CA2246756A1 - Fibrinogen receptor antagonists - Google Patents
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- CA2246756A1 CA2246756A1 CA002246756A CA2246756A CA2246756A1 CA 2246756 A1 CA2246756 A1 CA 2246756A1 CA 002246756 A CA002246756 A CA 002246756A CA 2246756 A CA2246756 A CA 2246756A CA 2246756 A1 CA2246756 A1 CA 2246756A1
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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Abstract
Fibrinogen receptor antagonists of the general formula (I): X-A-Y-Z-B, and which includes, for example, the compounds of formula (IV), are useful for inhibiting the binding of fibrinogen to blood platelets, inhibiting the aggregation of blood platelets, treating thrombus formation or embolus formation, and preventing thrombus or embolus formation.
Description
CA 022467~6 1998-08-18 ~ TITLE OF THE rNV~NTION
FIBRINOGEN RE(~EPTOR ANTAGONISTS
CROSS-REF~RENCE TO RELATE;D APPLICAT~ONS
S This application claims priority to U.S. provisional application No. 60/012,380, filed February 28, 1996.
BACKGROUND OF THE rNVENTION
The invention relates generally to modulating cell adhesion and to inhibiting the binding of fibrinogen and other proteins to blood platelets, and inhibiting the aggregation of blood platelets specifically to the gp IIb/IIIa fibrinogen receptor site. Fibrinogen is a glycoprotein present in blood plasma that participates in platelet aggregation and in fibrin forrnation. Platelets are cell-like anucleated fragments, found in the blood of all m~mm~l~, that also participate in blood coagulation.
Interaction of fibrinogen with the IIb/IIIa receptor site is known to be essential for normal platelet function.
When a blood vessel is damaged by an injury or other causative factor, platelets adhere to the disrupted subendothethial surface. The adherent platelets subsequently release biologically active constituents and aggregate. Aggregation is initiated by the binding of agonists, such as thrombin, epinephrine, or ADP to specific platelet membrane receptors. Stimulation by agonists results in exposure of latent fibrinogen receptors on the platelet surface, and binding of fibrinogen to the glycoprotein IIb/IIIa receptor complex.
Attempts have been made to use natural products and synthetic peptides to deterrnine the mech~ni~m of adhesion and platelet aggregation. Por example, Rouslahti and Pierschbacher in Scienc~, 23~, 491-497 (1987), describe adhesive proteins such as fibronectin, vitronectin, osteopontin, collagens, thrombospondin, fibrinogen, and von Willebrand factor that are present in extracellular matrices and in blood. The proteins contain the tripeptide arginine-glycine-aspartic acid (RGD) as their glycoprotein IIb/II~a recognition site. These arginine-glycine-aspartic acid cont~ining tripeptide~s are recognized by at least CA 022467~6 1998-08-18 WO 9'7/31910 PCT/US97/02712 one member of a family of structurally related receptors, integrins, which are heterodimeric proteins with two membrane-spanning subunits. The authors state that the conformation of the tripeptide sequence in the individual proteins may be critical to recognition 5 specificity.
Cheresh in P~oc. Nat'l Acad. Sci. U.S.A., 84, 6471-6475, (1987), describes an Arg-Gly-Asp directed adhesion receptor expressed by human endothethial cells that is structurally similar to the IIb/IIIa complex on platelets but is antigenically and functionally distinct. This 10 receptor is directly involved in endothelial cell attachment to fibrinogen, von Willebrand factor, and vitronectin.
Pierschbacher and Rouslahti, in J. of Biol. Chem., 262, (36), 1729~-17298 (1987) hypothesized thatthe Arg-~ly-Asp sec~uence alone would be a sufficient signal for receptor recognition and binding 15 and that, therefore, the conformation of the tri-peptide sequence would be determinative. Various synthetic peptides were produced and the authors concluded that the sterochemical conformation of Arg-Gly-Asp as influenced by enantiomeric substitutions or additions to this se~uence significantly in~luenced receptor-ligand interaction. The authors further 20 showed that cyclization of a decapeptide by forming a disul~ide bridge between non-terminal residues Pen and Cys, rendered the peptide much less effective at inhibiting attachment to fibronectin.
In Proc. Nat'l Acad. Sci. U.S.A., 81, 5985-5988 (1984), the same authors describe tetrapeptide variants of the cell recognition site of 25 fibronectin that retain attachrnent-promoting activity. Peptides having a tetrapeptide recognition site are described in U.S. Pat. Nos. 4,589,881 and 4,614,517. A number of large polypeptide fragments in the cell-binding domain of fibronectin have cell-attachment activity. For example, see U.S. Pat. Nos. 4,517,686, 4,661,I l l and U.S. Pat. No.
30 4,578,079.
Ruggeri et al., P~ c. Na~'l Acad. Sci. U.S.A., 83, 5708-5712 ~1986) explore a series of synthetic peptides designed in ~engths to 16 residLIes, that contain RGD and a valine attached to the aspartic acid CA 022467~6 1998-08-18 residue of RC~D that inhibit fibrinogen binding to platelets. See also Koczewiak et al., Biochem. 23, 1767-1774 (1984); Ginsberg et al., J. Biol. Chem. 260(7), 3931-3936 (1985); and Haverstick et al., Blo~d 66(4), 946-952 (1985). Other inhibitors are disclosed in Eur. Pat. App.
Nos. 275,748 and 298,820.
A number of low molecular weight polypeptide factors have been isolated from snake venom. These factors apparently have high affinity for the gp IIb/IlIa complex. For example, ~uang et al., J.
Biol Chem., 262, 16157-16163 (1987); Huang et al., Biochemistry, 28, 661-666 (1989) describe the primary structure of the venom trigramin which is a 72 amino acid polypeptide that contains the RGD subunit.
Echistatin is another compound which has high affinity for the gp IIb/IIIa complex. This polypeptide contains 49 amino acids and has the ~GD subunit and various disulfide bridges. Gan et al., J. Biol. Chem., 263, 19827-19832 (1988). See also, Dennis et al., Proc. Nat'l Acad. S~.
USA, 87, 2471-2475 (1989). However, these snake venom factors also have high affinity for other members of the adhesive protein receptor family including the vitronectin and fibronectin receptors so are not selective for the gp IIb/IIIa complex.
While it is known that the tripeptide sequence Arg-Gly-Asp is present in certain polypeptides that can duplicate or inhibit the cell attachment-promoting effects of fibronectin and vitronectin, the tripeptide Arg-Gly-Asp has low activity. At present, there is little understanding of how other amino acids coupled to this sequence influence binding specificity. U.S. Patent No 5,023,233 discloses small cyclic hexapeptides which contain the sequence Arg-Gly-Asp and are useful platelet aggregation inhibitors. U.S. Patent No. 5,037,808 discloses the use of indolyl platelet-aggregation inhibitors which are believed to act by antagonizing interactions between fibrinogen and/or extracellular matrix proteins and the platelet gp IIb/IIIa receptor. U.S.
Patent No. 5,037,808 discloses guanidino peptide mimetic compounds that retain an Asp residue which inhibit platelet aggregation.
WO9014103 describes the use of antibody-poly-peptide conjugates wherein said polypeptides contain the Arg-Gly-Asp (RGD) sequence.
CA 022467~6 1998-08-18 WO9111458 discloses the use of large cyclic peptide.s cont~ining RGD flanked by proline residues which are platelet aggregation inhibitors. WO91()1331 discloses small cyclic platelet aggregation inhibitors which are synthetic cyclic pentapeptides 5 conf~ining the tripeptide sequence Arg-Gly-Asp and a thioether linkage in the cycle. U.S. Patent No. 5,051,405 also discloses the use of peptides and pseudopeptides such as N-amidino-piperidine-3-carboxylglycyl-L-aspartyl-L-valine that inhibit platelet aggregation and thrombus formation in m~mm~lian blood. EP 445 796 discloses linear compounds 10 which can include internal piperazinyl or piperidinyl derivatives.
EP437 367 discloses linear polypeptide fibrinogen receptor antagonists.
U.S. Patent No. 5,256,812 discloses compounds of the R l-A-(W)a-X-(~H2)b-(Y)c-B-Z-~OOR wherein Rl is a guandidino or arnidino moiety and A and B are chosen from specific monosubstituted aryl or 15 heterocyclic rnoieties.
VVhile a multitude of compounds or peptide analogs believed to inhi~it platelet aggregation by inhibiting binding to a blood platelet by fibrinogen are known, the present invention provides novel fibrinogen receptor antagonists that have significant binding activity and 20 are, therefore, useful for the reasons stated herein. A number of very serious diseases and disorders involve hyperthrombotic complications which lead to intravascular thrombi and emboli. Myocardial infarction, stroke, phlebitis alld a number of other serious conditions create the need for novel and effective fibrinogen receptor antagonists.
SUMMARY OF THE rNVENTION
One object of this invention is to provide novel compounds which are active as fibrinogen receptor antagonists. Fibrinogen receptor antagonists of this invention have the general formula:
X-A-Y-Z-B I~
and include, for example, the compounds of formula CA 022467~6 1998-08-18 / \ ~ ~ ,CH--C_R6 R1a R2 IV, wherein the variable groups are defined in detail below.
Compounds of the invention are useful for inhibiting the binding of fibrinogen to blood platelets and for inhibiting the aggregation of blood platelets. Therefore, it is another object of this invention to provide methods of inhibiting the binding of fibrinogen to blood platelets, inhibiting the aggregation of blood platelets, treating thrombus formation or embolus formation, or preventing thrombus or embolus formation in a mammal, preferably a human, using the instant compounds. Combination therapies are also described which employ the instant compounds with other active agents such as a thrombolytic agent, an anticoagulant agent, and/or an antiplatelet agent. ~ further object of this invention is to provide pharmaceutical compositions which are useful in the above-described methods. Further objects of this invention will be apparent from the disclosure herein.
DETAILED Dl~SCRIPTION OF THE INVlENTION
The present invention provides compounds having the formula I
X-A-Y-Z-B
and the pharmaceutically acceptable salts, esters, solvates and stereoisomers thereof wherein:
X is heterocycle;
25 heterocycle is selected from:
(1 ) a five or six membered saturated, partially unsaturated or aromatic ring which consists of carbon atoms and one, two or three heteroatoms selected from the group -O-, -N-, -N(R 1 ) and -S-, wherein one of the carbon atoms may be substituted with a member selected from R 1 a and -NHR 1, . .
FIBRINOGEN RE(~EPTOR ANTAGONISTS
CROSS-REF~RENCE TO RELATE;D APPLICAT~ONS
S This application claims priority to U.S. provisional application No. 60/012,380, filed February 28, 1996.
BACKGROUND OF THE rNVENTION
The invention relates generally to modulating cell adhesion and to inhibiting the binding of fibrinogen and other proteins to blood platelets, and inhibiting the aggregation of blood platelets specifically to the gp IIb/IIIa fibrinogen receptor site. Fibrinogen is a glycoprotein present in blood plasma that participates in platelet aggregation and in fibrin forrnation. Platelets are cell-like anucleated fragments, found in the blood of all m~mm~l~, that also participate in blood coagulation.
Interaction of fibrinogen with the IIb/IIIa receptor site is known to be essential for normal platelet function.
When a blood vessel is damaged by an injury or other causative factor, platelets adhere to the disrupted subendothethial surface. The adherent platelets subsequently release biologically active constituents and aggregate. Aggregation is initiated by the binding of agonists, such as thrombin, epinephrine, or ADP to specific platelet membrane receptors. Stimulation by agonists results in exposure of latent fibrinogen receptors on the platelet surface, and binding of fibrinogen to the glycoprotein IIb/IIIa receptor complex.
Attempts have been made to use natural products and synthetic peptides to deterrnine the mech~ni~m of adhesion and platelet aggregation. Por example, Rouslahti and Pierschbacher in Scienc~, 23~, 491-497 (1987), describe adhesive proteins such as fibronectin, vitronectin, osteopontin, collagens, thrombospondin, fibrinogen, and von Willebrand factor that are present in extracellular matrices and in blood. The proteins contain the tripeptide arginine-glycine-aspartic acid (RGD) as their glycoprotein IIb/II~a recognition site. These arginine-glycine-aspartic acid cont~ining tripeptide~s are recognized by at least CA 022467~6 1998-08-18 WO 9'7/31910 PCT/US97/02712 one member of a family of structurally related receptors, integrins, which are heterodimeric proteins with two membrane-spanning subunits. The authors state that the conformation of the tripeptide sequence in the individual proteins may be critical to recognition 5 specificity.
Cheresh in P~oc. Nat'l Acad. Sci. U.S.A., 84, 6471-6475, (1987), describes an Arg-Gly-Asp directed adhesion receptor expressed by human endothethial cells that is structurally similar to the IIb/IIIa complex on platelets but is antigenically and functionally distinct. This 10 receptor is directly involved in endothelial cell attachment to fibrinogen, von Willebrand factor, and vitronectin.
Pierschbacher and Rouslahti, in J. of Biol. Chem., 262, (36), 1729~-17298 (1987) hypothesized thatthe Arg-~ly-Asp sec~uence alone would be a sufficient signal for receptor recognition and binding 15 and that, therefore, the conformation of the tri-peptide sequence would be determinative. Various synthetic peptides were produced and the authors concluded that the sterochemical conformation of Arg-Gly-Asp as influenced by enantiomeric substitutions or additions to this se~uence significantly in~luenced receptor-ligand interaction. The authors further 20 showed that cyclization of a decapeptide by forming a disul~ide bridge between non-terminal residues Pen and Cys, rendered the peptide much less effective at inhibiting attachment to fibronectin.
In Proc. Nat'l Acad. Sci. U.S.A., 81, 5985-5988 (1984), the same authors describe tetrapeptide variants of the cell recognition site of 25 fibronectin that retain attachrnent-promoting activity. Peptides having a tetrapeptide recognition site are described in U.S. Pat. Nos. 4,589,881 and 4,614,517. A number of large polypeptide fragments in the cell-binding domain of fibronectin have cell-attachment activity. For example, see U.S. Pat. Nos. 4,517,686, 4,661,I l l and U.S. Pat. No.
30 4,578,079.
Ruggeri et al., P~ c. Na~'l Acad. Sci. U.S.A., 83, 5708-5712 ~1986) explore a series of synthetic peptides designed in ~engths to 16 residLIes, that contain RGD and a valine attached to the aspartic acid CA 022467~6 1998-08-18 residue of RC~D that inhibit fibrinogen binding to platelets. See also Koczewiak et al., Biochem. 23, 1767-1774 (1984); Ginsberg et al., J. Biol. Chem. 260(7), 3931-3936 (1985); and Haverstick et al., Blo~d 66(4), 946-952 (1985). Other inhibitors are disclosed in Eur. Pat. App.
Nos. 275,748 and 298,820.
A number of low molecular weight polypeptide factors have been isolated from snake venom. These factors apparently have high affinity for the gp IIb/IlIa complex. For example, ~uang et al., J.
Biol Chem., 262, 16157-16163 (1987); Huang et al., Biochemistry, 28, 661-666 (1989) describe the primary structure of the venom trigramin which is a 72 amino acid polypeptide that contains the RGD subunit.
Echistatin is another compound which has high affinity for the gp IIb/IIIa complex. This polypeptide contains 49 amino acids and has the ~GD subunit and various disulfide bridges. Gan et al., J. Biol. Chem., 263, 19827-19832 (1988). See also, Dennis et al., Proc. Nat'l Acad. S~.
USA, 87, 2471-2475 (1989). However, these snake venom factors also have high affinity for other members of the adhesive protein receptor family including the vitronectin and fibronectin receptors so are not selective for the gp IIb/IIIa complex.
While it is known that the tripeptide sequence Arg-Gly-Asp is present in certain polypeptides that can duplicate or inhibit the cell attachment-promoting effects of fibronectin and vitronectin, the tripeptide Arg-Gly-Asp has low activity. At present, there is little understanding of how other amino acids coupled to this sequence influence binding specificity. U.S. Patent No 5,023,233 discloses small cyclic hexapeptides which contain the sequence Arg-Gly-Asp and are useful platelet aggregation inhibitors. U.S. Patent No. 5,037,808 discloses the use of indolyl platelet-aggregation inhibitors which are believed to act by antagonizing interactions between fibrinogen and/or extracellular matrix proteins and the platelet gp IIb/IIIa receptor. U.S.
Patent No. 5,037,808 discloses guanidino peptide mimetic compounds that retain an Asp residue which inhibit platelet aggregation.
WO9014103 describes the use of antibody-poly-peptide conjugates wherein said polypeptides contain the Arg-Gly-Asp (RGD) sequence.
CA 022467~6 1998-08-18 WO9111458 discloses the use of large cyclic peptide.s cont~ining RGD flanked by proline residues which are platelet aggregation inhibitors. WO91()1331 discloses small cyclic platelet aggregation inhibitors which are synthetic cyclic pentapeptides 5 conf~ining the tripeptide sequence Arg-Gly-Asp and a thioether linkage in the cycle. U.S. Patent No. 5,051,405 also discloses the use of peptides and pseudopeptides such as N-amidino-piperidine-3-carboxylglycyl-L-aspartyl-L-valine that inhibit platelet aggregation and thrombus formation in m~mm~lian blood. EP 445 796 discloses linear compounds 10 which can include internal piperazinyl or piperidinyl derivatives.
EP437 367 discloses linear polypeptide fibrinogen receptor antagonists.
U.S. Patent No. 5,256,812 discloses compounds of the R l-A-(W)a-X-(~H2)b-(Y)c-B-Z-~OOR wherein Rl is a guandidino or arnidino moiety and A and B are chosen from specific monosubstituted aryl or 15 heterocyclic rnoieties.
VVhile a multitude of compounds or peptide analogs believed to inhi~it platelet aggregation by inhibiting binding to a blood platelet by fibrinogen are known, the present invention provides novel fibrinogen receptor antagonists that have significant binding activity and 20 are, therefore, useful for the reasons stated herein. A number of very serious diseases and disorders involve hyperthrombotic complications which lead to intravascular thrombi and emboli. Myocardial infarction, stroke, phlebitis alld a number of other serious conditions create the need for novel and effective fibrinogen receptor antagonists.
SUMMARY OF THE rNVENTION
One object of this invention is to provide novel compounds which are active as fibrinogen receptor antagonists. Fibrinogen receptor antagonists of this invention have the general formula:
X-A-Y-Z-B I~
and include, for example, the compounds of formula CA 022467~6 1998-08-18 / \ ~ ~ ,CH--C_R6 R1a R2 IV, wherein the variable groups are defined in detail below.
Compounds of the invention are useful for inhibiting the binding of fibrinogen to blood platelets and for inhibiting the aggregation of blood platelets. Therefore, it is another object of this invention to provide methods of inhibiting the binding of fibrinogen to blood platelets, inhibiting the aggregation of blood platelets, treating thrombus formation or embolus formation, or preventing thrombus or embolus formation in a mammal, preferably a human, using the instant compounds. Combination therapies are also described which employ the instant compounds with other active agents such as a thrombolytic agent, an anticoagulant agent, and/or an antiplatelet agent. ~ further object of this invention is to provide pharmaceutical compositions which are useful in the above-described methods. Further objects of this invention will be apparent from the disclosure herein.
DETAILED Dl~SCRIPTION OF THE INVlENTION
The present invention provides compounds having the formula I
X-A-Y-Z-B
and the pharmaceutically acceptable salts, esters, solvates and stereoisomers thereof wherein:
X is heterocycle;
25 heterocycle is selected from:
(1 ) a five or six membered saturated, partially unsaturated or aromatic ring which consists of carbon atoms and one, two or three heteroatoms selected from the group -O-, -N-, -N(R 1 ) and -S-, wherein one of the carbon atoms may be substituted with a member selected from R 1 a and -NHR 1, . .
(2) an eight to ten membered bicyclic ring system which is saturated, or completely or partially unsaturated, and which consists of carbon atoms and one, two or three heteroatoms selected from the group -O-, -N-, -N(~ arld -S-, wherein one of the carbon atoms may be substituted with a member selected from R 1 a and -NHR 1, (3) a thirteen to fourteen membered tricyclic ring system which is saturated, or completely or partially unsaturated, and which consists of carbon atoms and one, two or three heteroatoms selected from the group -O-, -N-, -N(RI)- and -S-, wherein one o~ the carbon atoms may be substituted with a member selected from R 1 a and -NHR l;
A is a bond between X and Y or is selected from:
( 1 ) phenyl substituted with R 1 a, (2) -N(R1)-, and / /
(3) --N
R1a Y is selected from:
( 1 ) -C 1-8 aL~cyl-, (2) -C4 1 0 cycloalkyl-, (3) -Co g aL~cyl-NRl-CO-Co 8 aLkyl-, (4) -Co g aLkyl-CONR1-Co 8 alkyl-, (S) -Co g aLkyl-O-Co 8 all;:yl-, (6) -Co g alkyl-SOp-co-g alkyl-, (7) -(CH2)0 8-aryl-(CH2)0-8-, (8) (-CH2)0-6-aryl-sop-(9) -(CH2)0 8-aryl-CO-(CH2)0-8-, ( 10) -(cH2~o-6-aryl-sop-(cH2)o-6 (11) -(CH2)0 6-NR1-(CH2)0 6-, ( 12) -(cH2)o-6-aryl-cH(oH)-(cH2)o-6 ( 13 ) -(cH2)o-~-aryl-coNH-(cH2)o-8-~
CA 022467~6 1998-08-18 (14) -Co g alkyl-SOp-NR l-Co g alkyl-, (15) -Co g alkyl-CO-Co 8 alkyl-, and ~ (16) -Co g alkyl-CH(OH)-Co g-alkyl-;
A is a bond between X and Y or is selected from:
( 1 ) phenyl substituted with R 1 a, (2) -N(R1)-, and / /
(3) --N
R1a Y is selected from:
( 1 ) -C 1-8 aL~cyl-, (2) -C4 1 0 cycloalkyl-, (3) -Co g aL~cyl-NRl-CO-Co 8 aLkyl-, (4) -Co g aLkyl-CONR1-Co 8 alkyl-, (S) -Co g aLkyl-O-Co 8 all;:yl-, (6) -Co g alkyl-SOp-co-g alkyl-, (7) -(CH2)0 8-aryl-(CH2)0-8-, (8) (-CH2)0-6-aryl-sop-(9) -(CH2)0 8-aryl-CO-(CH2)0-8-, ( 10) -(cH2~o-6-aryl-sop-(cH2)o-6 (11) -(CH2)0 6-NR1-(CH2)0 6-, ( 12) -(cH2)o-6-aryl-cH(oH)-(cH2)o-6 ( 13 ) -(cH2)o-~-aryl-coNH-(cH2)o-8-~
CA 022467~6 1998-08-18 (14) -Co g alkyl-SOp-NR l-Co g alkyl-, (15) -Co g alkyl-CO-Co 8 alkyl-, and ~ (16) -Co g alkyl-CH(OH)-Co g-alkyl-;
5 p is an integer selected from 0, 1 and 2;
Z is selected from aryl and heterocycle;
aryl is a 5- or 6-membered aromatic ring system which is unsubstituted 10 or mono-, di- or tri-substituted with R2;
B is R3 l l CH--C ~ R5 -(CH2~m--N~ 4 R
wherein m is an integer selected from 0 and 1;
R ~ and R3 are independently selected at each oc~urrence from:
( 1 ) hydrogen, (2) C 1-10 alkyl-, (3) C3-8 cycloalkyl-, (4) aryl-Co 8 alkyl-, (5) amino-C0 g alkyl-, (6) C1 6 alkylamino-Co g alkyl-, (7) C1 6 dialkylamino-Co 8 alkyl-, (8) Cl 3 acylamino-Co g alkyl-, (9) C1 4 alkoxy-Co 6 alkyl-, (10) -C0-6 alkyl-CO2H, ( 1 1 ) -C0-6 alkyl-CO2Cl -3 alkyl, (12) -O-C0-6 alkyl-CO2H and ( 13) hydroxy-Co-6 alkyl-;
Rla is independently selected at each occurrence from:
( l ) hydrogen, WO 97/31910 rcT/uss7/o27l2 (2) halogen, (3) C1-10 alkyl-, (4) C3-8 cycloaLkyl-, (S) aryl-Co 8 alkyl-, (6) amino-C0 8 alkyl-, (7) C1 6 aLkylamino-Co 8 alkyl-, (8) C1 6 dialkylamino-Co 8 alkyl-, (9) Cl 3 acylamino-Co 8 alkyl-, ( 10) C 1 4 alkoxy-Co-6 alkyl-, (1 1 ) -C0-6 alkyl-C02H, (12) -C0-6 alkyl-C02C1 3 alkyl, ( 13 ) -0-C0-6 alkyl-C02H, (14) hydroxy C0-6 alkyl and ( 1 5) oxo (=0);
1~
R2 is independently selected at each occurrence from:
( 1 ) hydrogen, (2) halogen, (3) Cl 1o alkyl-, (4) C3-8 cycloalkyl-, (5) aryl-Co 8 alkyl-, (6) amino-C0 8 alkyl-, (7) C1 6 alkylamino-Co 8 aLkyl-, (8) C 1 6 dialkylamino-Co-8 alkyl-, (9) Cl 3 acylamino-Co 8 alkyl-, (10) Cl 4 alkoxy-Co 6 alkyl-, (1 1 ) -C0-6 alkyl-C02H, (12) -C0-6 alkyl-C02Cl 3 aLIcyl, (13) -0-C0-6 alkyl-C02H, and ( ~ 4) hydroxy C0-6 alkyl;
R4 is ~elected from ( 1 ) -(CH2)p-D-R6 wherein p i.s defined above, (2) ~ , and O D-(3) G~' D- or (4) when Z is unsubstituted or substituted phenyl and m is zero, R4 together with the nitrogen to which it is attached can S form a bicyclic structure with Z (phenyl) as follows:
~0 ~\J 2 R3 o R
D is selected from -SO2- and -C(O)-;
R5 is selected from:
(1) -OH, (2) C1 g alkyloxy-, (3) aryl C0-6 aLkyloxy-, (4) C 1 8 alkylcarbonyloxy C1 4 alkyloxy-, (5~ aryi C1 8 aikyicarbonyloxy Cl 4 aLkyloxy-, and (6) L- or D-amino acid joined by an amide linkage and wherein the carboxylic acid moiety of said amino acid is as the free acid or is esterified by C1 6 alkyl; and R6 is selected from:
(1) -Cl 6alkyl, unsusbstituted, mono- or di-substituted with Rla, - ~0 -(2) -(Co 6aL~cyl)aryl, wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rla, (3) -(Co 6alkyl)heterocycle, wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rla, (4) -NRl(Cl 6aLkYl), wherein the aLkyl group is unsusbstituted, mono- or di-substituted with R1a, (S) -NRl(Co 6alkylaryl), wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rla, (6) -NRl(Co 6aLlcylheterocycle), wherein the aLkyl group is unsusbstituted, mono- or di-substituted with R1a, (7) -C3-6 cycloalkyl, and (8) -CF3.
In a one embodiment of this invention are compounds of 15 formula I which have the particular formula II:
Rl 3 l l X-A-Y-Z--N~
and the pharmaceutically acceptable salts, solvates and stereoisomers 20 thereof wherein:
X-A- together represent a group selected from:
Z is selected from aryl and heterocycle;
aryl is a 5- or 6-membered aromatic ring system which is unsubstituted 10 or mono-, di- or tri-substituted with R2;
B is R3 l l CH--C ~ R5 -(CH2~m--N~ 4 R
wherein m is an integer selected from 0 and 1;
R ~ and R3 are independently selected at each oc~urrence from:
( 1 ) hydrogen, (2) C 1-10 alkyl-, (3) C3-8 cycloalkyl-, (4) aryl-Co 8 alkyl-, (5) amino-C0 g alkyl-, (6) C1 6 alkylamino-Co g alkyl-, (7) C1 6 dialkylamino-Co 8 alkyl-, (8) Cl 3 acylamino-Co g alkyl-, (9) C1 4 alkoxy-Co 6 alkyl-, (10) -C0-6 alkyl-CO2H, ( 1 1 ) -C0-6 alkyl-CO2Cl -3 alkyl, (12) -O-C0-6 alkyl-CO2H and ( 13) hydroxy-Co-6 alkyl-;
Rla is independently selected at each occurrence from:
( l ) hydrogen, WO 97/31910 rcT/uss7/o27l2 (2) halogen, (3) C1-10 alkyl-, (4) C3-8 cycloaLkyl-, (S) aryl-Co 8 alkyl-, (6) amino-C0 8 alkyl-, (7) C1 6 aLkylamino-Co 8 alkyl-, (8) C1 6 dialkylamino-Co 8 alkyl-, (9) Cl 3 acylamino-Co 8 alkyl-, ( 10) C 1 4 alkoxy-Co-6 alkyl-, (1 1 ) -C0-6 alkyl-C02H, (12) -C0-6 alkyl-C02C1 3 alkyl, ( 13 ) -0-C0-6 alkyl-C02H, (14) hydroxy C0-6 alkyl and ( 1 5) oxo (=0);
1~
R2 is independently selected at each occurrence from:
( 1 ) hydrogen, (2) halogen, (3) Cl 1o alkyl-, (4) C3-8 cycloalkyl-, (5) aryl-Co 8 alkyl-, (6) amino-C0 8 alkyl-, (7) C1 6 alkylamino-Co 8 aLkyl-, (8) C 1 6 dialkylamino-Co-8 alkyl-, (9) Cl 3 acylamino-Co 8 alkyl-, (10) Cl 4 alkoxy-Co 6 alkyl-, (1 1 ) -C0-6 alkyl-C02H, (12) -C0-6 alkyl-C02Cl 3 aLIcyl, (13) -0-C0-6 alkyl-C02H, and ( ~ 4) hydroxy C0-6 alkyl;
R4 is ~elected from ( 1 ) -(CH2)p-D-R6 wherein p i.s defined above, (2) ~ , and O D-(3) G~' D- or (4) when Z is unsubstituted or substituted phenyl and m is zero, R4 together with the nitrogen to which it is attached can S form a bicyclic structure with Z (phenyl) as follows:
~0 ~\J 2 R3 o R
D is selected from -SO2- and -C(O)-;
R5 is selected from:
(1) -OH, (2) C1 g alkyloxy-, (3) aryl C0-6 aLkyloxy-, (4) C 1 8 alkylcarbonyloxy C1 4 alkyloxy-, (5~ aryi C1 8 aikyicarbonyloxy Cl 4 aLkyloxy-, and (6) L- or D-amino acid joined by an amide linkage and wherein the carboxylic acid moiety of said amino acid is as the free acid or is esterified by C1 6 alkyl; and R6 is selected from:
(1) -Cl 6alkyl, unsusbstituted, mono- or di-substituted with Rla, - ~0 -(2) -(Co 6aL~cyl)aryl, wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rla, (3) -(Co 6alkyl)heterocycle, wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rla, (4) -NRl(Cl 6aLkYl), wherein the aLkyl group is unsusbstituted, mono- or di-substituted with R1a, (S) -NRl(Co 6alkylaryl), wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rla, (6) -NRl(Co 6aLlcylheterocycle), wherein the aLkyl group is unsusbstituted, mono- or di-substituted with R1a, (7) -C3-6 cycloalkyl, and (8) -CF3.
In a one embodiment of this invention are compounds of 15 formula I which have the particular formula II:
Rl 3 l l X-A-Y-Z--N~
and the pharmaceutically acceptable salts, solvates and stereoisomers 20 thereof wherein:
X-A- together represent a group selected from:
R 1--N3 R 1--N~N-- R 1_ N3~
R1a R1_N N~\ N~N
\ I , ~I , R1a R1a /~ R1--NH N , ~(R1~_, (C~ ~ R ~ (C~N
n is an integer selected from 2, 3, 4, and 5;
Q is selected from -N(R1)-, -S- and -0-;
S Y is selected from:
(1) -Co g aLkyl-NRI-Co-co-8 alkyl-, (2) -Co g a~kyl-CONRl-Co g alkyl-, (3) -C0-8 aLkyl-O-Co 8 alkyl-, (4) -Co g aLkyl-SOp-co-g alkyl-, (5) -(C H 2)0-6-N Rl-(C H 2)0 6-, (6) -C0-8 alkyl-S Op-~nRl-Co-8 alkyl-, (7) -Co g aLkyl-CO-CO 8 alkyl-, and (8) -Co g alkyl-CH(OH)-Co g-alkyl-;
15 p is an integer selected from 0, 1 and 2;
Z is selected from (1) aryl and (2) a five or six membered saturated, partially unsaturated or aromatic heterocyclic ring which is unsubstituted, or .
monosubstituted or disubstituted with R 1 a, which consists of carbon atoms and one, two or three heteroatoms selected from the group -O-, -N-, -N(Rl~- and -S-, and which may be fused to a benzene ring to form a bicyclic structure, for example, --N~ or ~ ~
aryl is a 5- or 6-membered aromatic carbon ring which is unsubstituted or mono-, di- or tri-substituted with R2;
Rl is independently selected at each occurrence from -H, Cl lo alkyl, C3-8 cycloalkyl-, aryl-Co 8 aLkyl- and hydroxy-Co 6 alkyl-;
Rla is independently selected at each occurrence from -H, halogen, -Cl-10 aLkyl, C3-8 cycloalkyl-, aryl-Co 8 aLkyl-, and amino-C0 8 alkyl-;
R2 is independently selected at each occur~ence ~rom -H7 halogen, -Cl lo aLkyl, C3-8 cycloalkyl-, aryl-Co 8 alkyl- and Cl 4 alkoxy-Co 8 aLkyl-;
R3 is independently selected at each occurrence from -H, -~1-10 alkyl, C3-8 cycloaLkyl- and aryl-Co 8 aLkyl-;
R5 is selected from:
( 1 ) -OH, (2) C1 8 alkyloxy-, (3) aryl-Co 6 aLkyloxy-, (4) C1 8 aLkylcarbonyloxy-Cl 4 alkyloxy-, and (S) aryl-C 1-8 alkylcarbonyloxy-C 1-4 alkyloxy-;
D is selected from -SO2- and -C(O)-; and R6 is selected from:
(1 ) -Cl 6aLkyl, unsusbstituted, mono- or di-substituted with Rla, (2) -(Co 6aL~cyl)aryl, wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rla, (3) -(Co 6alkyl)heterocycle, wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rla, (4) -NRl(Cl 6aL~cyl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (5) -NRl(Co 6alkylaryl~, wherein the aLkyl group is unsusbstituted, mono- or di-substituted with R1a, (6) -NRl(~0 6aLkylheterocycle), wherein the aLkyl group is unsusbstituted, mono- or di-substituted with R1a, (7) -C3-6 cycloaLkyl, (8) -CF3, (9) ~~ ~ (10)~?
O CH2 , and Cl H2 o OF
~1 l ) when Z is unsubstitu~d or substituted phenyl, D-R6 lS together with the nitrogen to which it is attached can form a bicyclic structure with Z (phenyl) as follows:
~0 'CH-C-R5 ~\iJ~ R3 1 1 R2 ; and heterocycle is selected from a five or six membered saturated, partiall~
unsaturated or aromatic ring which is unsubstituted, or monosubstituted or disubstituted with Rla, and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(R1)- and -S-;
and wherein the rem~ining variables are as defined above in formula I.
CA 022467=,6 1998-08-18 In a second, further embodiment of this invention are compounds of formula II and the pharmaceutically acceptable salts, solvates and stereoisomers thereof wherein X-A- together represent a group selected from:
Rl-N N~ R1-R1a R1a N3N/~} , and S R
and the rem~inin~ variable are as defined above in formula ~.
In a third, fur~er embodiment of this invention are 10 compounds of formula II and the ph~ eeutically acceptable salts, solvates and stereoisomers thereof wherein X-A- together represent a group selected from:
R1-N~ N~ R1_N3 R1a R1a 3 /~}, and /~
R1a 15 and the pha~naceutically acceptable salts, hydrates and stereoisomers thereof wherein:
Q is selected form -NH-, -O- and -S-;
Y is selected from:
( 1 ) -NR I -CO-, (2) -CONR I -, (3) -O-, (4) -SOp (5) -NRl (6) -SOp-NR 1 , (7) -CO-, and (8) -CH(OH)-;
p is an integer selected from 0, 1 and 2;~0 Z is selected from:
( 1 ) phenyl, (2) phenyl which is mono-, di- or tri-substituted with R2, (3) thienyl, --N~
(4) and (5) o R1 is independently selected at each occurrence from -H and -C1-10 alkyl;
R 1 a is independently selected at each occurrence from -H, halogen and -Cl 1o alkyl, R2 is independently selected at each occurrence from -H, halogen and -C l l o aIkyl;
R3 is independently selected at each occurrence from -H and -Cl lo alkyl;
25 R5 is selected from:
( 1 ) -OH, (2) C1 8 alkyloxy-, (3) aryl-Co 6 aLkyloxy-, (4) C 1-8 alkylcarbonyloxy-C l 4 alkyloxy-, and (5) aryl-Cl 8 aLkylcarbonyloxy-Cl 4 aLkyloxy-;
D is selected from -SO2- and -C(O)-; and R6 is selected from:
(1) -Cl 6aL~cyl, unsusbstituted, mono- or di-substituted with ~la, (2) -(Co 6aL~cyl)aryl, wherein the alkyl group is unsusbstituted, mono- or di-substituted with Rla, (3) -(Co 6alkyl)heterocycle, wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rla, (4) -NRl(Cl 6aLkyl), wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rl a, (5) -NRl(Co 6alkylaryl), wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rla, (6) -NRl(Co 6aLkylheterocycle), wherein the aLlcyl group is unsusbstituted, mono- or di-substituted with Rla, (7) -( ~3-6 cycloaLkyl, (8) -CF3, (g) ~ (10)~
O CH2 , and Cl H2 ~ or (1 ~ ) when Z is unsubstituted or substituted phenyl, D-R6 together with the nitrogen to which it is attached can form a bicyclic structure with Z (phenyl) as follows:
~0 CH- ICI -R~
R2 ; and heterocycle is selected from a five or six membered saturated, partially , -unsaturated or aromatic ring which is unsubstituted, or monosubstituted or disubstituted with Rla~ and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(Rl)- and -S-;
and any rem~ining variables are as defined in follnula II.
In a fourth, further embodiment of this invention are compounds of formula II having the particular formula III
R1-N~N~ \D-R6 R1a III
and the ph~ ceutically acceptable salts, solvates and stereoisomers thereof wherein:
15 Y is selected from:
(1) -NR1 CO, (2) -CONR 1 , (3) -O-, (4) -SOp (5) -NR ~ -, (6) -SOp-NR 1 , (7) -CO-, and (8) -CH(OH)-;
25 p is an integer selected from 0, 1 and 2;
Z is selected from:
( 1 ) phenyl, (2) phenyl which is mono-, di- or tri-substituted with R2, (3) thienyl, --N~ , N
(43 and (S) o Rl is independently selected at each occurrence from -H and 10 alkyI;
5 R I a is independently selected at each occurrence from -H, halogen and -Cl lo alkyl;
R2 is independently selected at each occurrence from -H, halogen and -Cl 1o alkyl;
R3 is independently selected at each occurrence from -H and -C~l-10 alkyl;
RS is selected from:
( 1 ) -OH, (2) C 1-8 alkyloxy-, (3) aryl-Co 6 aLkyloxy-, (4) C1 8 aLkylcarbonyloxy-Cl 4 aLkyloxy-, and (S) aryl-C 1-8 aLkylcarbonyloxy-C 1-4 aLkyloxy-;
D is selected from -SO2- and -C(O)-; and R6 is selected from:
(1) -Cl 6aLkyl, unsusbstituted, mono- or di-substituted with Rla, (2) -(Co 6aLkyl)aryl, wherein the aLkyl group is unsusbstituted, mono- or di-substituted with ~la, (3) -(Co 6alkyl)heterocycle, wherein the alkyl group is unsusbstituted, rnono- or di-substituted with Rl a, (~) -NRl(Cl 6alkyl), wherein the aLkyl group is unsusbstituted, mono- or di-substituted with R 1 a, (5) -NRl((:~0 6alkylaryl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (6) -NRl(Co 6aLkylheterocycle), wherein the aLkyl group is unsusbstituted, mono- or di-substituted with R1a, (7) -C3-6 cycloaLkyl~
(8) -CF3, (g) ~ (10) ~
O CH2 , and I , or S (11) when Z is unsubstituted or substituted phenyl, D-R6 together with the nitrogen to which it is attached can form a bicyclic structure with Z (phenyl) as follows:
~0 'CH-C-R5 ~\iJ~ R3 o R2 ; and heterocycle is selected from a five or six membered saturated, partially unsaturated or aromatic ring which is unsubstituted, or monosubstituted or disubstituted with R1a, and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(R1)- and -S-;
and the rem~ining variables are as defined in formula II.
In a fifth, further embodiment of this invention are compounds of formula III having the particular formula IV
Rl-N N~Y~ CH~ R5 Rla R2 IV
and the ph~ ceutically acceptable salts, solvates and stereoisomers thereo~ wherein:
Y is selected from -C(O)-N(R 1 )- and -N(R 1 )-C(O)-;
R1 is independently selected at each occurrence from -H and S -C~ lo aLkyl;
Rla is independently selected at each occurrence from -H, halogen and -Cl 10 alkyl;
R2 is independently selected at each occurrence from -H, halogen and -Cl lo alkyl;
R3 is independently selected at each occurrence from -H and -~1-10 alkyl;
RS is selected from:
(1) -OH, (2) C1 8 alkyloxy-, (3) aryl-Co-6 alkyloxy-, (4) C1 8 alkylcarbonyloxy-Cl 4 aLkyloxy-, and (5) aryl-Cl g aLkylcarbonyloxy-Cl 4 aLkyloxy-;
D is selected from -SO2- and -C~O)-; and R6 is selected from:
(1 ) -C~1 -6alkYl~ unsusbstituted, mono- or di-substituted with Rla, (2) -(Co 6aLkyl)aryl, wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rl a, (3) -(Co 6alkyl)heterocycle, wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rla, (4) -NRl(CI 6alkyl), wherein the aLkyl group is unsusbstituted, mono- or di-substituted with R 1 a, (S) -NRl(Co 6alkylaryl), wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rl a, (6) -NRl(Co 6aLkylheterocycle), wherein the alkyl group is unsusbstituted, mono- or di-substituted with Rla, (7) -C3-6 cycloalkyl, (8) -CF3, CA 022467~6 1998-08-18 ~ <
(g) ~ (10)~
OCH2 , and I , or (1 1 ) when Z is unsubstituted or substituted phenyl, D-R6 together with the nitrogen to which it is attached can form a bicyclic structure with Z (phenyl) as follows:
~0 J~ R3 li R2 ; and heterocycle is selected from a five or six membered saturated, partially unsaturated or aromatic ring which is unsubstituted, or monosubstituted or disubstituted with Rla, and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(R1)- and -S-;
and any rem~ining variables are as defined in formula III.
In a sixth, further embodiment of this invention are compounds of formula I~ wherein Y is selected from -C(O)-NH- and -NH-C~(O)-; and R6 is selected from (1) unsubstituted, mono and di-substituted phenyl, (2) methyl, (3) benzyl wherein the aryl portion may be unsubstituted, mono or di-substituted, and (4) thienyl; and any remaining variables are as defined in formula IV.
Tn one class of the instant six embodiments are compounds of formulas I, II, III, and IV as defined in the general definition wherein Y is -C(O)-NH-. Compounds in this class are exemplified, but not limited to, those of formula V as defined in Table I. The carbons around the phenyl rings in formula V have been arbitrarily numbered in order to clearly identify the substituent positions, where necessary.
TABLE I
HN~N~ C-NH--~ D-R6 R1a R2 V, R1a R_ R_ D R_ a) H H OCH2CH3 -C(O)- phenyl b) H H OH -C(O)- -CH3;
c) H H OH -C(O)- phenyl;
d) lH H OCH3 -C(O)- -CH3;
e) H H OH -C(O)- 2-F-phenyl;
f) H H OH -C(O)- cyclopropyl;
g) H H OH -C(O)- 3-pyridinyl;
h) H H OH -C(O)- 4-pyridinyl;
i) 6-CH3 H OH -C(O)- phenyl;
j) H 6-CH3 OH -C(O)- phenyl;
k) H S-CH3 OH -C(O)- phenyl;
1) H H OH -SO2- -CF3;
m~ H H O~ -SO2- 2-F-phenyl;
n) H H OC2HS -S02- 2-thienyl;
o) H H OH -so2- 2-thienyl;
p) H H OH -so2- phenyl;
q) H 6-CH3 O~ -SO2- phenyl;
r) H 2-Br OH -SO2- 2-F-phenyl;
s) H H OH -S~2-o CH2 CA 02246756 l998-08-l8 t) H H OH -S02- G~?
CH2 o ; and u) H H OH -C(O)- -CH2-CH2- bondedto D and the carbon denoted with * to form ~0 ~ CHz-~
In a second class of the instant embodiments are compounds of formulas I, II, m, and IV wherein Y is -NH-C(O)-. Compounds in this class are exemplified, but not limited to, those of formula VI as S defined in Table II.
TABLE II
~ 1~ CH2 B- R5 HN N~NH-C--Z--N
\=/ SO2-R6 Vl Z R_ R6 a) 1,4-phenyl OH CH3;
b) 1,4-phenyl OCH3 CH3;
c) 1,4-phenyl OCH(CH3)2 CH3;
d) 1,4-phenyl OH phenyl e) 1,4-phenyl OH 4-Br-phenyl;
f) 1,4-phenyl OH benzyl; and g) 2,5-thienyl OH phenyl.
Additional examples of compounds within the scope of this ~nvention are shown below but a~e not limited to, those of formula VII
as defined in Table III.
T~BLE III
Cl 12-C-OH
X~A~Y~Z~(CH2)n--N~ /=\
Vll SO2~
X-A Y Z n N~3 3 -C(O)NH- 1,4-phenyl 0 HN~ -C(O)NH- 1,4-phenyl 0 c) ~ ~ -C(O)NH- 1,4-phenyl 0 HN~
HN
HN~ CH2)2-HN~ } -(CH2)3-0- 1,4-phenyl s Wlhen any substituent (e.g., Rl, R2, etc.) occurs more than one time in any constituent, its definition on each occurrence is independent of its definition at any other occurrence. Also, combinations of substitutents and/or variables are pe~nissible only if such combinations result in stable compounds.
As used herein "aLkyl" is intended to include bo~
branched- and straight-chain saturated aliphatic hydrocarbon groups S having the specified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, heptyl, octyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), secbutyl (s-Bu), tertbutyl (t-Bu), isopentyl, isohexyl and the like. The term "cycloaLkyl" is intended to include cyclized alkyl chains having the 10 specified number of carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. "Alkoxy" or "alkyloxy"
represents an alkyl group having the indicated number of carbon atoms attached through an oxygen bridge, e.g., methoxy, ethoxy, propyloxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy 15 and the like.
The specified number of carbon atoms in the appropriate groups described herein may include a zero in the range, e.g., C0-6 or C0 8. When a zero is in the specified range, it means that a bond is present in place of that carbon group.
The term halo or halogen is meant to include fluoro, chloro, bromo and iodo. The term "oxy" means an oxygen (O) atom.
~e term "aryl" is defined above in the definition of Formula I; unsubstituted, mono-, di- and tri-substituted phenyl (Ph) 2~ is preferred.
The tellll heteroaryl is defined above in the definition of Formula I. The term heteroaryl encompasses a five or six-membered heteroaryl ring as defined in formula I ~used to a benzene, pyridine or pyrimidine ring. Examples of heteroaryl 30 groups include pyrrolyl, triazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, furanyl, pyranyl, thienyl, oxazolyl, isooxazolyl, thiazolyl, indolyl, benzimidazolyl, benzofuranyl, benzopyranyl, benzothienyl, quinolyl, isoquinolyl and the like. The heteroaryl ring may be attached within structural Formula I at any CA 022467~6 l998-08-l8 heteroatom or a carbon atom in the ring which results in the creation of a stable structure. Preferred heteroaryl groups include pyridyl, ~ thiazolyl, oxazolyl, thienyl, indolyl, benzofuranyl, and benzothienyl.
The term "C0-6 alkylaryl" as used herein includes an alkyl 5 group as defined above bonded to an aryl group as defined above. The C0-6 designation refers to the alkyl component of the alkylaryl unit.
Examples of C0-6 aL~cylaryl include phenyl-, benzyl-, fluorobenzyl-, chlorobenzyl-, phenylethyl-, phenylpropyl-, fluorophenylethyl-, and chlorophenylethyl-.
The term "C0-6 alkylheterocycle" as used herein includes an alkyl group as defined above bonded to a heterocycle group as defined above. The C0-6 designation refers to the aL~cyl component of the alkylheterocycle unit. Examples of C0-6 aLkylheterocycle include thienyl-, thienylmethyl-, thienylethyl-, and thienylpropyl-.
Arnino acids suitable for compounds of the present invention include naturally occurring L- or D-amino acids, for exarnple, those naturally occurring L-amino acids present in hllm~n~, e.g., protein amino acids, including L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glllt~mine, L-glutamic acid, L-glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenyl~l~nine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, and L-valine, and those naturally occurring D-amino acids which are non-protein arnino acids, such as those found, for example, in antibiotic substances produced by bacteria and fungi, including D-valine, D-asparagine, D-glllt~m~te, D-ornithine, D-phenyl~l~nine, D-leucine, D-cysteine, and D-aspartate. (see Zubay "BIOCHEMI~TRY" Addison-Wesley Publi~hing Company, Inc. (Reading, MA) 1983 pp. 867-870 and Stryer "BIOCHEMISTRY" W.H. Freeman and Company (New York, NY) 3rd Edition 1988 pp. 16-21).
The term "pharmaceutically acceptable salts" shall mean non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following salts:
acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glllt~m~le, glycollylarsanilate, 5 hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, ~ te, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote, palmitate, panthothenate, phosphate/diphosphate, polygalacturonate, 10 salicylate, stearate, subacetate, succinate, t~nn~te, tartrate, teoclate, tosylate, triethiodide, valerate.
Prodrugs, such as ester derivatives of described compounds, are compound derivatives which, when absorbed into the bloodstream of a warm-blooded ~nim~l, anabolize or cleave in such a 15 manner as to release the drug fo~n and permit the drug to afford improved therapeutic efficacy.
The compounds of the present invention are chiral and the present compounds may occur as racemates, racemic mixtures and as individual diasteriomers or enantiomers with all such isomeric 20 forms being included within the scope of this invention.
Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the instant invention may form solvates with water or 25 common organic solvents. Such solvates and hydrates, as well as anhydrous compositions, are encompassed within the scope of this invention.
The term "therapeutically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the biological 3(~ or medical response of a tissue, system, ~nim~l or human that is being sought ~y a researcher, veterinarian, medical doctor or o~er clinician, which includes alleviation of the symptoms oi~ the disease being treated.
- The term "m~mm~l" includes hllm~ns.
CA 022467~6 1998-08-18 The term "anti-coagulant" shall include heparin, and warfarin. The term "thrombolytic agent" shall include agents such as - streptokinase and tissue pl~minogen activator. The term "platelet anti-aggregation agent" shall include agents such as aspirin and S dipyridamole.
The compounds of the present invention can be ~1mini.~tered in such oral fo~ns as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
10 Likewise, they may be ~-lministered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramusculsar form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an anti-aggregation agent.
(~ompounds of the invention may be ~clmini~tered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex IIb/I~Ia receptor is desired. They are useful in surgery on peripheral arteries (arterial grafts, carotid endarterectomy) and in cardiovascular surgery 20 where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption. The aggregated platelets may form thrombi and thromboemboli. Compounds of this invention may be ~1mini~tered to these surgical patients to prevent the formation of thrombi and 2~ thromboemboli.
Extracorporeal circulation is routinely used for cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit. Adhesion is dependent on the interaction between gp IIb/~IIa on the platelet membranes and 30 fibrinogen adsorbed to the surface of the circuit. (Gluszko et al., Amer.
J. Physi~ol., 252(H), 615-621 (1987)). Platelets released from artificial surfaces show impaired hemostatic function. Compounds of the invention may be a~lrnini~tered to prevent adhesion.
Other applications of these compounds include prevention of platelet thrombosis, thromboembolism and reocclusion during and after thrombolytic therapy and prevention of platelet thrombosis, thromboembolism and reocclusion after angioplasty or coronary artery 5 bypass procedures. They may also be used to prevent myocardial infarction.
The dosage regimen l~tiTi~ing the compounds of the present invention is selected in accordance with a variety of ~actors including type, species, age, weight, sex and medical condition of the patient; the 10 severity of the condition to be treated; the route of a~lmini~tration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the 1 5 condition.
Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/lcg/day and preferably 0.01-100 mg/kg/day and most preferably 0.01-20 mg/kg/day.
20 Typically, oral dosages for an adult patient are, for example, 1 mg, lû
mg or 100 mg. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minllte during a constant rate infusion.
Advantageously, compounds of the present invention may be ~clmini~tered in divided doses of two, three, or four times daily.
25 Furthermore, preferred compounds for the present invention can be ~lmini~tered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those ~orms of transdermal skin patches well known to those of ordinary skill in that art. To be atlmini~tered in the form of a transdermal delivery system, the dosage 30 a-1mini~tration will, or course, be continuous rather that inteImittent throughout the dosage regirne.
In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically aflmini~tered in admixture with suitable pharmaceutical CA 022467~6 1998-08-18 diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form Of ~lministration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with convention pharmaceutical practices. As such, 5 a therapuetically effective amount of a compound of formula I can be used for the preparation of a medicament useful for inhibiting the binding of fibrinogen to blood platelets, inhibiting the aggregation of blood platelets, treating thrombus formation or embolus formation, or preventing thrombus or embolus formation in a m:~mm~l For example, 10 the medicament may be comprised of from 1 mg to 100 mgs of a compound of formula I, or more particularly, it may contain 1 mg, 10 mgs, 50 mgs, or 100 mgs of said compound.
Therapeutically effective amounts of a compound of formula I together with another active agent such as an anticoagulation 15 agent or a thrombolytic agent can be used for the preparation of a medicament useful for inhibiting the binding of fibrinogeh to blood platelets, inhibiting the aggregation of blood platelets, treating thrombus formation or embolus formation, or preventing thrombus or embolus formation in a m~mm~l. Examples of other active agents which may be 20 used include pl~minogen activators or streptokinase, heparin, aspirin, warfarin, ticlopidine and/or clopidogrel.
For instance, for oral ~(lministration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, 25 starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral a~lminietration in li~uid form, the oral drug components can be combined with any oral, non-toxic, ph~ ceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when 30 desired or necessary, suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage fo~ns include sodium oleate, sodium stearate, m~nesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limit~tion, starch methyl cellulose, agar, bentonite, 5 xanthan gum and the like.
The compounds of the present invention can also be ~1m;ni~tered in the form of liposome delivery systems, such as small unilamellar vesicles, large llnil:~mellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, 10 such as cholesterol, stearylamine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use o~ monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug 15 carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in 20 achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
2~ The compounds of the present inven~ion can also be co-~lmin;~tered with suitable anticoagulation agents or thrombolytic agents such as pl~minogen ac~ivators or streptokinase in the treatment of various vascular pathologies. They may also be combined with hepann, aspirin, warfarin, ticlopidine and/or clopidogrel. Co~(lmin;~tration 30 includes ~lmini~tration together at essentially the same time in a single dosage form or in separate dosage forms, or each agent ~lministered at separately staggered times in order to achieve beneficial thrombosis prevention or thrombolysis.
CA 022467~6 1998-08-18 The compounds of the present invention can be prepared readily according to the following Schemes and Examples or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. Those skilled in the 5 art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. The examples are not intended to be limitations on the scope of the instant invention in any way, and they should not be so construed. Furthermore, the compounds described 10 in the following examples are not to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus. Specific definitions of variables in the Schemes are illustrative only, and are not intended to limit the procedures described, unless otherwise 15 noted. All temperatures are degrees Celsius unless otherwise noted.
Some abbreviations used herein are as follows: TBAF is tetrabutylammonium fluoride; DEAD is diethyl azodicarboxylate;
PPh3 is triphenyl phosphine. Many of the compounds described in the examples were analyzed by FAB mass spectroscopy (FABMS), 20 and MS values are denoted.
In the schemes and examples below, various reagent symbols have the following meanings:
Ac: acyl (CH3-C(O)-) BOC (or Boc): t-butyloxycarbonyl BOC2O: di-t-butyl dicarbonate BOP: Benzotriazol-1-yloxytris(dimethylamino)phosphonium, hexafluorophosphate Bn: benzyl n-BuLi: n-butyllithium t-BuLi: tert-butyllithium CBZ: Carbobenzyloxy CH2C12: Methylene chloride - CHC13: chloroform Pd-C: Palladium on activated carbon catalyst DMF: Dimethylformarnide DMSO: Dimethylsulfoxide ~DC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride S EtOAc: ethyl acetate EtOH: ethanol HOAc: acetic acid LDA: Lithium diisopropylamide MeOH: methanol NMM: N-methyl morpholine NMP: N-methyl pyrrolidine Oxone: potassium peroxymonosulfate PYCLU: chloro N,N,N',N'-bis(pentamethylene)formamidinium hexafluorophosphate RT: room temperature TBDMS or TMS: t-butyldimethyl silyl TFA: trifluoroacetic acid THF: tetrahydrofuran;
TLC: thin layer chromatography BOC--N = I
+ DMF _ ~'O~CHO
HO~CHO ~ 3 NaCNBH3, NaOAc 4A sieves, CH30H
BOC--N=o~3 CH2NH/~CO2CH3 PhSO2CI
Pyridine CH2CI2, 0~C ~ RT
BOC--N ~ ~0~ S02Ph 1 N NaOH
EtOH
~CHEME 1 CONTINUED
BOC--N >~--o~3CH2N--co2H
HN~--O~ CH2N--C02H
Step 1: 4-13-(N-Boc-Piperidin-4-yl~propyloxylbenzaldehyde (1-3) A solution of 3-(N-Boc-piperidin-4-yl)propyl iodide 1 1 (5.0 g, 14.2 mmol) (preparation described in EP 478,328), 4-10 hydroxybenzaldehyde 1 2 (1.73 g, 14.2 mmol), Cs2CO3 (9.2 g, 28.4 mmol) and DMF (50 ml) was stirred at ambient temperature for 2.0 hours. The reaction mixture was diluted with ethyl acetate and then washed with H2O, sat. NaHCO3, 10% KHSO4, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 10% EtOAc/hexane) 15 provided 1 3 as a white solid.
TLC Rf 0.80 ~silica, 40% EtOAc/hexane) lH NMR (300 MHz, CDCl3) o 9.88 (s, lH), 7.83 (d, J=9Hz, 2H), 6.99 (d, J=9Hz, 2H), 4.11 (m, 2H), 4.04 (t, J=6Hz, 2EI), 2.69 (bt, 2H), l.84, (m, 2H), 1.69 (bd, 2H), 1.46 (m, 12H), 1.14 (m, 2H).
Step 2: N~ (N-Boc-Piperidin-4-yl)propyloxy)phen-4-yl-methyllglycine methvl ester (1-5) To a st~rred suspension of 4A molecular sieves (4 g) and CH30H (30 ml) was added NaOAc (1.18 g, 14.5 mmol), compound 1 3 ~ (1.0 g, 2.89 mmol), amine 1-4 (363 mg, 2.89 mmol)-and NaCNBH3 (546 mg, 8.67 mmol). After 18 h, the reaction mixt~lre was filtered - through a celite pad. The pH of the resulting solution was adjusted to ~2 by the dropwise addition of conc. HCI to decompose excess hydride.
The pH was adjusted to ~12 by the addition of K2C03. The mixture was extracted with EtOAc. The organic portion was washed with brine, dried (MgS04) and concentrated. Flash chromatography (silica, 80%
EtOAc/provided) amine 1 5 as a colorless oil.
TLC Rf 0.32 (silica, EtOAc) lH NMR (300 MHz, CD30D) ~ 7.22 (d, J=9Hz, 2H), 6.85 (d, J=9Hz, 2H), 4.10 (bd, 2H), 3.94 (t, J=6Hz, 2H), 3.70 (m, SH), 3.36 (s, 2H), 2.77 (m, 2H), 1.77 (m, 4H), 1.43 (m, 12H), 1.07 (m, 2H).
Step 3: N-~(3-(N-Boc-Piperidin-4-yl)propyloxy)phen-4-yl)-methyll-N'-phenylsulfonyl ~Iycine methyl ester (1-6) To a stirred solution of amine 1-5 (900 mg, 2.15 mrnol), pyridine (347 ,ul, 4.30 mmol) and CH2C12 (20 ml) at 0~C was added phenylsulfonylchloride (300 ,ul, 2.37 mmol) followed by the removal of the cooling bath. After 18 h, the reaction was diluted with EtOAc and then washed with H20, 10% KHS04, brine, dried (MgS04) and concentrated. Flash chromatography (silica, 20% EtOAc/hexane) gave ester 1-6 as a~ colorless oil.
TLF Rf 0.82 (silica, 50% EtOAc/hexane) 1H NMR (300 MHz, CDC13) ~ 7.88 (d, J=9H, 2H), 7.56 (m,3H), 7.14 (d, J=9Hz, 2H), 6.81 (d, J=9Hz, 2H), 4.43 (s, 2H), 4.12 (m, 2H), 3.91 (m, 4H), 3.53 (s, 3H), 2.68 (bt, 2H), 1.79 (m, 2H), 1.68 (bd, 2H), 1.46 (m, 12H), 1.10 (m, 2H).
Step 4: N-[(3-(N-Boc-Piperidin-4-yl)propyloxy)phen-4-yl-methyl]-N'-phenylsulfonyl glycine (1-7) A solution of ester 1 6 (900 mg, 1.61 mmol), lN NaOH (2 ml) and EtOH (5 ml) was stirred at ambient temperature for 30 minlltes.
The reaction mixture was then acidified with 10% KHS04, followed by extraction with EtO~c. The organic portion was washed with brine, -WO g7/31910 PCT/US97/02712 dried (MgS04) and concentrated to give the carboxylic acid 1 7 as a white solid.
TLC Rf 0.48 (silica, 9:0.5:0.5 CH2C12/MeOH/AcOH) lH NMR (300 MHz, CD30D) ~ 7.87 (d, J=8Hz, 2H), 7.59 (m, 3H), 7.09 S (d, J=8Hz, 2H), 6.82 (d, J=9H, 2H), 4.41 (s, 2H), 4.04 (bd, 2H), 3.93 (t, J=6Hz, 2H), 3.84 (s, 2H), 2.76 (m, 2H), 1.79 (m, 4H), 1.44 (m, 12H), 1.04 (m, 2H).
Step 5: N-[(3-(Piperidin-4-yl)propyloxy)phen-4-yl-methyl]-N'-phenylsulfonyl glycine (1-8) A solution of acid 1 7 (400 mg, 0.7334 mrnol), TFA (3 ml) and CH2C12 (3 ml) was stirred at ambient temperature for 1.0 hour.
The solution was concentrated and then azeotroped with toluene. Flash chromatography (silica, 20:1 :1 EtOH/NH40H/H20) furnished amine ~ as a white solid.
TLC Rf 0.41 (silica, 20:1:1 l~tOH/NH40H/H20) lH NMR (300 MHz, NaOD/D20) ~ 7.79 (d, J=8Hz, 2H), 7.66 (d, J=7Hz, lH), 7.56 (t, J=8Hz, 2H), 7.06 (d, J=8Hz, 2H), 8.45 (d, J=9Hz, 2H), 4.42 (s, 2H), 4.01 ~t, J=8Hz, 2H), 3.76 (s, 2H), 2.91 (m, 2H), 2.47 (t, J=12Hz, 2H), 1.74 (m, 4H), 1.32 (m, 3H), 1.06 (m, 2H).
WO 97/31910 PCT/~JS97/02712 Br~ NaN3 . ~Ç \
~ benzene u 2-1 ~ O 1, NaN(TMS)2, DMF
-1 5~C
Boc--N~ I
-1 5~C ~ RT
Boc--N~
tBuLi DMF, THF
-78~C
Boc--N ~ O C H0 HCI~H2N--CO2CH3 NaCNBH3, NaOAc 4A sieves, CH30H
CA 02246756 l998-08-l8 ~ --NH C02CH3 Boc--N~/ N~
PhSO2CI
Pyridine, CH2CI2 0~C ~ RT
~f I ~Co2cH3 E~oc--N~--N~ SO2Ph O \ EtOAC
2~ HCl(g)\
'~ ~N CO2CH3 HCI~HN~--N~ SO2Ph 1 N NaOH ~
EtOH 2-1 0 ~N~CO2H
Boc-N~ O SO2Ph HCI (g) EtOAc HCI-HN~ O SO2Ph 2-~
- Step 1: 6-Bromo-3~4-dihydroisoquinolin-1-one (2-2) To a stirred solution of bromide 2-1 (20.0 ~, 94.8 mmol), H2SO4 (25.4 ml) and benzene (130 ml) at ambient temperature was added NaN3 (8.88 g, 136.6 mmol) portionwise over a 30 minute period.
After 1.0 hour, the reaction was diluted with EtOAc and then washed with H20, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 40% EtOAc/hexanes ~ EtOAc) fuInished bromide 2-2 as an orange solid.
TLC Rf 0.31 1H NMR (300 MHz, CDCl3) o 7.93 (d, J=8Hz, lH), 7.49 (d, J=8Hz, lH), 7.40 (s, lH), 6.32 (bs, lH), 3.57 (m, 2H), 2.99 (t, J=7Hz, 2H).
Step 2: 6-Bromo-N-[(N-Boc-piperidin-4-yl)ethyl]-3,4,-dihydroisoquinolin-l-one (2-4) To a stirred solution of bromide 2-2 (1.33 g, 5.88 mmol) and DMF (30 ml) at -15~C was added NaN (TMS)2 (1.0 M/THF; 6.4 ml) dropwise over a 10 minute period. After 10 minlltes, a solution of iodide ~ (2.0 g, 5.88 mmol) and DMF (4 ml) was added to the reaction mixture followed by the removal of the cooling bath. After 1.0 hour, the solution was diluted with LtOAc and then washed with 10%
KHSO4, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 50% EtOAc/hexanes) afforded bromide 2-4 as a colorless oil.
TLC Rf 0.23 (silica, 50% EtOAc/hexanes) H NMR (300 MHz, CDC13) ~i 7.93 (d, J=8Hz, lH), 7.46 (d, J=8Hz, lH), 7.35 (s, lH), 4.12 (m, 2H), 3.56 (m, 4H), 2.97 (t, J=7Hz, 2H), 1.69 (m, 3H), 1.54 (m, 2H), 1.45 (s, 9H), 1.13 (m, 2H).
~tep 3: 6-Formyl-N-[(N-Boc-piperidin-4-yl)ethyl]-3,4-dihydroisoquinolin-1-one (2-5) To a stirred solution of bromide 2-4 (1.90 g, 4.34 mmol), DMF (342 ~1, 4.34 mmol) and THP (15 ml) at -78~C~ was added t-BuLi (1.7 M/pentane; 7.66 ml, 13.02 mmol) dropwise over a 5 minute period.
After 1.0 hour, the reaction was quenched with AcOH. The solution was diluted with EtOAc and then washed with 10% KHSO4, sat.
NaH~03, brine, dried (MgSO4) and concentrated. Flash S chromotography (silica, 30% ~ 50% EtOAc/hexanes) gave aldehyde ~i as a colorless oil.
TLC Rf 0.13 (silica, 50% EtOAc/hexanes) 1H NMR (300 MHz, CD~13) ~ 10.06 (s, lH), 8.24 (d, 8Hz, IH), 7.84 (d, J=8Hz, lH), 7.72 (s, lH), 4.12 (m, 2H), 3.61 (m, 4H), 3.08 (t, J=7Hz, 10 2H), 2.69 (t, 13Hz, 2H), 1.75 (d, J=13Hz, 2H), 1.59 (m, 2H), 1.45 (s, 10H), 1.19 (m, 2H).
Step 4: N-(N-[(N-Boc-Piperidin-4-yl)ethyl]-3,4-dihydro-isoquinolin-l-one-6-yl-methyl)~lycine methyl ester (2-6~
To a stirred suspension of 4A molecular sieves (3.60 g) and CH30H (30 ml) was added NaOAc (1.06 g, 12.95 mmol), benzaldehyde 2-5 (1.0 g, 2.59 mmol), amine 1 4 (326 mg, 2.59 mmol) and NaCNBH3 (490 mg, 7.77 mmol). After 1.0 h, the reaction mixture was filtered through a celite pad. The pH of the resulting solution was adjusted to ~2 20 by the dropwise addition of lN HCl. After 10 minutes, the pH was adjusted to ~12 by the addition of K2~03. The mixture was extracted with EtOAc. The organic portion was washed with brine, dried (MgSO4) and concentrated. Flash chromatography (silica, EtOAc) afforded amine 2-6 as a white solid.
25 TT.C Rf 0.09 (silica, EtOAc) 1H NMR (300 MHz, CD3OD) 7.89 (d, 3=8Hz, lH~, 7.33 (d, J=8~z, lH), 7.26 (s, lH), 4.07 ~m, 2H), 3.81 (s, 2H), 3.72 (s, 3H), 3.60 (m, 4H), 3.40 (s, 2H), 3.00 (t, J=7Hz, 2H), 2.73 (bt, 2H), 1.78 (bd, J=12Hz, 2H), 1.61 (m, 2H), 1.44 (s, 10H), 1.10 (m, 2H).
- Step 5: N-(N-[(N-Boc-Piperidin-4-yl)ethyl]3,4-dihydro-isoquinolin-l-one-6-yl-methyl)-N'-phenylsulfonyl glycine - methyl ester (2-7) To a stirred solution of amine 2-6 (800 mg, 1.75 mmol), S NMM (488 ,ul, 3.50 mmol) and CH2Cl2 (10 ml~ at 0~C was added benzenesulfonyl chloride (243 ~11, 1.93 mmol) in a single portion followed by the removal of the cooling bath. After 48 h, the heterogeneous mixture was diluted with EtOAc and then washed with H2O, sat. NaHCO3, 10% KHSO4, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 50% ~ 60%
EtOAc/hexanes) furnished ester 2-7 as a white solid.
TLC Rf 0.16 (silica, 50% EtOAc/hexanes) 1H NMR (300 MHz, CD30D) ~ 7.86 (m, 3H), 7.65 (d, J=7Hz, lH), 7.59 (d, J=9Hz, 2H), 7.20 (d, J=8Hz, lH), 7.14 (s, lH), 4.52 (s, 2H), 4.07 (m, 2H), 3.98 (s, 2H), 3.59 (m, 4H), 3.52 (s, 3H), 2.94 (t, J=8Hz, 2H), 2.76 (m, 2H), 1.78 (bd, J=13Hz, 2H), 1.57 (m, 2H), 1.44 (s, 10H), 1.15 (m, 2H).
Step 6: N-(N-[(N-Boc-Piperidin-4-yl)ethyll-3,4-dihydro-isoquinolin-1-one-6-yl-methyl)-N'-phenylsulfonyl glycine (2-8) A solution of ester 2-7 (600 mg, 1.00 mmol), IN NaOH
(2.0 ml) and EtOH (5 ml) was stirred at ambient temperature for 1.5 hours. The reaction mixture was then acidified with 10% KHSO4 followed by extraction with E~tOAc. The organic portion was washed with brine, dried (MgSO4~ and concentrated to give acid 2-8 as a white solid.
1H NMR (300 MHz, CD30D) ~ 7.86 (m, 3H), 7.64 (d, J=7Hz, lH), 7.57 (d, J=9Hz, 2H), 7.21 (d, J=8Hz, lH), 7.13 (s, lH), 4.54 (s, 2H), 4.04 ~ 30 (bd, J=l lHz, 2H), 3.93 (s, 2H), 3.59 (m, 4H), 2.94 (t, J=6Hz, 2H), 2.73 (m, 2H), 1.76 (bd, J=13Hz, 2H), 1.57 (m, 2H), 1.44 (s, 10H), 1.13 (m, 2~).
HCI~HN~N~X~ I CO2H
o Step 7: N-(N-[(Piperidin-4-yl)ethyl]-3,4-dihydroisoquinolin-1-one-6-yl-methyl)-N'-phenylsulfonyl glycine ~2-9) S EtOAc (8 ml) at 0~C was treated with HC~l (g) until saturated. A suspension of acid 2-8 (300 mg, 0.5124 mmol) and ~tOAc (2 ml) was added in a single portion. After 30 minlltes, argon was bubbled ~rough the solution. The solvent was removed in vacuo to give amine 2-9 as a white solid.
lH NMR (300 MHz, D20) ~ 7.79 (d, J=8Hz, 2EI), 7.74 (m, 2H), 7.57 (m, 2H), 7.18 (d, J=8Hz, lH), 7.01 (s, lH), 4.46 (s, 2H), 4.08 (s, 2H), 3.56 (m, 4H), 3.42 (bd, J=14Hz, 2H), 2.96 (t, J=13Hz, 2H), 2.86 (t, J=7Hz, 2H), 2.03 (d, J=14Hz, 2H), 1.64 (m, 3H), 1.45 (m, 2H).
N-(N-[(Piperidin-4-yl)ethyl~ -3,4-dihydroisoqllinolin- 1 -one-6-yl-mçthyl)-N'-phenylsulfonyl glycine methyl ester hydrochloride (2- 10) EtOAc (8 ml) at 0~C was treated with HCI (g) until saturated. A suspension of ester 2-7 (300 mg, 0.5004 mmol) and EtOAc (2 ml) was added in a single po~ion. After 30 minutes, argon was bubbled through the solution. The solvent was removed in vacuo to give amine 2-I0 as a white solid.
lH NMR (D20) ~; 7.82 (d, J=8Hz, 2H), 7.74 (m, 2H), 7.60 (t, J=8Hz, 2~ 21H), 7.21 (d, J=8Hz, lH), 7.07 (s, lH), 4.47 (s, 2H), 4.14 (s, 2H), 3.56 (m, 7H), 3.42 (d, J=13Hz, 2H), 2.90 (m, 4H), 2.03 (d, J=14Hz, 2H), 1.65 (m, 3H), 1.45 (m, 2H).
CA 02246756 l998-08-l8 ~--N~ 1. Boc20, Et3N, DMF ~ J3~NH2 HNJ 2. H2, Pd/C, EtOH BocNJ
Cl~ N~2 o ;~
~, NO2 H
I~--N
BocN J
1- H2, Pd/C, EtOH/
2. RSO2CI, pyridine R' S, ~2 ,~ N ~ ~ N~ H
BocNJ ~, R-Ph 2 aq. NaOH, TFA, CH2C12 ~-5c, R=Me ~, R=4-Br-Ph WO g7/31910 PCT/US97/02712 SCHEME 3 CON~I~lED
SO2 ~
'J~OH
N
~N~ ~
HN J 3-6a, R=Ph -6b, R=Bn f'-6c, R=Me ~, R=4-Br-Ph Step 1: 4-(4-tert-Butyloxycarbonyl-piperazin-l-yl)aniline (3-2) To a solution of 1-(4-nitrophenyl)piperazine C~) (9.8 g, 47.29 mmol) and triethylamine (7.3 mL, 52.37 mmol) in dichloro-10 methane (175 mL~ at RT, Boc2O (11.38 g, 52.14 mmol) was added portionwise. The resultant mixture was stirred at RT for 2 h. The product mixture was concentrated under vacuum, and the residue triturated with hexane (150 mL). The resultant yellow powder was obtained by filtration.
Without further puri~ication, the yellow solid was dissolved ethanol f~200 mL) and shaken under an atmosphe~e of hydrogen gas at 50 psi in the presence of 0.8 g of 5% Pd/C for 18 h at RT. The product solution was filtered through a pad of Celite, and the filtrate was concentrated under vacuum to give 2 as pink solid.
Step 2: 4-[4-(4-tert-Butyloxycarbonyl-piperazin-l-yl)phenylamino-carbonyll-nitrobenze f3-4) To a suspension of 4-nitrobenzoic acid (4.06 g, 24.29 mmol) in dichloromethane (40 mL) and DMF (200 ~lL) at RT, oxalyl 25 chloride (2.8 mL, 32 mmol) was added dropwise with a syringe pump CA 022467~6 l998-08-l8 over a period of 1 h. The resultant solution was stirred at RT for O.S h, and concentration under vacuum. The residue was dissolved in benzene and concentrated under vacuum to remove residua} oxalyl chloride.
The resultant 4-nitroben~oyl chloride (~) was dissolved in dichloro-methane (25 mL) and was added dropwisely to a cold (0~C) solution of ~niline 3-2 (6.12 g, 22.1 mmol) and DMAP (135 mg) in a mixture of dichloromethane (30 mL) and pyridine (4.5 mL) over a period of 30 min. The resultant slurry was diluted with dichloromethane (60 mL) and stirred at 0~C for 1 h. The product mixture was further diluted with dichloromethane (600 mL), washed successively with sat. a~.
sodium bicarbonate, sat aq. potassium hydrogen sulfate, water, and then brine until the aqueous extract was neutral. The dichloromethane solution was loaded directly onto a column of silica gel and the colurnn eluted with ethyl acetate. Collection and concentration of appropriate lS fractions provided the amide 3-4.
Step 3: N-Phenylsulfonyl-4-[4-(4-ter~ utyloxycarbonyl-piperazin-1-yl)-phenylaminocarbonyllaniline (3-Sa) A suspension of the nitrobenzene 3-4 (6.9 g, 16.18 mmol) and 5% Pd/C (0.93 g) in ethanol (110 mT .) was shaken under an atmosphere of hydrogen gas at 50 psi overnight at RT. The resultant mixture was filtered through a plug of Celite, and washed repetitively with methanol (500 mL). The filtrate was concentrated under vacuum.
The residue was treated with toluene and concentrated under vacuum to remove residual alcohols. The resultant aniline (4.49 g, 11.32 rnmol~
was treated with phenylsulfonyl chloride (1.75 mL, 13.7 mmol) in pyridine ~lS mL) at 100~C for 2 h. The resultant mixture was concentrated under vacuum. The residue was dissolved in methanol and concentrated onto silica gel. The resultant solid was loaded onto a column of silica gel and eluted with 80% ethyl acetate in hexane.
Collection and concentration of appropriate fractions provided the sulforlamide 3-Sa.
- ~8 -Step 4: N- { 4-[4-(Piperazin- 1 -yl)phenylaminocarbonyl3phenyl } -N-phenyl-sulfonylglycine (3-6a) To cold (0~C) solution of the sulfonamide 3-5a (2.02 g, 3.76 mmol) in DMF (15 mL), sodium hydride (96 mg, 3.99 mmol) was added. The mixture was stirred at RT ~or lS min. The resultant solution was cooled back to 0~C, and methyl bromoacetate (380 ,uL, 4.01 mmol) was added, and stirred at RT overnight. The product nnixture was concentrated under vacuum, and the residue dissolved in ethyl acetate. The organic fraction was washed successively with aq.
sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 60% ethyl acetate in hexane.
Collection and concentration of ~loL~riate fractions provided N-4-[4(4-tert-butyloxycarbonyl-piperazin- 1 -yl)phenylaminocarbonyl]phenyl-l 5 N-phenylsulfonylglycine methyl ester.
To a solution of the glycine methyl ester (430 mg, 0.7 mmol) in a mixture of methanol (10 mL) and ethanol (3 mL~ at RT, aq.
sodium hydroxide (2.8 mL, 1 M, 2.8 mmol) was added. The resultant mixture was stirred at RT for 5 h. The product mixtlIre was concentrated, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate (3 x 70 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was dissolved in dichloromethane (7 mL) and treated with trifluoroacetic acid (3 mL) at RT for 2.5 h. The product solution was concentrated under vacuum. The residue was dissolved in water, frozen and Iyophilized overnight to provide the sulfonylglycine ~ as a white fluffy solid.
lH NMR (CD30D): ~ 7.84 (2H, d, J=8.6Hz), 7.71-7.49 (7H, m), 7.36 (2H, d, J=8.6Hz), 7.03 (2H, J=9.0 Hz), 4.51 (2H, s), 3.38 (8H, br s).
Analysis calculated for C25H26N4OsS- 1.30 TFA-0.20 H2O
C, 51.28; H, 4.32; N, 8.67 Found: C, 51.29; H, 4.31; N, 8.90 CA 022467~6 1998-08-18 ~XAMPLE 3B
Step 1: N-Benzylsulfonyl-4-[4-(4-tert-butyloxycarbonyl-piperazin-1-yl)-phenylaminocarbonyll-aniline (3-5b) S Following the procedure described for 3-5a, but substituting benzylsulfonyl chloride for phenylsulfonyl chloride, 3-5b was prepared.
Step 2: N- { 4-[4-(Piperazin- 1 -yl)phenylaminocarbonyl]phenyl } -N-benzyl-sulfonylglycine (3-6b) Following the procedure described for 3-6a, but starting with N-benzylsulfonyl-4-[4-(4-tert-butyloxycarbonyl-piperazin-1-yl)-phenylaminocarbonyl~nilin~ (;~), 3-6b was prepared.
Analysis calculated for C26H2gN4OsS- 1.40 TFA-0.44 H2O
C, 51.16; H, 4.51; N, 8.29 Found: C, 51.16; H, 4.51; N, 8.55 ~0 Step 1: N-Methylsulfonyl-4-[4-(4-tert-butyloxycarbonyl-piperazin-1-yl)-phenylaminocarbonyllaniline (3-5c) Following the procedure described for 3-5a, but subsLiLu~ g methanesulfonyl chloride for phenylsulfonyl chloride, 3-5c was prepared.
Step 2: N- { 4-[4-(Piperazin- 1 -yl)phenylaminocarbonyl3phenyl } -N-methylsulfonyl~lycine (3-6c) Following the procedure described for 3-6a, but starting with N-methylsulfonyl-4-[4-(t-tert-butyloxycarbonyl-piperazin-1-30 yl)phenylaminocarbonyl]~nilin~ (3-5c), 3-6c was prepared.
Analysis calculated for C2oH24N4oss-l.48 TFA-0.14 H2O
C, 45.67; N, 4.30; N, 9.28 Found: C, 45.67; H, 4.30; N, 9.49 . , Step 1: N-4-bromo-phenylsulfonyl-4-r4-(4-tert-butyloxycarbonyl-piperazin-l-yl)-phenylamino-carbonyll-aniline (3-5d) Following the procedure described for 3-Sa, but substituting 4-bromophenylsulfonyl chloride ~or phenylsulfonyl chloride, 3-Sd was prepared.
Step 2: N- { 4-[4-(piperazin- 1 -yl)phenylaminocarbonyl]phenyl } -N-4-bromo-phenyl-sulfonylglycine (3-6d) Following the procedure described for 3-6a, but starting with N-4-bromo-phenylsulfonyl-4-~4-(4-tert-butyloxycarbonyl-piperazin-1-yl)-phenylamino-carbonyl3-aniline (3-5d), 3-6d was prepared.
Analysis calculated for C25H25BrN405S ~ 1.58 TFA ~ 0.34 H20 C, 44.52; H, 3.62; N, 7.37 Found: C, 44.51; H, 3.62; N, 7.50 1. RSO2CI,R-S02'N~oEt [~ 2. NaH, NO2 BDrMCFH2CO2Et, ~ Rl 1. H2, Pd/C, EtOH O
l N Cl BocN J
r ~
SO2 ~
O ~N~OEt ~N~ ~
BocN J 4-10 1. aq. NaOH
2. HCI, EtOAc SO~
HJ~
CA 02246756 l99X-08-18 WO ~7/31910 PCT/US97/OZ712 wherein the precursors (4-8, 4-10) and the corresponding final products (4-11) have lR and Rl defined as follows:
Compound R R 1 a) Ph H
b) 2-thienyl H
c) 2-F-Ph H
d) 3-F-Ph H
e) 4-F-Ph H
f) Ph CH3 g) 2-F-Ph B r h) CF3 H
i) (R)- H
camphor j) (S)-camphor H
~SO2 ~
~ ~OEt 02N~
4-8a Step 1: N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester ~4-8a) A solution of 4-nitroaniline (~Z) (13.8 g, 100 mrnol) and phenylsulfonyl chloride (14 rnL, 100 mmol) in pyridine (50 mL) was heated at 1 00~C for 2 h. The resultant solution was concentrated, and the residue dissolved in ethyl acetate. The organic extract was washed CA 022467~6 1998-08-18 WO 97/31910 PCT/US97/027~2 successively with 2 M hydrochloric acid, sat. aq. sodium bicarbonate brine, dried over magnesium sulfate, filtered and concentrated under - vacuum. The residue was dissolved in a minimum amount of ethyl acetate with warning, and hexane added until the solution turned cloudy.
S The mixture was allowed to cool slowly to RT and then chilled at 0~C.
The yellow solid precipitated was obtained by filtration. Further drying under vacuum overnight provide N-phenylsulfonyl-4-nitroz~ni1ine.
A cold (0~C) solution of N-phenylsulphonyl-4-nitro~niline (7.39 g, 30 mmol) in DMF (65 mL) was treated with sodium hydride (0.76 g, 32 mmol) portionwise over a period of 1.5 h. A solution of ethyl bromoacetate (4 mL) in DMF (10 mL) was added, and the resultant mixture stirred at RT overnight. The product mixture was concentrated under vacuum, and the residue dissolved in ethyl acetate.
The organic extract was washed with brine, dried over magnesium 15 sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 0.5%
methanol in chloroform. Collection and concentration of appropriate fractions provided N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (4-8a) as a clear gum.
~SO2 ~
o ~--N~J~o~t ,¢~ H
BocN J 4-1 oa Step 2: N- { 4-[4-(4-tert-Butyloxycarbonylpiperazin- l -yl)phenylcarbonyl-amino]phenyl } -N-phenylsulfonylglycine ethvl ester (4- l Oa) A solution of 4-8a (8.9 g, 24.4 mmol) in a mixture of ethanol (100 rnL) and ethyl acetate (25 mL) was hydrogenated under an atmosphere of hydrogen gas at 45 psi in the presence of 5% Pd/C (0.89 g) at RT for 1.5 h. The resultant mixture was filtered through a plug of Celite, and the filtrate concentrated under vacuum. The residue was redissolved in toluene and concentrated under vacuum to provide the corresponding aniline.
A solution of 4-[4-(tert-butyloxycarbonyl)piperazin- 1 -yl]-benzoic acid (4-9 wherein R2 = H) (1.0 g, 3.3 mmol) in dichloromethane (25 mL) and DMF (3 drops) at RT was treated with oxalyl chloride (0.43 mL, 4.9 mmol) over a period of 10 min. The resultant solution was stirred at RT for I h, and concentrated under 10 vacuum. The residue was dissolved in toluene and concentrated to remove residual oxalyl chloride. The resultant acid chloride 4-9 was redissolved in dichloromethane (5 mL~, and added to a cold (0~C) solution the above ~niline (1.1 g, 3.3 mmol) and DMAP (0.48 g, 3.9 mmol) in dichloromethane (25 mL). The resultant mixture was stirred 1~ at RT overnight, diluted with dichloromethane and washed successively with 10% aq citric acid, sat. sodium bicarbonate, and brine. The organic extract was dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 50% ethyl acetate in hexane.
20 Collection and concentration of appropriate fractions provided 4-lOa as a gum.
~SO2 ~
O ,~N~JI--OH
,~NH~J
~N
HN~J 4-11a Step 3: N- { 4-[4-~Piperazin- l -yl)phenylcarbonylarnino]phenyl } -N-2~ phenyl-sulfonyl~lvcine (4-lla~
- To a solution of the glycine ethyl ester 4-lOa (260 mg, 0.41mmol) in methanol (2.5 mL), aq. sodium hydroxide (0.85 mL, 1 M, 1.7 mmol) was added. The resultant mixture was stirred at RT for 2 h.
The product mixture was concentrated, acidified, and extracted into 5 dichloromethane. The combined organic extract were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was dissolved in ethyl acetate (30 rnL), cooled to 0~C, and treated with a steady stream of anhydrous hydrogen chloride gas for 10 min. The resultant solution was stirred at 0~C for 1 h, and concentrated under 10 vacuum. The residue was dissolved in water, frozen and lyophilized overnight to provide glycine 4-1 la as a white fluffy solid.
1H NMR (CD30D): ~ 7.89 (2H, d, J=8.8Hz), 7.69-7.50 (7H, m), 7.17 (2H, d, J=8.8Hz), 7.11 (2H, d, J=9.OHz), 4.42 (2H, s), 3.6 (4H, m), 3.4 (4H, m).
Analysis calculated for C2sH26N40sS-0.15 EtOAc C, 51.34; H, 5.00; N, 9.35 Found: C, 51.34; H, 4.96; N, 9.30 Following the procedures described in Example 4A, Steps 1-3, but substituting the applol~liate reagents as described below, the following compounds were made:
25 (1) N- { 4- [4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl } -N-thienylsulfonylglycine (4-1 lb) This product was prepared using 2-thiophene sulfonyl chloride in place of phenylsulfonyl chloride in Step 1.
Analysis calculated for C2sH26N405S- 1.40 TFA-0.15 H20 C, 46.74; H, 3.91; N, 8.45 Found: C, 46.73; H, 3.92; N, 8.72 (2) N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonyl~mino]phenyl } -N-2-fluoro-phenyl-sulfonylglycine (4- l l c) This product was prepared using 2-fluorophenyl-sulfonyl chloride in place of phenylsulfonyl chloride in Step 1.
Analysis calculated for C25H2sFN405S ~ 1.60 TF~
C, 48.74, H, 3.86; N, 8.06 Found: C, 48.37; H, 3.92, N, 8.46 (3) N- { 4-~4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl } -N-3-fluoro-phenylsulfonylglycine (4-1 1 d) This product was prepared using 3-fluorophenylsulfonyl chloride in place of phenylsulfonyl chloride in Step 1.
Analysis calculate for C25H25FN405S ~ 1.30 TFA ~ 0.35 H20 C, 49.69; H, 4.08; N, 8.40 Found: C, 49.68; H, 4.04; N, 8.44 (4) N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl } -N-4-fluorophenyl-sulfonylglycine (4- l 1 e) This product was prepared using 4-fluorophenylsulfonyl chloride in place of phenylsulfonyl chloride in Step 1..
Analysis calculated for C25H25FN405S ~ 1.35 TFA ~ 0.35 H20 C, 49.45; H, 4.05, N, 8.33 Found: C, 49.45; H, 4.00; N, 8.40 (5) N- ~ 4-~4-(Piperazin-1 -yl)phenylcarbonylamino] -3 -methylphenyl ~-N-phenylsulfonylglycine (4-1 1 f) This product was prepared using 3-methyl-4-nitro~niline in place of 4-nitroaniline in Step 1.
Analysis calculated for C26H2gN405S ~ 1.40 TFA ~ 0.42 H20 C, 51.19; H, 4.51; N, 8.29 Found: C, 51.17; H, 4.51; N, 8.53 (6) N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonylamino]-3 -bromo-phenyl ~ -N-2-fluoro-phenylsulfonyl~lycine (4- l l g) This product was made using 3-bromo-4-nitroaniline and 2-fluorophenylsulfonyl chloride in place of 4-nitroaniline and phenylsulfonyl chloride, respectively, in ~tep 1.
Analysis calculated for C25H24BrFN4oss ~ 1.50 TFA ~ 0.35 ~I20 CA 02246756 l998-08-l8 WO 97/31910 PCT/[~S97/02712 - C, 43.75; H, 3.44; N, 7.29 Found: C, 43.76; H, 3.41; N, 7.53 (7) N- { 4-t4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl } -N-trifluoro-methylsulfonylglycine (4- 11 h) This product was prepared using trifluoromethanesulfonic anhydride and tert-butyl bromoacetate in place of phenylsulfonyl chloride and ethylbromo acetate, respectively, in Step 1.
Analysis calculated for C20H2lF3N4oss ~ 1.25 TFA ~ 0.35 H20 C, 42.54; H, 3.64; N, 8.82 Found: C, 42.55; H, 3.60; N, 9.05 0~
SO2 ~
,3~N~'oH
f~--N 4-11 i HNJ
(8) N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonylamino~phenyl ~ -N-(1 R)- 10-camphorsulfonylsulfonyl~;lycine (4- 11 i) This product was prepared using (lR)-(-)-10-camphorsulfonyl chloride in place of phenylsulfonyl chloride in Step 1.
~ Analysis calculated for C29H36N406S ~ 1.50 TFA ~ 0.15 H20 C, 51.77; H, 5.13; N, 7.55 Found: C, 51.74; H, 5.13; N, 7.63 ~0 SO~2~' ~N ~i HN ~J
(9) N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonylamino lphenyl } -N-(lS)-10-camphorsulfonyl-sulfonyl-~lycine (4-1 lj) This product was prepared using (lS)-(-)-10-camphorsulfonyl chloride in place of phenylsulfonyl chloride in Step 1..
Analysis calculated for C29H36N406S ~ 1.50 TFA ~ 0.10 H20 C, 51.83; H, 5.12; N, 7.56 Found: C, 51.84; H, 5.14; N, 7.72 _ 59 _ SCHEME S
NH2 1. R3COCI, ~ O
R~ 'OEt NO2 BrcH2co2Et~ O N R1 5-13 1. H2, Pd/C, o EtoH ll ~NJ~ ~c BocN J
(4-9) ~ ~
,~ ~ H ~;
BocN J R2 5-14 1. aq. NaOH
2. TFA. CH2C12 R3~o O N~JI'OH
~ ~J'' H
SCH~ME 5 CON~I~UED
wherein the precursors (5-13, 5-14 and 4-9) and the corresponding final products (5-15) have R1, R2 and R3 defined as follows: ~
s Cmpd RI R2 R3 a) H H Ph b) H H 2-F-Ph c) H H 3-F-Ph d) H H 4-F-Ph e) H H 2-pyridyl f) H H 3-pyridyl g) H H 4-pyridyl h) H H ~H3 i) H H ~
J) H H CH2ocH2ph k) H H CH2OH
1) 3-CH3 H Ph m) 2-CH3 H Ph n) H 3-CH3 Ph o) H 2-CH3 Ph ~ EXAMPL~ SA
~00 ~ ~OEt 02N J'~ 5-1 3a 5 ~tep 1: N-4-Nitrophenyl-N-benzoyl~lycine ethyl ester (5-13a) A mixture of 4-nitroaniline (4-7) (10.0 g, 72 mmol) and anhydrous potassium carbonate (20 g, 1.44 mmol) in anhydrous THF
(240 mL) and benzoyl chloride (9.1 mL, 78 mmol) was stirred at RT
overnight. The resultant solution was poured into 10% aq. HCl (200 10 mL) and cooled to 0~C. The yellow solid precipitated was filtered, washed successively with water (200 mL) and hexane (200 mL).
Further drying under vacuum overnight provided the required 4-nitro-N-benzoylaniline.
A cold (0~C) solution of the above nitro aniline (4.8 g, 19.8 15 mrnol) in DMF (40 mL) was treated portionwise with sodium hydride (0.48 g, 20 mmol). After the mixture was stirred at 0~C for 0.5 h, a solution of ethyl bromoacetate (2.6 mL, 23.4 mmol) in DMF (20 mL) was added. The resultant mixture was stirred at 50~C overnight and concentrated under vacuum. The residue was partitioned between ethyl 20 acetate and water. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum to provide the nitrophenyl glycine ester 5-13a.
_ ~00 ,~ ~ N
BocN J 5-1 4a Step 2: N- { 4-L4-(4-tert-Butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino]phenyl } -N-benzoylglycine ethyl ester (5-14a) Following the procedure described for 4-lOa. but sub~lilulillg N-4-nitrophenyl-N-benzoyl-glycine ethyl ester (5-13a) for N-4-nitrophenyl-N-phenylsulfonyl-glycine ethyl ester (4-8a), 5-14a was prepared.
~0 0 ~ ~N~J~'OH
~N~
~ NJ~J
HN I ~-1 5a Step 3: N- { 4-t4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl } -N-benzoyl-glycine (5-15a) lS Following the procedure described for 4-1 la, but substituting N- ~4-[4-(4-tert-butyloxycarbonylpiperazin- l-yl)phenyl-carbonylamino~phenyl } -N-benzoylglycine ethyl ester (5-1 4a~ ~or N- { 4-~ [4-(4-tert-butyloxycarbonylpiperazin- 1 -yl)phenylcarbonyl-arnino]phenyl}-N-phenylsulfonylglycine ethyl ester (4-lOa~, 5-15a was - prepared.
Analysis calculated for C26H26N404 ~ 1.35 TFA ~ 0.30 H20 C~, 55.79; H, 4.56; N, 9.07 Found: C, 55.76, H, 4.57; N, 9.29 EXAMPLE SB
I~F
~ O
~ ~OEt 02N~ S-13b Step 1: N-4-Nitrophenyl-N-2-fluorobenzoyl-~1~,7cine ethyl ester ~5-13b~
Following the procedure described for 5-13a, but substituting 2-fluorobenzoyl chloride for benzoyl chloride, 5-13b was 1 S prepared.
~00 o ~ N~OEt ~NJi ~
BocN ~ 5-1 4b .
WO g7/31910 PCT/US97/02712 Step 2: N- { 4-~4-(4-tert-Butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino]phenyl }-N-2-fluorobenzoylglycine ethyl ester (5-14b) Following the procedure described for 4-lOa, but S substituting N-4-nitrophenyl-N-2-fluorobenzoyl-glycine ethyl ester (~
13b) for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (~), 5-14b was prepared.
~F
~0 0 O ~[3~N~'oH
~N
HN ~ 5-1 5b Step 3: N- { 4-~4-(Piperazin- 1 -yl)phenylcarbonylamino~phenyl } -N-2-fluoro-benzoyl~lycine (5-1 Sb) Following the procedure described for 4-1 la, but substituting N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-15 phenylcarbonylamino~phenyl}-N-2-fluorobenzoyl-glycine ethyl ester (5-1 4b) for N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylamino]phenyl}-N-phenylsulfonylglycine ethyl ester (4- l Oa), 5- l Sb was prepared.
Analysis calculated for C26H2sFN404 ~ 1.35 TFA ~ 0.15 H20 C, 54.45; H, 4.24; N, 8.85 Found: C, 54.45; H, 4.26; N, 8.78 WO 97/31910 PCT/US97/û2712 ~ EXAMPLE SC
F
~~O
~ ~OEt 02N~ 5-13c Step 1: N-4-Nitrophenyl-N-3-fluorobenzoyl~lycine ethyl ester (5-13c) Following the procedure described for 5-13a, but 5 substituting 3-fluorobenzoyl chloride for benzoyl chloride, 5-13c was prepared.
O ~N~OEt ~N~
BocN J 5-1 4c Step 2: N- { 4-[4-~4-tert-Butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino]phenyl }-N-3-fluorobenzoylglycine ethyl ester (5-14c) Following the procedure described for 4-lOa, but substituting N-4-nitrophenyl-N-3-fluorobenzoyl-glycine ethyl ester (5-13cl for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (4-8a), 15 5-14c was prepared.
CA 02246756 l998-08-l8 F
~~O
~ ~ H
HN~J 5-15c Step 3: N- { 4-[4-(piperazin- 1 -yl)phenylcarbonylamino]phenyl } -N-3-iluoro-benzoylglycine (5-lSc) Following the procedure described for 4-1 la. but 5 substituting N- { 4-L4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylamino]phenyl } -N-3-fluorobenzoyl-glycine ethyl ester (5-1 4c) for N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylarnino]phenyl}-N-phenylsulfonylglycine ethyl ester (4- l Oa), S- 1 5c was prepared.
Analysis calculated for C26H2sFN4o4 ~ 1.70 T~A ~ 0.35 H20 C, 52.19; H, 4.08; N, 8.28 Found: C~ 52.19; H, 4.08; N, 8.42 EXAMPLE SD
F~
~0 0 ,~ ~OEt 02N 5-1~d - Step 1: N-4-Nitrophenyl-N-4-fluorobenzoylglycine ethyl ester ~S-l 3d) - Following the procedure described for 5-13a. but substituting 4-fluorobenzoyl chloride for benzoyl chloride, 5-13d was prepared.
F~
~00 o ~.,~ N~J~oEt r~N~
~N~
5-14d BocN
Step 2: N- { 4-r4-(4-tert-Butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino]phenyl } -N-4-fluorobenzoylglycine ethyl ester (5-14d~
Following the procedure described for 4-lOa, but 10 substituting N-4-nitrophenyl-N-4-fluorobenzoylglycine ethyl ester (5-13d) for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (4-8a), 5-14d was prepared.
F~
~0 0 O ~N~J~OH
f N'¢ ~
HN ~,J 5-1 5d 15 Step 3: N-{4-[4-(Piperazin-1-yl)phenylcarbonylamino]phenyl}-N-4-fluoro-benzoylglycine (5-lSd) .
Following the procedure described for 4-lla, but substituting N- { 4-~4-(4-fert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylamino]phenyl } -N-4-fluorobenzoyl -glycine ethyl ester (5-1 4d) for N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-S phenylcarbonylamino]phenyl}-N-phenylsulfonylglycine ethyl ester (4- l Oa), S- l Sd was prepared.
Analysis calculated for C26H25FN404 ~ 1.40 TFA ~ 0.30 H20 C, 53.92; H, 4.24; N, 8.73 Found: C, 53.90; H, 4.23; N, 8.83 EXAMPLE SE
1~ IN
~0 0 ,~ ~OEt 02N 5-1 3e Step 1: N-4-Nitrophenyl-N-picolinoyl-~lycine ethyl ester (5-13d) lS Following the procedure described for 5-13a, but substituting picolinoyl chloride hydrochloride for benzoyl chloride, S-I3d was prepared.
I~IN
~0 0 ~N~oEt 1/' N
BocN ~,J 5-1 4e Step 2 N- {4-[4-(4-tert-Butyloxycarbonyl-piperazin- l -yl)-phenylcarbonyl-amino]phenyl ~-N-picolinoylglycine ethyl ester (5-14e) Following the procedure described for 4-lOa. but 5 substituting N-4-nitrophenyl-N-picolinoyl-glycine ethyl ester (5-13d~
for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (~), 5-14e was prepared.
I~N
~0 0 O ~N'J~OH
~ N
HNJ 5-15e Step 3 N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl } -N-picolinoyl-glycine (5- 15e) Following the procedure described for 4-1 la. but substituting N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-lS phenylcarbonylamino]phenyl}-N-picolinoylglycine ethyl ester (5-14e) for N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino]phenyl}-N-phenylsulfonylglycine ethyl ester (4-lOa), 5-15e was prepared.
Analysis calculated for C25H25N504 ~ 2.10 TFA ~ 0.20 H20 C, 49.92; H, 3.95; N, 9.97 ~ Found: C, 49.88; H, 3.95; N, 10.04 WO 97/31910 PCTtUS97/02712 EXAMPLE SF
~00 ,¢~ ~OEt 02N 5-13f Step 1: N-4-Nitrophenyl-N-nicotinoyl-glycine ethyl ester (5-13f) S Following the procedure described for 5-13a. but substituting nicotinoyl chloride hydrochloride for benzoyl chloride, S-13f was prepared.
~00 O ~ ~OEt ,¢~ H
I N 5-14f BocN ~,J
~0 Step 2: N- { 4-~4-(4-tert- Butyloxycarbonyl-piperazin- I -yl)-phenylcarbonyl amino]phenyl } -N-nicotinoylglycine ethyl ester (5-14f) Following the procedure described for 4-lOa. but substituting N-4-nitrophenyl-N-picolinoyl-glycine ethyl ester (S-L3f) for lS N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (4-8a), 5-14f was prepared.
~ ~I
~0 o ,~ HN J~
~f HN
Step 3 N- { 4-~4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl ~ -N-nicotinoyl-,elycine (5-lSf) Following the procedure described for 4-1 la. but substituting N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylamino]phenyl } -N-nicotinoylglycine ethyl ester (~
for N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino]phenyl}-N-phenylsulfonylglycine ethyl ester (4-lOa), 5-lSf was 1 0 prepared.
Analysis calculated for C25H25N504 ~ 2.20 TFA ~ 0.35 H20 C, 49.27; H, 3.92; N, 9.77 Found: C, 49.25; H, 3.92; N, 10.12 l S EXAMPLE 5G
N~
~0 0 ~ ~OEt 02N~ 5-139 Step 1: N-4-Nitrophenyl-N-isonicotinoyl-glycine ethyl ester (5-13~) CA 02246756 l998-08-l8 WO g7/31910 PCT/US97/02712 Following the procedure described for 5-13a, but substituting isonicotinoyl chloride hydrochloride for benzoyl chloride, 5-13g was prepared.
N~
~0 0 ,¢~ N
BocN J 5-14~
Step 2: N- { 4-[4-(4-tert-Butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-arnino~phenyl }-N-isonicotinoylglycine ethyl ester (5-14g) Following the procedure described for 4-lOa, but sub~ u~ g N-4-nitrophenyl-N-isonicotinoyl-glycine ethyl ester (5-13g) for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (4-8a), 5-14 was prepared.
N~
~00 --' N
lS HN
- Step 3: N-{4-~4-(Piperazin-l-yl)phenylcarbonylamino]phenyl~-N-isonicotin-oyl-glycine (5-lSg) Following the procedure described for 4-1 la, but substituting N- ~ 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -5 yl)phenylcarbonylamino]phenyl }-N-isonicotinoylglycine ethyl ester (5- 14g~ for N- { 4-[4-(4-fert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylamino}phenyl}-N-phenylsulfonylglycine ethyl ester (4-lOa), 5- 15~ was prepared.
Analysis calculated for C25H25N504 ~ 2.35 TFA ~ 0.65 H20 C, 4~.26; H, 3.91; N, 9.47 Found: C, 48.25; H, 3.90; N, 9.57 ~o o ,~ ~OEt 02N 5-1 3h Step 1: N-4-Nitrophenyl-N-acetyl-~lycine ethyl ester (5-13h) Following the procedure described for 5-13a, but substituting acetyl chloride for benzoyl chloride, S-13h was prepared.
~o o O ~ N~OEt ~N~
~N~
5-14h BocN
Step 2: N- { 4-1 4-(4-tert-Butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino~phenyl } -N-acetylglycine ethyl ester (5-14h) Following ~e procedure described for 4-lOa~ but S substituting N-4-nitrophenyl-N-acetyl-glycine ethyl ester (5-13h) for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (4-8a), 5-14h was prepared.
~ O
o ~ N~I~oH
~NJ~
HN
Step 3: N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl } -N-acetyl-~lycine (5-lSh) Following the procedure described for 4-1 la, but substituting N- ~ 4-L4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-15 phenylcarbonylamino3phenyl}-N-acetylglycine ethyl ester (5-14h) for N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino]phenyl}-N-phenylsulfonylglycine ethyl ester (4-lOa), S-lSh was prepared.
Analysis calculated for C21H24N404 ~ 1.30 TFA ~ 0.55 H20 C, Sl.l l; H, 4.80; N, 10.10 Found: C, 51.09; H, 4.74; N, 10.25 ~0 o ~ ~OEt 02N~ 5-13i Step 1: N-4-Nitrophenyl-N-cyclopropanecarboxylglycine ethyl ester (S-1 3i) Following the procedure described for 5-13a~ but substituting cyclopropanecarbonyl chloride for benzoyl chloride, 5-13i was prepared.
~0 0 ,3J HN~
BocN ~,J 5-1 4i Step 2: N- { 4-[4-(4-terf-Butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino]phenyl } -N-cyclopropane-ca~xylg~ycine e.hyl es.er (5-14i) Following the procedure described for 4-lOa. but 15 substituting N-4-nitrophenyl-N-cyclopropanecarboxylglycine ethyl ester (5-13i) for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (~), 5-14i was prepared.
~0 0 N
HNJ 5-15i Step 3: N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl } -3!1-cyclopropanecarboxylglycine (5- 15i3 Following the procedure described for 4-3 la, but substituting N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylaminolphenyl}-N-cyclopropanecarboxylglycine ethyl ester (~) for N-~4-[4-(4-tert-butyloxycarbonyl-piperazin-1-yl)-phenylcarbonylamino~phenyl}-N-phenylsulfonylglycine ethyl ester 10 (4- 1 Oa), 5- 1 Si was prepared.
Analysis calculated for C23H26N404 ~ 1.38 TFA ~ 0.62 H20 C, 52.35; H, 4.88; N, 9.48 Found: C, 52.35; H, 4.86; N, 9.65 ~XAMPLE 5J
~0 ~~ O
02N ~i Step 1: N-4-Nitrophenyl-N-benzyloxyacetyl-glycine ethyl ester (5-13j) Following the procedure described for 5-13a, but substitllting ben~;yloxyacetyl chloride for benzoyl chloride, 5-13; was 20 prepared.
.
~~~~ ~
O ~ N~OEt J3JI' H
--N
BocN J ~
Step 2: N-{4-[4-(4-tert-Butyloxycarbonyl-piperazin-1-yl)-phenylcarbonyl-amino]phenyl ~ -N-benzyloxyacetylglycine ethyl ester (5-14j) Following the procedure described for 4-lOa, but substituting N-4-nitrophenyl-N-benzyloxyacetylglycine ethyl ester (5-13j) for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (4-8a), 5-14j was prepared.
~~~~ ~
o ~N~I'oH
~NJ~
HN ~J ~-1 5j Step 3: N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl } -N-benzyloxy-acetylglycine (5- l Sj) Following the procedure described for 4-1 la, but substituting N- ~ 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylamino~phenyl } -N-benzyloxy-acetylglycine ethyl ester (5-1 4j) for N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylamino]phenyl } -N-phenylsulfonylglycine ethyl ester 20 (4- lOa), ~ was prepared.
WO g7/31910 PCT/US97/02712 Analysis calculated for C2gH30N4O5 ~ 1.56 TFA ~ 0.30 H2O
C, 54.50; H, 4.73; N, 8.17 found: C, 54.49; H, 4.73; N, 8.51 HO'--f5 O
O ~N'~OH
~N~
H
~N
HN~
N- { 4- [4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl } -N-hydroxy-acetylglycine (5-lSk) A mixture of N-{4-[4-(piperazin-1-yl)phenylcarbonyl-aminolphenyl}-N-benzyloxyacetylglycine (S-lSj, 100 mg), 5% Pd (10 mg) on charcoal, TFA (1 mL) and ethanol (10 mL) was stirred under a balloon of hydrogen gas for 18 h at RT. The resultant mixture was concentrated, and the residue subjected to column chromatography on a 15 reverse phase C-18 column to provide ~.
Analysis calculated for C21H24N4O5 ~ 1.45 TFA ~ 0.40 H2O
C, 49.07; H, 4.52; N, 9.58 Found: C, 49.08; H, 4.47; N, 9.68 CA 02246756 l998-08-l8 ~0 0 ~ ~OEt 02N~
c~3 Step 1: N-3-Methyl-4-nitrophenyl-N-benzoyl-glycine ethyl ester (5-131) Following the procedure described for 5-13a. but sub~liluting 3-methyl-4-nitroaniline for 4-nitroaniline, 5-131 was prepared.
~00 O ~ N~OEt ~N'¢~ CH3 BocN J 5-141 Step 2: N- { 4-[4-(4-tert-Butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino]-3-methyl-phenyl }-N-benzoyl~lycine ethyl ester (5-141) Following the procedure described for 4-lOa, but 15 substituting N-3-methyl-4-nitrophenyl-N-benzoyl-glycine ethyl ester WO g7/3~910 PCT/US97/02712 (5-131) for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl es~er (4-8a),5-141 was prepared.
~0 0 ~ N ~:~J''' C H3 HN ~,J
5-15i Step 3: N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonylaminol -3 -methyl-phenyl~-N-2-benzoyl~lycine (5-151) Following the procedure described for 4-1 la, but substituting N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-10 phenylcarbonylamino]-3-methyl-phenyl}-N-benzoylglycine ethyl ester (5-141) for N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylamino]phenyl}-N-phenylsulfonylglycine ethyl ester (4-IOa), 5-151 was prepared.
Analysis calculated for C27H2gN404 ~ 1.52 TFA ~ 0.54 H20 C, 55.04; H, 4.70; N, 8.55 found: C, 55.03; H, 4.71; N, 8.84 CA 02246756 l998-08-l8 WO 97/31910 PCT/IJS97/027~2 ~0 0 ,¢~ ~OEt 5-1 3m Step 1: N-2-Methyl-4-nitrophenyl-N-benzoyl-glycine ethyl ester (5-13m) Following the procedure described for 5-13a~ but substituting 2-methyl-4-nitroaniline for 4-nitroaniline, 5-13m was prepared.
~00 o ~N~OEt ,¢~ tNi ~ C H3 f N
BocN 'J
~-1 4m Step 2: N - { 4- [4-(4-tert-Butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino]-2-methyl-phenyl }-N-benzoylglycine ethyl ester (5-14m) Following the procedure described for 4-lOa. but substituting N-2-methyl-4-nitrophenyl-N-benzoylglycine ethyl ester (5-13m) for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (~), 5-14m was prepared.
~00 ~ ,¢~ ~OH
HNJ
5-t~m Step 3: N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonylamino} -2-methyl-phenyl ~ -N-2-benzoyl~lycine (S- l Sm) Following the procedure described for 4-1 la. but substituting N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-lO phenylcarbonylamino3-2-methyl-phenyl}-N-benzoylglycine ethyl ester (S- l 4m) for N- { 4-r4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylamino]phenyl}-N-phenylsulfonylglycine ethyl ester (4- l Oa), 5-1 5m was prepared.
Analysis calculated for C27H2gN40~ ~ 1.56 TFA ~ 0.58 H20 lS C~ 54.74; H, 4.69; N, 8.48 ~ound: C, 54.75, H, 4.69; N, 8.74 CA 02246756 l998-08-l8 WO 97/31910 P~'r/US97/OZ712 .
~ EXAMPLE SN
~~ O
O ~ N~OEt H J~
I--N
BocN J CH3 ~-14n Step 1: N-{4-~4-(4-tert-Butyloxycarbonyl-piperazin-1 -yl)-3-methylphenyl-carbonylamino3-phenyl } -N-benzoylglycine ethyl ester ~5-14n) Following the procedure described for 4-lOa, but substituting N-4-nitrophenyl-N-benzoylglycine ethyl ester (5-13a) for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (4-8a), and sub~liLu~ g 4-[4-(tert-butyloxycarbonyl)piperazin-1-yl]-3-methylbenzoic acid for 4-[4-(tert-butyloxycarbonyl~piperazin-1-yl]-benzoic acid, 5-14n was prepared.
~,00 N
H
~N' ~
HN ''J CH3 5-1 5n Step 2: N- ~ 4-[4-(Piperazin- 1 -yl)-3-methyl-phenylcarbonylamino]-phenyl ~ -N-benzoylglycine (5- 15n~
Following the procedure described for 4-l la, but 5 substituting N- { 4-~4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-3 -methylphenylcarbonylamino] -phenyl } -N -benzoylglycine ethyl ester (5-14n) for N-{4-[4-(4-tert-butyloxycarbonyl-piperazin-1-yl)-phenylcarbonylamino]phenyl}-N-phenylsulfonylglycine ethyl ester (4- 1 Oa), 5- 15n was prepared.
10 AnaIysis calculated for C27H28N404 ~ 1.42 TFA ~ 0.44 H20 C, 55.79; H, 4.75; N, 8.72 Found: C, 55.80; H, 4.76; N, 8.78 ~00 o ,~N~OEt ~H
~N Clt3 BocN ~J
5-14c Step 1: N- {4-[4-(4-tert-Butyloxycarbonyl-piperazin- 1 -yl)-2-methylphenyl-carbonylamino]-phenyl } -N-benzoylglycine ethyl ester (5-140) Following the procedure described for 4-lOa, but substituting N-4-nitrophenyl-N-benzoylglycine ethyl ester (5-13a) for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester ~4-8a), and substituting 4-[4-(tert-butyloxycarbonyl)piperazin- 1 -yl 3 -2-methyl-benzoic acid for 4-[4-(tert-butyloxycarbonyl)piperazin-1-yl3-benzoic acid, 5-140 was prepared.
.
~00 ,¢~ N J3' ~N CH3 HNJ
5-15c Step 2: N- { 4-[4-(Piperazin- 1 -yl)-2-methylphenylcarbonylamino]-S phenyl ~-N-benzoyl,~lYcine ~5-150) Following the procedure described for 4-1 la, but substituting N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-2-methylphenylcarbonylamino] -phenyl } -N -benzoylglycine ethyl ester (5-140) for N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-10 phenylcarbonylamino]phenyl}-N-phenylsulfonylglycine ethyl ester ~4-lOa), S-lSo was prepared.
Analysis calculated for C27H2gN404 ~ 1.56 TFA ~ 0.46 H20 C, 54.92; H, 4.66; N, 8.51 Found: C, 54.93; H, 4.67; N, 8.58 WO 97/31910 PCT/lJS97102712 S(~HEl~E 6 HN~ BOC20 tBuO N~Br 1. CH3MgBr 2. tBuLi 3. C~
tBuO~N~, ~OH SO2Ph 0 6-3 H2N~N~,CO2Et/PYCLU
--~ SO2Ph 1. HCI/EtOAc tBuO~N~ H H~N~CO2Et ~--~ SO2Ph HN~N H~N~CO2H
E~AMPLE 6 tBuO~N~O N~CO2Et ~g 1 . HCI/EtOAc 2. LiOH
HN~O SO2Ph S ~tep 1: 9-H-2-(1,1-Dimethylethoxycarbonyl)-7-bromo ,13-carboline (6-2) A suspension of 6-1, prepared by the method of Rinehart et al., (JACS, 1987,109, p 3378-3387) (0.366 g, 1.46 mmol) in CH2C12 (8 mL) was treated with triethylamine (0.61 mL, 4.4 mmol) followed by di-tert-butyldicarbonate (0.38 g, 1.7 mmol) for 1 hour at room temperature. The solution was concentrated and the residue chromatographed (20% EtOAc/Hexanes) to give 6-2 as a white solid.
Rf(20% EtOAc/Hexanes) 0.28 lH NMR (400 MHz, CDC13) ~ 8.0-7.6 (m, lH), 7.46 (s, lH), 7.33 (d, lS lH), 7.2 (d, lH), 4.6 (bs, 2H), 3.78 (bs, 2H), 2.76 (bs, 2H), 1.5 (s, 9H).
Step 2: 9-H-2-(1,1 -Dimethylethoxycarbonyl)-,13-carbolin-7-yl carboxylic acid (6-3) A solution of 6-2 (0.26 g, 0.734 mmol) in THF (10 mL) 20 was cooled to 0~C and treated with methylmagnesium chloride (3.0 M in THF, 0.29 mL, 0.87 mmol) to give a pale yellow solution. After 15 minutes the solution was cooled to -78~C and treated with t-BuLi (1.7M
in pentane, 4.35 mL, 7.39 mmol) to give a bright yellow solution.
After 10 minutes C02 gas was bubbled vigorously through the solution for I0 minutes. Saturated NH4CI, water and enough 6N NaOH to reach pH12 were added and the solution extracted with EtOAc. The EtOAc layer was back extracted with 0.5 NaOH and the aqueous layers combined, acidfied to pH 7 and extracted with EtOAc, the EtOAc layer S was dried (Na2S04) filtered and concentrated to give 6-3 as an off-white solid.
Rf(75:25:1 CHCl3/MeOH~lIOAc)0.48.
lH NMR (400 MHz, DMSO-d6) ~ 12.0 (bs, lH), 11.2 (s, lH), 7.93 (s, lH), 7.6 (d, lH), 7.45 (d, lH), 4.6 (s, 2H), 3.68 (m, 2H), 2.7 (m, 2H), 1.4 (s, 9H).
Step 3: N- f 4-{9-Boc-~B-carboline-7-yl)carbonyl~mino]phenyl } -N-phenvl-sulfonyl glycine (6-4) A solution of 6-3 (0.075 g, 0.24 mmol) and N-4-aminophenyl-N-phenylsul~onylglycine ethyl ester (0.086 g, 0.28 mmol) in CH2C12 (3 mL) was treated with diisopropyl~mine and PYCLU to give ~ as a white solid a~ter chromatography in a gradient of 40 to 50% EtOAc/Hexanes.
Rf(40% EtOAc/Hexanes)0.13 lH NMR (400 MHz, CDC13) ~; 8.5-8.2 ~m, lH), 8.0 (d, lH), 7.2 (2s, 2H), 7.6 (2s, 2H), 7.58 (m, lH), 7.53 (s, 2H), 7.47 (m, 2H), 7.2 (d, 2H), 4.68 (bs, 2H), 4.4 (s, 2H), 4.13 (q, 2H), 3.8 (bs, 2H), 2.7 (bs, 2H), 1.5 (s, 9H), 1.2 (t, 3H).
Step: 4 N- { 4-[(9-H-~-Carboline-7-yl)carbonylamino]phenyl ~ -N-phenyl-sulfonyl ~lycine (6-5) A solution of 6-4 (0.088 g, 0.139 mmol) in EtOAc (15 mL) was treated first with HCl gas, then with LiOH~H2O to give 6-5 as a white solid after chromatography in 18:1:I EtOH/H2O/NH4OH.
Rf(l 8:1:1 EtOH/H2O/NH4OH) 0.43 lH NMR (400 MHz, D20) ~ 7.79 (s, IH), 7.6 (m, 1H), 7.52 (m, 2H), 7.46 (m, 4H), 7.32 (d, 2H), 7.08 (d, 2H), 4.08 (s, 2H), 3.84 (s, 2H), 2.95 (m, 2H), 2.63 (m, 2H).
WO 97/31910 PCT/lJS97/02712 SC~IEME 7 N~CH3 Z~
KMnO4/H2o N~ CO2H 7-2 1. H2/PtO2/HOAc/MeOH
60 psi 2. BOC2O
BOCN~CO2H 7-3 so2C6H5 NJ~N PF6 H2N~N CO2Et [~ ~
i-Pr2NEt, CH2CI2 BOCN~ }~~ N ~,CO2Et LiOH
SCE~EME 7 CON~ED
BOCN~ SO2C6H~
H ~ N~,CO2H
HCUEtOAc HN/~N~SO2CGH
Step 1: 4-(4-Pyridyl)phenylcarboxylate (7-2) A slurry of 7-1 (5g, 29.6 mmol, prepared as described in Chambron, J.C.; Sauvage, J.P., Tetrahedron, 1987, 895 and Comins, D.L., Abdullah, A.H., J. Org. Chem., 1982, 47, 4315 method B) in 200 mL H20 was treated with 10% HCl until the solids dissolved. The solution was treated with solid KMn04 in portions (11.2 g, 888 mmol), stirred until the KMn04 had dissolved and heated to 90~C for 18 hr.
An additional 2 g of KMnO4 was added and the reaction was again 15 heated to 90~C for 2 hr. The reaction was cooled to ~60~C, filtered and the solids were washed with warm water. The filtrate was evaporated and the residue chromatographed (Silica gel, 10~ EtOH/H20/NH40H) to give 7-2 as an off-white solid.
lH NMR (400 MHz, DMSO) ~ 8.61 (m, 2H), 8.0 (m, 2H), 7.72 (m, 4H).
~ Step 2: 4-(4-N-BOC-piperidinyl)phenylcarboxylate (7-3) A solution of 7-2 (0.5 g7 2.5 mmol) in 20 mL 20%
HOAc/MeOH was treated with 250 mg PtO2 and hydrogenated at 50 psi for 4 hr. The solution was filtered through SoLka Floc, evaporated and S azeotroped with heptane to remove excess HOAc. The intermediate amino acid acetic acid salt was obtained as a white solid.
Rf(10:1:1 EtOH/H2O/NH4OH) 0.3.
lH NMR (400 MHz, CD3OD) ~ 8.96 ~m, 2H), 7.35 (m, 2H), 3.5 (bd, 2H), 3.4 (m, 2H), 3.2 (m, 2H), 3.0 (m, 2H).
A slurly of the amino acid (0.5 g, 1.9 mmol) in 30%
H2O/dioxane (12 mL) was treated with 1 N NaOH (4.8 mL) and di-ter~-butyldicarbonate (0.564 g, 2.58 mmol) at room temperature for 6 hr.
The reaction was acidified to pH S with 10% KHSO4 and extracted several times with EtOAc.
The EtOAc layers were combined and evaporated to give 7-3 as a white solid.
Rf(97:3:1 CHCl3/MeOH/HOAc) 0.39.
lH NMR (400 MHz, CD30D) ~i 7.95 (d, 2H), 7.33 (d, 2H), 4.2 (bd, 2H), 2.85 (b, 3H), 1.8 (bd, 2H), 1.6 (m, 2H), 1.48 (s, 9H).
Step 3: Ethyl 2-(1 -phenylsulfonamido-4-(4-(N-(1,1 -dimethylethoxycarbonyl)-piperidin-4-yl)phenyl-carboxamide~-phenyl)acetate (7-4) A solution of ~ (0.457 g, 1.5 mmol) N-4-aminophenyl-N-phenylsulfonylglycine ethyl ester (0.50 g, 1.5 mmol) in CH2CI2 (10 mL) was treated with diisopropylamine (0.287 mL, 1.65 mmol) and PYCLU (0.594 g, 1.65 rnmol) and stirred at room temperature for 24 hours. The solution was diluted with EtOAc and washed with H2O, 10% citric acid, saturated NaHCO3 and brine, dried over MgSO4, filtered and evaporated to give 7-4 as a tan oil. Rf(50%
EtOAc/Hexanes)0.16 1H NMR (400 MHz, CDC13) ~ 7.8 (d, lH), 7.7 (d, lH), 7.58 (m, 3H), 7.45 (m, 2H), 7.32 (d, lH), 7.2 (d, lH), 4.4 (s, 2H), 4.25 (m, 2H), 4.15 (q, 2H), 2.82 (m, 2H), 2.78 (m, lH), 1.82 (bd, 2H), 1.6 (m, 3H), 1.45 (s, 9H), 1.2 (t, 3H).
Step 4: N- { 4-[4-N-Boc-piperidin-4-yl)phenylcarboxylamino]-phenyl ~-N-phenylsulfonyl~lycine (7-5~
A solution of 7-4 (0.7 g, 1.12 mmol) in 1:1:1 MeOH/H20/rrHF was treated with LiOH-H20 (0.097 g, 1.12 mmol) for 24 hours. The solution was diluted with EtOAc and ln% KHS04 and the layers separated. The organic layer was dried over MgS04, filtered and evaporated to give 7-5 as a tan solid.
Rf(9: I: 1 CH2Cl2/MeOH/HOAc)0.55 1H NMR (400 MHz, CD30D) ~ 7.89 (m, 2H), 7.65 (m, 5H3, 7.05 (m, 2H), 7.8 (d, 2H), 7.18 (d, 2H), 4.4 (s, 2H), 4.2 (bd, 2H), 2.85 (m, 3H), 2.83 (bd, 2H), 1.6 (m, lH), 1.48 (s, 9H).
Step 5: N-{4-[4-Piperidin-4-yl)phenylcarbonylamino]phenyl } -N-phenyl-sulfonyl~lycine (7-6) ~ solution of 7-5 (0.4 g, 0.67 mmol) in EtOAc (5 mL) was cooled to -78~C, saturated with HCl gas, warmed to 0~C and stirred for 1 hour, then concentrated at ambient temperature to give 7-6 as a white solidafterchromatographyin 10:1:1 EtOH/H20/NH40H.
Rf(l o~ EtOH/H20/NH40H)0.34 ~H NMR (400 MHz, ~2~ + NaOD) ~ 7.65-7.4 (m, 7H), 7.35 (d, 2H), 7.26 (m, 2H), 7.05 ~m, 2H), 4.08 (bs, 2H), 2.95 (m, 2H), 2.55 (m, 3H), 1.65 (m, 2H), 1.45 (m, 2H).
~ + ~OEt 1. N-Methylmorpholine, NMP
N HN 2. LiOH, H20 o t. (COCI)2 ~OH SO2 O
f~N 2,~,N 'J~OEt N 8-t H2N
SO2 ~ NaOH
O r~ ~OEt ~NH~
N
~' SO2 ~
O ~N~J~OH
~N~
~,N
Il l 8-3 N ~
Step 1: 4-(Pyridyl)piperidin-4-yl-carboxylic acid (8-1) Ethyl isonipecotate (6.0 g, 38.66 mmol), 4-chloropyridine hydrochloride (5.9 g, 38.66 mmol) and N-methylrnorpholine ~9.3 mL, 85.0 mmol) were dissolved in N-methylpyrrolidinone (50 mL~ and the resulting solution heated at 100~ for 48 h. The solution was concentrated in vacuo and the residue dissolved in ethyl acetate (200 mL) and washed with water and brine (2 x 100 rnL), then dried IO (Na2S04) and evaporated. The resulting residue was purified by flash chromatography (5%MeOH/CH2Cl2) to afford ethyl 4-(pyridyl)piperidin-4-yl-carboxylate as a crystalline solid.
A solution of the above ester (10 g, 42.7 mmol) in THF (50 mL) was treated with lN LiOH (47 mL, 47.0 mmol) and H20 (50 mL).
The resulting solution was concentrated and the aqueous residue cooled to 0~C, then adjusted to p~ ~ 6 with IN HCI and the resulting solid 8-1, collected by filtration.
Step 2: N- { 4-[N-(4-Pyridyl)-piperidinyl-4-carbonylamino]phenyl } -N-phenvl-sulfonyl-~lycine methyl ester ~8-2) Following the procedure described for 4-lOa. but substituting N-(4-pyridyl)-piperidinyl-4-carboxylic acid (~) for 4-~4-(tert-butyloxycarbonyl)-piperazin-l-yl]benzoic acid, 8-2 was prepared.
Step 3: N-{4-[N-(4-Pyridyl)-piperidinyl-4-carbonylamino]phenyl}-N-phenylsulfonyl-glycine (8-3) Following the procedure described for 4-1 la, N-{4-rN-~4-pyridyl)-piperidinyl-4-carbonylamino]phenyl ~ -N-phenylsulfonylglycine methyl ester 8-2 was hydrolyzed. HPLC purification provided 8-3.
Analysis calculated for C2sH2sN40sS ~ 1.40 TFA ~ 0.80 H20 C, 50.02; H, 4.23; N, 8.39 ~ound: C, 50.00; H, 4.24; N, 8.65 CA 022467=,6 1998-08-18 ~OH
~, NO2 ~N
~ BocN J
HN~
~N~ 1. H2, Pt/C, THF
--N 2. PhSO2CI, pyridine BocN J 9-2 H ,~
,¢~N~N~o2 1. NaH, BrCH2CO2-t-Bu 2. TFA, CH2C12 f~N ~
BocNJ g ~SI02 ~
~N
HN
-WO 97131910 PCTllJS97/02712 Step 1: N-4-(4-tert-Butyloxycarbonylpiperaziny- 1 -y)-benzoyl] -5-S nitro-indoline (9-2) Following the procedure described for 4-lOa, but substituting 5-nitroindoline C~L) for N-4-aminophenyl-N-phenylsulfonylglycine e~yl ester, 2~ was prepared.
Step 2: N-[4-(4-tert-Butyloxycarbonylpiperaziny-1-y)-benzoyl]-5-phenyl-sulfonylamino-indoline (9-3) Following the procedure described for ~, but subtituting N-[4-(4-tert-butyloxycarbonylpiperaziny- 1 -y)-benzoyl~-5-nitro-indoline (2~) for nitrobenzene 3-4, ~ was prepared. The catalytic 15 hydrogenation was carried out in the presence of Pt/C in THF.
~tep 3: N- { N-[4-(4-tert-Butyloxycarbonylpiperaziny- 1 -yl)-benzoyll-5-indolinyl~-N-phenylsufonyl-glycine (9-4) Following the procedure described ~or ~, but 20 substit-ltin~ N-[4-(4-tert-butyloxycarbonylpiperaziny- 1 -y)-benzoyl~ -5 -phenylsulfonylamino-indoline ~) for sulfonamide 3-5a7 9-4 was prepared.
Analysis calculated for C27H2gN405S ~ 1.50 TFA
~, 52.10, H, 4.30; N, 8.10 Folmd: C, 52.13; H, 4.26; N, 8.23 CA 02246756 l998-08-l8 H ~N~2 H2O2, NaC102 HO~No2 O O
, NH2 (COCI)2 --N
BocN J y H ~NO2 1 . H2, Pt2S, MeOH ~ N ~S
2. PhSO2CI, pyridine ~N
BocN J 10-3 @' SO2 O 1. NaH, H ~N ~JI~OMe BrCH2CO2Me ,[3~N~S 2. aq NaOH; TFA, ~N
BocN J 10-4 ~
,02 ~
--OH
~N~S
~N~ ~
WO 97/31910 PCT/IJS97tO2712 Step 1: 5-Nitro-thiophene-2-carboxylic acid (10-2) S To a cold (0~C) mixture of S-nitro-thiophene-2-carboxaldehyde Cl~.) (7.86 g, 50 mmol), NaH2P04 ~1.86 g, dissolved in 20 mL water), 30% H2~2 (6 mL) m acetonitrile (S0 mL), a solution of NaClO2 (8 g) in water (70 mL) was added over a period of I h.
After stirr~ng at RT for S h, the reaction mixture was treated with 10 sodium sulfite (S00 mg) and 1 M aq. HCl. The resultant mixture was extracted with ethyl acetate (3X). The organic extracts were combined, washed with brine, dried over anhdrous magnesium sulfate, filtered, and concentrated under vacuum to provide acid 10-2.
~S Step 2: N-(S-Nitro-thiophene-2-carboxyl)-4-(4-tert-butyloxycarbonyl-piperaziny-1-yl)-~niline (10-3) Following the procedure described for 3-4, but substituting S-nitro-thiophene-2-carboxylic acid ~10-2) for 4-nitroben~oic acid, 10-3 was prepared.
Step 3: N- { 2-r4-(4-tert-Butyloxycarbonylpiperazin-yl)-phenylamino-carbonyllthien-5-vl ~-N-phenylsulfonyl-glycine methyl ester (104) Following the procedure described for 3-Sa, but 2~ substitu~ing N-(5-nitro-thiophene-2-carboxyl)-4-~4-tert-butyloxy-carbonylpiperaziny-1-yl)-aniline ClQ~) for 3-4. The reduction was carried out in methanol in the presence of Pt2S i~or three hour under a balloon of hydrogen gas. Phenylsulfonylation, was described for 3-Sa provided 10-4.
31) WO 97/31910 PCT/~JS97/02712 _ 99 _ Step 4: N-{ 2-[4-(1 -Piperazin-yl)-phenylaminocarbonyl3thien-5-yl } -N-phenvl-sulfonyl-glycine (10-5) Following the procedure described for,3-6a, but sub~liluLillg 10-4 for~, iO-5 was prepared.
S Analysis calculat~d for C23H24N405S2 ~ 1.72 TFA ~ 0.28 H20 C, 45.25; H, 3.77; N, 7.98 found: C, 45.25; H, 3.77; N, 8.13 WO 97/31910 PCTlaTS97/02712 [~H HNO3 ~&~H
NaHMDS, BrCH2CO2Me H2, Pd/C
~ 02N 11-3 f N
BocN ~J
O ~ ~OMe aq. NaOH;
H TFA, CH2CI2 ~N
BocN J 11-4 ~ ,~OH
CA 022467~6 l998-08-l8 EX~MPLE 1 1 Step 1: 6-Nitro-3.4-dihydroquinolin-2-(lH)-one (1 1-2) S To a solution of 3,4-dihydroquinolin-2-(lH)-one (1.50 g) in 78% sulfuric acid (300 mL) at RT, a mixture of 69% nitric acid (0.84 mL) in 78% sulfuric acid (60 mL) was added. The reacting mixture was stirred at RT for lS min, poured into ice-water, and extracted with methylene chloride (3 x 200 mL). The organic extracts were combined, washed with brine (4 x), dried over anhydrous m~gnesium sulfate, filtered and concentrated onto silica gel. The residue was loaded onto a column of silica gel, and eluted with 3% methanol in chloroform.
Collection and concentration of appropriate fractions provided the nitroquinolinone 1 1-2.
Step 2: 6-Nitro- 1 -carbomethoxymethyl-3.4-dihydroquinolin-2-( 1 H)-one (1 1-3) Following the procedure described for 5-13a, but substituting 6-nitro-3,4-dihydroquinolin-2-(lH)-one (~) for 4-nitro-N-benzoyl~nil;ne, 1 1-3 was prepared.
Step 3: 6-~4-(4-tert-Butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylamino I-1 -carbomethoxymethyl-3,4-dihydroquinolin-2-( 1 H3-one ( 1 1 -4) Following the procedure described for 4-lOa. but substituting 6-nitro- 1 -carbomethoxymethyl-3 ,4-dihydroquinolin-2-( 1 H)-one (11-3) for N-4-nitrophenyl-N-phenylsulfonyl-glycine ethyl ester (~L
8a), 11-4 was prepared.
Step 4: 6-[4-(4-Piperazin-1-yl)-phenylcarbonylamino]-1-carbohydroxymethyl-3.4-dihydroquinolin-2-( 1 H3-one ( 1 1 -5) Following the procedure described for 4-l l a. but substituting 6-[4-(4-tert-butyloxycarbonyl-piperazin-1-yl)-WO g7/31910 PCT/US97/OZ712 phenylcarbonylamino~ -1 -carbomethoxy-methyl -3 ,4-dihydroqu~nolin-2-(lH)-one (11 -4) for 4- l Oa~ l 1 -5 was prepared.
Analysis calculated for C~22H24N404 ~ 1.22 TFA ~ 0.84 H20 C, 52.17; H, 4.82, N, 9.96 Found: C, 52.15; H, 4.82; N, 10.13 Tablet Preparation Tablets containing 25.0, 50.0, and 100.0 mg., respectively, of the active compound p) from Table I are prepared as illus~rated below:
TABLE FOR DOSES CONTA~ING
FROM 25-lOOMG OF THE ACTIVE COMPOUND
Amount-m~
Active Compound 25:0 50.0 100.0 Microcrystalline cellulose 37.25 100.0 200.() Modified food corn starch 37.25 4.25 8.5 Magnesium stearate 0.50 0.75 1.5 All of the active compound, cellulose, and a portion of the com starch are mixed and gr~n~ ted to 10% corn starch paste. The 20 resulting granulation is sieved, dried and blended with ~e remainder of the corn starch and the m~gn~sium stearate. The resulting gr~n~ tion is then compressed into tablets containing 25.0, 50.0, and 100.0 mg, respectively, of active ingredient per tablet.
Intravenous fo~nulations An intravenous dosage form of the above-indicated active compound is prepared as follows:
Active Compound 0.5-10.Omg Sodium Citrate 5-50mg Citric Acid 1-15mg Sodium Chloride 1 -8mg Water for Injection (USP) q.s. to 1 L
Utilizing the above quantities, the active compound is dissolved at room temperature in a previously prepared solution of sodium chloride, citric acid, and sodium citrate in Water for Injection (USP, see page 1636 of United States Phzlrm~copeia/National Formulary for 1995, published by United States Pharmacopeial Convention, Inc., Rockville, Maryland, copyright 1~94.
Therapeutic Treatment Compounds of the invention may be ~lministered to patients where inhibition of hllm~n or m~mm~lian platelet aggregation or adhesion is desired.
Compounds of the invention are useful in inhibiting platelet aggregation and thus, they may find utility in surgery on peripheral arteries (arterial grafts, carotid endaterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interation of platelets with artificial surfaces, leads to platelet aggregation and consumption. The aggregated platelets may form thrombi and thromboemboli. Compounds of the invention may be ~flmini~tered to these surgical patients to prevent the formation of thrombi and thromboemboli.
R1a R1_N N~\ N~N
\ I , ~I , R1a R1a /~ R1--NH N , ~(R1~_, (C~ ~ R ~ (C~N
n is an integer selected from 2, 3, 4, and 5;
Q is selected from -N(R1)-, -S- and -0-;
S Y is selected from:
(1) -Co g aLkyl-NRI-Co-co-8 alkyl-, (2) -Co g a~kyl-CONRl-Co g alkyl-, (3) -C0-8 aLkyl-O-Co 8 alkyl-, (4) -Co g aLkyl-SOp-co-g alkyl-, (5) -(C H 2)0-6-N Rl-(C H 2)0 6-, (6) -C0-8 alkyl-S Op-~nRl-Co-8 alkyl-, (7) -Co g aLkyl-CO-CO 8 alkyl-, and (8) -Co g alkyl-CH(OH)-Co g-alkyl-;
15 p is an integer selected from 0, 1 and 2;
Z is selected from (1) aryl and (2) a five or six membered saturated, partially unsaturated or aromatic heterocyclic ring which is unsubstituted, or .
monosubstituted or disubstituted with R 1 a, which consists of carbon atoms and one, two or three heteroatoms selected from the group -O-, -N-, -N(Rl~- and -S-, and which may be fused to a benzene ring to form a bicyclic structure, for example, --N~ or ~ ~
aryl is a 5- or 6-membered aromatic carbon ring which is unsubstituted or mono-, di- or tri-substituted with R2;
Rl is independently selected at each occurrence from -H, Cl lo alkyl, C3-8 cycloalkyl-, aryl-Co 8 aLkyl- and hydroxy-Co 6 alkyl-;
Rla is independently selected at each occurrence from -H, halogen, -Cl-10 aLkyl, C3-8 cycloalkyl-, aryl-Co 8 aLkyl-, and amino-C0 8 alkyl-;
R2 is independently selected at each occur~ence ~rom -H7 halogen, -Cl lo aLkyl, C3-8 cycloalkyl-, aryl-Co 8 alkyl- and Cl 4 alkoxy-Co 8 aLkyl-;
R3 is independently selected at each occurrence from -H, -~1-10 alkyl, C3-8 cycloaLkyl- and aryl-Co 8 aLkyl-;
R5 is selected from:
( 1 ) -OH, (2) C1 8 alkyloxy-, (3) aryl-Co 6 aLkyloxy-, (4) C1 8 aLkylcarbonyloxy-Cl 4 alkyloxy-, and (S) aryl-C 1-8 alkylcarbonyloxy-C 1-4 alkyloxy-;
D is selected from -SO2- and -C(O)-; and R6 is selected from:
(1 ) -Cl 6aLkyl, unsusbstituted, mono- or di-substituted with Rla, (2) -(Co 6aL~cyl)aryl, wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rla, (3) -(Co 6alkyl)heterocycle, wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rla, (4) -NRl(Cl 6aL~cyl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (5) -NRl(Co 6alkylaryl~, wherein the aLkyl group is unsusbstituted, mono- or di-substituted with R1a, (6) -NRl(~0 6aLkylheterocycle), wherein the aLkyl group is unsusbstituted, mono- or di-substituted with R1a, (7) -C3-6 cycloaLkyl, (8) -CF3, (9) ~~ ~ (10)~?
O CH2 , and Cl H2 o OF
~1 l ) when Z is unsubstitu~d or substituted phenyl, D-R6 lS together with the nitrogen to which it is attached can form a bicyclic structure with Z (phenyl) as follows:
~0 'CH-C-R5 ~\iJ~ R3 1 1 R2 ; and heterocycle is selected from a five or six membered saturated, partiall~
unsaturated or aromatic ring which is unsubstituted, or monosubstituted or disubstituted with Rla, and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(R1)- and -S-;
and wherein the rem~ining variables are as defined above in formula I.
CA 022467=,6 1998-08-18 In a second, further embodiment of this invention are compounds of formula II and the pharmaceutically acceptable salts, solvates and stereoisomers thereof wherein X-A- together represent a group selected from:
Rl-N N~ R1-R1a R1a N3N/~} , and S R
and the rem~inin~ variable are as defined above in formula ~.
In a third, fur~er embodiment of this invention are 10 compounds of formula II and the ph~ eeutically acceptable salts, solvates and stereoisomers thereof wherein X-A- together represent a group selected from:
R1-N~ N~ R1_N3 R1a R1a 3 /~}, and /~
R1a 15 and the pha~naceutically acceptable salts, hydrates and stereoisomers thereof wherein:
Q is selected form -NH-, -O- and -S-;
Y is selected from:
( 1 ) -NR I -CO-, (2) -CONR I -, (3) -O-, (4) -SOp (5) -NRl (6) -SOp-NR 1 , (7) -CO-, and (8) -CH(OH)-;
p is an integer selected from 0, 1 and 2;~0 Z is selected from:
( 1 ) phenyl, (2) phenyl which is mono-, di- or tri-substituted with R2, (3) thienyl, --N~
(4) and (5) o R1 is independently selected at each occurrence from -H and -C1-10 alkyl;
R 1 a is independently selected at each occurrence from -H, halogen and -Cl 1o alkyl, R2 is independently selected at each occurrence from -H, halogen and -C l l o aIkyl;
R3 is independently selected at each occurrence from -H and -Cl lo alkyl;
25 R5 is selected from:
( 1 ) -OH, (2) C1 8 alkyloxy-, (3) aryl-Co 6 aLkyloxy-, (4) C 1-8 alkylcarbonyloxy-C l 4 alkyloxy-, and (5) aryl-Cl 8 aLkylcarbonyloxy-Cl 4 aLkyloxy-;
D is selected from -SO2- and -C(O)-; and R6 is selected from:
(1) -Cl 6aL~cyl, unsusbstituted, mono- or di-substituted with ~la, (2) -(Co 6aL~cyl)aryl, wherein the alkyl group is unsusbstituted, mono- or di-substituted with Rla, (3) -(Co 6alkyl)heterocycle, wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rla, (4) -NRl(Cl 6aLkyl), wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rl a, (5) -NRl(Co 6alkylaryl), wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rla, (6) -NRl(Co 6aLkylheterocycle), wherein the aLlcyl group is unsusbstituted, mono- or di-substituted with Rla, (7) -( ~3-6 cycloaLkyl, (8) -CF3, (g) ~ (10)~
O CH2 , and Cl H2 ~ or (1 ~ ) when Z is unsubstituted or substituted phenyl, D-R6 together with the nitrogen to which it is attached can form a bicyclic structure with Z (phenyl) as follows:
~0 CH- ICI -R~
R2 ; and heterocycle is selected from a five or six membered saturated, partially , -unsaturated or aromatic ring which is unsubstituted, or monosubstituted or disubstituted with Rla~ and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(Rl)- and -S-;
and any rem~ining variables are as defined in follnula II.
In a fourth, further embodiment of this invention are compounds of formula II having the particular formula III
R1-N~N~ \D-R6 R1a III
and the ph~ ceutically acceptable salts, solvates and stereoisomers thereof wherein:
15 Y is selected from:
(1) -NR1 CO, (2) -CONR 1 , (3) -O-, (4) -SOp (5) -NR ~ -, (6) -SOp-NR 1 , (7) -CO-, and (8) -CH(OH)-;
25 p is an integer selected from 0, 1 and 2;
Z is selected from:
( 1 ) phenyl, (2) phenyl which is mono-, di- or tri-substituted with R2, (3) thienyl, --N~ , N
(43 and (S) o Rl is independently selected at each occurrence from -H and 10 alkyI;
5 R I a is independently selected at each occurrence from -H, halogen and -Cl lo alkyl;
R2 is independently selected at each occurrence from -H, halogen and -Cl 1o alkyl;
R3 is independently selected at each occurrence from -H and -C~l-10 alkyl;
RS is selected from:
( 1 ) -OH, (2) C 1-8 alkyloxy-, (3) aryl-Co 6 aLkyloxy-, (4) C1 8 aLkylcarbonyloxy-Cl 4 aLkyloxy-, and (S) aryl-C 1-8 aLkylcarbonyloxy-C 1-4 aLkyloxy-;
D is selected from -SO2- and -C(O)-; and R6 is selected from:
(1) -Cl 6aLkyl, unsusbstituted, mono- or di-substituted with Rla, (2) -(Co 6aLkyl)aryl, wherein the aLkyl group is unsusbstituted, mono- or di-substituted with ~la, (3) -(Co 6alkyl)heterocycle, wherein the alkyl group is unsusbstituted, rnono- or di-substituted with Rl a, (~) -NRl(Cl 6alkyl), wherein the aLkyl group is unsusbstituted, mono- or di-substituted with R 1 a, (5) -NRl((:~0 6alkylaryl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (6) -NRl(Co 6aLkylheterocycle), wherein the aLkyl group is unsusbstituted, mono- or di-substituted with R1a, (7) -C3-6 cycloaLkyl~
(8) -CF3, (g) ~ (10) ~
O CH2 , and I , or S (11) when Z is unsubstituted or substituted phenyl, D-R6 together with the nitrogen to which it is attached can form a bicyclic structure with Z (phenyl) as follows:
~0 'CH-C-R5 ~\iJ~ R3 o R2 ; and heterocycle is selected from a five or six membered saturated, partially unsaturated or aromatic ring which is unsubstituted, or monosubstituted or disubstituted with R1a, and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(R1)- and -S-;
and the rem~ining variables are as defined in formula II.
In a fifth, further embodiment of this invention are compounds of formula III having the particular formula IV
Rl-N N~Y~ CH~ R5 Rla R2 IV
and the ph~ ceutically acceptable salts, solvates and stereoisomers thereo~ wherein:
Y is selected from -C(O)-N(R 1 )- and -N(R 1 )-C(O)-;
R1 is independently selected at each occurrence from -H and S -C~ lo aLkyl;
Rla is independently selected at each occurrence from -H, halogen and -Cl 10 alkyl;
R2 is independently selected at each occurrence from -H, halogen and -Cl lo alkyl;
R3 is independently selected at each occurrence from -H and -~1-10 alkyl;
RS is selected from:
(1) -OH, (2) C1 8 alkyloxy-, (3) aryl-Co-6 alkyloxy-, (4) C1 8 alkylcarbonyloxy-Cl 4 aLkyloxy-, and (5) aryl-Cl g aLkylcarbonyloxy-Cl 4 aLkyloxy-;
D is selected from -SO2- and -C~O)-; and R6 is selected from:
(1 ) -C~1 -6alkYl~ unsusbstituted, mono- or di-substituted with Rla, (2) -(Co 6aLkyl)aryl, wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rl a, (3) -(Co 6alkyl)heterocycle, wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rla, (4) -NRl(CI 6alkyl), wherein the aLkyl group is unsusbstituted, mono- or di-substituted with R 1 a, (S) -NRl(Co 6alkylaryl), wherein the aLkyl group is unsusbstituted, mono- or di-substituted with Rl a, (6) -NRl(Co 6aLkylheterocycle), wherein the alkyl group is unsusbstituted, mono- or di-substituted with Rla, (7) -C3-6 cycloalkyl, (8) -CF3, CA 022467~6 1998-08-18 ~ <
(g) ~ (10)~
OCH2 , and I , or (1 1 ) when Z is unsubstituted or substituted phenyl, D-R6 together with the nitrogen to which it is attached can form a bicyclic structure with Z (phenyl) as follows:
~0 J~ R3 li R2 ; and heterocycle is selected from a five or six membered saturated, partially unsaturated or aromatic ring which is unsubstituted, or monosubstituted or disubstituted with Rla, and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(R1)- and -S-;
and any rem~ining variables are as defined in formula III.
In a sixth, further embodiment of this invention are compounds of formula I~ wherein Y is selected from -C(O)-NH- and -NH-C~(O)-; and R6 is selected from (1) unsubstituted, mono and di-substituted phenyl, (2) methyl, (3) benzyl wherein the aryl portion may be unsubstituted, mono or di-substituted, and (4) thienyl; and any remaining variables are as defined in formula IV.
Tn one class of the instant six embodiments are compounds of formulas I, II, III, and IV as defined in the general definition wherein Y is -C(O)-NH-. Compounds in this class are exemplified, but not limited to, those of formula V as defined in Table I. The carbons around the phenyl rings in formula V have been arbitrarily numbered in order to clearly identify the substituent positions, where necessary.
TABLE I
HN~N~ C-NH--~ D-R6 R1a R2 V, R1a R_ R_ D R_ a) H H OCH2CH3 -C(O)- phenyl b) H H OH -C(O)- -CH3;
c) H H OH -C(O)- phenyl;
d) lH H OCH3 -C(O)- -CH3;
e) H H OH -C(O)- 2-F-phenyl;
f) H H OH -C(O)- cyclopropyl;
g) H H OH -C(O)- 3-pyridinyl;
h) H H OH -C(O)- 4-pyridinyl;
i) 6-CH3 H OH -C(O)- phenyl;
j) H 6-CH3 OH -C(O)- phenyl;
k) H S-CH3 OH -C(O)- phenyl;
1) H H OH -SO2- -CF3;
m~ H H O~ -SO2- 2-F-phenyl;
n) H H OC2HS -S02- 2-thienyl;
o) H H OH -so2- 2-thienyl;
p) H H OH -so2- phenyl;
q) H 6-CH3 O~ -SO2- phenyl;
r) H 2-Br OH -SO2- 2-F-phenyl;
s) H H OH -S~2-o CH2 CA 02246756 l998-08-l8 t) H H OH -S02- G~?
CH2 o ; and u) H H OH -C(O)- -CH2-CH2- bondedto D and the carbon denoted with * to form ~0 ~ CHz-~
In a second class of the instant embodiments are compounds of formulas I, II, m, and IV wherein Y is -NH-C(O)-. Compounds in this class are exemplified, but not limited to, those of formula VI as S defined in Table II.
TABLE II
~ 1~ CH2 B- R5 HN N~NH-C--Z--N
\=/ SO2-R6 Vl Z R_ R6 a) 1,4-phenyl OH CH3;
b) 1,4-phenyl OCH3 CH3;
c) 1,4-phenyl OCH(CH3)2 CH3;
d) 1,4-phenyl OH phenyl e) 1,4-phenyl OH 4-Br-phenyl;
f) 1,4-phenyl OH benzyl; and g) 2,5-thienyl OH phenyl.
Additional examples of compounds within the scope of this ~nvention are shown below but a~e not limited to, those of formula VII
as defined in Table III.
T~BLE III
Cl 12-C-OH
X~A~Y~Z~(CH2)n--N~ /=\
Vll SO2~
X-A Y Z n N~3 3 -C(O)NH- 1,4-phenyl 0 HN~ -C(O)NH- 1,4-phenyl 0 c) ~ ~ -C(O)NH- 1,4-phenyl 0 HN~
HN
HN~ CH2)2-HN~ } -(CH2)3-0- 1,4-phenyl s Wlhen any substituent (e.g., Rl, R2, etc.) occurs more than one time in any constituent, its definition on each occurrence is independent of its definition at any other occurrence. Also, combinations of substitutents and/or variables are pe~nissible only if such combinations result in stable compounds.
As used herein "aLkyl" is intended to include bo~
branched- and straight-chain saturated aliphatic hydrocarbon groups S having the specified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, heptyl, octyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), secbutyl (s-Bu), tertbutyl (t-Bu), isopentyl, isohexyl and the like. The term "cycloaLkyl" is intended to include cyclized alkyl chains having the 10 specified number of carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. "Alkoxy" or "alkyloxy"
represents an alkyl group having the indicated number of carbon atoms attached through an oxygen bridge, e.g., methoxy, ethoxy, propyloxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy 15 and the like.
The specified number of carbon atoms in the appropriate groups described herein may include a zero in the range, e.g., C0-6 or C0 8. When a zero is in the specified range, it means that a bond is present in place of that carbon group.
The term halo or halogen is meant to include fluoro, chloro, bromo and iodo. The term "oxy" means an oxygen (O) atom.
~e term "aryl" is defined above in the definition of Formula I; unsubstituted, mono-, di- and tri-substituted phenyl (Ph) 2~ is preferred.
The tellll heteroaryl is defined above in the definition of Formula I. The term heteroaryl encompasses a five or six-membered heteroaryl ring as defined in formula I ~used to a benzene, pyridine or pyrimidine ring. Examples of heteroaryl 30 groups include pyrrolyl, triazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, furanyl, pyranyl, thienyl, oxazolyl, isooxazolyl, thiazolyl, indolyl, benzimidazolyl, benzofuranyl, benzopyranyl, benzothienyl, quinolyl, isoquinolyl and the like. The heteroaryl ring may be attached within structural Formula I at any CA 022467~6 l998-08-l8 heteroatom or a carbon atom in the ring which results in the creation of a stable structure. Preferred heteroaryl groups include pyridyl, ~ thiazolyl, oxazolyl, thienyl, indolyl, benzofuranyl, and benzothienyl.
The term "C0-6 alkylaryl" as used herein includes an alkyl 5 group as defined above bonded to an aryl group as defined above. The C0-6 designation refers to the alkyl component of the alkylaryl unit.
Examples of C0-6 aL~cylaryl include phenyl-, benzyl-, fluorobenzyl-, chlorobenzyl-, phenylethyl-, phenylpropyl-, fluorophenylethyl-, and chlorophenylethyl-.
The term "C0-6 alkylheterocycle" as used herein includes an alkyl group as defined above bonded to a heterocycle group as defined above. The C0-6 designation refers to the aL~cyl component of the alkylheterocycle unit. Examples of C0-6 aLkylheterocycle include thienyl-, thienylmethyl-, thienylethyl-, and thienylpropyl-.
Arnino acids suitable for compounds of the present invention include naturally occurring L- or D-amino acids, for exarnple, those naturally occurring L-amino acids present in hllm~n~, e.g., protein amino acids, including L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glllt~mine, L-glutamic acid, L-glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenyl~l~nine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, and L-valine, and those naturally occurring D-amino acids which are non-protein arnino acids, such as those found, for example, in antibiotic substances produced by bacteria and fungi, including D-valine, D-asparagine, D-glllt~m~te, D-ornithine, D-phenyl~l~nine, D-leucine, D-cysteine, and D-aspartate. (see Zubay "BIOCHEMI~TRY" Addison-Wesley Publi~hing Company, Inc. (Reading, MA) 1983 pp. 867-870 and Stryer "BIOCHEMISTRY" W.H. Freeman and Company (New York, NY) 3rd Edition 1988 pp. 16-21).
The term "pharmaceutically acceptable salts" shall mean non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following salts:
acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glllt~m~le, glycollylarsanilate, 5 hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, ~ te, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote, palmitate, panthothenate, phosphate/diphosphate, polygalacturonate, 10 salicylate, stearate, subacetate, succinate, t~nn~te, tartrate, teoclate, tosylate, triethiodide, valerate.
Prodrugs, such as ester derivatives of described compounds, are compound derivatives which, when absorbed into the bloodstream of a warm-blooded ~nim~l, anabolize or cleave in such a 15 manner as to release the drug fo~n and permit the drug to afford improved therapeutic efficacy.
The compounds of the present invention are chiral and the present compounds may occur as racemates, racemic mixtures and as individual diasteriomers or enantiomers with all such isomeric 20 forms being included within the scope of this invention.
Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the instant invention may form solvates with water or 25 common organic solvents. Such solvates and hydrates, as well as anhydrous compositions, are encompassed within the scope of this invention.
The term "therapeutically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the biological 3(~ or medical response of a tissue, system, ~nim~l or human that is being sought ~y a researcher, veterinarian, medical doctor or o~er clinician, which includes alleviation of the symptoms oi~ the disease being treated.
- The term "m~mm~l" includes hllm~ns.
CA 022467~6 1998-08-18 The term "anti-coagulant" shall include heparin, and warfarin. The term "thrombolytic agent" shall include agents such as - streptokinase and tissue pl~minogen activator. The term "platelet anti-aggregation agent" shall include agents such as aspirin and S dipyridamole.
The compounds of the present invention can be ~1mini.~tered in such oral fo~ns as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
10 Likewise, they may be ~-lministered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramusculsar form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an anti-aggregation agent.
(~ompounds of the invention may be ~clmini~tered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex IIb/I~Ia receptor is desired. They are useful in surgery on peripheral arteries (arterial grafts, carotid endarterectomy) and in cardiovascular surgery 20 where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption. The aggregated platelets may form thrombi and thromboemboli. Compounds of this invention may be ~1mini~tered to these surgical patients to prevent the formation of thrombi and 2~ thromboemboli.
Extracorporeal circulation is routinely used for cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit. Adhesion is dependent on the interaction between gp IIb/~IIa on the platelet membranes and 30 fibrinogen adsorbed to the surface of the circuit. (Gluszko et al., Amer.
J. Physi~ol., 252(H), 615-621 (1987)). Platelets released from artificial surfaces show impaired hemostatic function. Compounds of the invention may be a~lrnini~tered to prevent adhesion.
Other applications of these compounds include prevention of platelet thrombosis, thromboembolism and reocclusion during and after thrombolytic therapy and prevention of platelet thrombosis, thromboembolism and reocclusion after angioplasty or coronary artery 5 bypass procedures. They may also be used to prevent myocardial infarction.
The dosage regimen l~tiTi~ing the compounds of the present invention is selected in accordance with a variety of ~actors including type, species, age, weight, sex and medical condition of the patient; the 10 severity of the condition to be treated; the route of a~lmini~tration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the 1 5 condition.
Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/lcg/day and preferably 0.01-100 mg/kg/day and most preferably 0.01-20 mg/kg/day.
20 Typically, oral dosages for an adult patient are, for example, 1 mg, lû
mg or 100 mg. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minllte during a constant rate infusion.
Advantageously, compounds of the present invention may be ~clmini~tered in divided doses of two, three, or four times daily.
25 Furthermore, preferred compounds for the present invention can be ~lmini~tered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those ~orms of transdermal skin patches well known to those of ordinary skill in that art. To be atlmini~tered in the form of a transdermal delivery system, the dosage 30 a-1mini~tration will, or course, be continuous rather that inteImittent throughout the dosage regirne.
In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically aflmini~tered in admixture with suitable pharmaceutical CA 022467~6 1998-08-18 diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form Of ~lministration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with convention pharmaceutical practices. As such, 5 a therapuetically effective amount of a compound of formula I can be used for the preparation of a medicament useful for inhibiting the binding of fibrinogen to blood platelets, inhibiting the aggregation of blood platelets, treating thrombus formation or embolus formation, or preventing thrombus or embolus formation in a m:~mm~l For example, 10 the medicament may be comprised of from 1 mg to 100 mgs of a compound of formula I, or more particularly, it may contain 1 mg, 10 mgs, 50 mgs, or 100 mgs of said compound.
Therapeutically effective amounts of a compound of formula I together with another active agent such as an anticoagulation 15 agent or a thrombolytic agent can be used for the preparation of a medicament useful for inhibiting the binding of fibrinogeh to blood platelets, inhibiting the aggregation of blood platelets, treating thrombus formation or embolus formation, or preventing thrombus or embolus formation in a m~mm~l. Examples of other active agents which may be 20 used include pl~minogen activators or streptokinase, heparin, aspirin, warfarin, ticlopidine and/or clopidogrel.
For instance, for oral ~(lministration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, 25 starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral a~lminietration in li~uid form, the oral drug components can be combined with any oral, non-toxic, ph~ ceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when 30 desired or necessary, suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage fo~ns include sodium oleate, sodium stearate, m~nesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limit~tion, starch methyl cellulose, agar, bentonite, 5 xanthan gum and the like.
The compounds of the present invention can also be ~1m;ni~tered in the form of liposome delivery systems, such as small unilamellar vesicles, large llnil:~mellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, 10 such as cholesterol, stearylamine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use o~ monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug 15 carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in 20 achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
2~ The compounds of the present inven~ion can also be co-~lmin;~tered with suitable anticoagulation agents or thrombolytic agents such as pl~minogen ac~ivators or streptokinase in the treatment of various vascular pathologies. They may also be combined with hepann, aspirin, warfarin, ticlopidine and/or clopidogrel. Co~(lmin;~tration 30 includes ~lmini~tration together at essentially the same time in a single dosage form or in separate dosage forms, or each agent ~lministered at separately staggered times in order to achieve beneficial thrombosis prevention or thrombolysis.
CA 022467~6 1998-08-18 The compounds of the present invention can be prepared readily according to the following Schemes and Examples or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. Those skilled in the 5 art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. The examples are not intended to be limitations on the scope of the instant invention in any way, and they should not be so construed. Furthermore, the compounds described 10 in the following examples are not to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus. Specific definitions of variables in the Schemes are illustrative only, and are not intended to limit the procedures described, unless otherwise 15 noted. All temperatures are degrees Celsius unless otherwise noted.
Some abbreviations used herein are as follows: TBAF is tetrabutylammonium fluoride; DEAD is diethyl azodicarboxylate;
PPh3 is triphenyl phosphine. Many of the compounds described in the examples were analyzed by FAB mass spectroscopy (FABMS), 20 and MS values are denoted.
In the schemes and examples below, various reagent symbols have the following meanings:
Ac: acyl (CH3-C(O)-) BOC (or Boc): t-butyloxycarbonyl BOC2O: di-t-butyl dicarbonate BOP: Benzotriazol-1-yloxytris(dimethylamino)phosphonium, hexafluorophosphate Bn: benzyl n-BuLi: n-butyllithium t-BuLi: tert-butyllithium CBZ: Carbobenzyloxy CH2C12: Methylene chloride - CHC13: chloroform Pd-C: Palladium on activated carbon catalyst DMF: Dimethylformarnide DMSO: Dimethylsulfoxide ~DC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride S EtOAc: ethyl acetate EtOH: ethanol HOAc: acetic acid LDA: Lithium diisopropylamide MeOH: methanol NMM: N-methyl morpholine NMP: N-methyl pyrrolidine Oxone: potassium peroxymonosulfate PYCLU: chloro N,N,N',N'-bis(pentamethylene)formamidinium hexafluorophosphate RT: room temperature TBDMS or TMS: t-butyldimethyl silyl TFA: trifluoroacetic acid THF: tetrahydrofuran;
TLC: thin layer chromatography BOC--N = I
+ DMF _ ~'O~CHO
HO~CHO ~ 3 NaCNBH3, NaOAc 4A sieves, CH30H
BOC--N=o~3 CH2NH/~CO2CH3 PhSO2CI
Pyridine CH2CI2, 0~C ~ RT
BOC--N ~ ~0~ S02Ph 1 N NaOH
EtOH
~CHEME 1 CONTINUED
BOC--N >~--o~3CH2N--co2H
HN~--O~ CH2N--C02H
Step 1: 4-13-(N-Boc-Piperidin-4-yl~propyloxylbenzaldehyde (1-3) A solution of 3-(N-Boc-piperidin-4-yl)propyl iodide 1 1 (5.0 g, 14.2 mmol) (preparation described in EP 478,328), 4-10 hydroxybenzaldehyde 1 2 (1.73 g, 14.2 mmol), Cs2CO3 (9.2 g, 28.4 mmol) and DMF (50 ml) was stirred at ambient temperature for 2.0 hours. The reaction mixture was diluted with ethyl acetate and then washed with H2O, sat. NaHCO3, 10% KHSO4, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 10% EtOAc/hexane) 15 provided 1 3 as a white solid.
TLC Rf 0.80 ~silica, 40% EtOAc/hexane) lH NMR (300 MHz, CDCl3) o 9.88 (s, lH), 7.83 (d, J=9Hz, 2H), 6.99 (d, J=9Hz, 2H), 4.11 (m, 2H), 4.04 (t, J=6Hz, 2EI), 2.69 (bt, 2H), l.84, (m, 2H), 1.69 (bd, 2H), 1.46 (m, 12H), 1.14 (m, 2H).
Step 2: N~ (N-Boc-Piperidin-4-yl)propyloxy)phen-4-yl-methyllglycine methvl ester (1-5) To a st~rred suspension of 4A molecular sieves (4 g) and CH30H (30 ml) was added NaOAc (1.18 g, 14.5 mmol), compound 1 3 ~ (1.0 g, 2.89 mmol), amine 1-4 (363 mg, 2.89 mmol)-and NaCNBH3 (546 mg, 8.67 mmol). After 18 h, the reaction mixt~lre was filtered - through a celite pad. The pH of the resulting solution was adjusted to ~2 by the dropwise addition of conc. HCI to decompose excess hydride.
The pH was adjusted to ~12 by the addition of K2C03. The mixture was extracted with EtOAc. The organic portion was washed with brine, dried (MgS04) and concentrated. Flash chromatography (silica, 80%
EtOAc/provided) amine 1 5 as a colorless oil.
TLC Rf 0.32 (silica, EtOAc) lH NMR (300 MHz, CD30D) ~ 7.22 (d, J=9Hz, 2H), 6.85 (d, J=9Hz, 2H), 4.10 (bd, 2H), 3.94 (t, J=6Hz, 2H), 3.70 (m, SH), 3.36 (s, 2H), 2.77 (m, 2H), 1.77 (m, 4H), 1.43 (m, 12H), 1.07 (m, 2H).
Step 3: N-~(3-(N-Boc-Piperidin-4-yl)propyloxy)phen-4-yl)-methyll-N'-phenylsulfonyl ~Iycine methyl ester (1-6) To a stirred solution of amine 1-5 (900 mg, 2.15 mrnol), pyridine (347 ,ul, 4.30 mmol) and CH2C12 (20 ml) at 0~C was added phenylsulfonylchloride (300 ,ul, 2.37 mmol) followed by the removal of the cooling bath. After 18 h, the reaction was diluted with EtOAc and then washed with H20, 10% KHS04, brine, dried (MgS04) and concentrated. Flash chromatography (silica, 20% EtOAc/hexane) gave ester 1-6 as a~ colorless oil.
TLF Rf 0.82 (silica, 50% EtOAc/hexane) 1H NMR (300 MHz, CDC13) ~ 7.88 (d, J=9H, 2H), 7.56 (m,3H), 7.14 (d, J=9Hz, 2H), 6.81 (d, J=9Hz, 2H), 4.43 (s, 2H), 4.12 (m, 2H), 3.91 (m, 4H), 3.53 (s, 3H), 2.68 (bt, 2H), 1.79 (m, 2H), 1.68 (bd, 2H), 1.46 (m, 12H), 1.10 (m, 2H).
Step 4: N-[(3-(N-Boc-Piperidin-4-yl)propyloxy)phen-4-yl-methyl]-N'-phenylsulfonyl glycine (1-7) A solution of ester 1 6 (900 mg, 1.61 mmol), lN NaOH (2 ml) and EtOH (5 ml) was stirred at ambient temperature for 30 minlltes.
The reaction mixture was then acidified with 10% KHS04, followed by extraction with EtO~c. The organic portion was washed with brine, -WO g7/31910 PCT/US97/02712 dried (MgS04) and concentrated to give the carboxylic acid 1 7 as a white solid.
TLC Rf 0.48 (silica, 9:0.5:0.5 CH2C12/MeOH/AcOH) lH NMR (300 MHz, CD30D) ~ 7.87 (d, J=8Hz, 2H), 7.59 (m, 3H), 7.09 S (d, J=8Hz, 2H), 6.82 (d, J=9H, 2H), 4.41 (s, 2H), 4.04 (bd, 2H), 3.93 (t, J=6Hz, 2H), 3.84 (s, 2H), 2.76 (m, 2H), 1.79 (m, 4H), 1.44 (m, 12H), 1.04 (m, 2H).
Step 5: N-[(3-(Piperidin-4-yl)propyloxy)phen-4-yl-methyl]-N'-phenylsulfonyl glycine (1-8) A solution of acid 1 7 (400 mg, 0.7334 mrnol), TFA (3 ml) and CH2C12 (3 ml) was stirred at ambient temperature for 1.0 hour.
The solution was concentrated and then azeotroped with toluene. Flash chromatography (silica, 20:1 :1 EtOH/NH40H/H20) furnished amine ~ as a white solid.
TLC Rf 0.41 (silica, 20:1:1 l~tOH/NH40H/H20) lH NMR (300 MHz, NaOD/D20) ~ 7.79 (d, J=8Hz, 2H), 7.66 (d, J=7Hz, lH), 7.56 (t, J=8Hz, 2H), 7.06 (d, J=8Hz, 2H), 8.45 (d, J=9Hz, 2H), 4.42 (s, 2H), 4.01 ~t, J=8Hz, 2H), 3.76 (s, 2H), 2.91 (m, 2H), 2.47 (t, J=12Hz, 2H), 1.74 (m, 4H), 1.32 (m, 3H), 1.06 (m, 2H).
WO 97/31910 PCT/~JS97/02712 Br~ NaN3 . ~Ç \
~ benzene u 2-1 ~ O 1, NaN(TMS)2, DMF
-1 5~C
Boc--N~ I
-1 5~C ~ RT
Boc--N~
tBuLi DMF, THF
-78~C
Boc--N ~ O C H0 HCI~H2N--CO2CH3 NaCNBH3, NaOAc 4A sieves, CH30H
CA 02246756 l998-08-l8 ~ --NH C02CH3 Boc--N~/ N~
PhSO2CI
Pyridine, CH2CI2 0~C ~ RT
~f I ~Co2cH3 E~oc--N~--N~ SO2Ph O \ EtOAC
2~ HCl(g)\
'~ ~N CO2CH3 HCI~HN~--N~ SO2Ph 1 N NaOH ~
EtOH 2-1 0 ~N~CO2H
Boc-N~ O SO2Ph HCI (g) EtOAc HCI-HN~ O SO2Ph 2-~
- Step 1: 6-Bromo-3~4-dihydroisoquinolin-1-one (2-2) To a stirred solution of bromide 2-1 (20.0 ~, 94.8 mmol), H2SO4 (25.4 ml) and benzene (130 ml) at ambient temperature was added NaN3 (8.88 g, 136.6 mmol) portionwise over a 30 minute period.
After 1.0 hour, the reaction was diluted with EtOAc and then washed with H20, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 40% EtOAc/hexanes ~ EtOAc) fuInished bromide 2-2 as an orange solid.
TLC Rf 0.31 1H NMR (300 MHz, CDCl3) o 7.93 (d, J=8Hz, lH), 7.49 (d, J=8Hz, lH), 7.40 (s, lH), 6.32 (bs, lH), 3.57 (m, 2H), 2.99 (t, J=7Hz, 2H).
Step 2: 6-Bromo-N-[(N-Boc-piperidin-4-yl)ethyl]-3,4,-dihydroisoquinolin-l-one (2-4) To a stirred solution of bromide 2-2 (1.33 g, 5.88 mmol) and DMF (30 ml) at -15~C was added NaN (TMS)2 (1.0 M/THF; 6.4 ml) dropwise over a 10 minute period. After 10 minlltes, a solution of iodide ~ (2.0 g, 5.88 mmol) and DMF (4 ml) was added to the reaction mixture followed by the removal of the cooling bath. After 1.0 hour, the solution was diluted with LtOAc and then washed with 10%
KHSO4, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 50% EtOAc/hexanes) afforded bromide 2-4 as a colorless oil.
TLC Rf 0.23 (silica, 50% EtOAc/hexanes) H NMR (300 MHz, CDC13) ~i 7.93 (d, J=8Hz, lH), 7.46 (d, J=8Hz, lH), 7.35 (s, lH), 4.12 (m, 2H), 3.56 (m, 4H), 2.97 (t, J=7Hz, 2H), 1.69 (m, 3H), 1.54 (m, 2H), 1.45 (s, 9H), 1.13 (m, 2H).
~tep 3: 6-Formyl-N-[(N-Boc-piperidin-4-yl)ethyl]-3,4-dihydroisoquinolin-1-one (2-5) To a stirred solution of bromide 2-4 (1.90 g, 4.34 mmol), DMF (342 ~1, 4.34 mmol) and THP (15 ml) at -78~C~ was added t-BuLi (1.7 M/pentane; 7.66 ml, 13.02 mmol) dropwise over a 5 minute period.
After 1.0 hour, the reaction was quenched with AcOH. The solution was diluted with EtOAc and then washed with 10% KHSO4, sat.
NaH~03, brine, dried (MgSO4) and concentrated. Flash S chromotography (silica, 30% ~ 50% EtOAc/hexanes) gave aldehyde ~i as a colorless oil.
TLC Rf 0.13 (silica, 50% EtOAc/hexanes) 1H NMR (300 MHz, CD~13) ~ 10.06 (s, lH), 8.24 (d, 8Hz, IH), 7.84 (d, J=8Hz, lH), 7.72 (s, lH), 4.12 (m, 2H), 3.61 (m, 4H), 3.08 (t, J=7Hz, 10 2H), 2.69 (t, 13Hz, 2H), 1.75 (d, J=13Hz, 2H), 1.59 (m, 2H), 1.45 (s, 10H), 1.19 (m, 2H).
Step 4: N-(N-[(N-Boc-Piperidin-4-yl)ethyl]-3,4-dihydro-isoquinolin-l-one-6-yl-methyl)~lycine methyl ester (2-6~
To a stirred suspension of 4A molecular sieves (3.60 g) and CH30H (30 ml) was added NaOAc (1.06 g, 12.95 mmol), benzaldehyde 2-5 (1.0 g, 2.59 mmol), amine 1 4 (326 mg, 2.59 mmol) and NaCNBH3 (490 mg, 7.77 mmol). After 1.0 h, the reaction mixture was filtered through a celite pad. The pH of the resulting solution was adjusted to ~2 20 by the dropwise addition of lN HCl. After 10 minutes, the pH was adjusted to ~12 by the addition of K2~03. The mixture was extracted with EtOAc. The organic portion was washed with brine, dried (MgSO4) and concentrated. Flash chromatography (silica, EtOAc) afforded amine 2-6 as a white solid.
25 TT.C Rf 0.09 (silica, EtOAc) 1H NMR (300 MHz, CD3OD) 7.89 (d, 3=8Hz, lH~, 7.33 (d, J=8~z, lH), 7.26 (s, lH), 4.07 ~m, 2H), 3.81 (s, 2H), 3.72 (s, 3H), 3.60 (m, 4H), 3.40 (s, 2H), 3.00 (t, J=7Hz, 2H), 2.73 (bt, 2H), 1.78 (bd, J=12Hz, 2H), 1.61 (m, 2H), 1.44 (s, 10H), 1.10 (m, 2H).
- Step 5: N-(N-[(N-Boc-Piperidin-4-yl)ethyl]3,4-dihydro-isoquinolin-l-one-6-yl-methyl)-N'-phenylsulfonyl glycine - methyl ester (2-7) To a stirred solution of amine 2-6 (800 mg, 1.75 mmol), S NMM (488 ,ul, 3.50 mmol) and CH2Cl2 (10 ml~ at 0~C was added benzenesulfonyl chloride (243 ~11, 1.93 mmol) in a single portion followed by the removal of the cooling bath. After 48 h, the heterogeneous mixture was diluted with EtOAc and then washed with H2O, sat. NaHCO3, 10% KHSO4, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 50% ~ 60%
EtOAc/hexanes) furnished ester 2-7 as a white solid.
TLC Rf 0.16 (silica, 50% EtOAc/hexanes) 1H NMR (300 MHz, CD30D) ~ 7.86 (m, 3H), 7.65 (d, J=7Hz, lH), 7.59 (d, J=9Hz, 2H), 7.20 (d, J=8Hz, lH), 7.14 (s, lH), 4.52 (s, 2H), 4.07 (m, 2H), 3.98 (s, 2H), 3.59 (m, 4H), 3.52 (s, 3H), 2.94 (t, J=8Hz, 2H), 2.76 (m, 2H), 1.78 (bd, J=13Hz, 2H), 1.57 (m, 2H), 1.44 (s, 10H), 1.15 (m, 2H).
Step 6: N-(N-[(N-Boc-Piperidin-4-yl)ethyll-3,4-dihydro-isoquinolin-1-one-6-yl-methyl)-N'-phenylsulfonyl glycine (2-8) A solution of ester 2-7 (600 mg, 1.00 mmol), IN NaOH
(2.0 ml) and EtOH (5 ml) was stirred at ambient temperature for 1.5 hours. The reaction mixture was then acidified with 10% KHSO4 followed by extraction with E~tOAc. The organic portion was washed with brine, dried (MgSO4~ and concentrated to give acid 2-8 as a white solid.
1H NMR (300 MHz, CD30D) ~ 7.86 (m, 3H), 7.64 (d, J=7Hz, lH), 7.57 (d, J=9Hz, 2H), 7.21 (d, J=8Hz, lH), 7.13 (s, lH), 4.54 (s, 2H), 4.04 ~ 30 (bd, J=l lHz, 2H), 3.93 (s, 2H), 3.59 (m, 4H), 2.94 (t, J=6Hz, 2H), 2.73 (m, 2H), 1.76 (bd, J=13Hz, 2H), 1.57 (m, 2H), 1.44 (s, 10H), 1.13 (m, 2~).
HCI~HN~N~X~ I CO2H
o Step 7: N-(N-[(Piperidin-4-yl)ethyl]-3,4-dihydroisoquinolin-1-one-6-yl-methyl)-N'-phenylsulfonyl glycine ~2-9) S EtOAc (8 ml) at 0~C was treated with HC~l (g) until saturated. A suspension of acid 2-8 (300 mg, 0.5124 mmol) and ~tOAc (2 ml) was added in a single portion. After 30 minlltes, argon was bubbled ~rough the solution. The solvent was removed in vacuo to give amine 2-9 as a white solid.
lH NMR (300 MHz, D20) ~ 7.79 (d, J=8Hz, 2EI), 7.74 (m, 2H), 7.57 (m, 2H), 7.18 (d, J=8Hz, lH), 7.01 (s, lH), 4.46 (s, 2H), 4.08 (s, 2H), 3.56 (m, 4H), 3.42 (bd, J=14Hz, 2H), 2.96 (t, J=13Hz, 2H), 2.86 (t, J=7Hz, 2H), 2.03 (d, J=14Hz, 2H), 1.64 (m, 3H), 1.45 (m, 2H).
N-(N-[(Piperidin-4-yl)ethyl~ -3,4-dihydroisoqllinolin- 1 -one-6-yl-mçthyl)-N'-phenylsulfonyl glycine methyl ester hydrochloride (2- 10) EtOAc (8 ml) at 0~C was treated with HCI (g) until saturated. A suspension of ester 2-7 (300 mg, 0.5004 mmol) and EtOAc (2 ml) was added in a single po~ion. After 30 minutes, argon was bubbled through the solution. The solvent was removed in vacuo to give amine 2-I0 as a white solid.
lH NMR (D20) ~; 7.82 (d, J=8Hz, 2H), 7.74 (m, 2H), 7.60 (t, J=8Hz, 2~ 21H), 7.21 (d, J=8Hz, lH), 7.07 (s, lH), 4.47 (s, 2H), 4.14 (s, 2H), 3.56 (m, 7H), 3.42 (d, J=13Hz, 2H), 2.90 (m, 4H), 2.03 (d, J=14Hz, 2H), 1.65 (m, 3H), 1.45 (m, 2H).
CA 02246756 l998-08-l8 ~--N~ 1. Boc20, Et3N, DMF ~ J3~NH2 HNJ 2. H2, Pd/C, EtOH BocNJ
Cl~ N~2 o ;~
~, NO2 H
I~--N
BocN J
1- H2, Pd/C, EtOH/
2. RSO2CI, pyridine R' S, ~2 ,~ N ~ ~ N~ H
BocNJ ~, R-Ph 2 aq. NaOH, TFA, CH2C12 ~-5c, R=Me ~, R=4-Br-Ph WO g7/31910 PCT/US97/02712 SCHEME 3 CON~I~lED
SO2 ~
'J~OH
N
~N~ ~
HN J 3-6a, R=Ph -6b, R=Bn f'-6c, R=Me ~, R=4-Br-Ph Step 1: 4-(4-tert-Butyloxycarbonyl-piperazin-l-yl)aniline (3-2) To a solution of 1-(4-nitrophenyl)piperazine C~) (9.8 g, 47.29 mmol) and triethylamine (7.3 mL, 52.37 mmol) in dichloro-10 methane (175 mL~ at RT, Boc2O (11.38 g, 52.14 mmol) was added portionwise. The resultant mixture was stirred at RT for 2 h. The product mixture was concentrated under vacuum, and the residue triturated with hexane (150 mL). The resultant yellow powder was obtained by filtration.
Without further puri~ication, the yellow solid was dissolved ethanol f~200 mL) and shaken under an atmosphe~e of hydrogen gas at 50 psi in the presence of 0.8 g of 5% Pd/C for 18 h at RT. The product solution was filtered through a pad of Celite, and the filtrate was concentrated under vacuum to give 2 as pink solid.
Step 2: 4-[4-(4-tert-Butyloxycarbonyl-piperazin-l-yl)phenylamino-carbonyll-nitrobenze f3-4) To a suspension of 4-nitrobenzoic acid (4.06 g, 24.29 mmol) in dichloromethane (40 mL) and DMF (200 ~lL) at RT, oxalyl 25 chloride (2.8 mL, 32 mmol) was added dropwise with a syringe pump CA 022467~6 l998-08-l8 over a period of 1 h. The resultant solution was stirred at RT for O.S h, and concentration under vacuum. The residue was dissolved in benzene and concentrated under vacuum to remove residua} oxalyl chloride.
The resultant 4-nitroben~oyl chloride (~) was dissolved in dichloro-methane (25 mL) and was added dropwisely to a cold (0~C) solution of ~niline 3-2 (6.12 g, 22.1 mmol) and DMAP (135 mg) in a mixture of dichloromethane (30 mL) and pyridine (4.5 mL) over a period of 30 min. The resultant slurry was diluted with dichloromethane (60 mL) and stirred at 0~C for 1 h. The product mixture was further diluted with dichloromethane (600 mL), washed successively with sat. a~.
sodium bicarbonate, sat aq. potassium hydrogen sulfate, water, and then brine until the aqueous extract was neutral. The dichloromethane solution was loaded directly onto a column of silica gel and the colurnn eluted with ethyl acetate. Collection and concentration of appropriate lS fractions provided the amide 3-4.
Step 3: N-Phenylsulfonyl-4-[4-(4-ter~ utyloxycarbonyl-piperazin-1-yl)-phenylaminocarbonyllaniline (3-Sa) A suspension of the nitrobenzene 3-4 (6.9 g, 16.18 mmol) and 5% Pd/C (0.93 g) in ethanol (110 mT .) was shaken under an atmosphere of hydrogen gas at 50 psi overnight at RT. The resultant mixture was filtered through a plug of Celite, and washed repetitively with methanol (500 mL). The filtrate was concentrated under vacuum.
The residue was treated with toluene and concentrated under vacuum to remove residual alcohols. The resultant aniline (4.49 g, 11.32 rnmol~
was treated with phenylsulfonyl chloride (1.75 mL, 13.7 mmol) in pyridine ~lS mL) at 100~C for 2 h. The resultant mixture was concentrated under vacuum. The residue was dissolved in methanol and concentrated onto silica gel. The resultant solid was loaded onto a column of silica gel and eluted with 80% ethyl acetate in hexane.
Collection and concentration of appropriate fractions provided the sulforlamide 3-Sa.
- ~8 -Step 4: N- { 4-[4-(Piperazin- 1 -yl)phenylaminocarbonyl3phenyl } -N-phenyl-sulfonylglycine (3-6a) To cold (0~C) solution of the sulfonamide 3-5a (2.02 g, 3.76 mmol) in DMF (15 mL), sodium hydride (96 mg, 3.99 mmol) was added. The mixture was stirred at RT ~or lS min. The resultant solution was cooled back to 0~C, and methyl bromoacetate (380 ,uL, 4.01 mmol) was added, and stirred at RT overnight. The product nnixture was concentrated under vacuum, and the residue dissolved in ethyl acetate. The organic fraction was washed successively with aq.
sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 60% ethyl acetate in hexane.
Collection and concentration of ~loL~riate fractions provided N-4-[4(4-tert-butyloxycarbonyl-piperazin- 1 -yl)phenylaminocarbonyl]phenyl-l 5 N-phenylsulfonylglycine methyl ester.
To a solution of the glycine methyl ester (430 mg, 0.7 mmol) in a mixture of methanol (10 mL) and ethanol (3 mL~ at RT, aq.
sodium hydroxide (2.8 mL, 1 M, 2.8 mmol) was added. The resultant mixture was stirred at RT for 5 h. The product mixtlIre was concentrated, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate (3 x 70 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was dissolved in dichloromethane (7 mL) and treated with trifluoroacetic acid (3 mL) at RT for 2.5 h. The product solution was concentrated under vacuum. The residue was dissolved in water, frozen and Iyophilized overnight to provide the sulfonylglycine ~ as a white fluffy solid.
lH NMR (CD30D): ~ 7.84 (2H, d, J=8.6Hz), 7.71-7.49 (7H, m), 7.36 (2H, d, J=8.6Hz), 7.03 (2H, J=9.0 Hz), 4.51 (2H, s), 3.38 (8H, br s).
Analysis calculated for C25H26N4OsS- 1.30 TFA-0.20 H2O
C, 51.28; H, 4.32; N, 8.67 Found: C, 51.29; H, 4.31; N, 8.90 CA 022467~6 1998-08-18 ~XAMPLE 3B
Step 1: N-Benzylsulfonyl-4-[4-(4-tert-butyloxycarbonyl-piperazin-1-yl)-phenylaminocarbonyll-aniline (3-5b) S Following the procedure described for 3-5a, but substituting benzylsulfonyl chloride for phenylsulfonyl chloride, 3-5b was prepared.
Step 2: N- { 4-[4-(Piperazin- 1 -yl)phenylaminocarbonyl]phenyl } -N-benzyl-sulfonylglycine (3-6b) Following the procedure described for 3-6a, but starting with N-benzylsulfonyl-4-[4-(4-tert-butyloxycarbonyl-piperazin-1-yl)-phenylaminocarbonyl~nilin~ (;~), 3-6b was prepared.
Analysis calculated for C26H2gN4OsS- 1.40 TFA-0.44 H2O
C, 51.16; H, 4.51; N, 8.29 Found: C, 51.16; H, 4.51; N, 8.55 ~0 Step 1: N-Methylsulfonyl-4-[4-(4-tert-butyloxycarbonyl-piperazin-1-yl)-phenylaminocarbonyllaniline (3-5c) Following the procedure described for 3-5a, but subsLiLu~ g methanesulfonyl chloride for phenylsulfonyl chloride, 3-5c was prepared.
Step 2: N- { 4-[4-(Piperazin- 1 -yl)phenylaminocarbonyl3phenyl } -N-methylsulfonyl~lycine (3-6c) Following the procedure described for 3-6a, but starting with N-methylsulfonyl-4-[4-(t-tert-butyloxycarbonyl-piperazin-1-30 yl)phenylaminocarbonyl]~nilin~ (3-5c), 3-6c was prepared.
Analysis calculated for C2oH24N4oss-l.48 TFA-0.14 H2O
C, 45.67; N, 4.30; N, 9.28 Found: C, 45.67; H, 4.30; N, 9.49 . , Step 1: N-4-bromo-phenylsulfonyl-4-r4-(4-tert-butyloxycarbonyl-piperazin-l-yl)-phenylamino-carbonyll-aniline (3-5d) Following the procedure described for 3-Sa, but substituting 4-bromophenylsulfonyl chloride ~or phenylsulfonyl chloride, 3-Sd was prepared.
Step 2: N- { 4-[4-(piperazin- 1 -yl)phenylaminocarbonyl]phenyl } -N-4-bromo-phenyl-sulfonylglycine (3-6d) Following the procedure described for 3-6a, but starting with N-4-bromo-phenylsulfonyl-4-~4-(4-tert-butyloxycarbonyl-piperazin-1-yl)-phenylamino-carbonyl3-aniline (3-5d), 3-6d was prepared.
Analysis calculated for C25H25BrN405S ~ 1.58 TFA ~ 0.34 H20 C, 44.52; H, 3.62; N, 7.37 Found: C, 44.51; H, 3.62; N, 7.50 1. RSO2CI,R-S02'N~oEt [~ 2. NaH, NO2 BDrMCFH2CO2Et, ~ Rl 1. H2, Pd/C, EtOH O
l N Cl BocN J
r ~
SO2 ~
O ~N~OEt ~N~ ~
BocN J 4-10 1. aq. NaOH
2. HCI, EtOAc SO~
HJ~
CA 02246756 l99X-08-18 WO ~7/31910 PCT/US97/OZ712 wherein the precursors (4-8, 4-10) and the corresponding final products (4-11) have lR and Rl defined as follows:
Compound R R 1 a) Ph H
b) 2-thienyl H
c) 2-F-Ph H
d) 3-F-Ph H
e) 4-F-Ph H
f) Ph CH3 g) 2-F-Ph B r h) CF3 H
i) (R)- H
camphor j) (S)-camphor H
~SO2 ~
~ ~OEt 02N~
4-8a Step 1: N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester ~4-8a) A solution of 4-nitroaniline (~Z) (13.8 g, 100 mrnol) and phenylsulfonyl chloride (14 rnL, 100 mmol) in pyridine (50 mL) was heated at 1 00~C for 2 h. The resultant solution was concentrated, and the residue dissolved in ethyl acetate. The organic extract was washed CA 022467~6 1998-08-18 WO 97/31910 PCT/US97/027~2 successively with 2 M hydrochloric acid, sat. aq. sodium bicarbonate brine, dried over magnesium sulfate, filtered and concentrated under - vacuum. The residue was dissolved in a minimum amount of ethyl acetate with warning, and hexane added until the solution turned cloudy.
S The mixture was allowed to cool slowly to RT and then chilled at 0~C.
The yellow solid precipitated was obtained by filtration. Further drying under vacuum overnight provide N-phenylsulfonyl-4-nitroz~ni1ine.
A cold (0~C) solution of N-phenylsulphonyl-4-nitro~niline (7.39 g, 30 mmol) in DMF (65 mL) was treated with sodium hydride (0.76 g, 32 mmol) portionwise over a period of 1.5 h. A solution of ethyl bromoacetate (4 mL) in DMF (10 mL) was added, and the resultant mixture stirred at RT overnight. The product mixture was concentrated under vacuum, and the residue dissolved in ethyl acetate.
The organic extract was washed with brine, dried over magnesium 15 sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 0.5%
methanol in chloroform. Collection and concentration of appropriate fractions provided N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (4-8a) as a clear gum.
~SO2 ~
o ~--N~J~o~t ,¢~ H
BocN J 4-1 oa Step 2: N- { 4-[4-(4-tert-Butyloxycarbonylpiperazin- l -yl)phenylcarbonyl-amino]phenyl } -N-phenylsulfonylglycine ethvl ester (4- l Oa) A solution of 4-8a (8.9 g, 24.4 mmol) in a mixture of ethanol (100 rnL) and ethyl acetate (25 mL) was hydrogenated under an atmosphere of hydrogen gas at 45 psi in the presence of 5% Pd/C (0.89 g) at RT for 1.5 h. The resultant mixture was filtered through a plug of Celite, and the filtrate concentrated under vacuum. The residue was redissolved in toluene and concentrated under vacuum to provide the corresponding aniline.
A solution of 4-[4-(tert-butyloxycarbonyl)piperazin- 1 -yl]-benzoic acid (4-9 wherein R2 = H) (1.0 g, 3.3 mmol) in dichloromethane (25 mL) and DMF (3 drops) at RT was treated with oxalyl chloride (0.43 mL, 4.9 mmol) over a period of 10 min. The resultant solution was stirred at RT for I h, and concentrated under 10 vacuum. The residue was dissolved in toluene and concentrated to remove residual oxalyl chloride. The resultant acid chloride 4-9 was redissolved in dichloromethane (5 mL~, and added to a cold (0~C) solution the above ~niline (1.1 g, 3.3 mmol) and DMAP (0.48 g, 3.9 mmol) in dichloromethane (25 mL). The resultant mixture was stirred 1~ at RT overnight, diluted with dichloromethane and washed successively with 10% aq citric acid, sat. sodium bicarbonate, and brine. The organic extract was dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 50% ethyl acetate in hexane.
20 Collection and concentration of appropriate fractions provided 4-lOa as a gum.
~SO2 ~
O ,~N~JI--OH
,~NH~J
~N
HN~J 4-11a Step 3: N- { 4-[4-~Piperazin- l -yl)phenylcarbonylarnino]phenyl } -N-2~ phenyl-sulfonyl~lvcine (4-lla~
- To a solution of the glycine ethyl ester 4-lOa (260 mg, 0.41mmol) in methanol (2.5 mL), aq. sodium hydroxide (0.85 mL, 1 M, 1.7 mmol) was added. The resultant mixture was stirred at RT for 2 h.
The product mixture was concentrated, acidified, and extracted into 5 dichloromethane. The combined organic extract were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was dissolved in ethyl acetate (30 rnL), cooled to 0~C, and treated with a steady stream of anhydrous hydrogen chloride gas for 10 min. The resultant solution was stirred at 0~C for 1 h, and concentrated under 10 vacuum. The residue was dissolved in water, frozen and lyophilized overnight to provide glycine 4-1 la as a white fluffy solid.
1H NMR (CD30D): ~ 7.89 (2H, d, J=8.8Hz), 7.69-7.50 (7H, m), 7.17 (2H, d, J=8.8Hz), 7.11 (2H, d, J=9.OHz), 4.42 (2H, s), 3.6 (4H, m), 3.4 (4H, m).
Analysis calculated for C2sH26N40sS-0.15 EtOAc C, 51.34; H, 5.00; N, 9.35 Found: C, 51.34; H, 4.96; N, 9.30 Following the procedures described in Example 4A, Steps 1-3, but substituting the applol~liate reagents as described below, the following compounds were made:
25 (1) N- { 4- [4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl } -N-thienylsulfonylglycine (4-1 lb) This product was prepared using 2-thiophene sulfonyl chloride in place of phenylsulfonyl chloride in Step 1.
Analysis calculated for C2sH26N405S- 1.40 TFA-0.15 H20 C, 46.74; H, 3.91; N, 8.45 Found: C, 46.73; H, 3.92; N, 8.72 (2) N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonyl~mino]phenyl } -N-2-fluoro-phenyl-sulfonylglycine (4- l l c) This product was prepared using 2-fluorophenyl-sulfonyl chloride in place of phenylsulfonyl chloride in Step 1.
Analysis calculated for C25H2sFN405S ~ 1.60 TF~
C, 48.74, H, 3.86; N, 8.06 Found: C, 48.37; H, 3.92, N, 8.46 (3) N- { 4-~4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl } -N-3-fluoro-phenylsulfonylglycine (4-1 1 d) This product was prepared using 3-fluorophenylsulfonyl chloride in place of phenylsulfonyl chloride in Step 1.
Analysis calculate for C25H25FN405S ~ 1.30 TFA ~ 0.35 H20 C, 49.69; H, 4.08; N, 8.40 Found: C, 49.68; H, 4.04; N, 8.44 (4) N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl } -N-4-fluorophenyl-sulfonylglycine (4- l 1 e) This product was prepared using 4-fluorophenylsulfonyl chloride in place of phenylsulfonyl chloride in Step 1..
Analysis calculated for C25H25FN405S ~ 1.35 TFA ~ 0.35 H20 C, 49.45; H, 4.05, N, 8.33 Found: C, 49.45; H, 4.00; N, 8.40 (5) N- ~ 4-~4-(Piperazin-1 -yl)phenylcarbonylamino] -3 -methylphenyl ~-N-phenylsulfonylglycine (4-1 1 f) This product was prepared using 3-methyl-4-nitro~niline in place of 4-nitroaniline in Step 1.
Analysis calculated for C26H2gN405S ~ 1.40 TFA ~ 0.42 H20 C, 51.19; H, 4.51; N, 8.29 Found: C, 51.17; H, 4.51; N, 8.53 (6) N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonylamino]-3 -bromo-phenyl ~ -N-2-fluoro-phenylsulfonyl~lycine (4- l l g) This product was made using 3-bromo-4-nitroaniline and 2-fluorophenylsulfonyl chloride in place of 4-nitroaniline and phenylsulfonyl chloride, respectively, in ~tep 1.
Analysis calculated for C25H24BrFN4oss ~ 1.50 TFA ~ 0.35 ~I20 CA 02246756 l998-08-l8 WO 97/31910 PCT/[~S97/02712 - C, 43.75; H, 3.44; N, 7.29 Found: C, 43.76; H, 3.41; N, 7.53 (7) N- { 4-t4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl } -N-trifluoro-methylsulfonylglycine (4- 11 h) This product was prepared using trifluoromethanesulfonic anhydride and tert-butyl bromoacetate in place of phenylsulfonyl chloride and ethylbromo acetate, respectively, in Step 1.
Analysis calculated for C20H2lF3N4oss ~ 1.25 TFA ~ 0.35 H20 C, 42.54; H, 3.64; N, 8.82 Found: C, 42.55; H, 3.60; N, 9.05 0~
SO2 ~
,3~N~'oH
f~--N 4-11 i HNJ
(8) N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonylamino~phenyl ~ -N-(1 R)- 10-camphorsulfonylsulfonyl~;lycine (4- 11 i) This product was prepared using (lR)-(-)-10-camphorsulfonyl chloride in place of phenylsulfonyl chloride in Step 1.
~ Analysis calculated for C29H36N406S ~ 1.50 TFA ~ 0.15 H20 C, 51.77; H, 5.13; N, 7.55 Found: C, 51.74; H, 5.13; N, 7.63 ~0 SO~2~' ~N ~i HN ~J
(9) N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonylamino lphenyl } -N-(lS)-10-camphorsulfonyl-sulfonyl-~lycine (4-1 lj) This product was prepared using (lS)-(-)-10-camphorsulfonyl chloride in place of phenylsulfonyl chloride in Step 1..
Analysis calculated for C29H36N406S ~ 1.50 TFA ~ 0.10 H20 C, 51.83; H, 5.12; N, 7.56 Found: C, 51.84; H, 5.14; N, 7.72 _ 59 _ SCHEME S
NH2 1. R3COCI, ~ O
R~ 'OEt NO2 BrcH2co2Et~ O N R1 5-13 1. H2, Pd/C, o EtoH ll ~NJ~ ~c BocN J
(4-9) ~ ~
,~ ~ H ~;
BocN J R2 5-14 1. aq. NaOH
2. TFA. CH2C12 R3~o O N~JI'OH
~ ~J'' H
SCH~ME 5 CON~I~UED
wherein the precursors (5-13, 5-14 and 4-9) and the corresponding final products (5-15) have R1, R2 and R3 defined as follows: ~
s Cmpd RI R2 R3 a) H H Ph b) H H 2-F-Ph c) H H 3-F-Ph d) H H 4-F-Ph e) H H 2-pyridyl f) H H 3-pyridyl g) H H 4-pyridyl h) H H ~H3 i) H H ~
J) H H CH2ocH2ph k) H H CH2OH
1) 3-CH3 H Ph m) 2-CH3 H Ph n) H 3-CH3 Ph o) H 2-CH3 Ph ~ EXAMPL~ SA
~00 ~ ~OEt 02N J'~ 5-1 3a 5 ~tep 1: N-4-Nitrophenyl-N-benzoyl~lycine ethyl ester (5-13a) A mixture of 4-nitroaniline (4-7) (10.0 g, 72 mmol) and anhydrous potassium carbonate (20 g, 1.44 mmol) in anhydrous THF
(240 mL) and benzoyl chloride (9.1 mL, 78 mmol) was stirred at RT
overnight. The resultant solution was poured into 10% aq. HCl (200 10 mL) and cooled to 0~C. The yellow solid precipitated was filtered, washed successively with water (200 mL) and hexane (200 mL).
Further drying under vacuum overnight provided the required 4-nitro-N-benzoylaniline.
A cold (0~C) solution of the above nitro aniline (4.8 g, 19.8 15 mrnol) in DMF (40 mL) was treated portionwise with sodium hydride (0.48 g, 20 mmol). After the mixture was stirred at 0~C for 0.5 h, a solution of ethyl bromoacetate (2.6 mL, 23.4 mmol) in DMF (20 mL) was added. The resultant mixture was stirred at 50~C overnight and concentrated under vacuum. The residue was partitioned between ethyl 20 acetate and water. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum to provide the nitrophenyl glycine ester 5-13a.
_ ~00 ,~ ~ N
BocN J 5-1 4a Step 2: N- { 4-L4-(4-tert-Butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino]phenyl } -N-benzoylglycine ethyl ester (5-14a) Following the procedure described for 4-lOa. but sub~lilulillg N-4-nitrophenyl-N-benzoyl-glycine ethyl ester (5-13a) for N-4-nitrophenyl-N-phenylsulfonyl-glycine ethyl ester (4-8a), 5-14a was prepared.
~0 0 ~ ~N~J~'OH
~N~
~ NJ~J
HN I ~-1 5a Step 3: N- { 4-t4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl } -N-benzoyl-glycine (5-15a) lS Following the procedure described for 4-1 la, but substituting N- ~4-[4-(4-tert-butyloxycarbonylpiperazin- l-yl)phenyl-carbonylamino~phenyl } -N-benzoylglycine ethyl ester (5-1 4a~ ~or N- { 4-~ [4-(4-tert-butyloxycarbonylpiperazin- 1 -yl)phenylcarbonyl-arnino]phenyl}-N-phenylsulfonylglycine ethyl ester (4-lOa~, 5-15a was - prepared.
Analysis calculated for C26H26N404 ~ 1.35 TFA ~ 0.30 H20 C~, 55.79; H, 4.56; N, 9.07 Found: C, 55.76, H, 4.57; N, 9.29 EXAMPLE SB
I~F
~ O
~ ~OEt 02N~ S-13b Step 1: N-4-Nitrophenyl-N-2-fluorobenzoyl-~1~,7cine ethyl ester ~5-13b~
Following the procedure described for 5-13a, but substituting 2-fluorobenzoyl chloride for benzoyl chloride, 5-13b was 1 S prepared.
~00 o ~ N~OEt ~NJi ~
BocN ~ 5-1 4b .
WO g7/31910 PCT/US97/02712 Step 2: N- { 4-~4-(4-tert-Butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino]phenyl }-N-2-fluorobenzoylglycine ethyl ester (5-14b) Following the procedure described for 4-lOa, but S substituting N-4-nitrophenyl-N-2-fluorobenzoyl-glycine ethyl ester (~
13b) for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (~), 5-14b was prepared.
~F
~0 0 O ~[3~N~'oH
~N
HN ~ 5-1 5b Step 3: N- { 4-~4-(Piperazin- 1 -yl)phenylcarbonylamino~phenyl } -N-2-fluoro-benzoyl~lycine (5-1 Sb) Following the procedure described for 4-1 la, but substituting N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-15 phenylcarbonylamino~phenyl}-N-2-fluorobenzoyl-glycine ethyl ester (5-1 4b) for N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylamino]phenyl}-N-phenylsulfonylglycine ethyl ester (4- l Oa), 5- l Sb was prepared.
Analysis calculated for C26H2sFN404 ~ 1.35 TFA ~ 0.15 H20 C, 54.45; H, 4.24; N, 8.85 Found: C, 54.45; H, 4.26; N, 8.78 WO 97/31910 PCT/US97/û2712 ~ EXAMPLE SC
F
~~O
~ ~OEt 02N~ 5-13c Step 1: N-4-Nitrophenyl-N-3-fluorobenzoyl~lycine ethyl ester (5-13c) Following the procedure described for 5-13a, but 5 substituting 3-fluorobenzoyl chloride for benzoyl chloride, 5-13c was prepared.
O ~N~OEt ~N~
BocN J 5-1 4c Step 2: N- { 4-[4-~4-tert-Butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino]phenyl }-N-3-fluorobenzoylglycine ethyl ester (5-14c) Following the procedure described for 4-lOa, but substituting N-4-nitrophenyl-N-3-fluorobenzoyl-glycine ethyl ester (5-13cl for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (4-8a), 15 5-14c was prepared.
CA 02246756 l998-08-l8 F
~~O
~ ~ H
HN~J 5-15c Step 3: N- { 4-[4-(piperazin- 1 -yl)phenylcarbonylamino]phenyl } -N-3-iluoro-benzoylglycine (5-lSc) Following the procedure described for 4-1 la. but 5 substituting N- { 4-L4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylamino]phenyl } -N-3-fluorobenzoyl-glycine ethyl ester (5-1 4c) for N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylarnino]phenyl}-N-phenylsulfonylglycine ethyl ester (4- l Oa), S- 1 5c was prepared.
Analysis calculated for C26H2sFN4o4 ~ 1.70 T~A ~ 0.35 H20 C, 52.19; H, 4.08; N, 8.28 Found: C~ 52.19; H, 4.08; N, 8.42 EXAMPLE SD
F~
~0 0 ,~ ~OEt 02N 5-1~d - Step 1: N-4-Nitrophenyl-N-4-fluorobenzoylglycine ethyl ester ~S-l 3d) - Following the procedure described for 5-13a. but substituting 4-fluorobenzoyl chloride for benzoyl chloride, 5-13d was prepared.
F~
~00 o ~.,~ N~J~oEt r~N~
~N~
5-14d BocN
Step 2: N- { 4-r4-(4-tert-Butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino]phenyl } -N-4-fluorobenzoylglycine ethyl ester (5-14d~
Following the procedure described for 4-lOa, but 10 substituting N-4-nitrophenyl-N-4-fluorobenzoylglycine ethyl ester (5-13d) for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (4-8a), 5-14d was prepared.
F~
~0 0 O ~N~J~OH
f N'¢ ~
HN ~,J 5-1 5d 15 Step 3: N-{4-[4-(Piperazin-1-yl)phenylcarbonylamino]phenyl}-N-4-fluoro-benzoylglycine (5-lSd) .
Following the procedure described for 4-lla, but substituting N- { 4-~4-(4-fert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylamino]phenyl } -N-4-fluorobenzoyl -glycine ethyl ester (5-1 4d) for N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-S phenylcarbonylamino]phenyl}-N-phenylsulfonylglycine ethyl ester (4- l Oa), S- l Sd was prepared.
Analysis calculated for C26H25FN404 ~ 1.40 TFA ~ 0.30 H20 C, 53.92; H, 4.24; N, 8.73 Found: C, 53.90; H, 4.23; N, 8.83 EXAMPLE SE
1~ IN
~0 0 ,~ ~OEt 02N 5-1 3e Step 1: N-4-Nitrophenyl-N-picolinoyl-~lycine ethyl ester (5-13d) lS Following the procedure described for 5-13a, but substituting picolinoyl chloride hydrochloride for benzoyl chloride, S-I3d was prepared.
I~IN
~0 0 ~N~oEt 1/' N
BocN ~,J 5-1 4e Step 2 N- {4-[4-(4-tert-Butyloxycarbonyl-piperazin- l -yl)-phenylcarbonyl-amino]phenyl ~-N-picolinoylglycine ethyl ester (5-14e) Following the procedure described for 4-lOa. but 5 substituting N-4-nitrophenyl-N-picolinoyl-glycine ethyl ester (5-13d~
for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (~), 5-14e was prepared.
I~N
~0 0 O ~N'J~OH
~ N
HNJ 5-15e Step 3 N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl } -N-picolinoyl-glycine (5- 15e) Following the procedure described for 4-1 la. but substituting N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-lS phenylcarbonylamino]phenyl}-N-picolinoylglycine ethyl ester (5-14e) for N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino]phenyl}-N-phenylsulfonylglycine ethyl ester (4-lOa), 5-15e was prepared.
Analysis calculated for C25H25N504 ~ 2.10 TFA ~ 0.20 H20 C, 49.92; H, 3.95; N, 9.97 ~ Found: C, 49.88; H, 3.95; N, 10.04 WO 97/31910 PCTtUS97/02712 EXAMPLE SF
~00 ,¢~ ~OEt 02N 5-13f Step 1: N-4-Nitrophenyl-N-nicotinoyl-glycine ethyl ester (5-13f) S Following the procedure described for 5-13a. but substituting nicotinoyl chloride hydrochloride for benzoyl chloride, S-13f was prepared.
~00 O ~ ~OEt ,¢~ H
I N 5-14f BocN ~,J
~0 Step 2: N- { 4-~4-(4-tert- Butyloxycarbonyl-piperazin- I -yl)-phenylcarbonyl amino]phenyl } -N-nicotinoylglycine ethyl ester (5-14f) Following the procedure described for 4-lOa. but substituting N-4-nitrophenyl-N-picolinoyl-glycine ethyl ester (S-L3f) for lS N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (4-8a), 5-14f was prepared.
~ ~I
~0 o ,~ HN J~
~f HN
Step 3 N- { 4-~4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl ~ -N-nicotinoyl-,elycine (5-lSf) Following the procedure described for 4-1 la. but substituting N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylamino]phenyl } -N-nicotinoylglycine ethyl ester (~
for N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino]phenyl}-N-phenylsulfonylglycine ethyl ester (4-lOa), 5-lSf was 1 0 prepared.
Analysis calculated for C25H25N504 ~ 2.20 TFA ~ 0.35 H20 C, 49.27; H, 3.92; N, 9.77 Found: C, 49.25; H, 3.92; N, 10.12 l S EXAMPLE 5G
N~
~0 0 ~ ~OEt 02N~ 5-139 Step 1: N-4-Nitrophenyl-N-isonicotinoyl-glycine ethyl ester (5-13~) CA 02246756 l998-08-l8 WO g7/31910 PCT/US97/02712 Following the procedure described for 5-13a, but substituting isonicotinoyl chloride hydrochloride for benzoyl chloride, 5-13g was prepared.
N~
~0 0 ,¢~ N
BocN J 5-14~
Step 2: N- { 4-[4-(4-tert-Butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-arnino~phenyl }-N-isonicotinoylglycine ethyl ester (5-14g) Following the procedure described for 4-lOa, but sub~ u~ g N-4-nitrophenyl-N-isonicotinoyl-glycine ethyl ester (5-13g) for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (4-8a), 5-14 was prepared.
N~
~00 --' N
lS HN
- Step 3: N-{4-~4-(Piperazin-l-yl)phenylcarbonylamino]phenyl~-N-isonicotin-oyl-glycine (5-lSg) Following the procedure described for 4-1 la, but substituting N- ~ 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -5 yl)phenylcarbonylamino]phenyl }-N-isonicotinoylglycine ethyl ester (5- 14g~ for N- { 4-[4-(4-fert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylamino}phenyl}-N-phenylsulfonylglycine ethyl ester (4-lOa), 5- 15~ was prepared.
Analysis calculated for C25H25N504 ~ 2.35 TFA ~ 0.65 H20 C, 4~.26; H, 3.91; N, 9.47 Found: C, 48.25; H, 3.90; N, 9.57 ~o o ,~ ~OEt 02N 5-1 3h Step 1: N-4-Nitrophenyl-N-acetyl-~lycine ethyl ester (5-13h) Following the procedure described for 5-13a, but substituting acetyl chloride for benzoyl chloride, S-13h was prepared.
~o o O ~ N~OEt ~N~
~N~
5-14h BocN
Step 2: N- { 4-1 4-(4-tert-Butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino~phenyl } -N-acetylglycine ethyl ester (5-14h) Following ~e procedure described for 4-lOa~ but S substituting N-4-nitrophenyl-N-acetyl-glycine ethyl ester (5-13h) for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (4-8a), 5-14h was prepared.
~ O
o ~ N~I~oH
~NJ~
HN
Step 3: N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl } -N-acetyl-~lycine (5-lSh) Following the procedure described for 4-1 la, but substituting N- ~ 4-L4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-15 phenylcarbonylamino3phenyl}-N-acetylglycine ethyl ester (5-14h) for N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino]phenyl}-N-phenylsulfonylglycine ethyl ester (4-lOa), S-lSh was prepared.
Analysis calculated for C21H24N404 ~ 1.30 TFA ~ 0.55 H20 C, Sl.l l; H, 4.80; N, 10.10 Found: C, 51.09; H, 4.74; N, 10.25 ~0 o ~ ~OEt 02N~ 5-13i Step 1: N-4-Nitrophenyl-N-cyclopropanecarboxylglycine ethyl ester (S-1 3i) Following the procedure described for 5-13a~ but substituting cyclopropanecarbonyl chloride for benzoyl chloride, 5-13i was prepared.
~0 0 ,3J HN~
BocN ~,J 5-1 4i Step 2: N- { 4-[4-(4-terf-Butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino]phenyl } -N-cyclopropane-ca~xylg~ycine e.hyl es.er (5-14i) Following the procedure described for 4-lOa. but 15 substituting N-4-nitrophenyl-N-cyclopropanecarboxylglycine ethyl ester (5-13i) for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (~), 5-14i was prepared.
~0 0 N
HNJ 5-15i Step 3: N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl } -3!1-cyclopropanecarboxylglycine (5- 15i3 Following the procedure described for 4-3 la, but substituting N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylaminolphenyl}-N-cyclopropanecarboxylglycine ethyl ester (~) for N-~4-[4-(4-tert-butyloxycarbonyl-piperazin-1-yl)-phenylcarbonylamino~phenyl}-N-phenylsulfonylglycine ethyl ester 10 (4- 1 Oa), 5- 1 Si was prepared.
Analysis calculated for C23H26N404 ~ 1.38 TFA ~ 0.62 H20 C, 52.35; H, 4.88; N, 9.48 Found: C, 52.35; H, 4.86; N, 9.65 ~XAMPLE 5J
~0 ~~ O
02N ~i Step 1: N-4-Nitrophenyl-N-benzyloxyacetyl-glycine ethyl ester (5-13j) Following the procedure described for 5-13a, but substitllting ben~;yloxyacetyl chloride for benzoyl chloride, 5-13; was 20 prepared.
.
~~~~ ~
O ~ N~OEt J3JI' H
--N
BocN J ~
Step 2: N-{4-[4-(4-tert-Butyloxycarbonyl-piperazin-1-yl)-phenylcarbonyl-amino]phenyl ~ -N-benzyloxyacetylglycine ethyl ester (5-14j) Following the procedure described for 4-lOa, but substituting N-4-nitrophenyl-N-benzyloxyacetylglycine ethyl ester (5-13j) for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (4-8a), 5-14j was prepared.
~~~~ ~
o ~N~I'oH
~NJ~
HN ~J ~-1 5j Step 3: N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl } -N-benzyloxy-acetylglycine (5- l Sj) Following the procedure described for 4-1 la, but substituting N- ~ 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylamino~phenyl } -N-benzyloxy-acetylglycine ethyl ester (5-1 4j) for N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylamino]phenyl } -N-phenylsulfonylglycine ethyl ester 20 (4- lOa), ~ was prepared.
WO g7/31910 PCT/US97/02712 Analysis calculated for C2gH30N4O5 ~ 1.56 TFA ~ 0.30 H2O
C, 54.50; H, 4.73; N, 8.17 found: C, 54.49; H, 4.73; N, 8.51 HO'--f5 O
O ~N'~OH
~N~
H
~N
HN~
N- { 4- [4-(Piperazin- 1 -yl)phenylcarbonylamino]phenyl } -N-hydroxy-acetylglycine (5-lSk) A mixture of N-{4-[4-(piperazin-1-yl)phenylcarbonyl-aminolphenyl}-N-benzyloxyacetylglycine (S-lSj, 100 mg), 5% Pd (10 mg) on charcoal, TFA (1 mL) and ethanol (10 mL) was stirred under a balloon of hydrogen gas for 18 h at RT. The resultant mixture was concentrated, and the residue subjected to column chromatography on a 15 reverse phase C-18 column to provide ~.
Analysis calculated for C21H24N4O5 ~ 1.45 TFA ~ 0.40 H2O
C, 49.07; H, 4.52; N, 9.58 Found: C, 49.08; H, 4.47; N, 9.68 CA 02246756 l998-08-l8 ~0 0 ~ ~OEt 02N~
c~3 Step 1: N-3-Methyl-4-nitrophenyl-N-benzoyl-glycine ethyl ester (5-131) Following the procedure described for 5-13a. but sub~liluting 3-methyl-4-nitroaniline for 4-nitroaniline, 5-131 was prepared.
~00 O ~ N~OEt ~N'¢~ CH3 BocN J 5-141 Step 2: N- { 4-[4-(4-tert-Butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino]-3-methyl-phenyl }-N-benzoyl~lycine ethyl ester (5-141) Following the procedure described for 4-lOa, but 15 substituting N-3-methyl-4-nitrophenyl-N-benzoyl-glycine ethyl ester WO g7/3~910 PCT/US97/02712 (5-131) for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl es~er (4-8a),5-141 was prepared.
~0 0 ~ N ~:~J''' C H3 HN ~,J
5-15i Step 3: N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonylaminol -3 -methyl-phenyl~-N-2-benzoyl~lycine (5-151) Following the procedure described for 4-1 la, but substituting N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-10 phenylcarbonylamino]-3-methyl-phenyl}-N-benzoylglycine ethyl ester (5-141) for N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylamino]phenyl}-N-phenylsulfonylglycine ethyl ester (4-IOa), 5-151 was prepared.
Analysis calculated for C27H2gN404 ~ 1.52 TFA ~ 0.54 H20 C, 55.04; H, 4.70; N, 8.55 found: C, 55.03; H, 4.71; N, 8.84 CA 02246756 l998-08-l8 WO 97/31910 PCT/IJS97/027~2 ~0 0 ,¢~ ~OEt 5-1 3m Step 1: N-2-Methyl-4-nitrophenyl-N-benzoyl-glycine ethyl ester (5-13m) Following the procedure described for 5-13a~ but substituting 2-methyl-4-nitroaniline for 4-nitroaniline, 5-13m was prepared.
~00 o ~N~OEt ,¢~ tNi ~ C H3 f N
BocN 'J
~-1 4m Step 2: N - { 4- [4-(4-tert-Butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonyl-amino]-2-methyl-phenyl }-N-benzoylglycine ethyl ester (5-14m) Following the procedure described for 4-lOa. but substituting N-2-methyl-4-nitrophenyl-N-benzoylglycine ethyl ester (5-13m) for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (~), 5-14m was prepared.
~00 ~ ,¢~ ~OH
HNJ
5-t~m Step 3: N- { 4-[4-(Piperazin- 1 -yl)phenylcarbonylamino} -2-methyl-phenyl ~ -N-2-benzoyl~lycine (S- l Sm) Following the procedure described for 4-1 la. but substituting N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-lO phenylcarbonylamino3-2-methyl-phenyl}-N-benzoylglycine ethyl ester (S- l 4m) for N- { 4-r4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylamino]phenyl}-N-phenylsulfonylglycine ethyl ester (4- l Oa), 5-1 5m was prepared.
Analysis calculated for C27H2gN40~ ~ 1.56 TFA ~ 0.58 H20 lS C~ 54.74; H, 4.69; N, 8.48 ~ound: C, 54.75, H, 4.69; N, 8.74 CA 02246756 l998-08-l8 WO 97/31910 P~'r/US97/OZ712 .
~ EXAMPLE SN
~~ O
O ~ N~OEt H J~
I--N
BocN J CH3 ~-14n Step 1: N-{4-~4-(4-tert-Butyloxycarbonyl-piperazin-1 -yl)-3-methylphenyl-carbonylamino3-phenyl } -N-benzoylglycine ethyl ester ~5-14n) Following the procedure described for 4-lOa, but substituting N-4-nitrophenyl-N-benzoylglycine ethyl ester (5-13a) for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (4-8a), and sub~liLu~ g 4-[4-(tert-butyloxycarbonyl)piperazin-1-yl]-3-methylbenzoic acid for 4-[4-(tert-butyloxycarbonyl~piperazin-1-yl]-benzoic acid, 5-14n was prepared.
~,00 N
H
~N' ~
HN ''J CH3 5-1 5n Step 2: N- ~ 4-[4-(Piperazin- 1 -yl)-3-methyl-phenylcarbonylamino]-phenyl ~ -N-benzoylglycine (5- 15n~
Following the procedure described for 4-l la, but 5 substituting N- { 4-~4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-3 -methylphenylcarbonylamino] -phenyl } -N -benzoylglycine ethyl ester (5-14n) for N-{4-[4-(4-tert-butyloxycarbonyl-piperazin-1-yl)-phenylcarbonylamino]phenyl}-N-phenylsulfonylglycine ethyl ester (4- 1 Oa), 5- 15n was prepared.
10 AnaIysis calculated for C27H28N404 ~ 1.42 TFA ~ 0.44 H20 C, 55.79; H, 4.75; N, 8.72 Found: C, 55.80; H, 4.76; N, 8.78 ~00 o ,~N~OEt ~H
~N Clt3 BocN ~J
5-14c Step 1: N- {4-[4-(4-tert-Butyloxycarbonyl-piperazin- 1 -yl)-2-methylphenyl-carbonylamino]-phenyl } -N-benzoylglycine ethyl ester (5-140) Following the procedure described for 4-lOa, but substituting N-4-nitrophenyl-N-benzoylglycine ethyl ester (5-13a) for N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester ~4-8a), and substituting 4-[4-(tert-butyloxycarbonyl)piperazin- 1 -yl 3 -2-methyl-benzoic acid for 4-[4-(tert-butyloxycarbonyl)piperazin-1-yl3-benzoic acid, 5-140 was prepared.
.
~00 ,¢~ N J3' ~N CH3 HNJ
5-15c Step 2: N- { 4-[4-(Piperazin- 1 -yl)-2-methylphenylcarbonylamino]-S phenyl ~-N-benzoyl,~lYcine ~5-150) Following the procedure described for 4-1 la, but substituting N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-2-methylphenylcarbonylamino] -phenyl } -N -benzoylglycine ethyl ester (5-140) for N- { 4-[4-(4-tert-butyloxycarbonyl-piperazin- 1 -yl)-10 phenylcarbonylamino]phenyl}-N-phenylsulfonylglycine ethyl ester ~4-lOa), S-lSo was prepared.
Analysis calculated for C27H2gN404 ~ 1.56 TFA ~ 0.46 H20 C, 54.92; H, 4.66; N, 8.51 Found: C, 54.93; H, 4.67; N, 8.58 WO 97/31910 PCT/lJS97102712 S(~HEl~E 6 HN~ BOC20 tBuO N~Br 1. CH3MgBr 2. tBuLi 3. C~
tBuO~N~, ~OH SO2Ph 0 6-3 H2N~N~,CO2Et/PYCLU
--~ SO2Ph 1. HCI/EtOAc tBuO~N~ H H~N~CO2Et ~--~ SO2Ph HN~N H~N~CO2H
E~AMPLE 6 tBuO~N~O N~CO2Et ~g 1 . HCI/EtOAc 2. LiOH
HN~O SO2Ph S ~tep 1: 9-H-2-(1,1-Dimethylethoxycarbonyl)-7-bromo ,13-carboline (6-2) A suspension of 6-1, prepared by the method of Rinehart et al., (JACS, 1987,109, p 3378-3387) (0.366 g, 1.46 mmol) in CH2C12 (8 mL) was treated with triethylamine (0.61 mL, 4.4 mmol) followed by di-tert-butyldicarbonate (0.38 g, 1.7 mmol) for 1 hour at room temperature. The solution was concentrated and the residue chromatographed (20% EtOAc/Hexanes) to give 6-2 as a white solid.
Rf(20% EtOAc/Hexanes) 0.28 lH NMR (400 MHz, CDC13) ~ 8.0-7.6 (m, lH), 7.46 (s, lH), 7.33 (d, lS lH), 7.2 (d, lH), 4.6 (bs, 2H), 3.78 (bs, 2H), 2.76 (bs, 2H), 1.5 (s, 9H).
Step 2: 9-H-2-(1,1 -Dimethylethoxycarbonyl)-,13-carbolin-7-yl carboxylic acid (6-3) A solution of 6-2 (0.26 g, 0.734 mmol) in THF (10 mL) 20 was cooled to 0~C and treated with methylmagnesium chloride (3.0 M in THF, 0.29 mL, 0.87 mmol) to give a pale yellow solution. After 15 minutes the solution was cooled to -78~C and treated with t-BuLi (1.7M
in pentane, 4.35 mL, 7.39 mmol) to give a bright yellow solution.
After 10 minutes C02 gas was bubbled vigorously through the solution for I0 minutes. Saturated NH4CI, water and enough 6N NaOH to reach pH12 were added and the solution extracted with EtOAc. The EtOAc layer was back extracted with 0.5 NaOH and the aqueous layers combined, acidfied to pH 7 and extracted with EtOAc, the EtOAc layer S was dried (Na2S04) filtered and concentrated to give 6-3 as an off-white solid.
Rf(75:25:1 CHCl3/MeOH~lIOAc)0.48.
lH NMR (400 MHz, DMSO-d6) ~ 12.0 (bs, lH), 11.2 (s, lH), 7.93 (s, lH), 7.6 (d, lH), 7.45 (d, lH), 4.6 (s, 2H), 3.68 (m, 2H), 2.7 (m, 2H), 1.4 (s, 9H).
Step 3: N- f 4-{9-Boc-~B-carboline-7-yl)carbonyl~mino]phenyl } -N-phenvl-sulfonyl glycine (6-4) A solution of 6-3 (0.075 g, 0.24 mmol) and N-4-aminophenyl-N-phenylsul~onylglycine ethyl ester (0.086 g, 0.28 mmol) in CH2C12 (3 mL) was treated with diisopropyl~mine and PYCLU to give ~ as a white solid a~ter chromatography in a gradient of 40 to 50% EtOAc/Hexanes.
Rf(40% EtOAc/Hexanes)0.13 lH NMR (400 MHz, CDC13) ~; 8.5-8.2 ~m, lH), 8.0 (d, lH), 7.2 (2s, 2H), 7.6 (2s, 2H), 7.58 (m, lH), 7.53 (s, 2H), 7.47 (m, 2H), 7.2 (d, 2H), 4.68 (bs, 2H), 4.4 (s, 2H), 4.13 (q, 2H), 3.8 (bs, 2H), 2.7 (bs, 2H), 1.5 (s, 9H), 1.2 (t, 3H).
Step: 4 N- { 4-[(9-H-~-Carboline-7-yl)carbonylamino]phenyl ~ -N-phenyl-sulfonyl ~lycine (6-5) A solution of 6-4 (0.088 g, 0.139 mmol) in EtOAc (15 mL) was treated first with HCl gas, then with LiOH~H2O to give 6-5 as a white solid after chromatography in 18:1:I EtOH/H2O/NH4OH.
Rf(l 8:1:1 EtOH/H2O/NH4OH) 0.43 lH NMR (400 MHz, D20) ~ 7.79 (s, IH), 7.6 (m, 1H), 7.52 (m, 2H), 7.46 (m, 4H), 7.32 (d, 2H), 7.08 (d, 2H), 4.08 (s, 2H), 3.84 (s, 2H), 2.95 (m, 2H), 2.63 (m, 2H).
WO 97/31910 PCT/lJS97/02712 SC~IEME 7 N~CH3 Z~
KMnO4/H2o N~ CO2H 7-2 1. H2/PtO2/HOAc/MeOH
60 psi 2. BOC2O
BOCN~CO2H 7-3 so2C6H5 NJ~N PF6 H2N~N CO2Et [~ ~
i-Pr2NEt, CH2CI2 BOCN~ }~~ N ~,CO2Et LiOH
SCE~EME 7 CON~ED
BOCN~ SO2C6H~
H ~ N~,CO2H
HCUEtOAc HN/~N~SO2CGH
Step 1: 4-(4-Pyridyl)phenylcarboxylate (7-2) A slurry of 7-1 (5g, 29.6 mmol, prepared as described in Chambron, J.C.; Sauvage, J.P., Tetrahedron, 1987, 895 and Comins, D.L., Abdullah, A.H., J. Org. Chem., 1982, 47, 4315 method B) in 200 mL H20 was treated with 10% HCl until the solids dissolved. The solution was treated with solid KMn04 in portions (11.2 g, 888 mmol), stirred until the KMn04 had dissolved and heated to 90~C for 18 hr.
An additional 2 g of KMnO4 was added and the reaction was again 15 heated to 90~C for 2 hr. The reaction was cooled to ~60~C, filtered and the solids were washed with warm water. The filtrate was evaporated and the residue chromatographed (Silica gel, 10~ EtOH/H20/NH40H) to give 7-2 as an off-white solid.
lH NMR (400 MHz, DMSO) ~ 8.61 (m, 2H), 8.0 (m, 2H), 7.72 (m, 4H).
~ Step 2: 4-(4-N-BOC-piperidinyl)phenylcarboxylate (7-3) A solution of 7-2 (0.5 g7 2.5 mmol) in 20 mL 20%
HOAc/MeOH was treated with 250 mg PtO2 and hydrogenated at 50 psi for 4 hr. The solution was filtered through SoLka Floc, evaporated and S azeotroped with heptane to remove excess HOAc. The intermediate amino acid acetic acid salt was obtained as a white solid.
Rf(10:1:1 EtOH/H2O/NH4OH) 0.3.
lH NMR (400 MHz, CD3OD) ~ 8.96 ~m, 2H), 7.35 (m, 2H), 3.5 (bd, 2H), 3.4 (m, 2H), 3.2 (m, 2H), 3.0 (m, 2H).
A slurly of the amino acid (0.5 g, 1.9 mmol) in 30%
H2O/dioxane (12 mL) was treated with 1 N NaOH (4.8 mL) and di-ter~-butyldicarbonate (0.564 g, 2.58 mmol) at room temperature for 6 hr.
The reaction was acidified to pH S with 10% KHSO4 and extracted several times with EtOAc.
The EtOAc layers were combined and evaporated to give 7-3 as a white solid.
Rf(97:3:1 CHCl3/MeOH/HOAc) 0.39.
lH NMR (400 MHz, CD30D) ~i 7.95 (d, 2H), 7.33 (d, 2H), 4.2 (bd, 2H), 2.85 (b, 3H), 1.8 (bd, 2H), 1.6 (m, 2H), 1.48 (s, 9H).
Step 3: Ethyl 2-(1 -phenylsulfonamido-4-(4-(N-(1,1 -dimethylethoxycarbonyl)-piperidin-4-yl)phenyl-carboxamide~-phenyl)acetate (7-4) A solution of ~ (0.457 g, 1.5 mmol) N-4-aminophenyl-N-phenylsulfonylglycine ethyl ester (0.50 g, 1.5 mmol) in CH2CI2 (10 mL) was treated with diisopropylamine (0.287 mL, 1.65 mmol) and PYCLU (0.594 g, 1.65 rnmol) and stirred at room temperature for 24 hours. The solution was diluted with EtOAc and washed with H2O, 10% citric acid, saturated NaHCO3 and brine, dried over MgSO4, filtered and evaporated to give 7-4 as a tan oil. Rf(50%
EtOAc/Hexanes)0.16 1H NMR (400 MHz, CDC13) ~ 7.8 (d, lH), 7.7 (d, lH), 7.58 (m, 3H), 7.45 (m, 2H), 7.32 (d, lH), 7.2 (d, lH), 4.4 (s, 2H), 4.25 (m, 2H), 4.15 (q, 2H), 2.82 (m, 2H), 2.78 (m, lH), 1.82 (bd, 2H), 1.6 (m, 3H), 1.45 (s, 9H), 1.2 (t, 3H).
Step 4: N- { 4-[4-N-Boc-piperidin-4-yl)phenylcarboxylamino]-phenyl ~-N-phenylsulfonyl~lycine (7-5~
A solution of 7-4 (0.7 g, 1.12 mmol) in 1:1:1 MeOH/H20/rrHF was treated with LiOH-H20 (0.097 g, 1.12 mmol) for 24 hours. The solution was diluted with EtOAc and ln% KHS04 and the layers separated. The organic layer was dried over MgS04, filtered and evaporated to give 7-5 as a tan solid.
Rf(9: I: 1 CH2Cl2/MeOH/HOAc)0.55 1H NMR (400 MHz, CD30D) ~ 7.89 (m, 2H), 7.65 (m, 5H3, 7.05 (m, 2H), 7.8 (d, 2H), 7.18 (d, 2H), 4.4 (s, 2H), 4.2 (bd, 2H), 2.85 (m, 3H), 2.83 (bd, 2H), 1.6 (m, lH), 1.48 (s, 9H).
Step 5: N-{4-[4-Piperidin-4-yl)phenylcarbonylamino]phenyl } -N-phenyl-sulfonyl~lycine (7-6) ~ solution of 7-5 (0.4 g, 0.67 mmol) in EtOAc (5 mL) was cooled to -78~C, saturated with HCl gas, warmed to 0~C and stirred for 1 hour, then concentrated at ambient temperature to give 7-6 as a white solidafterchromatographyin 10:1:1 EtOH/H20/NH40H.
Rf(l o~ EtOH/H20/NH40H)0.34 ~H NMR (400 MHz, ~2~ + NaOD) ~ 7.65-7.4 (m, 7H), 7.35 (d, 2H), 7.26 (m, 2H), 7.05 ~m, 2H), 4.08 (bs, 2H), 2.95 (m, 2H), 2.55 (m, 3H), 1.65 (m, 2H), 1.45 (m, 2H).
~ + ~OEt 1. N-Methylmorpholine, NMP
N HN 2. LiOH, H20 o t. (COCI)2 ~OH SO2 O
f~N 2,~,N 'J~OEt N 8-t H2N
SO2 ~ NaOH
O r~ ~OEt ~NH~
N
~' SO2 ~
O ~N~J~OH
~N~
~,N
Il l 8-3 N ~
Step 1: 4-(Pyridyl)piperidin-4-yl-carboxylic acid (8-1) Ethyl isonipecotate (6.0 g, 38.66 mmol), 4-chloropyridine hydrochloride (5.9 g, 38.66 mmol) and N-methylrnorpholine ~9.3 mL, 85.0 mmol) were dissolved in N-methylpyrrolidinone (50 mL~ and the resulting solution heated at 100~ for 48 h. The solution was concentrated in vacuo and the residue dissolved in ethyl acetate (200 mL) and washed with water and brine (2 x 100 rnL), then dried IO (Na2S04) and evaporated. The resulting residue was purified by flash chromatography (5%MeOH/CH2Cl2) to afford ethyl 4-(pyridyl)piperidin-4-yl-carboxylate as a crystalline solid.
A solution of the above ester (10 g, 42.7 mmol) in THF (50 mL) was treated with lN LiOH (47 mL, 47.0 mmol) and H20 (50 mL).
The resulting solution was concentrated and the aqueous residue cooled to 0~C, then adjusted to p~ ~ 6 with IN HCI and the resulting solid 8-1, collected by filtration.
Step 2: N- { 4-[N-(4-Pyridyl)-piperidinyl-4-carbonylamino]phenyl } -N-phenvl-sulfonyl-~lycine methyl ester ~8-2) Following the procedure described for 4-lOa. but substituting N-(4-pyridyl)-piperidinyl-4-carboxylic acid (~) for 4-~4-(tert-butyloxycarbonyl)-piperazin-l-yl]benzoic acid, 8-2 was prepared.
Step 3: N-{4-[N-(4-Pyridyl)-piperidinyl-4-carbonylamino]phenyl}-N-phenylsulfonyl-glycine (8-3) Following the procedure described for 4-1 la, N-{4-rN-~4-pyridyl)-piperidinyl-4-carbonylamino]phenyl ~ -N-phenylsulfonylglycine methyl ester 8-2 was hydrolyzed. HPLC purification provided 8-3.
Analysis calculated for C2sH2sN40sS ~ 1.40 TFA ~ 0.80 H20 C, 50.02; H, 4.23; N, 8.39 ~ound: C, 50.00; H, 4.24; N, 8.65 CA 022467=,6 1998-08-18 ~OH
~, NO2 ~N
~ BocN J
HN~
~N~ 1. H2, Pt/C, THF
--N 2. PhSO2CI, pyridine BocN J 9-2 H ,~
,¢~N~N~o2 1. NaH, BrCH2CO2-t-Bu 2. TFA, CH2C12 f~N ~
BocNJ g ~SI02 ~
~N
HN
-WO 97131910 PCTllJS97/02712 Step 1: N-4-(4-tert-Butyloxycarbonylpiperaziny- 1 -y)-benzoyl] -5-S nitro-indoline (9-2) Following the procedure described for 4-lOa, but substituting 5-nitroindoline C~L) for N-4-aminophenyl-N-phenylsulfonylglycine e~yl ester, 2~ was prepared.
Step 2: N-[4-(4-tert-Butyloxycarbonylpiperaziny-1-y)-benzoyl]-5-phenyl-sulfonylamino-indoline (9-3) Following the procedure described for ~, but subtituting N-[4-(4-tert-butyloxycarbonylpiperaziny- 1 -y)-benzoyl~-5-nitro-indoline (2~) for nitrobenzene 3-4, ~ was prepared. The catalytic 15 hydrogenation was carried out in the presence of Pt/C in THF.
~tep 3: N- { N-[4-(4-tert-Butyloxycarbonylpiperaziny- 1 -yl)-benzoyll-5-indolinyl~-N-phenylsufonyl-glycine (9-4) Following the procedure described ~or ~, but 20 substit-ltin~ N-[4-(4-tert-butyloxycarbonylpiperaziny- 1 -y)-benzoyl~ -5 -phenylsulfonylamino-indoline ~) for sulfonamide 3-5a7 9-4 was prepared.
Analysis calculated for C27H2gN405S ~ 1.50 TFA
~, 52.10, H, 4.30; N, 8.10 Folmd: C, 52.13; H, 4.26; N, 8.23 CA 02246756 l998-08-l8 H ~N~2 H2O2, NaC102 HO~No2 O O
, NH2 (COCI)2 --N
BocN J y H ~NO2 1 . H2, Pt2S, MeOH ~ N ~S
2. PhSO2CI, pyridine ~N
BocN J 10-3 @' SO2 O 1. NaH, H ~N ~JI~OMe BrCH2CO2Me ,[3~N~S 2. aq NaOH; TFA, ~N
BocN J 10-4 ~
,02 ~
--OH
~N~S
~N~ ~
WO 97/31910 PCT/IJS97tO2712 Step 1: 5-Nitro-thiophene-2-carboxylic acid (10-2) S To a cold (0~C) mixture of S-nitro-thiophene-2-carboxaldehyde Cl~.) (7.86 g, 50 mmol), NaH2P04 ~1.86 g, dissolved in 20 mL water), 30% H2~2 (6 mL) m acetonitrile (S0 mL), a solution of NaClO2 (8 g) in water (70 mL) was added over a period of I h.
After stirr~ng at RT for S h, the reaction mixture was treated with 10 sodium sulfite (S00 mg) and 1 M aq. HCl. The resultant mixture was extracted with ethyl acetate (3X). The organic extracts were combined, washed with brine, dried over anhdrous magnesium sulfate, filtered, and concentrated under vacuum to provide acid 10-2.
~S Step 2: N-(S-Nitro-thiophene-2-carboxyl)-4-(4-tert-butyloxycarbonyl-piperaziny-1-yl)-~niline (10-3) Following the procedure described for 3-4, but substituting S-nitro-thiophene-2-carboxylic acid ~10-2) for 4-nitroben~oic acid, 10-3 was prepared.
Step 3: N- { 2-r4-(4-tert-Butyloxycarbonylpiperazin-yl)-phenylamino-carbonyllthien-5-vl ~-N-phenylsulfonyl-glycine methyl ester (104) Following the procedure described for 3-Sa, but 2~ substitu~ing N-(5-nitro-thiophene-2-carboxyl)-4-~4-tert-butyloxy-carbonylpiperaziny-1-yl)-aniline ClQ~) for 3-4. The reduction was carried out in methanol in the presence of Pt2S i~or three hour under a balloon of hydrogen gas. Phenylsulfonylation, was described for 3-Sa provided 10-4.
31) WO 97/31910 PCT/~JS97/02712 _ 99 _ Step 4: N-{ 2-[4-(1 -Piperazin-yl)-phenylaminocarbonyl3thien-5-yl } -N-phenvl-sulfonyl-glycine (10-5) Following the procedure described for,3-6a, but sub~liluLillg 10-4 for~, iO-5 was prepared.
S Analysis calculat~d for C23H24N405S2 ~ 1.72 TFA ~ 0.28 H20 C, 45.25; H, 3.77; N, 7.98 found: C, 45.25; H, 3.77; N, 8.13 WO 97/31910 PCTlaTS97/02712 [~H HNO3 ~&~H
NaHMDS, BrCH2CO2Me H2, Pd/C
~ 02N 11-3 f N
BocN ~J
O ~ ~OMe aq. NaOH;
H TFA, CH2CI2 ~N
BocN J 11-4 ~ ,~OH
CA 022467~6 l998-08-l8 EX~MPLE 1 1 Step 1: 6-Nitro-3.4-dihydroquinolin-2-(lH)-one (1 1-2) S To a solution of 3,4-dihydroquinolin-2-(lH)-one (1.50 g) in 78% sulfuric acid (300 mL) at RT, a mixture of 69% nitric acid (0.84 mL) in 78% sulfuric acid (60 mL) was added. The reacting mixture was stirred at RT for lS min, poured into ice-water, and extracted with methylene chloride (3 x 200 mL). The organic extracts were combined, washed with brine (4 x), dried over anhydrous m~gnesium sulfate, filtered and concentrated onto silica gel. The residue was loaded onto a column of silica gel, and eluted with 3% methanol in chloroform.
Collection and concentration of appropriate fractions provided the nitroquinolinone 1 1-2.
Step 2: 6-Nitro- 1 -carbomethoxymethyl-3.4-dihydroquinolin-2-( 1 H)-one (1 1-3) Following the procedure described for 5-13a, but substituting 6-nitro-3,4-dihydroquinolin-2-(lH)-one (~) for 4-nitro-N-benzoyl~nil;ne, 1 1-3 was prepared.
Step 3: 6-~4-(4-tert-Butyloxycarbonyl-piperazin- 1 -yl)-phenylcarbonylamino I-1 -carbomethoxymethyl-3,4-dihydroquinolin-2-( 1 H3-one ( 1 1 -4) Following the procedure described for 4-lOa. but substituting 6-nitro- 1 -carbomethoxymethyl-3 ,4-dihydroquinolin-2-( 1 H)-one (11-3) for N-4-nitrophenyl-N-phenylsulfonyl-glycine ethyl ester (~L
8a), 11-4 was prepared.
Step 4: 6-[4-(4-Piperazin-1-yl)-phenylcarbonylamino]-1-carbohydroxymethyl-3.4-dihydroquinolin-2-( 1 H3-one ( 1 1 -5) Following the procedure described for 4-l l a. but substituting 6-[4-(4-tert-butyloxycarbonyl-piperazin-1-yl)-WO g7/31910 PCT/US97/OZ712 phenylcarbonylamino~ -1 -carbomethoxy-methyl -3 ,4-dihydroqu~nolin-2-(lH)-one (11 -4) for 4- l Oa~ l 1 -5 was prepared.
Analysis calculated for C~22H24N404 ~ 1.22 TFA ~ 0.84 H20 C, 52.17; H, 4.82, N, 9.96 Found: C, 52.15; H, 4.82; N, 10.13 Tablet Preparation Tablets containing 25.0, 50.0, and 100.0 mg., respectively, of the active compound p) from Table I are prepared as illus~rated below:
TABLE FOR DOSES CONTA~ING
FROM 25-lOOMG OF THE ACTIVE COMPOUND
Amount-m~
Active Compound 25:0 50.0 100.0 Microcrystalline cellulose 37.25 100.0 200.() Modified food corn starch 37.25 4.25 8.5 Magnesium stearate 0.50 0.75 1.5 All of the active compound, cellulose, and a portion of the com starch are mixed and gr~n~ ted to 10% corn starch paste. The 20 resulting granulation is sieved, dried and blended with ~e remainder of the corn starch and the m~gn~sium stearate. The resulting gr~n~ tion is then compressed into tablets containing 25.0, 50.0, and 100.0 mg, respectively, of active ingredient per tablet.
Intravenous fo~nulations An intravenous dosage form of the above-indicated active compound is prepared as follows:
Active Compound 0.5-10.Omg Sodium Citrate 5-50mg Citric Acid 1-15mg Sodium Chloride 1 -8mg Water for Injection (USP) q.s. to 1 L
Utilizing the above quantities, the active compound is dissolved at room temperature in a previously prepared solution of sodium chloride, citric acid, and sodium citrate in Water for Injection (USP, see page 1636 of United States Phzlrm~copeia/National Formulary for 1995, published by United States Pharmacopeial Convention, Inc., Rockville, Maryland, copyright 1~94.
Therapeutic Treatment Compounds of the invention may be ~lministered to patients where inhibition of hllm~n or m~mm~lian platelet aggregation or adhesion is desired.
Compounds of the invention are useful in inhibiting platelet aggregation and thus, they may find utility in surgery on peripheral arteries (arterial grafts, carotid endaterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interation of platelets with artificial surfaces, leads to platelet aggregation and consumption. The aggregated platelets may form thrombi and thromboemboli. Compounds of the invention may be ~flmini~tered to these surgical patients to prevent the formation of thrombi and thromboemboli.
Claims (28)
1. A compound of formula I
X-A-Y-Z-B I
and the pharmaceutically acceptable salts, esters, solvates and stereoisomers thereof wherein:
X is heterocycle;
heterocycle is selected from:
(1) a five or six membered saturated, partially unsaturated or aromatic ring which consists of carbon atoms and one, two or three heteroatoms selected from the group -O-, -N-, -N(R1)- and -S-, wherein one of the carbon atoms may be substituted with a member selected from R1 a and -NHR1, (2) an eight to ten membered bicyclic ring system which is saturated, or completely or partially unsaturated, and which consists of carbon atoms and one, two or three heteroatoms selected from the group -O-, -N-, -N(R1)- and -S-, wherein one of the carbon atoms may be substituted with a member selected from R1a and -NHR1, (3) a thirteen to fourteen membered tricyclic ring system which is saturated, or completely or partially unsaturated, and which consists of carbon atoms and one, two or three heteroatoms selected from the group -O-, -N-, -N(R1)- and -S-, wherein one of the carbon atoms may be substituted with a member selected from R1a and -NHR1;
A is a bond between X and Y or is selected from:
(1) phenyl substituted with R1a, (2) -N(R1), and (3) ;
Y is selected from:
(1) -C1-8 alkyl-, (2) -C4-10 cycloalkyl-, (3) -C0-8 alkyl-NR1-CO-C0-8 alkyl-, (4) -C0-8 alkyl-CONR1-C0-8 alkyl-, (5) -C0-8 alkyl-O-C0-8 alkyl-, (6) -C0-8 alkyl-SO p-C0-8 alkyl-, (7) -(CH2)0-8-aryl-(CH2)0-8-, (8) (-CH2)0-6-aryl-SO p-(9) -(CH2)0-8-aryl-CO-(CH2)0-8-, (10) -(CH2)0-6-aryl-SO p-(CH2)0-6, (11) -(CH2)0-6-NR1-(CH2)0-6, (12) -(CH2)0-6-aryl-CH(OH)-(CH2)0-6, (13) -(CH2)0-8-aryl-CONH-(CH2)0-8-, (14) -C0-8 alkyl-SO p-NR1-C0-8 alkyl-, (15) -C0-8 alkyl-CO-C0-8 alkyl-, and (16) -C0-8 alkyl-CH(OH)-C0-8-alkyl-;
p is an integer selected from 0, 1 and 2;
Z is selected from aryl and heterocycle;
aryl is a 5- or 6-membered aromatic ring system which is unsubstituted or mono-, di- or tri-substituted with R2;
B is wherein m is an integer selected from 0 and 1;
R1 and R3 are independently selected at each occurrence from:
(1) hydrogen, (2) C1-10 alkyl-, (3) C3-8 cycloalkyl-, (4) aryl-Co 8 alkyl-, (5) amino-Co 8 aLkyl-, (6) Cl-6 aL~cylamino-Co 8 a~cyl-, (7) C1 6 diaLkylamino-Co 8 aLkyl-, (8) Cl 3 acylamino-Co g aLkyl-, (9) Cl 4 aLkoxy-Co 6 alkyl-, (10) -C0-6 alkyl-CO2H, (1 1 ) -C0-6 alkyl-CO2C 1-3 aLkyl, (12) -O-Co-6 alkyl-CO2H and (13) hydroxy-Co 6 aLkyl-;
Rla is independently selected at each occurrence from:
( 1 ) hydrogen, (2) halogen, (3) Cl lo aLkyl-, (4) C3-8 cycloaLkyl-, (S) aryl-Co-8 alkyl-, (6) amino-C0 8 aLkyl-, (7) C1 6 aLkylamino-Co 8 aLkyl-, (8) C1 6 diaL~cylamino-Co g aLkyl-, (9) Cl 3 acylamino-Co 8 alkyl-, (10) Cl 4 aLkoxy-Co 6 aLkyl-, (1 1 ) -CO-6 aLkyl-C02H, (12) -Co-6 aLkyl-CO2C1 3 aLkyl, (13) -0-C0-6 aLkyl-CO2H, (14) hydroxy C0-6 alkyl and (I 5) oxo (=O), R2 is independently selected at each occurrence from:
( 1 ) hydrogen, (2) halogen, (3) Cl 10 aLkyl-, (4) C3-8 cycloaLkyl-, (5) aryl-C0-8 alkyl-, (6) amino-C0-8 alkyl-, (7) C1-6 alkylamino-C0-8 alkyl-, (8) C1-6 dialkylamino-C0-8 alkyl-, (9) C1-3 acylamino-C0-8 alkyl-, (10) C1-4 alkoxy-C0-6 alkyl-, (11) -C0-6 alkyl-CO2H, (12) -C0-6 alkyl-CO2C1-3 alkyl, (13) -O-C0-6 alkyl-CO2H, and (14) hydroxy C0-6 alkyl;
R4 is selected from (1) -(CH2)p-D-R6 wherein p is defined above, (2) , and (3) , or (4) when Z is unsubstituted or substituted phenyl and m is zero, R4 together with the nitrogen to which it is attached can form a bicyclic structure with Z (phenyl) as follows:
D is selected from -SO2- and -C(O)-;
R5 is selected from:
(1) -OH, (2) C1-8 alkyloxy-, (3) aryl C0-6 alkyloxy-, (4) C1-8 alkylcarbonyloxy C1-4 alkyloxy-, (5) aryl C1-8 alkylcarbonyloxy C1-4 alkyloxy-, and (6) L- or D-amino acid joined by an amide linkage and wherein the carboxylic acid moiety of said amino acid is as the free acid or is esterified by C1-6 alkyl; and R6 is selected from:
(1) -C1-6alkyl, unsusbstituted, mono- or di-substituted with R1a, (2) -(C0-6alkyl)aryl, wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (3) -(C0-6alkyl)heterocycle, wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (4) -NR1(C1-6alkyl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (5) -NR1(C0-6alkylaryl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (6) -NR1(C0-6alkylheterocycle), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (7) -C3-6 cycloalkyl, and (8) -CF3.
X-A-Y-Z-B I
and the pharmaceutically acceptable salts, esters, solvates and stereoisomers thereof wherein:
X is heterocycle;
heterocycle is selected from:
(1) a five or six membered saturated, partially unsaturated or aromatic ring which consists of carbon atoms and one, two or three heteroatoms selected from the group -O-, -N-, -N(R1)- and -S-, wherein one of the carbon atoms may be substituted with a member selected from R1 a and -NHR1, (2) an eight to ten membered bicyclic ring system which is saturated, or completely or partially unsaturated, and which consists of carbon atoms and one, two or three heteroatoms selected from the group -O-, -N-, -N(R1)- and -S-, wherein one of the carbon atoms may be substituted with a member selected from R1a and -NHR1, (3) a thirteen to fourteen membered tricyclic ring system which is saturated, or completely or partially unsaturated, and which consists of carbon atoms and one, two or three heteroatoms selected from the group -O-, -N-, -N(R1)- and -S-, wherein one of the carbon atoms may be substituted with a member selected from R1a and -NHR1;
A is a bond between X and Y or is selected from:
(1) phenyl substituted with R1a, (2) -N(R1), and (3) ;
Y is selected from:
(1) -C1-8 alkyl-, (2) -C4-10 cycloalkyl-, (3) -C0-8 alkyl-NR1-CO-C0-8 alkyl-, (4) -C0-8 alkyl-CONR1-C0-8 alkyl-, (5) -C0-8 alkyl-O-C0-8 alkyl-, (6) -C0-8 alkyl-SO p-C0-8 alkyl-, (7) -(CH2)0-8-aryl-(CH2)0-8-, (8) (-CH2)0-6-aryl-SO p-(9) -(CH2)0-8-aryl-CO-(CH2)0-8-, (10) -(CH2)0-6-aryl-SO p-(CH2)0-6, (11) -(CH2)0-6-NR1-(CH2)0-6, (12) -(CH2)0-6-aryl-CH(OH)-(CH2)0-6, (13) -(CH2)0-8-aryl-CONH-(CH2)0-8-, (14) -C0-8 alkyl-SO p-NR1-C0-8 alkyl-, (15) -C0-8 alkyl-CO-C0-8 alkyl-, and (16) -C0-8 alkyl-CH(OH)-C0-8-alkyl-;
p is an integer selected from 0, 1 and 2;
Z is selected from aryl and heterocycle;
aryl is a 5- or 6-membered aromatic ring system which is unsubstituted or mono-, di- or tri-substituted with R2;
B is wherein m is an integer selected from 0 and 1;
R1 and R3 are independently selected at each occurrence from:
(1) hydrogen, (2) C1-10 alkyl-, (3) C3-8 cycloalkyl-, (4) aryl-Co 8 alkyl-, (5) amino-Co 8 aLkyl-, (6) Cl-6 aL~cylamino-Co 8 a~cyl-, (7) C1 6 diaLkylamino-Co 8 aLkyl-, (8) Cl 3 acylamino-Co g aLkyl-, (9) Cl 4 aLkoxy-Co 6 alkyl-, (10) -C0-6 alkyl-CO2H, (1 1 ) -C0-6 alkyl-CO2C 1-3 aLkyl, (12) -O-Co-6 alkyl-CO2H and (13) hydroxy-Co 6 aLkyl-;
Rla is independently selected at each occurrence from:
( 1 ) hydrogen, (2) halogen, (3) Cl lo aLkyl-, (4) C3-8 cycloaLkyl-, (S) aryl-Co-8 alkyl-, (6) amino-C0 8 aLkyl-, (7) C1 6 aLkylamino-Co 8 aLkyl-, (8) C1 6 diaL~cylamino-Co g aLkyl-, (9) Cl 3 acylamino-Co 8 alkyl-, (10) Cl 4 aLkoxy-Co 6 aLkyl-, (1 1 ) -CO-6 aLkyl-C02H, (12) -Co-6 aLkyl-CO2C1 3 aLkyl, (13) -0-C0-6 aLkyl-CO2H, (14) hydroxy C0-6 alkyl and (I 5) oxo (=O), R2 is independently selected at each occurrence from:
( 1 ) hydrogen, (2) halogen, (3) Cl 10 aLkyl-, (4) C3-8 cycloaLkyl-, (5) aryl-C0-8 alkyl-, (6) amino-C0-8 alkyl-, (7) C1-6 alkylamino-C0-8 alkyl-, (8) C1-6 dialkylamino-C0-8 alkyl-, (9) C1-3 acylamino-C0-8 alkyl-, (10) C1-4 alkoxy-C0-6 alkyl-, (11) -C0-6 alkyl-CO2H, (12) -C0-6 alkyl-CO2C1-3 alkyl, (13) -O-C0-6 alkyl-CO2H, and (14) hydroxy C0-6 alkyl;
R4 is selected from (1) -(CH2)p-D-R6 wherein p is defined above, (2) , and (3) , or (4) when Z is unsubstituted or substituted phenyl and m is zero, R4 together with the nitrogen to which it is attached can form a bicyclic structure with Z (phenyl) as follows:
D is selected from -SO2- and -C(O)-;
R5 is selected from:
(1) -OH, (2) C1-8 alkyloxy-, (3) aryl C0-6 alkyloxy-, (4) C1-8 alkylcarbonyloxy C1-4 alkyloxy-, (5) aryl C1-8 alkylcarbonyloxy C1-4 alkyloxy-, and (6) L- or D-amino acid joined by an amide linkage and wherein the carboxylic acid moiety of said amino acid is as the free acid or is esterified by C1-6 alkyl; and R6 is selected from:
(1) -C1-6alkyl, unsusbstituted, mono- or di-substituted with R1a, (2) -(C0-6alkyl)aryl, wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (3) -(C0-6alkyl)heterocycle, wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (4) -NR1(C1-6alkyl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (5) -NR1(C0-6alkylaryl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (6) -NR1(C0-6alkylheterocycle), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (7) -C3-6 cycloalkyl, and (8) -CF3.
2. The compound of claim 1 having the formula II
and the pharmaceutically acceptable salts, solvates and stereoisomers thereof wherein:
X-A- together represent a group selected from:
, , , , , , , ;
, , and ;
n is an integer selected from 2, 3, 4, and 5;
Q is selected from -N(R1)-, -S- and -O-;
Y is selected from:
(1) -C0-8 alkyl-NR1-CO-C0-8 alkyl-, (2) -C0-8 alkyl-CONR1-C0-8 alkyl-, (3) -C0-8 alkyl-O-C0-8 alkyl-, (4) -C0-8 alkyl-SO p-C0-8 alkyl-, (5) -(CH2)0-6-NR1-(CH2)0-6-, (6) -C0-8 alkyl-SO p-NR1-C0-8 alkyl-, (7) -C0-8 alkyl-CO-C0-8 alkyl-, and (8) -C0-8 alkyl-CH(OH)-C0-8-alkyl-;
p is an integer selected from 0, 1 and 2;
Z is selected from (1) aryl and (2) a five or six membered saturated, partially unsaturated or aromatic heterocyclic ring which is unsubstituted, or monosubstituted or disubstituted with R1a, which consists of carbon atoms and one, two or three heteroatoms selected from the group -O-, -N-, -N(R1)- and -S-, and which may be fused to a benzene ring to form a bicyclic structure, for example, or ;
aryl is a 5- or 6-membered aromatic carbon ring which is unsubstituted or mono-, di- or tri-substituted with R2;
R1 is independently selected at each occurrence from -H, C1-10 alkyl, C3-8 cycloalkyl-, aryl-C0-8 alkyl- and hydroxy-C0-6 alkyl-;
R1a is independently selected at each occurrence from -H, halogen, -C1-10 alkyl, C3-8 cycloalkyl-, aryl-C0-8 alkyl-, and amino-C0-8 alkyl-;
R2 is independently selected at each occurrence from -H, halogen, -C1-10 alkyl, C3-8 cycloalkyl-, aryl-C0-8 alkyl- and C1-4 alkoxy-C0-8 alkyl-;
R3 is independently selected at each occurrence from -H, -C1-10 alkyl, C3-8 cycloalkyl- and aryl-C0-8 alkyl-;
R5 is selected from:
(1) -OH, (2) C1-8 alkyloxy-, (3) aryl-C0-6 alkyloxy-, (4) C1-8 alkylcarbonyloxy-C1-4 alkyloxy-, and (5) aryl-C1-8 alkylcarbonyloxy-C1-4 alkyloxy-, D is selected from -SO2- and -C(O)-; and R6 is selected from:
(1) -C1-6alkyl, unsusbstituted, mono- or di-substituted with R1a, (2) -(C0-6alkyl)aryl, wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (3) -(C0-6alkyl)heterocycle, wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (4) -NR1(C1-6alkyl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (5) -NR1(C0-6alkylaryl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (6) -NR1(C0-6alkylheterocycle), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (7) -C3-6 cycloalkyl, (8) -CF3, (9) , and (10) , or (11) when Z is unsubstituted or substituted phenyl, D-R6 together with the nitrogen to which it is attached can form a bicyclic structure with Z (phenyl) as follows:
; and heterocycle is selected from a five or six membered saturated, partially unsaturated or aromatic ring which is unsubstituted, or monosubstituted or disubstituted with R1a, and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(R1)- and -S-.
and the pharmaceutically acceptable salts, solvates and stereoisomers thereof wherein:
X-A- together represent a group selected from:
, , , , , , , ;
, , and ;
n is an integer selected from 2, 3, 4, and 5;
Q is selected from -N(R1)-, -S- and -O-;
Y is selected from:
(1) -C0-8 alkyl-NR1-CO-C0-8 alkyl-, (2) -C0-8 alkyl-CONR1-C0-8 alkyl-, (3) -C0-8 alkyl-O-C0-8 alkyl-, (4) -C0-8 alkyl-SO p-C0-8 alkyl-, (5) -(CH2)0-6-NR1-(CH2)0-6-, (6) -C0-8 alkyl-SO p-NR1-C0-8 alkyl-, (7) -C0-8 alkyl-CO-C0-8 alkyl-, and (8) -C0-8 alkyl-CH(OH)-C0-8-alkyl-;
p is an integer selected from 0, 1 and 2;
Z is selected from (1) aryl and (2) a five or six membered saturated, partially unsaturated or aromatic heterocyclic ring which is unsubstituted, or monosubstituted or disubstituted with R1a, which consists of carbon atoms and one, two or three heteroatoms selected from the group -O-, -N-, -N(R1)- and -S-, and which may be fused to a benzene ring to form a bicyclic structure, for example, or ;
aryl is a 5- or 6-membered aromatic carbon ring which is unsubstituted or mono-, di- or tri-substituted with R2;
R1 is independently selected at each occurrence from -H, C1-10 alkyl, C3-8 cycloalkyl-, aryl-C0-8 alkyl- and hydroxy-C0-6 alkyl-;
R1a is independently selected at each occurrence from -H, halogen, -C1-10 alkyl, C3-8 cycloalkyl-, aryl-C0-8 alkyl-, and amino-C0-8 alkyl-;
R2 is independently selected at each occurrence from -H, halogen, -C1-10 alkyl, C3-8 cycloalkyl-, aryl-C0-8 alkyl- and C1-4 alkoxy-C0-8 alkyl-;
R3 is independently selected at each occurrence from -H, -C1-10 alkyl, C3-8 cycloalkyl- and aryl-C0-8 alkyl-;
R5 is selected from:
(1) -OH, (2) C1-8 alkyloxy-, (3) aryl-C0-6 alkyloxy-, (4) C1-8 alkylcarbonyloxy-C1-4 alkyloxy-, and (5) aryl-C1-8 alkylcarbonyloxy-C1-4 alkyloxy-, D is selected from -SO2- and -C(O)-; and R6 is selected from:
(1) -C1-6alkyl, unsusbstituted, mono- or di-substituted with R1a, (2) -(C0-6alkyl)aryl, wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (3) -(C0-6alkyl)heterocycle, wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (4) -NR1(C1-6alkyl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (5) -NR1(C0-6alkylaryl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (6) -NR1(C0-6alkylheterocycle), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (7) -C3-6 cycloalkyl, (8) -CF3, (9) , and (10) , or (11) when Z is unsubstituted or substituted phenyl, D-R6 together with the nitrogen to which it is attached can form a bicyclic structure with Z (phenyl) as follows:
; and heterocycle is selected from a five or six membered saturated, partially unsaturated or aromatic ring which is unsubstituted, or monosubstituted or disubstituted with R1a, and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(R1)- and -S-.
3. The compound of claim 2 wherein X-A- together represent a group selected from:
, , , and
, , , and
4. The compound of claim 3 wherein:
Q is selected form -NH-, -O- and -S-;
Y is selected from:
(1) -NR1-CO-, (2) -CONR1-, (3) -O-, (4) -SO p-, (5) -NR1-, (6) -SO p-NR1-, (7) -CO-, and (8) -CH(OH)-, p is an integer selected from 0, 1 and 2;
Z is selected from:
(1) phenyl, (2) phenyl which is mono-, di- or tri-substituted with R2, (3) thienyl, (4) and (5) ;
R1 is independently selected at each occurrence from -H and -C1-10 alkyl;
R1a is independently selected at each occurrence from -H, halogen and -C1-10 alkyl;
R2 is independently selected at each occurrence from -H, halogen and -C1-10 alkyl;
R3 is independently selected at each occurrence from -H and -C1-10 alkyl;
R5 is selected from:
(1) -OH, (2) C1-8 alkyloxy-, (3) aryl-C0-6 alkyloxy-, (4) C1-8 alkylcarbonyloxy-C1-4 alkyloxy-, and (5) aryl-C1-8 alkylcarbonyloxy-C1-4 alkyloxy-;
D is selected from -SO2- and -C(O)-, and R6 is selected from:
(1) -C1-6alkyl, unsusbstituted, mono- or di-substituted with R1a (2) -(C0-6alkyl)aryl, wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (3) -(C0-6alkyl)heterocycle, wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (4) -NR1(C1-6alkyl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (5) -NR1(C0-6alkylaryl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (6) -NR1(C0-6alkylheterocycle), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (7) -C3-6 cycloalkyl, (8) -CF3, (9) , and (10) , or (11) when Z is unsubstituted or substituted phenyl, D-R6 together with the nitrogen to which it is attached can form a bicyclic structure with Z (phenyl) as follows:
; and heterocycle is selected from a five or six membered saturated, partially unsaturated or aromatic ring which is unsubstituted, or monosubstituted or disubstituted with R1a, and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(R1)- and -S-.
Q is selected form -NH-, -O- and -S-;
Y is selected from:
(1) -NR1-CO-, (2) -CONR1-, (3) -O-, (4) -SO p-, (5) -NR1-, (6) -SO p-NR1-, (7) -CO-, and (8) -CH(OH)-, p is an integer selected from 0, 1 and 2;
Z is selected from:
(1) phenyl, (2) phenyl which is mono-, di- or tri-substituted with R2, (3) thienyl, (4) and (5) ;
R1 is independently selected at each occurrence from -H and -C1-10 alkyl;
R1a is independently selected at each occurrence from -H, halogen and -C1-10 alkyl;
R2 is independently selected at each occurrence from -H, halogen and -C1-10 alkyl;
R3 is independently selected at each occurrence from -H and -C1-10 alkyl;
R5 is selected from:
(1) -OH, (2) C1-8 alkyloxy-, (3) aryl-C0-6 alkyloxy-, (4) C1-8 alkylcarbonyloxy-C1-4 alkyloxy-, and (5) aryl-C1-8 alkylcarbonyloxy-C1-4 alkyloxy-;
D is selected from -SO2- and -C(O)-, and R6 is selected from:
(1) -C1-6alkyl, unsusbstituted, mono- or di-substituted with R1a (2) -(C0-6alkyl)aryl, wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (3) -(C0-6alkyl)heterocycle, wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (4) -NR1(C1-6alkyl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (5) -NR1(C0-6alkylaryl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (6) -NR1(C0-6alkylheterocycle), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (7) -C3-6 cycloalkyl, (8) -CF3, (9) , and (10) , or (11) when Z is unsubstituted or substituted phenyl, D-R6 together with the nitrogen to which it is attached can form a bicyclic structure with Z (phenyl) as follows:
; and heterocycle is selected from a five or six membered saturated, partially unsaturated or aromatic ring which is unsubstituted, or monosubstituted or disubstituted with R1a, and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(R1)- and -S-.
5. The compound of claim 4 having the formula III
and the pharmaceutically acceptable salts, solvates and stereoisomers thereof wherein:
Y is selected from:
(1) -NR1-CO-, (2) -CONR1-, (3) -O-, (4) -SO p-, (5) -NR1-, (6) -SO p-NR1-, (7) -CO-, and (8) -CH(OH)-;
p is an integer selected from 0, 1 and 2;
Z is selected from:
(1) phenyl, (2) phenyl which is mono-, di- or tri-substituted with R2, (3) thienyl, (4) and (5) ;
R1 is independently selected at each occurrence from -H and -C1-10 alkyl;
R1a is independently selected at each occurrence from -H, halogen and -C1-10 alkyl;
R2 is independently selected at each occurrence from -H, halogen and -C1-10 alkyl;
R3 is independently selected at each occurrence from -H and -C1-10 alkyl;
R5 is selected from:
(1) -OH, (2) C1-8 alkyloxy-, (3) aryl-C0-6 alkyloxy-, (4) C1-8 alkylcarbonyloxy-C1-4 alkyloxy-, and (5) aryl-C1-8 alkylcarbonyloxy-C1-4 alkyloxy-;
D is selected from -SO2- and -C(O)-; and R6 is selected from:
(1) -C1-6alkyl, unsusbstituted, mono- or di-substituted with R1a, (2) -(C0-6alkyl)aryl, wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (3) -(C0-6alkyl)heterocycle, wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (4) -NR1(C1-6alkyl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (5) -NR1(C0-6alkylaryl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (6) -NR1(C0-6alkylheterocycle), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (7) -C3-6 cycloalkyl, (8) -CF3, (9) , and (10) , or (11) when Z is unsubstituted or substituted phenyl, D-R6 together with the nitrogen to which it is attached can form a bicyclic structure with Z (phenyl) as follows:
; and heterocycle is selected from a five or six membered saturated, partially unsaturated or aromatic ring which is unsubstituted, or monosubstituted or disubstituted with R1a, and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(R1)- and -S-.
and the pharmaceutically acceptable salts, solvates and stereoisomers thereof wherein:
Y is selected from:
(1) -NR1-CO-, (2) -CONR1-, (3) -O-, (4) -SO p-, (5) -NR1-, (6) -SO p-NR1-, (7) -CO-, and (8) -CH(OH)-;
p is an integer selected from 0, 1 and 2;
Z is selected from:
(1) phenyl, (2) phenyl which is mono-, di- or tri-substituted with R2, (3) thienyl, (4) and (5) ;
R1 is independently selected at each occurrence from -H and -C1-10 alkyl;
R1a is independently selected at each occurrence from -H, halogen and -C1-10 alkyl;
R2 is independently selected at each occurrence from -H, halogen and -C1-10 alkyl;
R3 is independently selected at each occurrence from -H and -C1-10 alkyl;
R5 is selected from:
(1) -OH, (2) C1-8 alkyloxy-, (3) aryl-C0-6 alkyloxy-, (4) C1-8 alkylcarbonyloxy-C1-4 alkyloxy-, and (5) aryl-C1-8 alkylcarbonyloxy-C1-4 alkyloxy-;
D is selected from -SO2- and -C(O)-; and R6 is selected from:
(1) -C1-6alkyl, unsusbstituted, mono- or di-substituted with R1a, (2) -(C0-6alkyl)aryl, wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (3) -(C0-6alkyl)heterocycle, wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (4) -NR1(C1-6alkyl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (5) -NR1(C0-6alkylaryl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (6) -NR1(C0-6alkylheterocycle), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (7) -C3-6 cycloalkyl, (8) -CF3, (9) , and (10) , or (11) when Z is unsubstituted or substituted phenyl, D-R6 together with the nitrogen to which it is attached can form a bicyclic structure with Z (phenyl) as follows:
; and heterocycle is selected from a five or six membered saturated, partially unsaturated or aromatic ring which is unsubstituted, or monosubstituted or disubstituted with R1a, and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(R1)- and -S-.
6. The compound of claim 5 having the formula IV
and the pharmaceutically acceptable salts, solvates and stereoisomers thereof wherein:
Y is selected from -C(O)-N(R1)- and -N(R1)-C(O)-;
R1 is independently selected at each occurrence from -H and -C1-10 alkyl;
R1a is independently selected at each occurrence from -H, halogen and -C1-10 alkyl;
R2 is independently selected at each occurrence from -H, halogen and -C1-10 alkyl;
R3 is independently selected at each occurrence from -H and -C1-10 alkyl;
R5 is selected from:
(1) -OH, (2) C1-8 alkyloxy-, (3) aryl-C0-6 alkyloxy-, (4) C1-8 alkylcarbonyloxy-C1-4 alkyloxy-, and (5) aryl-C1-8 alkylcarbonyloxy-C1-4 alkyloxy-;
D is selected from -SO2- and -C(O)-; and R6 is selected from:
(1) -C1-6alkyl, unsusbstituted, mono- or di-substituted with R1a, (2) -(C0-6alkyl)aryl, wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (3) -(C0-6alkyl)heterocycle, wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (4) -NR1(C1-6alkyl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (5) -NR1(C0-6alkylaryl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (6) -NR1(C0-6alkylheterocycle), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (7) -C3-6 cycloalkyl, (8) -CF3, (9) , and (10) , or (11) when Z is unsubstituted or substituted phenyl, D-R6 together with the nitrogen to which it is attached can form a bicyclic structure with Z (phenyl) as follows:
; and heterocycle is selected from a five or six membered saturated, partially unsaturated or aromatic ring which is unsubstituted, or monosubstituted or disubstituted with R1a, and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(R1) and -S-.
and the pharmaceutically acceptable salts, solvates and stereoisomers thereof wherein:
Y is selected from -C(O)-N(R1)- and -N(R1)-C(O)-;
R1 is independently selected at each occurrence from -H and -C1-10 alkyl;
R1a is independently selected at each occurrence from -H, halogen and -C1-10 alkyl;
R2 is independently selected at each occurrence from -H, halogen and -C1-10 alkyl;
R3 is independently selected at each occurrence from -H and -C1-10 alkyl;
R5 is selected from:
(1) -OH, (2) C1-8 alkyloxy-, (3) aryl-C0-6 alkyloxy-, (4) C1-8 alkylcarbonyloxy-C1-4 alkyloxy-, and (5) aryl-C1-8 alkylcarbonyloxy-C1-4 alkyloxy-;
D is selected from -SO2- and -C(O)-; and R6 is selected from:
(1) -C1-6alkyl, unsusbstituted, mono- or di-substituted with R1a, (2) -(C0-6alkyl)aryl, wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (3) -(C0-6alkyl)heterocycle, wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (4) -NR1(C1-6alkyl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (5) -NR1(C0-6alkylaryl), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (6) -NR1(C0-6alkylheterocycle), wherein the alkyl group is unsusbstituted, mono- or di-substituted with R1a, (7) -C3-6 cycloalkyl, (8) -CF3, (9) , and (10) , or (11) when Z is unsubstituted or substituted phenyl, D-R6 together with the nitrogen to which it is attached can form a bicyclic structure with Z (phenyl) as follows:
; and heterocycle is selected from a five or six membered saturated, partially unsaturated or aromatic ring which is unsubstituted, or monosubstituted or disubstituted with R1a, and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(R1) and -S-.
7. The compound of claim 6 wherein Y is selected from -C(O)-NH- and -NH-CH(O)-; and R6 is selected from (1) unsubstituted, mono and di-substituted phenyl, (2) methyl, (3) benzyl wherein the aryl portion may be unsubstituted, mono or di-substituted, and (4) thienyl.
8. The compound of claim 1 wherein Y is -C(O)-NH-.
9. The compound of claim 8 having the formula V
wherein R1a, R2, R5, D, and R6 are defined as follows:
R1a R2 R5 D R6 a) H H OCH2CH3 -C(O)- phenyl b) H H OH -C(O)- -CH3;
c) H H OH -C(O)- phenyl;
d) H H OCH3 -C(O)- -CH3;
e) H H OH -C(O)- 2-F-phenyl;
f) H H OH -C(O)- cyclopropyl;
g) H H OH -C(O)- 3-pyridinyl;
h) H H OH -C(O)- 4-pyridinyl;
i) 6-CH3 H OH -C(O)- phenyl;
j) H 6-CH3 OH -C(O)- phenyl;
k) H 5-CH3 OH -C(O)- phenyl;
l) H H OH -SO2- -CF3;
m) H H OH -SO2- 2-F-phenyl;
n) H H OC2H5 -SO2- 2-thiophene;
o) H H OH -SO2- 2-thiophene;
p) H H OH -SO2- phenyl;
q) H 6-CH3 OH -SO2- phenyl;
r) H 2-Br OH -SO2- 2-F-phenyl;
s) H H OH -SO2- ;
t) H H OH -SO2- ; and u) H H OH -C(O)- -CH2-CH2- bonded to D and the carbon denoted with * to form .
wherein R1a, R2, R5, D, and R6 are defined as follows:
R1a R2 R5 D R6 a) H H OCH2CH3 -C(O)- phenyl b) H H OH -C(O)- -CH3;
c) H H OH -C(O)- phenyl;
d) H H OCH3 -C(O)- -CH3;
e) H H OH -C(O)- 2-F-phenyl;
f) H H OH -C(O)- cyclopropyl;
g) H H OH -C(O)- 3-pyridinyl;
h) H H OH -C(O)- 4-pyridinyl;
i) 6-CH3 H OH -C(O)- phenyl;
j) H 6-CH3 OH -C(O)- phenyl;
k) H 5-CH3 OH -C(O)- phenyl;
l) H H OH -SO2- -CF3;
m) H H OH -SO2- 2-F-phenyl;
n) H H OC2H5 -SO2- 2-thiophene;
o) H H OH -SO2- 2-thiophene;
p) H H OH -SO2- phenyl;
q) H 6-CH3 OH -SO2- phenyl;
r) H 2-Br OH -SO2- 2-F-phenyl;
s) H H OH -SO2- ;
t) H H OH -SO2- ; and u) H H OH -C(O)- -CH2-CH2- bonded to D and the carbon denoted with * to form .
10. The compound of claim 9 selected from those wherein:
a) R1a is H, R2 is H, R5 is OH, D is -SO2-, and R6 is phenyl; and b) R1a is H, R2 is H, R5 is OH, D is -SO2-, and R6 is 2-thiophene.
a) R1a is H, R2 is H, R5 is OH, D is -SO2-, and R6 is phenyl; and b) R1a is H, R2 is H, R5 is OH, D is -SO2-, and R6 is 2-thiophene.
11. The compound of claim 1 wherein Y is -NH-C(O)-.
12. The compound of claim 11 having the formula VI
wherein Z, R5 and R6 are defined as follows:
a) 1,4-phenyl OH CH3;
b) 1,4-phenyl OCH3 CH3;
c) 1,4-phenyl OCH(CH3)2 CH3;
d) 1,4-phenyl OH phenyl;
e) 1,4-phenyl OH 4-Br-phenyl;
f) 1,4-phenyl OH benzyl; and g) 2,5-thiophene OH phenyl.
wherein Z, R5 and R6 are defined as follows:
a) 1,4-phenyl OH CH3;
b) 1,4-phenyl OCH3 CH3;
c) 1,4-phenyl OCH(CH3)2 CH3;
d) 1,4-phenyl OH phenyl;
e) 1,4-phenyl OH 4-Br-phenyl;
f) 1,4-phenyl OH benzyl; and g) 2,5-thiophene OH phenyl.
13. The compound of claim 12 selected from those wherein Z, R5 and R6 are defined as follows:
a) 1,4-phenyl OH CH3;
b) 1,4-phenyl OH phenyl; and c) 1,4-phenyl OH benzyl.
a) 1,4-phenyl OH CH3;
b) 1,4-phenyl OH phenyl; and c) 1,4-phenyl OH benzyl.
14. The compound of claim 1 having the formula VII
wherein X-A, Y, Z and n are defined as follows:
X-A Y Z n a) -C(O)NH- 1,4-phenyl 0;
b) -C(O)NH- 1,4-phenyl 0;
c) -C(O)NH- 1,4-phenyl 0;
d) -(CH2)2- 1; and e) -(CH2)3-O- 1,4-phenyl 1.
wherein X-A, Y, Z and n are defined as follows:
X-A Y Z n a) -C(O)NH- 1,4-phenyl 0;
b) -C(O)NH- 1,4-phenyl 0;
c) -C(O)NH- 1,4-phenyl 0;
d) -(CH2)2- 1; and e) -(CH2)3-O- 1,4-phenyl 1.
15. The use of a compound of Claim 1 for inhibiting the binding of fibrinogen to blood platelets, inhibiting the aggregation of blood platelets, treating thrombus formation or embolus formation, or preventing thrombus or embolus formation in a mammal.
16. A composition for inhibiting the binding of fibrinogen to blood platelets in a mammal, comprising a therapeutically effective amount of a compound of Claim 1 and a pharmaceutically acceptable carrier.
17. A composition for inhibiting the aggregation of blood platelets in a mammal, by blocking fibrinogen from acting at its receptor site, comprising a therapeutically effective amount of a compound of Claim 1 and a pharmaceutically acceptable carrier.
18. A composition for inhibiting the aggregation of blood platelets in a mammal, by blocking fibrinogen from acting at its receptor site, comprising a therapeutically effective amount of a compound of Claim 1 in combination with a thrombolytic agent and a pharmaceutically acceptable carrier.
19. A composition for inhibiting the aggregation of blood platelets in a mammal, by blocking fibrinogen from acting at its receptor site, comprising a therapeutically effective amount of a compound of Claim 1 in combination with an anticoagulant agent and pharmaceutically acceptable carrier.
20. A method for inhibiting the binding of fibrinogen to blood platelets in a mammal, comprising treating the mammal with a composition of Claim 16.
21. A method for inhibiting the aggregation of blood platelets in a mammal, by blocking fibrinogen from acting at its receptor site, comprising treating the mammal with a composition of Claim 17.
22. A method for inhibiting the aggregation of blood platelets in a mammal, by blocking fibrinogen from acting at its receptor site, comprising treating the mammal with a composition of Claim 18.
23. A method for inhibiting the aggregation of blood platelets in a mammal, by blocking fibrinogen from acting at its receptor site, comprising treating the mammal with a composition of Claim 19.
24. A composition for inhibiting the aggregation of blood platelets in a mammal, by blocking fibrinogen from acting at its receptor site, comprising a a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 1 in combination with a therapeutically effective amount of two or more agents selected from a thrombolytic agent, an anticoagulant agent, and an antiplatelet agent.
25. A method for inhibiting the aggregation of blood platelets in a mammal, by blocking fibrinogen from acting at its receptor site, comprising treating the mammal with the composition of Claim 24.
26. A compound of Claim 6 for use in inhibiting the binding of fibrinogen to blood platelets, inhibiting the aggregation of blood platelets, treating thrombus formation or embolus formation, or preventing thrombus or embolus formation in a mammal.
27. A composition for inhibiting the binding of fibrinogen to blood platelets, in a mammal, comprising a therapeutically effective amount of a compound of Claim 6 and a pharmaceutically acceptable carrier.
28. A composition for inhibiting the aggregation of blood platelets, in a mammal, by blocking fibrinogen from acting at its receptor site, comprising a therapeutically effective amount of a compound of Claim 6 and a pharmaceutically acceptable carrier.
29. A method for inhibiting the binding of fibrinogen to blood platelets in a mammal, by blocking fibrinogen from acting at its receptor site, comprising treating the mammal with a composition of
27. A composition for inhibiting the binding of fibrinogen to blood platelets, in a mammal, comprising a therapeutically effective amount of a compound of Claim 6 and a pharmaceutically acceptable carrier.
28. A composition for inhibiting the aggregation of blood platelets, in a mammal, by blocking fibrinogen from acting at its receptor site, comprising a therapeutically effective amount of a compound of Claim 6 and a pharmaceutically acceptable carrier.
29. A method for inhibiting the binding of fibrinogen to blood platelets in a mammal, by blocking fibrinogen from acting at its receptor site, comprising treating the mammal with a composition of
Claim 27.
30. A method for inhibiting the aggregation of blood platelets in a mammal, by blocking fibrinogen from acting at its receptor site, comprising treating the mammal with a composition of
30. A method for inhibiting the aggregation of blood platelets in a mammal, by blocking fibrinogen from acting at its receptor site, comprising treating the mammal with a composition of
Claim 28.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1238096P | 1996-02-28 | 1996-02-28 | |
| US60/012,380 | 1996-02-28 | ||
| GB9606489.4 | 1996-03-27 | ||
| GBGB9606489.4A GB9606489D0 (en) | 1996-03-27 | 1996-03-27 | Fibrinogen receptor antagonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2246756A1 true CA2246756A1 (en) | 1997-09-04 |
Family
ID=26309005
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002246756A Abandoned CA2246756A1 (en) | 1996-02-28 | 1997-02-24 | Fibrinogen receptor antagonists |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0885205A4 (en) |
| JP (1) | JP2000505471A (en) |
| AU (1) | AU712082B2 (en) |
| CA (1) | CA2246756A1 (en) |
| WO (1) | WO1997031910A1 (en) |
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| JP2000514061A (en) * | 1996-06-28 | 2000-10-24 | メルク エンド カンパニー インコーポレーテッド | Fibrinogen receptor antagonist |
| JP2001026506A (en) * | 1999-04-28 | 2001-01-30 | Takeda Chem Ind Ltd | Sulfonamide derivative |
| US6586617B1 (en) * | 1999-04-28 | 2003-07-01 | Sumitomo Chemical Takeda Agro Company, Limited | Sulfonamide derivatives |
| AU7052300A (en) | 1999-08-27 | 2001-03-26 | Eli Lilly And Company | Hypoglycemic n,n-arylsulfonylglycine compounds |
| US6713467B2 (en) | 2000-11-07 | 2004-03-30 | Bristol-Myers Squibb Company | Acid derivatives useful as serine protease inhibitors |
| US6906192B2 (en) | 2000-11-07 | 2005-06-14 | Bristol Myers Squibb Company | Processes for the preparation of acid derivatives useful as serine protease inhibitors |
| HUP0400651A2 (en) | 2000-11-07 | 2004-06-28 | Bristol-Myers Squibb Company | Acid derivatives useful as serine protease inhibitors and pharmaceutical compositions containing them |
| DE60226441D1 (en) * | 2001-06-18 | 2008-06-19 | Ono Pharmaceutical Co | TETRAHYDROCHINOLINE DERIVATIVE COMPOUND AND THE COMPOUND OF AN ACTIVE MEDICAMENT CONTAINING ACTIVE SUBSTANCE |
| US20070275956A1 (en) * | 2003-10-14 | 2007-11-29 | Lohray Braj B | Novel Heterocyclic Compounds |
| GB0421908D0 (en) | 2004-10-01 | 2004-11-03 | Angeletti P Ist Richerche Bio | New uses |
| NZ564759A (en) * | 2005-06-30 | 2011-08-26 | Prosidion Ltd | GPCR agonists |
| WO2009050201A2 (en) | 2007-10-16 | 2009-04-23 | Novartis Ag | 4-phenyl-5-oxo-imidazole derivatives, pharmaceutical compositions and uses therof |
| CA2727055C (en) | 2008-01-11 | 2016-12-20 | Albany Molecular Research, Inc. | (1-azinone) -substituted pyridoindoles as mch antagonists |
| WO2011003021A1 (en) | 2009-07-01 | 2011-01-06 | Albany Molecular Research, Inc. | Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine mch-1 antagonists, methods of making, and use thereof |
| WO2011003005A1 (en) | 2009-07-01 | 2011-01-06 | Albany Molecular Research, Inc. | Azinone-substituted azepino[b]indole and pyrido-pyrrolo-azepine mch-1 antagonists, methods of making, and use thereof |
| US8618299B2 (en) | 2009-07-01 | 2013-12-31 | Albany Molecular Research, Inc. | Azinone-substituted azapolycycle MCH-1 antagonists, methods of making, and use thereof |
| WO2011003007A1 (en) | 2009-07-01 | 2011-01-06 | Albany Molecular Research, Inc. | Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine mch-1 antagonists, methods of making, and use thereof |
| WO2011027888A1 (en) * | 2009-09-07 | 2011-03-10 | 大日本住友製薬株式会社 | Diamide-phenyl derivative and pharmaceutically acceptable salt thereof |
| WO2012088124A2 (en) | 2010-12-21 | 2012-06-28 | Albany Molecular Research, Inc. | Tetrahydro-azacarboline mch-1 antagonists, methods of making, and uses thereof |
| US8697700B2 (en) | 2010-12-21 | 2014-04-15 | Albany Molecular Research, Inc. | Piperazinone-substituted tetrahydro-carboline MCH-1 antagonists, methods of making, and uses thereof |
| BR112015030399B8 (en) | 2013-06-05 | 2023-01-10 | C&C Res Lab | HETEROCYCLIC DERIVATIVES, USE OF SUCH DERIVATIVES AND PHARMACEUTICAL COMPOSITION FOR THE PREVENTION OR TREATMENT OF DISEASES ASSOCIATED WITH STAT3 PROTEIN ACTIVATION |
| ES2896400T3 (en) | 2014-08-01 | 2022-02-24 | Nuevolution As | Active compounds against bromdomains |
| KR102445054B1 (en) | 2018-02-13 | 2022-09-22 | 길리애드 사이언시즈, 인코포레이티드 | PD-1/PD-L1 inhibitors |
| CA3093130C (en) | 2018-04-19 | 2023-10-17 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
| US10774071B2 (en) | 2018-07-13 | 2020-09-15 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
| AU2019366355B2 (en) | 2018-10-24 | 2022-10-13 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56115769A (en) * | 1980-02-18 | 1981-09-11 | Tanabe Seiyaku Co Ltd | Piperazine derivative and its preparation |
| US4760064A (en) * | 1984-12-18 | 1988-07-26 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril compounds, compositions containing same and processes for preparing same |
| DE3622865A1 (en) * | 1986-07-08 | 1988-01-21 | Bayer Ag | N-Phenyl-substituted glycines |
| US5183810A (en) * | 1990-02-13 | 1993-02-02 | Merck & Co., Inc. | Imidazole angiotensin II antagonists incorporating a substituted benzyl element |
| IL99537A (en) * | 1990-09-27 | 1995-11-27 | Merck & Co Inc | Fibrinogen receptor antagonists and pharmaceutical compositions containing them |
| NZ239846A (en) * | 1990-09-27 | 1994-11-25 | Merck & Co Inc | Sulphonamide derivatives and pharmaceutical compositions thereof |
| JPH04182481A (en) * | 1990-11-19 | 1992-06-30 | Nisshin Flour Milling Co Ltd | Rhodanine derivative |
| CA2121148A1 (en) * | 1992-08-19 | 1994-03-03 | Satoru Nakai | Apoptosis regulator |
| US5358956A (en) * | 1992-10-14 | 1994-10-25 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
| CA2150550A1 (en) * | 1992-12-01 | 1994-06-09 | Melissa S. Egbertson | Fibrinogen receptor antagonists |
| IL109144A (en) * | 1993-03-29 | 2000-02-29 | Zeneca Ltd | Glycoprotein IIB/IIIA inhibiting 4-pyridylamino heterocyclic derivatives process for their preparation and pharmaceutical compositions containing them |
| US5523302A (en) * | 1993-11-24 | 1996-06-04 | The Du Pont Merck Pharmaceutical Company | Aromatic compounds containing basic and acidic termini useful as fibrinogen receptor antagonists |
| US5700801A (en) * | 1994-12-23 | 1997-12-23 | Karl Thomae, Gmbh | Piperazine derivatives, pharmaceutical compositions containing these compounds, their use and processes for preparing them |
-
1997
- 1997-02-24 EP EP97906712A patent/EP0885205A4/en not_active Withdrawn
- 1997-02-24 JP JP9531013A patent/JP2000505471A/en active Pending
- 1997-02-24 AU AU21332/97A patent/AU712082B2/en not_active Ceased
- 1997-02-24 WO PCT/US1997/002712 patent/WO1997031910A1/en not_active Application Discontinuation
- 1997-02-24 CA CA002246756A patent/CA2246756A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EP0885205A1 (en) | 1998-12-23 |
| JP2000505471A (en) | 2000-05-09 |
| EP0885205A4 (en) | 2002-11-27 |
| AU2133297A (en) | 1997-09-16 |
| AU712082B2 (en) | 1999-10-28 |
| WO1997031910A1 (en) | 1997-09-04 |
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