4, 34.0, 35.7, 39.2, 41.3, 44.4, 46.9, 56.4, 60.6, 68.5, 127.6, 128.8, 129.4, 135.5,

154.7, 170.7, 171.4, 176.7.

Example 13

2-Methylpropanoic acid, 2-[[[[amino[4-[[[1-[N- (methylsulfonyl)-D-phenyl-alanyl]-L-prolyl]amino]- methyl]-1-piperidinyl]methyl]imino]carbonyl]oxy]-2- propylpentyl ester, trifluoroacetate

CeCl₃ (12.3 g, 50.0 mmol) was stirred vigorously in dry THF (75 ml) for 2.0 hrs and cooled to -78°C. To this suspension was added a solution of 1.0 M vinyl magnesium bromide in THF (50 ml, 50.0 mmol), dropwise via an additional funnel while kept the internal temperature below -72°C. The mixture was stirred for 1.0 hr at -78°C. A solution of 4-heptanone (3.49 ml, 25.0 mmol) in 20 ml of dry THF was then added via a syringe and the mixture was stirred for 3.0 hrs at -78°C. Saturated NH₄CI aq. solution (20 ml) was added slowly and the mixture was diluted with ether. The solid was removed by filtration through a pad of Celite. The filtrate was extracted with ether (x3) and the extracts were washed with brine, dried over anhydrous Na₂SO₄. Concentration in vacuo gave 3.68 g (100%) of essentially pure vinyl

tertiary alcohol

as a pale yellow oil.

Ozone was bubbled into the solution of vinyl tertiary alcohol (3.68 g, 25.0 mmol) in 100 ml of dry MeOH for 35 min at -78°C. A blue color was developped and argon was then bubbled into the reaction mixture for 5 min to remove the excess ozone. NaBH₄ (2.36 g, 62.5 mmol) was added in small protions at -78°C and the mixture was stirred at -78°C for 15 min, 0°C for 1.0 hr and room temperature overnight. Concentration in vacuo and the crude product was purified by flash

chromatography (hexane-EtOAc: 2:1) on silica gel to give 2.48 g (68%) of diol

as a

colorless oil. The mixture of diol (350 mg, 2.39 mmol), isobutyric anhydride (0.437 ml, 2.63 mmol), 0.5 ml of triethylamine (3.59 mmol) and 29 mg of DMAP in 5 ml of CH₂Cl₂ was stirred overnight at room temperature. EtOAc was added and the mixture was washed with water, brine and dried over

anhydrous Na₂SO₄. Concentration in vacuo followed by flash chromatography (hexane-EtOAc: 9:1) on silica gel gave 489 mg (95%) of required title tertiary alcohol as a colorless oil.

To the mixture of Part A tertiary alcohol (602 mg, 2.79 mmol) in 1.0 ml of CH₂Cl₂ and 0.6 ml of dry pyridine cooled at 0°C was added a solution of para-nitrophenol chloroformate (842 mg, 4.18 mmol) in 1.5 ml of dry CH₂Cl₂. The mixture was stirred for 1.0 hr at 0°C and then overnight at room temperature. The mixture was diluted with 1.5 ml of CH₂Cl₂ and heated at 45°C for 4.0 hrs. After cooled to room temperature, the reaction mixture was partitioned between a 1:1 mixture of EtOAc and water (50 ml). The aqueous layer was extracted with EtOAc (2 x 50 ml). The combined organic extracts were washed with sat'd NaHCO₃ (x3) and brine, dried over anhydrous Na₂SO₄. Concentration in vacuo followed by flash chromatography (hexane- EtOAc: 15:1) on silica gel afforded 0.79 g of title para-nitrophenol carbonate (74%) as a colorless oil.

To the solution of Part B para-nitrophenol carbonate (381 mg, 1.0 mmol) in 2.0 ml of dry DMF cooled at 0°C was added i-Pr₂NEt (0.435 ml, 2.5 mmol), followed by 1-guanopyrazole HCl salt (147 mg, 1.0 mmol) in one portion. The mixture was stirred at room temperature overnight. The reaction mixture was poured into a mixture of EtOAc-water. The aqueous layer was extracted once with EtOAc. The combined organic extracts were washed with water, saturated NaHCO₃ and brine, dried over anhydrous Na₂SO₄. Concentration in vacuo followed by flash chromatography (hexane- EtOAc: 9:1) on silica gel afforded 337 g (96%) of title guanylpyrazole mono-carbamate as a colorless oil. D. 2-Methylpropanoic acid, 2-[[[[amino[4- [[[1-[N-(methylsulfonyl)-D-phenyl-alanyl]- L-prolyl]amino]methyl]-1-piperidinyl]- methyl]imino]carbonyl]oxy]-2-propylpentyl ester, trifluoroacetate

To a mixture of Part C mono-carbamate (315 mg, 0.894 mmol) and [4-[piperidinyl]-methyl]-1-[N- (methylsulfonyl)-D-phenylalanyl]-L-prolinamide (492 mg, 0.894 mmol) in 1.0 ml of dry CH₃CN was added DBU (0.334 ml, 2.24 mmol). The mixture was stirred overnight at room temperature. Concentration in vacuo followed by flash chromatography (CH₂Cl₂-

MeOH: 98:2 to 95:5) on silica gel afforded 447 mg of coupling product (69%) as a white foam. Further purification by prep. HPLC (MeOH-H₂O-0.1%TFA: 60- 100% over 20 min linear gradient) gave 494 mg (66%) of title compound as a white lyophilate. mp: 64-68°C. [α]_D = -49.0° (c0.82, MeOH).

Anal. Calcd. for C₃₅H₅₆N₆O₈S · 1.25TFA- 0.38 H₂O:

C, 51.77, H, 6.72, N, 9.66, S, 3.69, F, 8.26

Found: C, 51.77, H, 6.75, N, 9.37, S, 3.69,

F, 8.16.

Using the above procedure, the following compounds were prepared: Example 14

[S-(R*,R*)]-N-[[1-[Amino[[[2-(benzoyloxy)-1-methyl- propoxy]carbonyl]imino] methyl]-4-piperidinyl]- methyl]-1-[N-(methylsulfonyl)-D-phenylalanyl]-L- prolinamide, trifluoroacetate

mp: 105-107°C. [α]_D = -26.7° (c 0.17, MeOH).

Anal. Calcd. for C₃₄H₄₆N₆0₈S- 1.67 TFA·1.03H₂O:

C, 49.40, H, 5.52, N, 9.26, S, 3.53, F, 10.35

Found: C, 49.40, H, 5.24, N, 9.19, S, 3.65,

F, 10.35.

Example 15

[R-(R*,R*)]-2,2-Dimethylpropanoic acid, 2- [[[[Amino[4-[[[1-[(methylsulfonyl)-D-phenyl- alanyl]-L-prolyl]amino]methyl]-1-piperidinyl]- methyl]imino]carbonyl]oxy]-1-methylpropyl ester, trifluoroacetate

mp: 108-111°C. [α]_D = -51.6° (c 0.25, MeOH). Anal. Calcd. for C₃₂H₅₀N₆O₈S · 1.44 TFA·0.93H₂O:

C, 48.73, H, 6.25, N, 9.78, S, 3.73, F, 9.55

Found: C, 48.73, H, 6.10, N, 9.71, S, 3.99,

F, 9.49

Example 16

[S-(R*,R*)]-2,2-Dimethylpropanoic acid, 2- [[[[Amino[4-[[[1-[(methylsulfonyl)-D-phenylalanyl]- L-prolyl]amino]methyl]-1-piperidinyl]methyl]- imino]carbonyl]oxy]-1-methylpropyl ester,

trifluoroacetate

mp: 102-104°C. [α]_D = -41.4° (c 0.39, MeOH) .

Anal. Calcd. for C₃₂H₅₀N₆O₈S· 1.80 TFA·1.13H₂O:

C, 47.28, H, 6.02, N, 9.29, S, 3.54, F, 11.34

Found: C, 47.28, H, 5.84, N, 9.19, S, 3.75,

F, 11.29.

Example 17

[R-(R*,R*)]-3,3-Dimethylbutanoic acid, 2-

[[[[Amino[4-[[[1-[(methylsulfonyl)-D-phenylalanyl] L-prolyl]amino]methyl]-1-piperidinyl]methyl]- imino]carbonyl]oxy]-1-methylpropyl ester,

trifluoroacetate

mp: 108-110°C. [α]_D = -52.6° (c 0.15, MeOH) Anal. Calcd. for C3₃H₅₂N₆O₈S· 1.60 TFA·0.48H₂O:

C, 49.19, H, 6.22, N, 9.51, S, 3.63,

F, 10.32

Found: C, 49.19, H, 6.19, N, 9.48, S, 3.96,

F, 10.40.

Example 18

[S-(R*,R*)]-3,3-Dimethylbutanoic acid, 2- [[[[Amino[4-[[[1-[(methylsulfonyl)-D-phenylalanyl] L-prolyl]amino]methyl]-1-piperidinyl]methyl]- imino]carbonyl]oxy]-1-methylpropyl ester,

trifluoroacetate

mp: 103-106°C. [α]_D = -43.7° (c 0.19, MeOH) Anal. Calcd. for C₃₃H₅₂N₆O₈S · 1.67 TFA·0.74H₂O:

C, 48.68, H, 6.20, N, 9.37, S, 3.58,

F, 10.62

Found: C, 48.68, H, 6.11, N, 9.36, S, 3.66,

F, 10.79. Example 19

2,2-Dimethylpropanoic acid, 2-[[[[imino[4-[[[1-[N- (methylsulfonyl)-D-phenylalanyl]-L-prolyl]amino]- methyl]-1-piperidinyl]methyl]amino]carbonyl]oxy]-2- methyloropyl ester, trifluoroacetate

mp: 107-110°C. [α]_D = -52.0° (c 0.15, MeOH).

Anal. Calcd. for C₃₂H₅₀N₆O₈S· 1.65 TFA·1.00H₂O:

C, 47.91, H, 6.11, N, 9.50, S, 3.62, F, 10.63

Found: C, 47.91, H, 6.28, N, 9.38, S, 3.60,

F, 10.62.

Example 20

3,3-Dimethylbutanoic acid, 2-[[[[amino[4-[[[1-[N- (methylsulfonyl)-D-phenylalanyl]-L-prolyl]amino]- methyl]-1-piperidinyl]methyl]imino]carbonyl]oxy]-2- propylpentyl ester, trifluoroacetate

mp: 66-70°C. [α]_D = -44.6° (c1.26, MeOH).

Anal. Calcd. for C₃₇H₆₀N₆O₈S· 1.13TFA· 1.27H₂O: C, 52.35, H, 7.13, N, 9.33, S, 3.56,

F, 7.15

Found: C, 52.35, H, 7.18, N, 8.96, S, 3.34,

F, 7.16.

It will be appreciated that the Z

substructure in Examples 1 to 20 may be replaced by any of the other Z substructures Z(l) to Z(6) disclosed hereinbefore and may be prepared

employing procedures as set out hereinbefore.

Furthermore, compounds which include Het other than O and Het¹ other than a bond may be prepared employing procedures as set out hereinbefore.

Examples of other compounds of the

invention which may be prepared employing

procedures as outlined above are set out below.

Claims

What is Claimed is:

1. A compound having the structure

wherein Z is a substructure which when linked to the guanidino or amidino

forms a prodrug of a pharmaceutically active compound; with the proviso that Z is exclusive of boron containing moieties, and Ax and A'x may be the same or

different and are independently selected from H or alkyl and at least one of Ax and A'x will form a

Carbamyl group with a nitrogen of the guanidino or amidino group, with the proviso that Carbamyl is exclusive of a group of the structure

including all stereoisomers thereof, and

pharmaceutically acceptable salts thereof.

2. The compound as defined in Claim 1 wherein the Carbamyl group includes the following moiety attached to the nitrogen of the guanidino or amidino:

wherein R^I is H, alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, substituted alkyl or substituted aryl; and

Het is O, NH, N-lower alkyl or S;

Het¹ is a bond, O, NH, N-lower alkyl or S; Q^I is alkyl of at least 2 carbons in the chain, cycloalkyl, aryl, heterocycloalkyl, substituted alkyl, substituted aryl or heteroaryl.

3. The compound as defined in Claim 2 wherein Carbamyl includes the moiety

where Q^I is alkyl or cycloalkyl, and where R^IV is alkyl or aryl or heteroaryl.

4. The compound as defined in Claim 2 wherein Carbamyl includes the moiety

where R^IV is CH₃, t-butyl, C₆H₅ or pyridyl.

5. The compound as defined in Claim 2 wherein -N-Ax is a Carbamyl and A'x-N- is a Carbamyl which may be the same or different from -N-Ax, or wherein one of -N-Ax or A'x-N- is Carbamyl and the other is H.

6. The compound as defined in Claim 2 wherein R¹ is an alkyl group.

7. The compound as defined in Claim 1 having the name or formula

N-[[1-[[[[2-(acetyloxy)-1,1-dimethyl- ethoxy]carbonyl]amino]iminomethyl]-4- piperidinyl]methyl]-1-[N-(methylsulfonyl)-D- phenylalanyl]-L-prolinamide;

N-[[1-[amino[[[2-(benzoyloxy)-2-methyl- propoxy]carbonyl]imino]methyl]-4-piperidinyl]- methyl]-1-[N-(methylsulfonyl)-D-phenylalanyl]-L- prolinamide;

cis-N-[[1-[[amino[[[[2-(benzoyloxy)cyclohexyl]oxy]carbonyl]imino]methyl]-4-piperidinyl]- methyl]-1-[N-(methylsulfonyl)-D-phenylalanyl]-L- prolinamide;

(1R,2R)-N-[[1-[amino[[[2-(benzoyloxy)-1- methylpropoxy]carbonyl]imino]methyl]-4- piperidinyl]-methyl]-1-[N-(methylsulfonyl)-D- phenylalanyl]-L-prolinamide;

N-[[1-[amino[[[[2-(benzoyloxy)-1,1- dimethyl-ethoxy]carbonyl]amino]imino]methyl]-4- piperidinyl]-methyl]-1-[N-(methylsulfonyl)-D- phenylalanyl]-L-prolinamide;

2-methylpropanoic acid, 2-[[[[amino[4-[[[1- [N-(methylsulfonyl)-D-phenylalanyl]-L-prolyl]- amino]methyl]-1-piperidinyl]methyl]imino]- carbonyl]oxy]-2-methylpropylester;

N-[[1-[amino[[[2-methyl-2-(2-methyl-1-oxo- propoxy)propoxy]carbonyl]imino]methyl]-4-piperidinyl]methyl]-1-[N-(methylsulfonyl)-D-phenylalanyl]-L-prolinamide;

2,2-dimethylpropanoic acid, 2-[[[amino[4- [[1-[N-(methylsulfonyl)-D-phenylalanyl]-L- prolyl]amino]methyl]-1-piperidinyl]methyl]imino]- carbonyl]oxy]-1,1-dimethylethyl ester;

3-pyridinecarboxylic acid, 2-[[[amino[4- [[1-[N-(methylsulfonyl)-D-phenylalanyl]-L- prolyl]amino]methyl]-1-piperidinyl]methyl]imino]- carbonyl]oxy]-2-methylpropyl ester;

N-[[1-[[[[2-(acetyloxy)-1,1-dimethyl- ethoxy]carbonyl]amino][[[2-(acetyloxy)-1,1- dimethylethoxy]carbonyl]imino]methyl]-4- piperidinyl]methyl]-1-[N-(methylsulfonyl)-D- phenylalanyl]-L-prolinamide;

N-[[1-[[[[2-(acetyloxy)ethoxy]carbonyl]- amino][[[2-(acetyloxy)ethoxy]carbonyl]-imino]- methyl]-4-piperidinyl]methyl]-1-[N-methyl-N- (methylsulfonyl)-D-phenyl-alanyl]-N-methyl-L- prolinamide;

[S-(R*,R*)]-N-[[1-[amino[[[2-(benzoyloxy)- 1-methylpropoxy]carbonyl]imino]methyl]-4- piperidinyl]methyl]-1-[N-(methylsulfonyl)-D- phenylalanyl]-L-prolinamide; [R-(R*,R*)]-2,2-dimethylpropanoic acid, 2- [[[[amino[4-[[[1-[(methylsulfonyl)-D-phenylalanyl]- L-prolyl]amino]methyl]-1-piperidinyl]methyl]imino]- carbonyl]-oxy]-1-methylpropyl ester;

[S-(R*,R*)]-2,2-dimethylpropanoic acid, 2-

[[[[amino[4-[[[1-[(methylsulfonyl)-D-phenylalanyl]- L-prolyl]amino]methyl]-1-piperidinyl]methyl]imino]- carbonyl]oxy]-1-methylpropyl ester;

R-(R*,R*)]-3,3-dimethylbutanoic acid, 2- [[[[amino[4-[[[1-[(methylsulfonyl)-D-phenylalanyl]- L-prolyl]amino]methyl]-1-piperidinyl]methyl]imino]- carbonyl]oxy]-1-methylpropyl ester;

[S-(R*,R*)]-3,3-dimethylbutanoic acid, 2- [[[[amino[4-[[[1-[(methylsulfonyl)-D-phenylalanyl]- L-prolyl]amino]methyl]-1-piperidinyl]methyl]imino]- carbonyl]oxy]-1-methylpropyl ester;

2,2-dimethylpropanoic acid, 2-[[[[imino[4- [[[1-[N-(methylsulfonyl)-D-phenylalanyl]-L-prolyl]- amino]methyl]-1-piperidinyl]methyl]amino]carbonyl]- oxy]-2-methylpropyl ester;

N-[[1-[[[[1,1-dimethyl-2-(2-methyl-1- oxopropoxy)ethoxy]carbonyl]amino][[[1,l-dimethyl-2- (2-methyl-1-oxopropoxy)ethoxy]carbonyl] imino]- methyl]-4-piperidinyl]methyl]-1-[N-(methyl- sulfonyl)-D-phenylalanyl]-L-prolinamide;

2-methylpropanoic acid, 2-[[[[amino[4-[[[1- [N-(methylsulfonyl)-D-phenylalanyl]-L-prolyl]- amino]methyl]-1-piperidinyl]methyl]imino]- carbonyl]oxy]-2-propylpentyl ester;

3,3-dimethylbutanoic acid, 2-[[[[amino[4- [[[1-[N-(methylsulfonyl)-D-phenylalanyl]-L- prolyl]amino]methyl]-1-piperidinyl]methyl]imino]- carbonyl]oxy]-2-propylpentyl ester;

or the trifluoroacetate thereof or other pharmaceutically acceptable salt of any of the above compounds.

8. The compound as defined in Claim 1 wherein Z when linked to

has activity as a thrombin inhibitor, a platelet aggregation inhibitor, a fibrinogen receptor antagonist, a GPIIb/IIIa receptor blocker, an antihypertensive, an antidepressant, an antibiotic, a viricide, an immunostimulant, an anti-inflammatory agent, a peptide hydrolase inhibitor, a Factor Xa inhibitor, an antianaphylatic or an antiulcer agent.

9. The compound as defined in Claim 1 wherein Z when linked to

is a thrombin inhibitor.

10. A prodrug of a guanidine,

thioguanidine or amidine-containing

pharmaceutically active compound, the prodrug moiety being linked to the guanidine, thioguanidine or amidine portion of the pharmaceutically active compound as shown in the formula

with the proviso that the pharmaceutically active compound is exclusive of boron containing moieties, and Ax and Ax may be the same or different and are independently selected from H or alkyl, where at least one of Ax and Ax forms a Carbamyl group with a nitrogen of the guanidino or amidino group, with the proviso that Carbamyl is exclusive of a group which is

including all stereoisomers thereof , and pharmaceutically acceptable salts thereof .

11. The compound as defined in Claim 10 wherein Carbamyl includes the moiety

wherein R^I is H, alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, substituted alkyl or substituted aryl;

Het is 0, NH, N-lower alkyl or S;

Het¹ is a bond, O, NH, N-loweralkyl or S; and

Q^I is alkyl of at least 2 carbons in the chain, cycloalkyl, aryl, heterocycloalkyl,

substituted alkyl, substituted aryl or heteroaryl.

12. A compound having the structure z

wherein Ax and A'x may be the same or different and are independently selected from H or alkyl, with at least one of Ax and A'x forming a Carbamyl with the nitrogen of the guanidino or amidino group; with the proviso that Carbamyl is exclusive of a group which is

including all stereoisomers thereof, and

pharmaceutically acceptable salts thereof, and wherein Z is

including all stereoisomers, wherein n is 0, 1 or 2;

G is an amido moiety which optionally includes a cyclic member;

R is hydrogen, hydroxyalkyl, aminoalkyl, alkyl, cycloalkyl, cycloalkylalkyl, aryl,

arylalkyl, alkenyl, alkynyl, amidoalkyl,

arylalkoxyalkyl or an amino acid side chain, either protected or unprotected;

R¹ and R² are independently hydrogen, lower alkyl, cycloalkyl, aryl, hydroxy, alkoxy, oxo, thioxo, thioketal, thioalkyl, thioaryl, amino or alkylamino; or R¹ and R² together with the carbons to which they are attached form a cycloalkyl, aryl or heteroaryl ring;

R³ is alkyl, arylalkyl, aryl, heteroaryl, quinolinyl, tetrahydroquinolinyl, 10-camphoryl or pentamethylchromanyl, pentaalkylphenyl, pentahalophenyl, trialkylphenyl, 3-carboxyphenyl, 3- trifluoromethylphenyl or 4-carboxyphenyl;

wherein G is

m is 0, 1, 2 or 3;

Y is NH or S;

p is 0, 1 or 2;

Q is a single bond or

Y₁ is a bond or -NH-;

A is aryl or cycloalkyl, or an

azacycloalkyl ring A of 4 to 8 ring members, or an azacycloalkenyl ring A of 5 to 9 ring members, or an azaheterocyclo-alkyl ring A of 6 to 8 ring members ,

where X is CH₂, -CH=CH- , O, S or NH; q is 0, 1, 2, 3 or 4 if X is CH₂ or CH=CH; q is 2, 3 or 4 if X is O, S or NH;

Y¹ and Y² are independently H, lower alkyl, oxo or halo;

if A is an azacycloalkyl, azacycloalkenyl, or azaheterocycloalkyl ring A, then Y₁ is a bond and the carbamylamidme group

is attached to the nitrogen atom in the ring as indicated below

including pharmaceutically acceptable salts thereof; or

wherein Z is

including all stereoisomers, wherein n is 0, 1 or 2;

Xa is S, SO, SO₂ or O;

R'_a is -A¹-, or A¹-NH-, where A¹ is an alkyl, alkenyl, or alkynyl chain; with the proviso that there is at least one carbon between any S or 0 and an alkenyl or alkynyl moiety; or

R'_a is -(CH₂)_p-A²- where A² is an

where X is CH₂ , -CH=CH- , O , S or NH ; p is 0 , 1 or

2; and provided that the

group is attached to the nitrogen atom in the ring as indicated below

q is 0, 1, 2, 3 or 4 if X is CH₂ or CH=CH; q is 2, 3 or 4 if X is 0, S or NH;

Y¹ and Y² are independently H, lower alkyl, oxo or halo;

provided that where X is a hetero atom, that is, A² is azaheteroalkyl, then there must be at least a 2-carbon chain between X and any heteroatom in the ring A or outside ring A; or

R'_a is -(CH₂)_p-A³-NH- or -(CH₂)_p-A³-, wherein A³ is aryl or cycloalkyl;

arylalkyl, alkenyl, alkynyl, amidoalkyl,

arylalkoxyalkyl or an amino acid side chain, either protected or unprotected;

R¹ and R² are independently hydrogen, lower alkyl, cycloalkyl, aryl, hydroxy, alkoxy, oxo, thioxo, thioketal, thioalkyl, thioaryl, amino or alkylamino; or R¹ and R² together with the carbons to which they are attached form a cycloalkyl, aryl, or heteroaryl ring;

R⁶' is hydrogen,

-SO₂R³ or -CO₂R⁷ wherein R⁷ is lower alkyl, aryl, arylalkyl,

cycloheteroalkyl or heteroaryl; and

R³ is alkyl, arylalkyl, aryl, heteroaryl, quinolinyl, tetrahydroquinolinyl, 10-camphoryl, pentamethylchromanyl, pentaalkylphenyl, pentahalophenyl, trialkylphenyl, 3-carboxyphenyl, 3- trifluoromethylphenyl or 4-carboxyphenyl;

including pharmaceutically acceptable salts thereof; or

wherein Z is

including all stereoisomers, wherein n is 0, 1 or

2;

R'_b is -A¹-, -CO-A¹- or -SO₂-A¹-, -A¹-NH- , -CO-A¹-NH- or -SO₂A¹-NH, wherein A¹ is an alkyl, alkenyl or alkynyl chain; with the proviso that there is at least one carbon between any NH, S or O, and an alkenyl or alkynyl moiety; or

R'_b is -(CH₂)_p-A²-, -(CH₂)_p-CO-A²- or - (CH₂)_p-SO₂-A²- where p is 0, 1 or 2; and

A² is an azacycloalkyl ring A of 4 to 8 ring members, or an azacycloalkenyl ring A of 5 to 9 ring members, or an azaheterocycloalkyl ring A of 6 to 8 ring members,

where X is CH₂, -CH=CH-, O, S or NH; and the

group is attached to the nitrogen atom in the ring as indicated below

q is 0, 1, 2, 3 or 4 if X is CH₂ or -CH=CH-; q is 2, 3 or 4 if X is O, S or NH;

Y¹ and Y² are independently H, lower alkyl, oxo or halo;

provided that where X is a hetero atom, that is, A is azaheteroalkyl, then there must be at least a 2-carbon chain between X and any N atom in the ring A or outside ring A.

R'_b is -(CH₂)_p-A³-, -(CH₂)_p-CO-A³-, or

-(CH₂)_p-SO₂-A³-, -(CH₂)_p-A³-NH-, - (CH₂)_p-CO-A³-NH- or - (CH₂)_p-SO₂-A³-NH, wherein A³ is aryl or

cycloalkyl;

R is hydrogen, hydroxyalkyl, aminoalkyl,

alkyl, cycloalkyl, cycloalkylalkyl, aryl,

arylalkyl, alkenyl, alkynyl, amidoalkyl,

arylalkoxyalkyl or an amino acid side chain, either protected or unprotected;

R¹ and R² are independently hydrogen, lower alkyl, cycloalkyl, aryl, hydroxy, alkoxy, oxo,

thioxo, thioketal, thioalkyl, thioaryl, amino or alkylamino; or R¹ and R² together with the carbons to which they are attached form a cycloalkyl, aryl, or heteroaryl ring;

R⁶ is hydrogen,

-SO₂R³ or -CO₂R⁷, wherein R⁷ is lower alkyl, aryl, arylalkyl,

cycloheteroalkyl or heteroaryl; and

including pharmaceutically acceptable salts thereof; or

where Z is

including all stereoisomers, wherein n is 0, 1 or

2;

R⁸ is H, or -CO₂R⁷ wherein R⁷ is

lower alkyl, aryl, arylalkyl, cycloheteroalkyl or heteroaryl;

arylalkyl, alkenyl, alkynyl, amidoalkyl,

arylalkoxyalkyl or an amino acid side chain, either protected or unprotected; R¹ and R² are independently hydrogen, lower alkyl, cycloalkyl, aryl, hydroxy, alkoxy, oxo, thioxo, thioketal, thioalkyl, thioaryl, amino or alkylamino; or R¹ and R² together with the carbons to which they are attached form a cycloalkyl, aryl, or heteroaryl ring;

p is 0, 1 or 2;

Q is a single bond or C=O;

Y₁ is a bond or -NH-;

A is aryl or cycloalkyl, or an

azacycloalkyl ring A of 4 to 8 ring members, or an azacycloalkenyl ring A of 5 to 9 ring members, or an azaheterocycloalkyl ring A of 6 to 8 ring members,

wherein X is CH₂, -CH=CH-, O, S or NH;

if A is an azacycloalkyl, azacycloalkenyl, or azaheterocycloalkyl ring A, then Y₁ is a bond and the carbamylamidine group is

attached to the nitrogen atom in the ring as indicated below

Y¹ and Y² are independently H, lower alkyl, oxo or halo; provided that where X is a hetero atom, that is, A is azaheterocycloalkyl, then there must be at least a 2-carbon chain between X and any N atom in the ring A or outside ring A; or

wherein Z is

including all stereoisomers thereof wherein m' is

2, 3, 4 or 5; n is 0, 1 or 2; p is 0, 1 or 2;

R^x is cycloalkyl, heteroaryl, CO₂H, CONR^sR^t (where R^s and R^t are independently selected from H, alkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl), or aryl optionally substituted with

NO₂, OH, alkoxy, acyloxy,

halogen, alkyl, aryl, CO₂alkyl, CONHalkyl, alkylthio, arylthio, NHalkyl or NHcycloalkyl;

R^y is an amino acid sidechain;

R^z is H, alkyl, cycloalkyl, aryl,

cyclohetero-alkyl or heteroaryl;

R^v is H, alkyl, CO₂R^u or CONR^sR^t;

wherein R^u is H or alkyl;

including pharmaceutically acceptable salts thereof; or

wherein Z is

including all stereoisomers, wherein n is 0, 1 or 2; Z_q is NR¹¹ or 0, where R¹¹ is H, lower alkyl, aryl or arylalkyl;

G is an amido moiety which is

R is hydrogen, hydroxyalkyl, hydroxyalkyl- (alkyl), aminoalkyl, lower alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, alkenyl, alkynyl, amidoalkyl, arylalkoxyalkyl or an amino acid side chain, either protected or unprotected;

R⁹ is lower alkyl, cycloalkyl, aryl, or arylalkyl; or R⁹ and R² together with the carbons to which they are attached form a cycloalkyl, aryl or heteroaryl ring;

R² and R¹ are independently hydrogen, lower alkyl, cycloalkyl, aryl, arylalkyl, hydroxy, alkoxy, oxo, thioketal, thioalkyl, thioaryl, amino or alkylamino; or R² and R¹ together with the carbons to which they are attached form a

cycloalkyl, aryl or heteroaryl ring;

R¹⁰ is H, lower alkyl, arylalkyl, aryl,

o

or -CO₂R^7', where R^{7 '} is lower alkyl, aryl,

arylalkyl, cycloheteroalkyl, heteroaryl, quinolinyl or tetrahydroquinolinyl; and

n is 0, 1 or 2;

m is 0, 1, 2 or 3;

p is 0, 1 or 2;

Q is a single bond or

Y is NH or S;

Y₁ is a bond or -NH-;

A is aryl or cycloalkyl, or an

azacycloalkyl ring A of 4 to 8 ring members, or an azacycloalkenyl ring A of 4 to 8 ring members, or an azaheterocyclo-alkyl ring A of 6 to 8 ring members,

where X is CH₂ , -CH=CH- , O , S or NH;

if A is an azacycloalkyl, azacycloalkenyl or azaheterocycloalkyl ring A, then Yi is a bond and the carbamylamidine group

is attached to the nitrogen atom in the ring as indicated below

q is 0, 1, 2, 3 or 4 if X is CH₂ or -CH=CH-; q is 2, 3 or 4 if X is O, S or NH; Y¹ and Y² are independently H, lower alkyl, oxo or halo; provided that where X is a hetero atom, that is, A is azaheteroalkyl, then there must be at least a 2-carbon chain between X and any N atom in the ring A or outside ring A; and R¹⁰ is hydrogen,

or -CO₂R⁷, wherein

R⁷ is lower alkyl, aryl, arylalkyl or

cycloheteroalkyl; including pharmaceutically acceptable salts thereof.

13. A compound having the structure

including all stereoisomers, wherein n is 0, 1 or 2;

G is an amido moiety which optionally includes a cyclic member;

arylalkyl, alkenyl, alkynyl, amidoalkyl,

arylalkoxyalkyl or an amino acid side chain, either protected or unprotected;

R³ is alkyl, arylalkyl, aryl, heteroaryl, quinolinyl, tetrahydroquinolinyl; 10-camphoryl, pentamethylchromanyl, pentaalkylphenyl, pentahalo- phenyl, trialkylphenyl, 3-carboxyphenyl, 3- trifluoromethylphenyl or 4-carboxyphenyl; and Ax and Ax may be the same or different and are independently selected from H or alkyl, with at least one of Ax and Ax forming a Carbamyl with a nitrogen of the guanidino or amidino group, and with the proviso that Carbamyl is exclusive of a group which is

including all stereoisomers thereof and pharmaceutically acceptable salts thereof .

14 . The compound as defined in Claim 13 wherein G is

wherein p is 0, 1 or 2;

Q is a single bond or

Y₁ is a bond or -NH-;

A is aryl or cycloalkyl, or an

azacycloalkyl ring A of 4 to 8 ring members, or an azacycloalkenyl ring A of 5 to 9 ring members, or an azaheterocyclo-alkyl ring A of 6 to 8 ring members, of the structure

where X is CH₂, -CH=CH-, O, S or NH;

if A is an azacycloalkyl, azacycloalkenyl or azaheterocycloalkyl ring, then Yi is a bond and the

is attached to the nitrogen atom in the ring;

q is 0, 1, 2, 3 or 4, provided that q is 0, 1, 2, 3 or 4 if X is CH₂ or -CH=CH-; q is 2, 3 or 4 if X is 0, S or NH;

Y¹ and Y² are independently H, lower alkyl, oxo or halo; with the proviso that where A is azaheteroalkyl, then there must be at least a 2- carbon chain between X and any N atom in the ring or outside the ring.

15. The compound as defined in Claim 14 wherein G is

q is 1 or 2, p is 1 or 2,

R¹ and R² are each H, R³ is alkyl, arylalkyl or aryl, n is 0 or 1 and R is arylalkyl or

hydroxyalkyl.

16. The compound as defined in Claim 14 having the structure

17. The compound as defined in Claim 14 where one of Ax or ^to is a Carbamyl and the other is H or the same or different Carbamyl.

18. A method of inhibiting or preventing formation of blood clots, which comprises

administering to a patient in need of treatment a therapeutically effective amount of a compound as defined in Claim 1.

19. A pharmaceutical composition

comprising a compound as defined in Claim 1 and a pharmaceutically acceptable carrier therefor.

20. The compound as defined in Claim 12 having the structure

including all stereoisomers, wherein n is 0, 1 or

2;

Xa is S, SO, SO₂ or O;

R'_a is -A¹- or -A¹-NH-, where A¹ is an alkyl, alkenyl, or alkynyl chain; with the proviso that there is at least one carbon between any S or O and an alkenyl or alkynyl moiety; or

R'_a is -(CH₂)_p-A²- where A² is an

where X is CH₂, -CH=CH-, O, S, NH; and provided that

group is attached to the nitrogen atom in the ring as indicated below

Y¹ and Y² are independently H, lower alkyl, oxo or halo;

provided that where X is a hetero atom, that is, A² is azaheterocycloalkyl, then there must be at least a 2-carbon chain between X and any heteroatom in the ring A or outside ring A; or

R'_a is -(CH₂)_P-A³- or - (CH₂)_p-A³-NH- , where

A³ is aryl or cycloalkyl;

R¹ and R² are independently hydrogen, lower alkyl, cycloalkyl, aryl, hydroxy, alkoxy, keto, thioketal, thioalkyl, thioaryl, amino or

alkylamino, or R¹ and R² together with the carbons to which they are attached form a cycloalkyl, aryl or heteroaryl ring;

arylalkyl, alkenyl, alkynyl, amidoalkyl,

arylalkoxyalkyl or an amino acid side chain, either protected or unprotected;

R⁶ is hydrogen,

-SO₂R³ or -CO₂R⁷ wherein R⁷ is lower alkyl, aryl, arylalkyl, cycloheteroalkyl or heteroaryl; and

including pharmaceutically acceptable salts thereof.

21. The compound as defined in Claim 12 having the structure

including all stereoisomers, wherein n is 0, 1 or 2;

R'_b is -A¹-, -CO-A¹-, -SO₂-A¹-, -A¹-NH-, -CO-

A¹-NH-, or -SO₂A¹-NH-; wherein A¹ is an alkyl, alkenyl or alkynyl chain; with the proviso that there is at least one carbon between any NH, S or O, and an alkenyl or alkynyl moiety; or

R'_b is -(CH₂)_p-A²-, -(CH₂)_p-CO-A²- or

- (CH₂)_p-SO₂-A²- where p is 0, 1 or 2, and

where X is CH₂, -CH=CH-, O, S or NH; and the

group is attached to the nitrogen atom in the ring as indicated below

Y¹ and Y² are independently H, lower alkyl, oxo or halo;

provided that where X is a hetero atom, that is, A is azaheteroalkyl, then there must be at least a 2-carbon chain between X and any N atom in the ring A or outside ring A; or

R'_b is -(CH₂)_p-A³-, -(CH₂)_p-CO-A³-, or

-(CH₂)_p-SO₂-A³-, -(CH₂)_p-A³-NH-, - (CH₂)_p-CO-A³-NH, - (CH₂)_p-SO₂-A³-NH; wherein A³ is aryl or

cycloalkyl;

alkylamino; or R¹ and R² together with the carbons to which they are attached form a cycloalkyl, aryl or heteroaryl ring;

arylalkyl, alkenyl, alkynyl, amidoalkyl,

arylalkoxyalkyl or an amino acid side chain, either protected or unprotected; and R⁶ is hydrogen,

-SO₂R³ or -CO₂R⁷ , wherein R⁷ is lower alkyl, aryl, arylalkyl, cycloheteroalkyl or heteroaryl; and

R³ is alkyl, arylalkyl, aryl, heteroaryl, quinolinyl, tetrahydroquinolinyl, 10-camphoryl, pentamethylchromanyl, pentaalkylphenyl, pentahalophenyl, trialkylphenyl, 3-carboxyphenyl, 3- trifluoromethylphenyl or 4-carboxyphenyl; including pharmaceutically acceptable salts thereof.

22. The compound as defined in Claim 21 having the structure