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WO1997033576A1 - Bioprecurseurs de carbamyl guanidine et d'amidine - Google Patents

Bioprecurseurs de carbamyl guanidine et d'amidine Download PDF

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Publication number
WO1997033576A1
WO1997033576A1 PCT/US1997/003640 US9703640W WO9733576A1 WO 1997033576 A1 WO1997033576 A1 WO 1997033576A1 US 9703640 W US9703640 W US 9703640W WO 9733576 A1 WO9733576 A1 WO 9733576A1
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WIPO (PCT)
Prior art keywords
ring
aryl
alkyl
methyl
amino
Prior art date
Application number
PCT/US1997/003640
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English (en)
Inventor
Ping Chen
S. David Kimball
Original Assignee
Bristol-Myers Squibb Company
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Priority to AU19901/97A priority Critical patent/AU1990197A/en
Publication of WO1997033576A1 publication Critical patent/WO1997033576A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • 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.
  • 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;
  • R 1 is H, alkyl, cycloalkyl, heterocycloalkyl, hetero-aryl, aryl, substituted alkyl or substituted aryl;
  • R 1 ' 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.
  • Z thrombin inhibitor substructure examples include substructures Z(l) to Z(6) as set out below:
  • G is an amido moiety which is
  • Substituted carbamyl groups represented by alkanoyl-, aroyl- or arylalkanoyl-oxyalkoxycarbonyl (AOAC) groups, wherein a single carbon atom
  • the oxyalkoxy moiety is a diacylated acetal or ketal
  • 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
  • Z is a substructure which when linked to the guanidino or amidino moiety
  • a fibrinogen receptor antagonist 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
  • Z is preferably a thrombin inhibitor substructure containing residues binding at the distal and proximal sites (which sites are
  • 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;
  • Cambamyl as employed in formula I more preferably includes a moiety of the
  • 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,
  • Het is O, NH, N-lower alkyl or S;
  • Het 1 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, NH 2 , SH, OR II , NHR II , NR II R III , SR II , SSR II , CHO, COR II , alkyl, arylalkyl,
  • 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, NH 2 , SH, OR II , NHR II , NR II R 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,
  • heterocyclyl may include 1 to 3 rings and may be heteroaryl or cycloheteroalkyl.
  • Het is oxygen
  • the preferred Carbamyl moiety will be where Het is 0, Het 1 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.
  • Q I is alkyl or cycloalkyl
  • R IV is alkyl, aryl or heteroaryl. More preferred are compounds where Carbamyl includes the moiety
  • R II and R III are lower alkyl such as CH 3 or n-propyl, where R IV is alkyl such as CH 3 or t- butyl, aryl such as phenyl, or heteroaryl such as pyridyl.
  • 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 Het 1 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.
  • 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
  • R is hydrogen, hydroxyalkyl, aminoalkyl, airtidoalkyl, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkenyl, alkynyl, arylalkoxyalkyl, or an amino acid side chain, either protected or unprotected;
  • R 1 and R 2 are independently hydrogen, lower alkyl, cycloalkyl, aryl, hydroxy, alkoxy, oxo, thioxo, thioketal, thioalkyl, thioaryl, amino or alkylamino; or R 1 and R 2 together with the carbons to which they are attached form a cycloalkyl, aryl, or heteroaryl ring; and R 3 is alkyl, aryl, arylalkyl, heteroaryl, quinolinyl, tetrahydroquinolinyl, 10-camphoryl, pentamethyIchromanyl, pentaalkylphenyl, pentahalophenyl, trialkylphenyl, 3-carboxyphenyl,
  • n 0, 1 or 2;
  • n 0, 1, 2 or 3 ;
  • Y is NH or S
  • p 0, 1 or 2 ;
  • 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 is an azacycloalkyl, azacycloalkenyl, or azaheterocycloalkyl ring A
  • Y 1 is a bond and the acylamidine group is attached to the nitrogen atom in the ring as indicated below
  • Y 1 and Y 2 are independently H, lower alkyl, oxo or halo;
  • X is a hetero atom (that is, A is azaheterocycloalkyl)
  • A is azaheterocycloalkyl
  • a ring (azacycloalkyl, azacycloalkenyl or azaheterocycloalkyl) which may be employed herein include
  • R 3 is lower alkyl or arylalkyl
  • R is arylalkyl or hydroxyalkyl
  • R 1 and R 2 are each H;
  • n 0 or 1
  • Ax or A'x is
  • Q 1 is alkyl or cycloalkyl
  • Het is O, Het 1 is a bond, and R 1 is alkyl or arylalkyl, and the other is H.
  • heterocyclic thrombin inhibitors of the invention has the structure IxA
  • R is arylalkyl (preferably benzyl), aryl (preferably phenyl), substituted alkyl (preferably cyclohexylmethyl) or arylalkoxyalkyl (preferably benzyloxymethyl) and R 3 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.
  • n 0, 1 or 2;
  • Xa is S, SO, SO 2 or O
  • R a is -A 1 -R 3a , where A 1 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 A 1 radicals having from 2 to 6 carbon atoms, and R 3a is
  • R a is - (CH 2 ) P -A 2 -R 2 ' where A 2 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,
  • a 3 is aryl or cycloalkyl
  • R, R 1 and R 2 are as defined hereinbefore;
  • R 6' is hydrogen, -SO 2 R 3 or -CO 2 R 7 (wherein R 7 is lower alkyl, aryl, arylalkyl, cycloheteroalkyl or heteroaryl; and R 3 is alkyl, arylalkyl, aryl, heteroaryl, quinolinyl,
  • Ax or A'x is
  • Q I is alkyl or cycloalkyl
  • Het is 0, Het 1 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
  • R 1 and R 2 are each H
  • R is H or -CH 2 OH
  • Xa is S
  • R 6' is
  • 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
  • n 0, 1 or 2;
  • R b is -A 1 -R 3a , -CO-A 1 -R 3a or -SO 2 -A 1 -R 3a ;
  • a 1 is an alkyl, alkenyl or alkynyl chain, each of the A 1 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 -(CH 2 ) P -A 2 -R 2 ' or - (CH 2 ) p -CO-A 2 -R 2 ' or (CH 2 ) p -SO 2 -A 2 -R 2 ' where p is 0, 1 or 2, R 2 ' is and A 2 is an azacycloalkyl ring A of 4 to 8 ring members, or an azacycloalkenyl ring
  • Y 1 , Y 2 are independently H, lower alkyl, oxo or hale;
  • R b is -(CH 2 ) P -A 3 -R 4 , - (CH 2 ) p -CO-A 3 -R 4 , or
  • R 4 is N X
  • a 3 is aryl or cycloalkyl, and p is as defined above;
  • R, R 1 and R 2 are as defined hereinbefore;
  • R 6 is hydrogen, -SO 2 R 3 or -CO 2 R 7
  • R 7 is lower alkyl, aryl, arylalkyl, cycloheteroalkyl or heteroaryl; and R 3 is alkyl, arylalkyl, aryl, heteroaryl, quinolinyl,
  • R b is A 3 is phenyl and compounds of formula Iq wherein R b is
  • p is 0 or 1
  • a 2 is azacycloalkyl or
  • R 1 and R 2 are each H, R is hydroxymethyl, -CH 2 COOalkyl, or benzyl and R 6 is
  • Ax or A'x is
  • Q I is alkyl or cycloalkyl
  • Het is 0, Het 1 is a bond, and R I is alkyl or arylalkyl, and the other is H.
  • R 1 and R 2 are each H, R is hydroxymethyl,
  • 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
  • n 0, 1 or 2;
  • A is aryl or cycloalkyl (in which case R 4 is either of the acylguanidine or acylamidine group set out above), or an azacycloalkyl ring A of 4 to
  • R 4 is the acylamidine group which is attached to the nitrogen atom in the ring as indicated below
  • Y 1 and Y 2 are independently H, lower alkyl, oxo or halo;
  • R, R 1 and R 2 are as defined hereinbefore;
  • R 8 is hydrogen, or -CO 2 R 7 (wherein R 7
  • R 4 includes guanidine or amidine
  • R 4 includes amidine.
  • n 0 or 1
  • R 8 is H; R is aralkyl or hydroxyalkyl, R 1 and R 2 are each H, p is 0 or 1,
  • Q is a single bond
  • A is an azacycloalkyl ring
  • R 4 includes amidine ;
  • Ax or A'x is
  • Q I is alkyl or cycloalkyl
  • Het is 0, Het 1 is a bond, and R I is alkyl or arylalkyl, and the other is H.
  • R is arylalkyl such as benzyl
  • 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
  • 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, CO 2 H, CONR s R t
  • R s and R t are independently selected from H, alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl), or aryl optionally substituted with NO 2 , OH, alkoxy, acyloxy, - halogen, alkyl, aryl, CO 2 alkyl, CONHalkyl, alkylthio, arylthio,
  • R y is an amino acid sidechain (either protected or unprotected);
  • R z is H, alkyl, aryl, cycloalkyl,
  • R v is H, alkyl, CO 2 R u or CONR s R t ;
  • R u is H or alkyl
  • 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.
  • Ax or A'x is
  • Q I is alkyl or cycloalkyl
  • Het is O, Het 1 is a bond, and R I is alkyl or arylalkyl, and the other is H.
  • R x is p-NO 2 C 6 H 5 , -o-FC 6 H 5 , or C 6 H 5 ;
  • R z is C 6 H 5 , or
  • R v is HOCH 2 - 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
  • R, R 1 and R 2 are as defined hereinbefore;
  • R 9 is lower alkyl, cycloalkyl, aryl, or arylalkyl; or R 9 and R 2 together with the carbons to which they are attached form a cycloalkyl, aryl or heteroaryl ring;
  • R 10 is hydrogen, lower alkyl, aryl, arylalkyl,
  • R 7' is lower alkyl, aryl, arylalkyl, cycloheteroalkyl, heteroaryl, quinolinyl or tetrahydroquinolinyl; and R 3 is alkyl,
  • arylalkyl aryl, heteroaryl, quinolinyl
  • n 0, 1 or 2;
  • n 0, 1, 2 or 3;
  • Z q is NR 11 or 0 (where R 11 is H, lower alkyl, aryl or arylalkyl);
  • Y is NH or S
  • p 0, 1 or 2;
  • Q is a s ingle bond
  • Y 1 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,
  • A is an azacycloalkyl, azacycloalkenyl, or azaheterocycloalkyl ring A
  • Y 1 is a bond and the acylamidine group is a ttached to the nitrogen atom in the ring as indicated below
  • Y 1 and Y 2 are independently H, lower alkyl, oxo or halo;
  • X is a hetero atom (that is, A is azaheteroalkyl)
  • R is H, p is 1, Q is a single bond, A is an azacycloalkyl ring ; Y 1 is a bond;
  • R 9 is arylalkyl such as benzyl, or alkyl
  • R 2 and R 1 are independently H and/or alkyl
  • R 10 is benzyloxycarbonyl, alkylsulfonyl, such as methylsulfonyl, or alkyl such as ethyl;
  • n 0 or 1
  • Ax or A'x is
  • Q I is alkyl or cycloalkyl
  • Het is 0, Het 1 is a bond, and R I' is alkyl or arylalkyl, and the other is H.
  • R 10 is benzyloxycarbonyl, or alkylsulfonyl such as methyl sulfonyl
  • Z q is NH
  • R is H
  • R 9 is arylalkyl such as benzyl
  • R 2 and R 1 are independently H and/or alkyl
  • m is 2 and Y is NH;
  • Ax or A'x is
  • Q I is alkyl or cycloalkyl
  • Het is 0, Het 1 is a bond, and R I is alkyl or arylalkyl, and the other is H.
  • Z thrombin inhibitor substructure examples include substructures Z(1) to Z(6) as set out below:
  • 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
  • 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.
  • any of the A, A 1 or A 3 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
  • 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:
  • 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;
  • RO44-9883 (LAMIFIBAN) as disclosed in published European Patent Application 92/505868 and U.S. Patent No. 5,378,712;
  • 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
  • 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);
  • deoxyspergualin as disclosed in U.S. Patent Nos. 4,518,532, 4,658,058 and 4,983,328; and arginine.
  • guanidine prodrugs as employed in conjunction with the Reaction Schemes I and II encompasses guanidine prodrugs and thioguanidine prodrugs.
  • 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.
  • ZH is an amino-containing thrombin inhibitor substructure
  • 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.
  • a base such as sodium hydride, potassium hydride, lithium hydride, lithium hexamethyl
  • 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.
  • a base such as 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU)
  • DBU 1,8-diazabicyclo [5.4.0]undec-7-ene
  • 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
  • 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.
  • a base such as sodium hydride in THF, potassium hydride, lithium-hexamethyldisilazide (LHMDS) or potassium t-butoxide
  • 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.
  • a base such as DBU (1,8-diazabicyclo[5.4.0]undec-7-ene
  • 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
  • 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.
  • PG protecting group
  • 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.
  • 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.
  • a base such as diisopropylethylamine or N,N-dimethylamino- pyridine
  • a chloroformate such
  • N, N' -biscarbamyl amidine or guanidine- containing prodrugs lb can be prepared by
  • 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,
  • 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.
  • 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
  • prodrug (s) refers to a class of drugs the pharmacologic action of which results from conversion by processes within the body (biotransformation).
  • 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 CF 3 or CF 3 CH 2 ) and/or 1 or 2 of the following
  • substituents an aryl substituent (for example, to form benzyl or phenethyl), a heteroaryl
  • alkylcycloalkyl substituent an alkenyl
  • 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
  • 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.
  • R 3 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.
  • aralkyl refers to lower alkyl groups as discussed above having an aryl substituent, such as benzyl.
  • lower alkoxy includes any of the above lower alkyl, alkyl or aralkyl groups linked to an oxygen atom.
  • 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.
  • 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 -(CH 2 ) 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.
  • 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.
  • 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
  • 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 CF 3 ), lower alkyl, lower alkoxy, carboxy, amino, lower alkylamino and/or dilower alkylamino.
  • heterocycloalkyl 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
  • azacycloalkenyl refers to a 4- to 8-membered ring which includes a double bond, such as
  • 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,
  • prodrug compounds of formula I of the invention will have the same utility as the Z substructure employed therein linked to
  • 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).
  • the compounds of the present invention may be serine protease inhibitors, and in particular may inhibit thrombin, Factor Xa, and/or trypsin.
  • compounds of the present invention are useful for the treatment or prophylaxis of those processes which involve the production and/or action of thrombin.
  • DIC disseminated intravascular coagulopathy
  • Kasabach-Merritt syndrome pulmonary embolism
  • myocardial infarction stroke
  • thromboembolic complications of surgery such as hip replacement and endarterectomy
  • thrombin has been shown to activate a large number of cells (such as
  • 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
  • the compounds of the invention 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.
  • 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
  • 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
  • streptokinse (natural or recombinant), streptokinse, urokinase, prourokinase, anisolated streptokinase plasminogen activator complex (ASPAC), animal salivary gland plasminogen activators, and the like.
  • ASPAC anisolated streptokinase plasminogen activator complex
  • thrombin inhibitors as thrombin inhibitors, platelet aggregation inhibitors or fibrinogen receptor antagonists may act in a synergistic fashion to prevent reocclusion
  • thrombolytic agents 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.
  • the compounds of the present invention as thrombin inhibitors, platelet aggregation
  • antithrombotic or anticoagulant drugs such as thromboxane receptor antagonists, prostacyclin mimetics, phosphodiesterase inhibitors, fibrinogen antagonists, aspirin and the like.
  • the compounds of the invention can be administered orally or parenterally such as
  • 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.
  • Example 1 The following working Examples represent preferred embodiments of the present invention.
  • Example 1 Part B 4- nitrophenol carbonate in 5.0 ml of dry DMF cooled at 0°C was added i-Pr 2 NEt (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
  • 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

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Abstract

L'invention concerne des composés carbamyl guanidine, thioguanidine et amidine de structure (I), dans laquelle Z est une sous-structure qui, lorsqu'elle est liée à (II), forme un bioprécurseur de composés présentant des propriétés pharmaceutiquement actives. Selon des modes de réalisation préférés, Z est une sous-structure inhibant la thrombine, contenant des résidus se liant sur les sites distal et proximal. Ax et A'x peuvent être identiques ou différents, et sont choisis indépendamment dans le groupe constitué de carbamyl, H ou alkyle, l'un au moins des deux radicaux Ax et A'x étant carbamyle. Sont inclus tous les stéréo-isomères de ces composés ainsi que leurs sels pharmaceutiquement acceptables.
PCT/US1997/003640 1996-03-12 1997-03-07 Bioprecurseurs de carbamyl guanidine et d'amidine WO1997033576A1 (fr)

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US60/013,191 1996-03-12

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6265397B1 (en) 1997-06-19 2001-07-24 Astrazeneca Ab Amidino derivatives and their use as thrombin inhibitors
US6433186B1 (en) 2000-08-16 2002-08-13 Astrazeneca Ab Amidino derivatives and their use as thormbin inhibitors
US6552047B2 (en) 1998-11-17 2003-04-22 Nitromed, Inc. H2 receptor antagonist compounds in combination with nitric oxide donors, compositions and methods of use
US6599894B1 (en) 1999-01-13 2003-07-29 AstŕaZeneca AB Amidinobenzylamine derivatives and their use as thrombin inhibitors
US6716834B2 (en) 2000-05-16 2004-04-06 Astrazeneca Ab Thiochromane derivatives and their use as thrombin inhibitors
US7241757B2 (en) 1998-12-14 2007-07-10 Astrazeneca Ab Amidino derivatives and their use as thrombin inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0567966A1 (fr) * 1992-04-28 1993-11-03 Dr. Karl Thomae GmbH Composés imino cycliques, médicaments les contenant et procédés pour leur préparation
EP0601459A2 (fr) * 1992-12-02 1994-06-15 Bristol-Myers Squibb Company Inhibiteurs hétérocycliques de thrombine contenant un groupe sulfonamid
EP0669317A1 (fr) * 1994-01-27 1995-08-30 Mitsubishi Chemical Corporation Dérivés de la prolinamide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0567966A1 (fr) * 1992-04-28 1993-11-03 Dr. Karl Thomae GmbH Composés imino cycliques, médicaments les contenant et procédés pour leur préparation
EP0601459A2 (fr) * 1992-12-02 1994-06-15 Bristol-Myers Squibb Company Inhibiteurs hétérocycliques de thrombine contenant un groupe sulfonamid
EP0669317A1 (fr) * 1994-01-27 1995-08-30 Mitsubishi Chemical Corporation Dérivés de la prolinamide

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6265397B1 (en) 1997-06-19 2001-07-24 Astrazeneca Ab Amidino derivatives and their use as thrombin inhibitors
US6576657B2 (en) 1997-06-19 2003-06-10 Astrazeneca Ab Amidino derivatives and their use as thrombin inhibitors
US6552047B2 (en) 1998-11-17 2003-04-22 Nitromed, Inc. H2 receptor antagonist compounds in combination with nitric oxide donors, compositions and methods of use
US6936627B2 (en) 1998-11-17 2005-08-30 Nitromed, Inc. Nitrosated and nitrosylated H2 receptor antagonist compounds, compositions and methods of use
US7129251B2 (en) 1998-11-17 2006-10-31 Nitromed, Inc. Nitrosated and nitrosylated H2 receptor antagonist compounds, compositions and methods of use
US7256205B2 (en) 1998-11-17 2007-08-14 Nitromed, Inc. Nitrosated and nitrosylated H2 receptor antagonist compounds, compositions and methods of use
US7241757B2 (en) 1998-12-14 2007-07-10 Astrazeneca Ab Amidino derivatives and their use as thrombin inhibitors
US6599894B1 (en) 1999-01-13 2003-07-29 AstŕaZeneca AB Amidinobenzylamine derivatives and their use as thrombin inhibitors
US6716834B2 (en) 2000-05-16 2004-04-06 Astrazeneca Ab Thiochromane derivatives and their use as thrombin inhibitors
US6433186B1 (en) 2000-08-16 2002-08-13 Astrazeneca Ab Amidino derivatives and their use as thormbin inhibitors

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