AU709631B2 - Fibrinogen receptor antagonist prodrugs - Google Patents
Fibrinogen receptor antagonist prodrugs Download PDFInfo
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- AU709631B2 AU709631B2 AU35033/97A AU3503397A AU709631B2 AU 709631 B2 AU709631 B2 AU 709631B2 AU 35033/97 A AU35033/97 A AU 35033/97A AU 3503397 A AU3503397 A AU 3503397A AU 709631 B2 AU709631 B2 AU 709631B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D295/16—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 acylated on ring nitrogen atoms
- C07D295/20—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 acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
- C07D213/71—Sulfur atoms to which a second hetero atom is attached
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Description
WO 98/00144 PCT/US97/11037 -2sequence in the individual proteins may be critical to recognition specificity.
Cheresh in Proc. Nat'l Acad. Sci. 84, 6471-6475, (1987), describes an Arg-Gly-Asp directed adhesion receptor expressed by human endothethial cells that is structurally similar to the IIb/HIa complex on platelets but is antigenically and functionally distinct. This receptor is directly involved in endothelial cell attachment to fibrinogen, von Willebrand factor, and vitronectin.
Pierschbacher and Rouslahti, in J. of Biol. Chem., 262, 17294-17298 (1987) hypothesized that the Arg-Gly-Asp sequence alone would be a sufficient signal for receptor recognition and binding and that, therefore, the conformation of the tri-peptide sequence would be determinative. Various synthetic peptides were produced and the authors concluded that the stereochemical conformation of Arg-Gly-Asp as influenced by enantiomeric substitutions or additions to this sequence significantly influenced receptor-ligand interaction. The authors further showed that cyclization of a decapeptide by forming a disulfide bridge between non-terminal residues Pen and Cys, rendered the peptide much less effective at inhibiting attachment to fibronectin.
In Proc. Nat'l Acad. Sci. 81, 5985-5988 (1984), the same authors describe tetrapeptide variants of the cell recognition site of fibronectin that retain attachment-promoting activity. Peptides having a tetrapeptide recognition site are described in U.S. Pat. Nos. 4,589,881 and 4,614,517. A number of large polypeptide fragments in the cellbinding domain of fibronectin have cell-attachment activity. For example, see U.S. Pat. Nos. 4,517,686, 4,661,111 and U.S. Pat. No.
4,578,079.
Ruggeri et al., Proc. Nat'l Acad. Sci. 83, 5708- 5712 (1986) explore a series of synthetic peptides designed in lengths to 16 residues, that contain RGD and a valine attached to the aspartic acid residue of RGD that inhibit fibrinogen binding to platelets. See also Koczewiak et al., Biochem. 23, 1767-1774 (1984); Ginsberg et al., WO 98/00144 PCT/US97/11037 -3- J. Biol. Chem. 260(7), 3931-3936 (1985); and Haverstick et al., Blood 66(4), 946-952 (1985). Other inhibitors are disclosed in Eur. Pat. App.
Nos. 275,748 and 298,820.
A number of low molecular weight polypeptide factors have been isolated from snake venom. These factors apparently have high affinity for the gp IIb/IIIa complex. For example, Huang et al., J.
Biol Chem., 262, 16157-16163 (1987); Huang et al., Biochemistry, 28, 661-666 (1989) describe the primary structure of the venom trigramin which is a 72 amino acid polypeptide that contains the RGD subunit.
Echistatin is another compound which has high affinity for the gp IIb/IIIa complex. This polypeptide contains 49 amino acids and has the RGD subunit and various disulfide bridges. Gan et al., J. Biol. Chem., 263, 19827-19832 (1988). See also, Dennis et al., Proc. Nat'l Acad. Sci.
USA, 87, 2471-2475 (1989). However, these snake venom factors also have high affinity for other members of the adhesive protein receptor family including the vitronectin and fibronectin receptors so are not selective for the gp IIb/IIIa complex.
While it is known that the tripeptide sequence Arg-Gly-Asp is present in certain polypeptides that can duplicate or inhibit the cell attachment-promoting effects of fibronectin and vitronectin, the tripeptide Arg-Gly-Asp has low activity. At present, there is little understanding of how other amino acids coupled to this sequence influence binding specificity. U.S. Pat. No 5,023,233 discloses small cyclic hexapeptides which contain the sequence Arg-Gly-Asp and are useful platelet aggregation inhibitors. U.S. Pat. No. 5,037,808 discloses the use of indolyl platelet-aggregation inhibitors which are believed to act by antagonizing interactions between fibrinogen and/or extracellular matrix proteins and the platelet gp IIb/IIIa receptor. U.S. Pat. No.
5,037,808 discloses guanidino peptide mimetic compounds that retain an Asp residue which inhibit platelet aggregation. W09014103 describes the use of antibody-polypeptide conjugates wherein said polypeptides contain the Arg-Gly-Asp (RGD) sequence.
W09111458 discloses the use of large cyclic peptides containing RGD flanked by proline residues which are platelet WO 98/00144 PCT/US97/11037 -4aggregation inhibitors. W09101331 discloses small cyclic platelet aggregation inhibitors which are synthetic cyclic pentapeptides containing the tripeptide sequence Arg-Gly-Asp and a thioether linkage in the cycle. U.S. Patent No. 5,051,405 also discloses the use of peptides and pseudopeptides such as N-amidino-piperidine-3-carboxylglycyl-Laspartyl-L-valine that inhibit platelet aggregation and thrombus formation in mammalian blood. EP 445 796 discloses linear compounds 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 Rl-A-(W)a-X- (CH2)b-(Y)c-B-Z-COOR wherein RI is a guandidino or amidino moiety and A and B are chosen from specific monosubstituted aryl or heterocyclic moieties.
While a multitude of compounds or peptide analogs believed to inhibit platelet aggregation by inhibiting binding to a blood platelet by fibrinogen are known, the present invention provides novel fibrinogen receptor antagonist prodrugs of antagonists that have significant binding activity and are, therefore, useful for the reasons stated herein.
SUMMARY OF THE INVENTION The invention relates to compounds having the formula
X'-A-B
and pharmaceutically acceptable salts, wherein X' is a moiety, comprising between 8 and 11 contiguous atoms selected from carbon and nitrogen, terminating at the non-A bond end in an amino, aliphatic amino, aromatic amino, amidino, or guanidino substituent having a pKa of between about 5-14, wherein the atom attached to A is selected from carbon and nitrogen; WO 98/00144 PCTIUS97/11037 A is a 5 or 6 membered aromatic ring, having 0, 1, 2 or 3 heteroatoms selected from N, 0, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R 5 disubstituted on carbon and nitrogen atoms with R5 and R 6 or trisubstituted on carbon and nitrogen with R 5
R
6 and R 9 where
R
5
R
6 and R 9 are independently selected from the group consisting of hydrogen, halogen, CI-iG alkyl, C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino C 1 -8 alkyl, Ci1-3 acylamnino, C 1 3 acylammno Cl1- 8 alkyl, C 1 -6 alkylamino, C1-6 alkylammno CI-8 alkyl, Ci1 -6 dialkylamino, Clp6 dialkylamino Cl..8 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, aryl CI-6 alkyloxy, aryl C1-6 alkyloxy CI-6 alkyl, carboxy C1-6 alkyl, Cj -3 alkoxycarbonyl, C 1-3 alkoxycarbonyl C 1-6 alkyl, carboxy, carboxy CI-6 alkyloxy, hydroxy, and hydroxy .Ci -6 alkyl, or WO 98/00144 PTU9I13 PCTIUS97/11037 -6a 9 or 10 membered fuised aromatic ring, having 0, 1, 2 or 3 heteroatoms selected from N, 0, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R 5 disubstituted on carbon and nitrogen atoms with R 5 and R 6 or trisubstituted on carbon and nitrogen with R 5
R
6 and R 9 where
R
5
R
6 and R 9 are independently selected from the group consisting of hydrogen, halogen, CI-1loalkyl, C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino C1-8 alkyl, CI-3 acylamino, Cl-3 acylamino, C1..8 alkyl, Ci1 -6 alkylamino, C 1-6 alkylammno C 1-8 alkyl, C1-6 dialkylamino, CI-6 dialkylammno C1-8 alkyl, C 1-6 alkoxy, C.1-6 alkoxy C.1-6 alkyl, aryl C1-6 alkyloxy, aryl C 1-6 alkyloxy C 1-6 alkyl, carboxy CI-6 alkyl, C 1 -3 alkoxycarbonyl, C 1-3 alkoxycarbonyl C 1-6 alkyl, carboxy, earboxy Ci1 -6 alkyloxy, hydroxy, and hydroxy C1-6 alkyl; and WO 98/00144 PCTIUS97/1 1037 -7- B is -o (CH 2 )nCH 2
OR
8
-CH
2
(CH
2 )mCH 2
OR
8 or
-CH(CH
2 )mCH 2
OR
8 wherein nlis 1 or 2, and m isO0, 1, or 2;
R
7 is selected from the group consisting of hydrogen, halogen, CI-1G alkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, amino, amino CI-8 alkyl, C 1-3 acylamino, C 1-3 acylamino C 1-8 alkyl, Ci1 -6 alkylammno, C 1-6 alkylamino Ci1-x alkyl, Ci1 -6 dialkylamino, C 1-6 dialkylamino C 1-8 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, aryl C 1 -6 alkyloxy, aryl C 1-6 alkyloxy C 1-6 alkyl, carboxy, carboxy C 1-6 alkyl, C 1-3 alkoxycarbonyl, C 1-3 -alkoxycarbonyl C 1-6 alkyl, carboxy, carboxy C1-6 alkyloxy, hydroxy, and hydroxy C1-6 alkyl; WO 98/00144 PCT/US97/11037 -8-
R
8 is selected from the group consisting of hydrogen, -C(O)-Cl-8alkyl, -C(O)-C3-8cycloalkyl, -C(O)-aryl, and -3alkylaryl.
The compounds are useful as prodrugs of fibrinogen receptor antagonists.
The invention also includes the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the aggregation of blood platelets, preventing platelet thrombosis, preventing thromboembolism or preventing reocclusion, in a mammal.
DETAILED DESCRIPTION OF THE INVENTION The invention relates to compounds having the formula
X'-A-B
and pharmaceutically acceptable salts, wherein X' is a moiety, comprising between 8 and 11 contiguous atoms selected from carbon and nitrogen, terminating at the non-A bond end in an amino, aliphatic amino, aromatic amino, amidino, or guanidino substituent having a pKa of between about 5-14, wherein the atom attached to A is selected from carbon and nitrogen; A is a 5 or 6 membered aromatic ring, having 0, 1, 2 or 3 heteroatoms selected from N, 0, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R 5 disubstituted on carbon and nitrogen atoms with R 5 and R 6 or trisubstituted on carbon and nitrogen with R 5
R
6 and R 9 where I II Il WO 98/00144 PCTJUS97/1 1037 -9-
R
5
R
6 and R 9 are independently selected from the group consisting of hydrogen, halogen, CI-1loalkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, amino, amino C 1-8 alkyl, C 1 -3 acylamino, Ci1 -3 acylamino Ci -8 alkyl, Ci1 -6 alkylamino, C 1-6 alkylamino Ci1 alkyl, CI1-6 dialkylamino, Ci1 -6 dialkylamino C I -8 alkyl, C 1 -6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, aryl C 1-6 alkyloxy, aryl C 1-6 alkyloxy C1 -6 alkyl, carboxy Ci1 -6 alkyl, Ci1 -3 alkoxycarbonyl, CI-3 alkoxycarbonyl C1..6 alkyl, carboxy, carboxy Ci -6 alkyloxy, hydroxy, and hydroxy C1-6 alkyl, or a 9 or 10 membered fused aromatic ring, having 0, 1, 2 or 3 heteroatoms selected from N, 0, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R- 5 disubstituted on carbon and nitrogen atoms with R 5 and R 6 or trisubstituted on carbon and nitrogen with R 5
R
6 and R 9 where WO 98/00144 PCT/US97/1 1037 10
R
5
R
6 and R 9 are independently selected from the group consisting of hydrogen, halogen, CI1l alkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, amino, amino C.1-8 alkyl, C 1 -3 acylamino, C 1-3 acylamino CI -g alkyl, Ci1 -6 alkylamnino, C1 -6 alkylammno C 1 8 alkyl, Ci1 -6 dialkylamino, Cl1 -6 dialkylamnino Cl1-8 alkyl, Ci1 -6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, aryl CI -6 alkyloxy, aryl CI-6 alkyloxy C.1-6 alkyl, carboxy CI-6 alkyl, C 1 -3 alkoxycarbonyl, Ci1 -3 alkoxycarbonyl Ci1 -6 alkyl, carboxy, carboxy C.1-6 alkyloxy, hydroxy, and hydroxy CI-6 alkyl; and B is
-(CH
2
),CH
2
OR
8
-CH
2 (0H 2 )mOH 2 OR 8 or
CH(CH
2 )mCH 2
OR
8 WO 98/00144 PCTIUS97/1 1037 wherein n is 1 or 2, and m is 0, 1, or 2;
R
7 is selected from the group consisting of hydrogen, halogen, Ci-1loalkyl, C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino C 1-8 alkyl, Ci1 -3 acylamnino, Cl1-3 acylamino Cl1.8 alkyl, C 1-6 alkylamino, CI-6 alkylamino CI-8. alkyl, C 1-6 dialkylamino, Cl1 -6 dialkylamnino C 1-8 alkyl, CL1-6 alkoxy, CI1-6 alkoxy Cl1-6 alkyl, aryl C 1-6 alkyloxy, aryl C 1-6 alkyloxy C 1.-6 alkyl, carboxy, carboxy C 1-6 alkyl, Cl 1 3 alkoxycarbonyl, Cl1-3 alkoxycarbonyl CI1-6 alkyl, carboxy, carboxy Cp-6 alkyloxy, hydroxy, and hydroxy C1-6 alkyl; R9 is selected from the group consisting of hydrogen, 1 -8alkyl, -C(O)-C3-8cycloalkyl, -C(O)-aryl, and WO 98/00144 PCT/US97/11037 -12- -3alkylaryl.
In one class of the invention, the compound has the formula
X-Y-Z-A-B
and pharmaceutically acceptable salts, wherein X is a 5, 6 or 7 membered aromatic or nonaromatic ring, having 1, 2 or 3 heteroatoms selected from N, 0, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with Rl or disubstituted with R1 and R 2 where R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, C1-IO alkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, amino, amino C1-8 alkyl, C1-3 acylamino, C1-3 acylamino C1-8 alkyl, C1-6 alkylamino, C1-6 alkylamino C1-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino C1-8 alkyl, Cl-6 alkoxy, C1-6 alkoxy C1-6 alkyl, aryl C1-6 alkyloxy, aryl C1-6 alkyloxy C1-6 alkyl, carboxy C1-6 alkyl, C -3 alkoxycarbonyl, WO 98/00144 WO 9809144PCT/US97/1 1037 13 Ci1 -3 alkoxycarbonyl C 1 -6 alkyl, carboxy, carboxy CI-6 alkyloxy, hydroxy, and hydroxy CI-6 alkyl, or a 9 or 10 membered fused aromatic or nonaromatic ring, having 1, 2 or 3 heteroatoms selected from N, 0, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R I or disubstituted with R I and R 2 where R I and R 2 are independently selected from the group consisting of hydrogen, halogen, alkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, amino, amino C1I- 8 alkyl, Ci1 -3 acylamino, C 1-3 acylamino C 1-8 alkyl, C 1-6 alkylamino, C1-6 alkylamnino C1-8 alkyl, Ci1 -6 dialkylamino, C 1-6 dialkylamino C 1-9 alkyl, Ci1 -6 alkoxy, Ci1 -6 alkoxy Ci1 -6 alkyl, aryl CI-6 alkyloxy, aryl Cl1-6 alkyloxy C 1-6 alkyl, ca-rboxy C1-6 alkyl, C 1-3 alkoxycarbonyl, Ci1-3 alkoxycarbonyl C 1 6 alkyl, carboxy, carboxy Ci-6 alkyloxy, WO 98/00144 PCTUS97/1 1037 14 hydroxy, and hydroxy C 1 -6 alkyl; Y is a 5 or 6 membered aromatic or nonaromatic ring, having 0, 1, 2 or 3 heteroatoms selected from N, 0, and S, and either unsubstituted or substituted on carbon and nitrogen atoms with R 3 selected from the group consisting of halogen, CI-l0 alkyl, C3-8 cycloalkyl, aryl, aryl CI-8 alkyl, amino, amino C 1-8 alkyl, Ci1 -3 acylamino, C 1-3 acylamino C1I- 8 alkyl, Ci1 -6 alkylamino, C1-6 alkylamino Ci-8 alkyl, Ci1 -6 dialkylamino, CI1-6 dialkylamino C 1 -8 alkyl, CI1-6 alkoxy, C1 -6 alkoxy C 1-6 alkyl, aryl C 1-6 alkyloxy, aryl C 1-6 alkyloxy C 1 6 alkyl, carboxy C1-6 alkyl, CI -3 alkoxycarbonyl, Ci -3 alkoxycarbonyl Ci -6 alkyl, carboxy, carboxy CI -6 alkyloxy, hydroxy, and hydroxy Ci -6 alkyl; WO 98/00144 WO 9800144PCTIUS97/1 1037 15 X and Y combined together form the structure
R
1
NN
QN R 1 or
H
R'N
Z is O R 4
-C-N-
R 4 0 1 11
-N-C-
-CH
2
CH
2
-CH=CH-
CH
2
-O-
-0-OH 2 WO 98/00144 WO 9800144PCTIUS97/11037 16 0 11
-C-OH
2 0 11
CH
2
NR
4 NR 4
CH-
OH
-OH-OH
2
OH
-0H 2
-O;H-
Z represents a bond;
R
4 is selected from the group consisting of hydrogen, halogen, alkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, amino, amino C1-8 alkyl, Ci1 -3 acylamino, C 1-3 acylamino C1I8- alkyl, Ci1 -6 alkylammno, C1-6 alkylamino C189 alkyl, C 1 -6 dialkylamino, C 1-6 dialkylamino C 1-8 alkyl, Ci1 -4 alkoxy, WO 98/00144 PCTJUS97/11037 -17 Ci1 -4 alkoxy C 1 -6 alkyl, carboxy, carboxy 1-6 alkyl, Cj1 -3 alkoxycarbonyl, Ci 1 -3 alkoxycarbonyl Ci1 -6 alkyl, carboxy CL-6 alkyloxy, hydroxy, and hydroxy Ci -6 alkyl; A is a 5 or 6 membered aromatic ring, having 0, 1, 2 or 3 heteroatoms selected from N, 0, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R 5 disubstituted on carbon and nitrogen atoms with R 5 and R 6 or.
trisubstituted on carbon and nitrogen with R 5
R
6 and R 9 where
R
5
R
6 and R 9 are independently selected from the group consisting of hydrogen, halogen, CI-io alkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, amino, amino C1-8 alkyl, C 1-3 acylamino, C 1 -3 acylamino C 1-8 alkyl, C 1-6 alkylamino, CI-6 alkylammno C1-8 alkyl, Ci1 -6 dialkylamino, C 1-6 dialkylamnino Ci1-9 alkyl, C1 -6 alkoxy, C 1.-6 alkoxy C 1-6 alkyl, aryl CI-6 aikyloxy, WO 98/00144 PCTIUS97/1 1037 18 aryl C 1-6 alkyloxy C 1-6 alkyl, carboxy C 1-6 alkyl, C 1 -3 alkoxycarbonyl, C 1 -3 alkoxycarbonyl Ci1 -6 alkyl, carboxy, carboxy Ci -6 alkyloxy, hydroxy, and hydroxy Ci -6 alkyl, or a 9 or 10 membered fused aromatic ring, having 0, 1, 2 or 3 heteroatoms selected from N, 0, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R 5 disubstituted on carbon and nitrogen atoms with R 5 and R 6 or trisubstituted on carbon and nitrogen with R 5
R
6 and R 9 where
R
5
R
6 and R 9 are independently selected from the group consisting of hydrogen, halogen, alkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, amino, amino C1-8 alkyl, Ci1 -3 acylamino, C 1-3 acylamino C 1-8 alkyl, Cl1 -6 alkylamino, C 1-6 alkylammno C1I-S alkyl, Ci1 -6 dialkylamino, C1-6 dialkylamino Cl-S alkyl, Ci1 -6 alkoxy, C 1-6 alkoxy C1 -6 alkyl, aryl C 1-6 alkyloxy, aryl C 1-6 alkyloxy C 1 -6 alkyl, WO 98/00144 WO 98/0 144PCTIUS97I1 1037 19 carboxy C 1 -6 alkyl, Cj 3 alkoxycarbonyl, C 1-3 alkoxycarbonyl C1 -6 alkyl, carboxy, carboxy C 1-6 alkyloxy, hydroxy, and hydroxy CI-6 alkyl; B is -o0 (CH 2 )nCH 2 OR 8
-CH
2 (0H 2 )mCH 2
OR'
8 or CH(0H 2 )mCH 2 0R" wherein n is 1 or 2, and m is 0, 1, or 2;
R
7 is selected from the group consisting of hydrogen, halogen, CI-1loalkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, amino, amino C1-8 alkyl, C1 -3 acylamino, C 1-3 acylamnino C 1 alkyl, C 1-6 alkylamino, CI-6 alkylamino alkyl, Ci1 -6 dialkylamino, CI -6-dialkylamino C1..8 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, aryl C 1-6 akyloxy, aryl C 1-6 alkyloxy C 1-6 alkyl, WO 98/00144 PCT/US97/11037 carboxy, carboxy C1-6 alkyl, C1-3 alkoxycarbonyl, Cl-3 alkoxycarbonyl C1-6 alkyl, carboxy, carboxy C1-6 alkyloxy, hydroxy, and hydroxy C1-6 alkyl;
R
8 is selected from the group consisting of hydrogen, -C(O)-C1-8alkyl, -C(O)-C3-8cycloalkyl, -C(O)-aryl, and -3alkylaryl.
In a subclass of the class, the compounds have the formula
O
II
X-Y -C-NH-A-OCH2CH 2 0H and pharmaceutically acceptable salts, wherein X is a 6-membered aromatic or nonaromatic ring having 1, 2 or 3 nitrogen atoms; Y is a 6-membered aromatic or nonaromatic ring having 0, 1, 2 or 3 nitrogen atoms; A is a 6-membered aromatic ring unsubstituted, monosubstituted with a moiety selected from the group consisting of halogen, Cl-3alkyl, and C1-3alkylsulfonylamino, disubstituted with one or more moieties, same or different, selected from the group consisting of halogen, CI-3alkyl, and C1-3alkylsulfonylamino or trisubstituted with one or WO 98/00144 PCT/US97/11037 -21 more moieties, same or different, selected from the group consisting of halogen, CI-3alkyl, and Cl- 3alkylsulfonylamino, and all other substituents are as previously defined.
In a group of this subclass, the compounds have the formula 0
II
X-Y-C-NH-A-OCH
2
CH
2
OH
and pharmaceutically acceptable salts, wherein X is a 6-membered aromatic or nonaromatic ring having 1 or 2 nitrogen atoms; Y is a 6-membered aromatic or nonaromatic ring having 0 or 1 nitrogen atoms; A is a 6-membered aromatic ring unsubstituted, monosubstituted with a moiety selected from the group consisting of Br, CH3, and NHSO2CH3, disubstituted with one or more moieties, same or different, selected from the group consisting of Br, CH3, and NHS02CH3, or trisubstituted with one or more moieties, same or different, selected from the group consisting of Br, CH3, and NHS02CH3; and and all other substituents are as previously defined.
In a subgroup of this group, the compounds have the formula
O
II
X-Y-C -NH-A-OCH 2
CH
2
OH
and pharmaceutically acceptable salts, wherein
I
WO 98/00144 WO 9800144PCTIUS97/1 1037 22 X is HN or N a or N and Y is
O-
A is
O-
OH
3 Br
NHSO
2
CH
3 s CH 3 Br and all other substituents are as previously defined.
Examples of this subgroup include -Piperazinyl)phenylcarbonylamino)phenoxy)ethanol, 2-(3 -Methyl-4-(4-( 1-piperazinyl)phenylcarbonylamino)phenoxy)ethanol, 2-(4-(4-(4-Piperazin- 1 -yl)phenylcarbonylamino)-2-methanesulfonylaminophenoxy)ethanol, 2-(3-Methyl-4-(fP-carbolin-7-yl-carboxamido)phenoxy)ethanol, WO 98/00144 PCT/US97/11037 -23- 2-(2,6-Dibromo-3-methyl-4-(4-(piperizin-4-yl)phenylcarboxamide)phenoxy) ethanol, 4-(Pyridyl)(piperidin)-4-carbonylamino-3-methylphenoxyethanol and pharmaceutically acceptable salts, e.g. hydrochloride salts.
The active acids of these compounds have been evaluated in vitro and found to have an IC50 for inhibiting platelet aggregation of between about 0.008 jgM and 2 [tM.
The prodrugs may be administered in low amounts relative to achieve inhibition of fibrinogen binding to the fibrinogen receptor.
The prodrugs may be administered orally. The prodrugs retain structural integrity while passing though the gastrointestinal system, and are effectively delivered to cells. They are subjected to oxidative enzymes such as alcohol and aldehyde dehydrogenase to form the active acid which then interacts with the platelet receptor site.
A number of very serious diseases and disorders involve hyperthrombotic complications which lead to intravascular thrombi and emboli. Myocardial infarction, stroke, phlebitis and a number of other serious conditions create the need for novel and effective fibrinogen receptor antagonists.
One test which is used to evaluate fibrinogen receptor antagonist activity is based on evaluation of inhibition of ADPstimulated platelets. Aggregation requires that fibrinogen bind to and occupy the platelet fibrinogen receptor site. Inhibitors of fibrinogen binding inhibit aggregation. In the ADP-stimulated platelet aggregation assay used to determine inhibition associated with the acids of the compounds claimed in the instant invention, human platelets are isolated from fresh blood, collected into acid citrate/dextrose by differential centrifugation followed by gel filtration on Sepharose 2B in divalent ion-free Tyrode's buffer (pH 7.4) containing 2% bovine serum albumin.
Platelet aggregation is measured at 37 0 C in a Chronolog aggregometer. The reaction mixture contains gel-filtered human platelets (2 x 108 per ml), fibrinogen (100 micrograms per ml (ug/ml)), WO 98/00144 PCT/US97/11037 -24 Ca 2 (1 mM), and the compound to be tested. The aggregation is initiated by adding 10 mM ADP 1 minute after the other components are added. The reaction is then allowed to proceed for at least 2 minutes. The extent of inhibition of aggregation is expressed as the percentage of the rate of aggregation observed in the absence of inhibitor. The IC50 is the dose of a particular compound inhibiting aggregation by 50% relative to a control lacking the compound.
Additionally, these compounds are useful for treating mammals suffering from a bone condition caused or mediated by increased bone resorption, who are in need of such therapy.
Pharmacologically effective amounts of the compounds, including pharamaceutically acceptable salts thereof, are administered to the mammal, to inhibit the activity of mammalian osteoclasts.
Additionally, these compounds are useful for treating angiogenesis (formation of new blood vessels). It has been postulated that the growth of tumors depends on an adequate blood supply, which in turn is dependent on the growth of new vessels into the tumor.
Inhibition of angiogenesis can cause tumor regression in animal models.
(See, Harrison's Principles of Internal Medicine, 12th ed., 1991). These compounds are therefore useful in the treatment of cancer for inhibiting tumor growth. (See Brooks et al., Cell, 79:1157-1164 (1994)).
The term "pharmaceutically acceptable salts" shall mean non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote, palmitate, panthothenate, phosphate/diphosphate, polygalacturonate, WO 98/00144 PCT/US97/11037 salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, valerate.
Some of the compounds of the present invention are chiral; included within the scope of the present invention are racemic mixtures and separated enantiomers of the general formula. Furthermore, all diastereomers, including E, Z isomers, of the general formula are included in the present scope. Furthermore, hydrates as well as anhydrous compositions and polymorphs of the general formula are within the present invention.
The compounds of the invention are prodrugs of active acids which inhibit fibrinogen binding to the gpllb/IIa platelet receptor site. For example, these acids form in vivo, subsequent to administration to the patient, according to successive alcohol dehydrogenase and aldehyde dehydrogenase reactions: alcohol 0 dehydrogenase
|I
R'-CH
2 0H
R'-CH
NAD+ NADH aldehyde 0 dehydrogenase
II
R'-CH R'-COOH NAD+ NADH Other mechanisms may contribute to the conversion of alcohol to acid.
Compounds of the invention of the general formula R'-CH20R 8 where
R
8 is an acyl moiety, may be esters which metabolize into the active acid.
WO 98/00144 PCT/US97/11037 -26- The invention also includes the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the binding of fibrinogen to blood platelets, inhibiting the aggregation of blood platelets, treating thrombus formation or embolus formation, or preventing thrombus or embolus formation in a mammal.
The term "a moiety comprising between 8 and 11 contiguous atoms" means a series of sequentially bonded atoms, including a series of atoms that are sequentially bonded in linear relation, wherein none of the atoms are part of a cyclic moiety, and a series of atoms that are sequentially bonded in a linear relation, wherein some of the atoms are part of a cyclic moiety.
For example, the following is an example of 10 continguous carbon or nitrogen atoms bonded in linear relation, wherein none of the atoms are part of cyclic moiety: 10 8 6 4 2 H2N 9 7 5 3 1 The following is an example of 10 continguous carbon or nitrogen atoms bonded in linear relation, wherein 8 of the atoms are part of one or more cyclic moieties:
O
H-N N 3 2 N 7 6 o 9 8 5 4 H The following is an example of a structure having 11 continguous carbon or nitrogen atoms (atoms numbered bonded in linear relation, wherein 7 of the atoms are part of one or more cyclic moieties: WO 98/00144 PCT/US97/11037 -27- 0 9' 7' 5 3, N H-N
H
12 9 7 5 4 11 The above structure also has 12 continguous carbon or nitrogen atoms (atoms numbered 1-12) bonded in linear relation, wherein 8 of the atoms are part of one or more cyclic moieties. Since the above structure has 11 continguous carbon or nitrogen atoms bonded in linear relation, wherein 7 of the atoms are part of one or more cyclic moieties, the structure falls within the definition of X'.
The term "pharmaceutically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician. The term "anti-coagulant" shall include heparin, and warfarin. The term "thrombolytic agent" shall include agents such as streptokinase and tissue plasminogen activator.
The term "platelet anti-aggregation agent" shall include agents such as aspirin and dipyridamole.
The term "alkyl" means straight or branched alkane containing 1 to about 10 carbon atoms, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexy, octyl radicals and the like, straight or branched alkene containing 2 to about 10 carbon atoms, propylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2,2-methylbuten- 1-yl, 3-methylbuten- l-yl, hexen-1-yl, hepten-1-yl, and octen-l-yl radicals and the like, or straight or branched alkyne containing 2 to about 10 carbon atoms, ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutyn-l-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-l-yl radicals and the like.
The term "aryl" means a 5- or 6-membered aromatic ring containing 0, 1, or 2 heteroatoms selected from 0, N, and S, e.g.
phenyl, pyridine, pyrimidine, imidazole, thiophene, oxazole, isoxazole, thiazole, and amino- and halogen- substituted derivatives thereof.
WO 98/00144 PCT/US97/11037 -28- The terms "alkyloxy" or "alkoxy" include an alkyl portion where alkyl is as defined above, methyloxy, propyloxy, and butyloxy.
The terms "arylalkyl" and "alkylaryl" include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above. The CO-n or Cl-n designation where n may be an integer from 1-10 or 2-10 respectively refers to the alkyl component of the arylalkyl or alkylaryl unit. Examples of arylalkyl include benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl. Examples of alkylaryl include toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine, butylpyridine, butenylpyridine, and pentenylpyridine.
The term "halogen" includes fluorine, chlorine, iodine and bromine.
The term "oxy" means an oxygen atom. The term "thio" means a sulfur atom. Under standard nonmenclature used throughout this disclosure, the terminal portion of the designated side chain is described first followed by the adjacent functionality toward the point of attachment. For example, a Cl-6 alkyl substituted with alkyl-carbonylamino is equivalent to
HO
I II Cl-6-alkyl-N-C-C1-5-alkyl wherein the C1-5alkyl moiety attaches to the substituted molecule.
In the schemes and examples below, various reagent symbols have the following meanings:
BOC
(or Boc): t-butyloxycarbonyl Pd-C: palladium on activated carbon catalyst DMF: dimethylformamide DMSO: dimethylsulfoxide CBZ: carbobenzyloxy WO 98/00144 PCT/US97/11037 -29- CH2C12: CHC13: EtOH: MeOH: EtOAc: HOAc:
BOP:
EDC:
methylene chloride chloroform ethanol methanol ethyl acetate acetic acid benzotriazol-1 -yloxytris(dimethylamino)phosphonium, hexafluorophosphate 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride potassium peroxymonosulfate lithium diisopropylamide Chloro N,N,N'N'-bis(pentamethylene)formamidinium hexafluorophosphate Oxone:
LDA:
PYCLU:
The compounds of the present invention can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
Likewise, they may be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular 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.
Compounds of the invention may be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex IIb/IIIa receptor is desired. They are useful in surgery on peripheral arteries (arterial grafts, carotid endarterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption. The aggregated platelets may form thrombi and thromboemboli. Compounds of this invention may be administered to WO 98/00144 PCT/US97/11037 these surgical patients to prevent the formation of thrombi and thromboemboli.
Extracorporeal circulation is routinely used for cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit. Adhesion is dependent on the interaction between gp IIb/IIIa on the platelet membranes and fibrinogen adsorbed to the surface of the circuit. (Gluszko et al., Amer.
J. Physiol., 252(H), 615-621 (1987)). Platelets released from artificial surfaces show impaired hemostatic function. Compounds of the invention may be administered to prevent adhesion.
Other applications of these compounds include prevention of platelet thrombosis, thromboembolism and reocclusion during and after thrombolytic therapy and prevention of platelet thrombosis, thromboembolism and reocclusion after angioplasty or coronary artery bypass procedures. They may also be used to prevent myocardial infarction.
The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day and preferably 0.01-100 mg/kg/day and most preferably 0.01-20 mg/kg/day. For example, a typical 90 kg patient would receive oral dosages ranging between about 0.9 mg/day and about 9 g/day, most preferably between about 0.9 mg/day and 1.8 g/day. Suitable pharmaceutical oral compositions such as tablets or capsules may contain 10-500 mg, for example, 10 mg, 100 mg, 200 mg and 500 mg. Intravenously, the most WO 98/00144 PCT/US97/11037 -31 preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion.
Advantageously, compounds of the present invention may be administered in divided doses of two, three, or four times daily.
Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, or course, be continuous rather that intermittent throughout the dosage regime.
In the methods of the present invention, the compounds herein described in detail form the active ingredient of the prodrug, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with convention pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active ingredient prodrug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral prodrug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
Moreover, when desired or necessary, suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
WO 98/00144 PCT/US97/11037 -32- Disintegrators include, without limitation, starch methyl cellulose, agar, bentonite, xanthan gum and the like.
Active drug can also be co-administered with the usual doses of suitable anticoagulation agents, such as heparin or warfarin (typically given in tablet doses between 1 and 20 mg daily during administration of the active drug), or thrombolytic agents such as tissue plasminogen activator (typically given in i.v. doses of between 20 and 150 mg over two hour period prior to or during administration of the active drug), to achieve beneficial effects in the treatment of various vascular pathologies. Such co-administration also includes administration if the active drug with doses of anticoagulant agents or thrombolyric agents less than the usual doses of those agents.
In the examples below, field strength for NMR analysis is either 300 MHz or 400 MHz.
In one general procedure for making compounds of the invention, 4-aminophenol is reacted with halogenated ethanol to produce 4-aminophenoxy ethanol, which is combined with a piperazinyl benzoic acid to produce an alcohol prodrug of the invention.
In another general procedure, 4-aminomethylphenol is combined with halogenated ethyl acetate to form ethyl 4-amino-3methylphenoxyacetate, which is then reacted with halogenated ethanol to produce a 3 -methyl-4-aminophenoxyethanol. The 3-methyl-4aminophenoxyethanol is reacted with piperazinyl benzoic acid to produce an alcohol prodrug of the invention.
WO 98/00144 WO 9890144PCT/US97/11037 33 SCHEME 1
H
2 N 0 2
CH
3 n-butanol
A
HN \IjN 00 2
CH
3 1-3
HCI*HN
L\
CI
B00 2 0, NEt 3
DMF
BOC-N N CO 2
CH
3 1iN NaOH/ /EtOH BOO-N C0 2
H
1-4 HN N CO 2
CH
3 -3 Methyl 4-(N-Viperazinyl )benzoate (1-3) -A solution of amnine 1-1 (20.0 g, 132 mmol), amine 1-2 (23.6 g, 132 mmol) and n-butanol (500 ml) was refluxed for 168 h.
The solution was allowed to cool to ambient temperature. The crystals were collected, wa~shed with Et2O and dried in vacuo to give ester 1-3 as a white solid.
WO 98/00144 WO 9800144PCTIUS97/1 1037 34 1H NMR (CD3OD): 5 7.86 J=9Hz, 2H), 7.98 J=9Hz, 211), 3.78 3H), 3.53 (in, 4H), 3.31 (in, 4H).
BocN 1 ~N-O Q 0 2 0H 3 Methyl .1-dimethylethoxycarbonyl)piperazin- 1-yl)benzoate (1-4) To a stirred solution of amnine 1-3 (15.0 g, 61.1 mmol), NEt3 (7.42 g, 73.4 mmnol) and DMF (150 ml) was added BOC20 (14.7 g, 67.2 mmol). After 1.0 h, the solution was diluted with EtOAc and then washed with H20, 10% KHSO4, brine, dried (MgSO4) and concentrated to furnish ester 1-4 as a yellow solid.
TLC Rf 0.63 (silica, 40% EtOAc/hexanes) I H NMR (CD3OD): 8 7.91 J=9Hz, 2H), 7.01 J=9Hz, 2H), 3.88 3H), 3.59 (mn, 4H), 3.38 (in, 4H).
BocN C0 2
H
1,1-Dimethylethoxycarbonyl)piperazin- 1 -v)benzoic acid A solution of ester 1-4 (21.1 g, 61.1 mmol) 1 N NaGH (100 ml, 100 mmol) and EtOH (200 ml) was heated to 60'C for 2.0 h. The solution was acidifed with 10% KHS04 and then extracted with EtOAc.
The EtOAc phase was washed with brine, dried (MgSO4) and concentrated to furnish acid 1-5 as a white solid.
1 H NMR (CD3OD): 8 7.81 J=9Hz, 2H), 6.88 J=9Hz, 2H), 3.49 (mn, 4H), 3.24 (in, 4H), 1.40 9H).
WO 98/00144 WO 9800144PCT/US97/11037 35 SCHEME2 OH OH s- Boc 2 O, CHCI 3 N ref lux Br~~O Aliquot 336 NaOH-
H
2 0 'Dc PhCH 3
RT
NH
2 NHB NHBoc 2-3
COOH
HOI (gas) EtOAc, 000 .HCl
NH-
2 2-4 ~I PF 6 0N
CN
N
Boo 2-4 i-Pr 2 NEt, CH 2
CI
2 0 Boc-N N O/ OH WO 98/00144 PCT/US97/11037 -36- SCHEME 2 CONTINUED
.HCI
HCI (gas) 0 2 HN N EtOAc, 0 0 C 5/ NN
OH
H -O
OH
2-6 4-(1.1 -Dimethylethoxycarbonyl)aminophenol (2-2) To a 500 mL round bottomed flask with a stirring bar, reflux condenser and an argon inlet was added 4-aminophenol (10.00 g, 91.6 mmol), di-tert-butylpyrocarbonate (20.00 g, 91.6 mmol) and CHC13 (250 mL). This heterogeneous mixture was heated at reflux for 6 h during which time all of the solids dissolved. The mixture was cooled to room temperature and the solid product was collected by filtration. The material was triturated with a mixture of EtOAc-hexanes collected on a frit and dried in vacuo to give 4-(1,1dimethylethoxycarbonyl)aminophenol mp: 143-144°C.
1 H NMR (CDC13): 8 1.51 9H), 5.27 (br s, 1H), 6.34 (br s, 1H), 6.73 j=8.5Hz, 2H), 7.16 j=8.5Hz, 2H).
11 -Dimethvlethoxvcarbonvl)aminophenoxy)ethanol (2-3) To a 500 mL round bottomed flask with a stirring bar and an argon inlet was added aqueous NaOH (50 mL of a 5N solution), 4- (1,1 -Dimethylethoxycarbonyl)aminophenol (5.00 g, 23.90 mmol), toluene (100 mL), Aliquot 336 (0.88 g, 2.19 mmol), and 2bromoethanol (1.86 mL, 26.29 mmol). This mixture was stirred vigorously at ambient temperature for 4 h. An additional 2 mL of 2bromoethanol was added, and the reaction was continued for a total of 72 h. The mixture was diluted with EtOAc and the layers were separated. The organic phase was washed with water and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave 5.2 g of WO 98/00144 PCT/US97/11037 -37an oil. This material was chromatographed on 100 g of silica gel using EtOAc-hexane as eluant. dimethylethoxycarbonyl)aminophenoxy)ethanol was obtained as white needles.
1H NMR (CDC13): 8 1.51 9H), 2.02 j=6.2Hz, 1H), 3.93 2H), 4.05 2H), 6.35 (br s, 1H), 6.86 j=9.0Hz, 2H), 7.26 2H).
2-(4-Aminophenoxv)ethanol, hydrochloride (2-4) To a 200 mL round bottomed flask with a gas dispersion tube was added a solution of 2-(4-(1,1-dimethylethoxycarbonyl)aminophenoxy)ethanol (2.15 g, 8.49 mmol) in EtOAc (100 mL). This solution was cooled in an ice bath and dry HCI gas was sparged through the solution, vigorously, for 5 min. The resulting mixture was aged for 15 min. at 0°C. The excess HCI and solvent were removed in vacuo and the product was triturated with 50 mL of EtOAc and collected on a frit.
The crystals were washed with additional EtOAc and dried in vacuo to give 1.26 g of 2-(4-aminophenoxy)ethanol, hydrochloride 1 H NMR (CD30D): 5 3.88 j=4.2Hz, 2H), 4.08(t, j=4.2Hz, 2H), 7.07 j=9.0Hz, 2H), 7.32 j=9.0Hz, 2H).
2-(4-(4-(1-(1,1-Dimethylethoxycarbonyl)piperazinyl)phenylcarbonylamino)phenoxv)ethanol To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1yl)benzoic acid (1.00 g, 3.26 mmol), 2-(4-aminophenoxy)ethanol hydrochloride (0.65 g, 3.43 mmol), chloro-N,N,N',N',-bis(pentamethylene)formamidinium hexafluorophosphate (1.24 g, 3.43 mmol), and CH2C12 (20 mL). This mixture was cooled in an ice bath and diisopropylethylamine (1.5 mL, 8.58 mmol) was added. The ice bath was allowed to expire and the solution was stirred at ambient temperature for 18 h. The CH2C12 was removed in vacuo and the residue was dissolved/suspended in 300 mL of EtOAc. This mixture was washed with 10% aqueous citric acid, saturated aqueous NaHCO3, WO 98/00144 PCT/US97/11037 -38 and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave a white solid. This material was chromatographed on 100 g of silica gel using 70% EtOAc-hexane as eluant. There was obtained 1.30 g of 2-(4-(4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1yl)phenyl)carbonylamino)phenoxy)ethanol as a crystalline solid.
1 H NMR (CDC13): 8 1.49 9H), 2.02 (br s, 1H), 3.28 4H), 3.59 4H), 3.96 2H), 4.09 2H), 6.93 4H), 7.52 2H), 7.78 j=9.0Hz, 2H).
2-(4-(4-(1-Piperazinyl)phenylcarbonylamino)phenoxy)ethanol, hydrochloride (2-6) To a 1L round bottomed flask equipped with a stirring bar and a gas dispersion tube was added 2-(4-(4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)phenylcarbonylamino)phenoxy)ethanol (1.30 g, 2.94 mmol) and 500 mL of dry EtOAc. This well stirred suspension was cooled in an ice bath and HCI gas was sparged through the solution for 15 min. This mixture was aged 30 min. at 0°C then the excess HCI was removed with a stream of argon and the EtOAc was removed in vacuo. The product was recrystallized from boiling MeOH/EtOAc (2X) to give 700 mg of 2-(4-(4-(1-piperazinyl)phenylcarbonylamino)phenoxy)ethanol, hydrochloride, mp: >260 0
C.
1 H NMR (DMSO-d6): 8 3.31 4H), 3.56 4H), 3.81 2H), 4.02 2H), 4.40 (br s, 3H), 6.94 j=9.0Hz, 2H), 7.09 2H), 7.52 j=9.0Hz, 2H), 7.90 j=9.0Hz, 2H).
WO 98/00144 WO 9800144PCTIUS97/1 1037 39 SCHEME 3 OH
OH
SBoc 2 O, CHC1 3
H
3 C reflux H 3 C 'N
NH
2 NHBoc Br COQEt
CS
2 00 3
DMF
0,,OEt 0
H
3 C NHBoc HOI (gas) EtOAc, 0 0 C
H
3
C
*HCI
NH
2 3-4 1.1-dimethvlethoxvcarbonyl)amino-3 -methyipheno 1 (3-2) To a 1 L round bottomed flask with a stirring bar, reflux condenser and an argon inlet was added 4-amino-3-methylphenol (15.00 g, 121.79 mmol), di-tert-butylpyrocarbonate (27.25 g, 124.84 mmol) and CHC13 (300 mL). This heterogeneous mixture was heated at reflux for 24 h during which time all of the solids dissolved. The mixture was cooled to room temperature and the solid product was collected by filtration. The material was triturated with a mixture of Et2O-hexanes collected on a frit and dried in vacuo to give 21.25 g of 4- (1,1 -dimethylethoxycarbonyl)amino-3-methyiphenol mp: 143- 144 0
C.
I H NMR (CDC13): 8 1.51 9H), 2.14 3H1), 6.08 (br s, I1H), 6.48 (in, 2H), 6.60 (br s, 111), 7.20 j=8.5Hz, IlH).
WO 98/00144 PCT/US97/11037 Ethyl 4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenoxyacetate (3-3) To a 200 mL round bottomed flask with a stirring bar, and an argon inlet was added 4-(1,1-dimethylethoxycarbonyl)amino-3methylphenol (5.00 g, 22.39 mmol), Cs2CO3 (14.59 g, 44.78 mmol), DMF (50 mL), and ethyl bromoacetate (2.61 mL, 23.51 mmol). This mixture was stirred vigorously at ambient temperature for 24 h. The mixture was filtered through a frit and the DMF was removed under high vacuum. The residue was dissolved in EtOAc (300 mL) and washed with H20 (2x) and brine Drying (MgSO4), filtration, and removal of the solvent in vacuo gave a solid. This material was triturated with 5% Et20-hexane, the solid was collected by filtration and dried in vacuo to give 5.40 g of ethyl 4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenoxyacetate as a white, crystalline solid.
1 H NMR (CDC13): 5 1.29 j=7.2Hz, 3H), 1.51 9H), 2.22 3H), 4.26 j=7.2Hz, 2H), 4.57 2H), 6.08 (br s, 1H), 6.72 2H), 7.56
IH).
Ethyl 4-amino-3-methylphenoxyacetate, hydrochloride (3-4) To a 500 mL round bottomed flask with a gas dispersion tube was added a solution of ethyl 4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenoxyacetate (5.31 g, 17.13 mmol) in EtOAc (200 mL). This solution was cooled in an ice bath and dry HCI gas was sparged through the solution, vigorously, for 10 min. The resulting mixture was aged for 15 min. at 0°C. The excess HCI gas was removed with a stream of argon and the solvent was removed in vacuo. The product was triturated with 50 mL of EtOAc and collected on a frit.
The crystals were washed with additional EtOAc and dried in vacuo to give 4.21 g (100%) of ethyl 4 -amino-3-methylphenoxyacetate, hydrochloride as white crystals, mp: 198-200°C.
1H NMR (DMSO-d6): 6 1.21 j=7.1Hz, 3H), 2.33 3H), 4.17 (q, j=7.1Hz, 2H), 4.78 2H), 6.82 (dd, j=3,9Hz, 1H), 6.92 j=3Hz, 1H), 7.39 j=9Hz, 1H), 10.21 (br s, 3H).
WO 98/00144 WO 9800144PCTJUS97/1 1037 41 SCHEME 4
OH
NHBoc 3-2 HG! (gas) EtOAc, 000
BK,'OH
Aliquot 336 NaOH- H 2 0 PhCH 3
RT
1- 3
C
4-1
NH
2
COOH
(N)
IBoo pi *PF6 4-2 i-Pr 2 NEt, CH 2
CI
2 WO 98/00144 WO 9800144PCT/US97/11037 42 SCHEME 4 CONTINED Boo-N N- Q N OH
H
3
C
4-3 eHOI HCI (gas) -N 0- EtOAc,0 0 OC I~JN 0 OH
H
3 0 4-4 2-(3-Methyl-4-( 1,1 -dimethylethoxycarbonyl)aminophenoxy)ethanol (4-1) In a manner similar to that described for compound 2-3, 2- (3 -methyl-4- (1,1 -dimethylethoxycarbonyl)aminophenoxy)ethanol was prepared.
1 H NMR (CDC13): 5 1.50 9H), 2.20 3H), 2.59 j=6.lIHz, I1H), 3.89 (in, 2H), 4.05 (in, 2H), 6.22 (hr s, 1H), 6.69 (in, 2H), 7.48 (br s, 1H).
2-(3 -Methyl -4-aminophenoxy)ethanol. hydrochloride (4-2) In a manner similar to that described for compound 2-4, 2-(3 -methyl-4-aininophenoxy)ethanol hydrochloride was prepared.
I H NMR (DMSO-d6): 6 2.33 3H), 3.69 j=4.2Hz, 2H), 4.04 (t, j=4.2Hz, 2H), 4.58 (hr s, 1H), 6.91 (mn, 2H), 7.37 j=9.OHz, 1H1), 10.18 (hr s, 3H).
WO 98/00144 PCTIUS97/111037 43 2-(3-Methyl-4-(4-( 1 -dimethylethoxycarbonyl)piperazinyl).
p2henvicarbonylamino )phenoxv)ethanoI (4-3) In a manner similar to that described for compound 2-5, 2- (3-methyl-4-(4-( 1 -dimethylethoxycarbonyl)piperazinyl)phenyl.
carbonyl-amino)phenoxy)ethanol was prepared.
I H NMR (CDCI3): 5 1.49 9H), 2.04 (br s, lH), 2.28 3H), 3.28 (in, 4H1), 3.59 (in, 4H1), 3.96 (in, 2H1), 4.08 (in, 2H1), 6.79 (in, 2H), 6.92 j=9.OHz, 2H), 7.46 I1H), 7.67 j=8.OHz, I1H), 7.80 j=9.OHz, 2H).
2-(3 -Methyl-4-(4-( I -piperazinyl)phenylcarbonylaniino)phenox y)ethanol, hydrochloride (4-4) In a manner similar to that described for compound 2-, 2-(3 -methyl-4-(4-( 1 -piperazinyl)phenylcarbonylamino)phenoxy)ethano 1, hydrochloride was prepared, mp: >260'C.
I H NMR (DMSO-d6): 6 2.17 3H), 3.21 (mn, 4H), 3.53 (in, 4H), 3.71 j=5.2Hz, 2H), 3.97 j=5.2Hz, 2H), 4.86 (br s, 1H), 6.76 (mn, IH), 6.83 j=2.5Hz, I1H), 7.06 j=9.OHz 2H), 7.15 j=8.4Hz, IlH), 7.89 j=9.OHz, 2H), 9.40 (br s, 214), 9.54 1H).
WO 98/00144 PTU9/13 PCT/US97/11037 44 SCHEME H 2
OH
B0C20 O0H tBuO N N0
HNO
5-1
CS
2 00 3 /BrCH 2 C0 2 Et 0 tBuO~ N
H
1. H 2 Pd/C 2. CH 3
SO
2
CI
t~O'H
NHSO
2
CH
3 5-3 tBuO
H
5-3a HOI /EtOAc H2N O 0 N- 02
H
2 N NHSO 2
CH
3 5-4 WO 98/00144 WO 9800144PCT/US97/1 1037 45 SCHEME 5 (CONT'D) 5-4
PYCLU
tBuO N' 0 0
/OH
tBuO 0 H -C0 2 Et
NHSO
2
CH
3 1. HCI tc 2. H 0 rN HNJ 5-6 ja 0O--C0 2
H
N
NHSO
2
CH
3 Ht LiBH 4 J:::NHS0 2
CH
3 tBuO yNJ 0 WO 98/00144 WO 9800144PCT'JS97/1 1037 46 SCHEME 5 CONT'D
I
0 rN HCI HNJ H CI/EtOAc NHS0 2
CH
3 WO 98/00144 WO 9800144PCTIUS97/11037 47 SCHEME 5 (CONT'D)
NO
2 5-2 BocN N -O C0 2
H
EtOH, HOI tBuO N~0 H kCO 2 Et 5-9 N0 2 LiOH.H 2 0 NN-0O H -Q
\-CO
2
H
5-10
NO
2 WO 98/00144 WO 9800144PCTIUS97/1 1037 48 SCHEME 5 (CONTh} 0~ O,-C 2 Et tBuO 'kN ~N0 2
H
1. H 2 Pd/C 2. C S 2O
Q
ox- a0,_C 2 Et tBuO J N NHS02O 5-11N I HI /EtOAc HCIH2NI: 011-C0 2 Et
HCI.H
2 NNHS0 2 5-12
N
tBuO 0 PYCLU>/ 2 -4OH WO 98/00144 WO 9800144PCTIUS97/1 1037 49 SCHEME 5 (CONT'D) 0 O CO 2 Et NHS0 2
I-
N)
5-1l3 1. HOI/EtOAc 2. LIOH O, C 2
H
rlN
HN
5-14 WO 98/00144 WO 9800144PCT/US97/1 1037 50 SCHEME 5 (CONTUD
OH
SOCH
3
NO
2 (Aldrich) ICsCO 3 IBrC H 2 00 2 Et 0
NNIICO
2 Et 0 2 N 00H 3 5-15 Pd/C
H
2 H2N,,a 0
-C
2 Et
H
2 N OCH 3 5-16 WO 98/00144 PCT/US97/11037 -51 0 ,C OH tBuO N NO 2
H
2-Nitro-4-( 1, -dimethylethoxycarbonylamino)phenol (5-1) A solution of 2-nitro-4-amino phenol (Aldrich) (20 g, 130 mmol) in THF (500 mL) was cooled to o0C and treated with di-tertbutyldicarbonate (64 g, 293 mmol) and triethylamine (37 mL, 265 mmol). After 24 hours the solution was concentrated and the residue dissolved in EtOAc, washed with 10% KHSO4, saturated NaHCO3, and brine, dried over Na2SO4, filtered and evaporated. The crude bisprotected material (Rf (40% EtOAc/Hexanes) 0.69) was then dissolved in 400 mL 1:1 THF/H20 and treated with LiOH*H20 (38 g, 1.3 mol).
After stirring at room temperature overnight the solvent was removed and the residue was dissolved in EtOAc and washed with brine, dried with Na2SO4, filtered and concentrated to give 5-1 as a reddish, oily solid.
Rf(20% EtOAc/Hexanes)=0.41 1H NMR (400 MHz, CDC13) 5 10.35 1H), 8.18 1H), 7.58 1H), 7.13 1H), 6.45 (bs, 1H), 1.55 9H).
WO 98/00144 PCT/US97/11037 -52- 0 O C 0 2 E t tBuO N NO 2
H
5-2 Ethyl 2-(2-nitro-4-(1,1 -dimethylethoxycarbonylamino)phenoxy)acetate (5-2) A solution of 5-1 (5 g, 19.7 mmol) in DMF (125 mL) was treated with cesium carbonate (3.17 g, 9.73 mmol), stirred for minutes and treated with ethyl bromoacetate (2.2 mL, 19.8 mmol) at room temperature. After 1.5 hours the solution was concentrated under high vacuum and the residue was absorbed to silica gel and chromatographed in a gradient of 20 to 30% EtOAc/hexanes to give 5-2 as a bright yellow solid.
EtOAc/hexanes) 0.26 IH NMR (400 MHz, CDC13) 5 7.95 1H), 7.5 1H), 6.97 1H), 6.62 (bs, 1H), 4.72 2H), 4.25 2H), 1.5 9H), 1.28 3H).
OvCO2Et HCIo H 2 N NHSO 2
CH
3 5-4 Ethyl 2 -methanesulfonylamino-4-aminophenoxy)acetate hydrochloride (5-4) A solution of 5-2 (2 g, 5.88 mmol) in EtOAc (25 mL) was treated with 10% Pd/C (0.67 and hydrogenated under balloon pressure for 1.5 hours. The solution was filtered through SolkaFloc, and the cake rinsed with EtOAc. The filtrate was not concentrated but was treated directly with methanesulfonyl chloride (3.0 mL, 39 mmol) and pyridine (5.0 mL, 62 mmol) and stirred overnight. The solution was concentrated and the residue was dissolved in EtOAc and washed WO 98/00144 PCT/US97/11037 -53with 10% KHSO4, saturated Na2CO3, and brine, dried with Na2SO4, filtered and concentrated to give a yellow oil that was chromatographed EtOAc/hexanes) to give 5-3 (Rf 30% EtOAc/hexanes) 0.19) contaminated with 5-3a. The mixture (1.7 g) was dissolved in EtOAc (75 mL), cooled to -78 0 C and saturated with HCI gas, warmed to 0 C for 1 hour and concentrated. The residue was partitioned between CH2C12 and saturated NaCO3, the layers separated and the aqueous layer extracted with CH2C12. The organic layer was dried over Na2SO4, filtered and evaporated and the residue chromatographed (60% EtOAc/hexanes) to give 5-4 as an off-white solid.
EtOAc/hexanes)=0.3 IH NMR (400 MHz, CDC13) 5 7.7 (bs, 1H), 6.95 1H), 6.74 1H), 6.4 1H), 4.6 2H), 4.33 2H), 2.98 3H), 1.3 3H).
tB u O N 0 0N N 0 H ^-COEt 15
NHSO
2
CH
3 Ethyl -dimethylethoxycarbonyl)piperazin-1 -yl)phenylcarbonylamino)-2'-methanesulfonylaminophenox)acetate A suspension of 5-4 (0.125 g, 0.433 mmol) and 1-5 (0.136 g, 0.444 mmol) in CH2C12 (4 mL) was treated with diisopropylamine (0.3 mL, 1.7 mmol) and PYCLU (0.173 g, 0.48 mmol) and stirred at room temperature for three days. The solution was concentrated and the residue was absorbed to silica gel and chromatographed in a gradient of 20 to 60% EtOAc/hexanes to give 5-5 as a pale yellow oil.
Rf (60% EtOAc/hexanes) 0.27 1H NMR (400 MHz, CDC13) 8 7.82 (dd, 1H), 7.79 1H), 7.77 1H), 7.54 (bs, 1H), 7.48 1H), 6.90 3H), 4.7 2H), 4.25 2H), 3.6 4H), 3.3 4H), 3.03 3H), 1.5 9H), 1.3 3H).
WO 98/00144 WO 9809144PCTIUS97/11037 54 o "a O, -CO 2
H
N NHSO 2
CH
3 I H rN 2- (4-(4-(Piperazin- 1 -yl)phenylcarbonylamino)-2'-methanesulfonylaminophenoxv)acetic acid (5-6) A solution of 5-5 (0.093 g, 0.16 mmol) was dissolved in EtOAc (10 mL), cooled to -78'C and saturated with HCI gas, warmed to 0 0 C for 1 hour and concentrated. The resulting white solid was dissolved in 1: 1: 1 H20/THF/MeOH, treated with LiOH*H20 (0.03 8 g, 0.9 mmol) and stirred at room temperature for 1 hour. The reaction was concentrated and chromatographed (18: 1: 1 EtOH/H20/N1440H) to give a yellow oil that was diluted with CH2Cl2 and evaporated to give 5-6 as white solid.
Rf(9: 1:1 EtOHIH2OINH4OH)=0.48 I H NMR (400 MHz, D20 NaOD) 8 7.74 I1H), 7.72 I1H), 7.21 (s, lH), 7.07 lH), 7.05 IH), 6.9 1H), 6.74 1H), 4.38 2H), 3.15 (in, 4H), 2.85 (in, 7H).
0 N NHSO 2
CH
3 I H 'Ne tBuO YN,, 0 1,1 -Dimethylethoxycarbonyl)piperazin- 1 -yl)phenylcarbonvlamino)-2 t -methanesulfonylaminophenoxv)ethanol (5-7) A solution of 5- (0.196 g, 0.34 minol) was dissolved in THE (5 mL), cooled to 0 0 C and treated with LiBH4 (2M in THE, 0.51 WO 98/00144 PCT/US97/11037 mL, 1.0 mmol) and allowed to warm to room temperature and stir overnight. The solution was poured into 10% KHSO4 and extracted with EtOAc. The organic layer was washed with satruated NaHCO3, brine, and dried over Na2SO4, filtered and evaporated. The residue was absorbed to silica gel and chromatographed in 100% EtOAc to give 5-7 as a white solid.
Rf(EtOAc)=0.28 1 H NMR (400 MHz, CDC13 CD30D) 8 8.78 1H), 7.85 1H), 7.83 1H), 7.71 1H), 7.5 1H), 6.93 3H), 4.1 2H), 3.9 2H), 3.6 4H), 3.3 4H), 3.0 3H), 1.5 9H).
0
°--OH
N NHSO 2
CH
3
H
N
HCI- HN, 5-8 2-(4-(4-(4-Piperazin- 1 -yl)phenylcarbonylamino)-2'-methanesulfonylaminophenoxy)ethanol hydrochloride (5-8) A solution of 5-7 (0.294 g, 0.466 mmol) was dissolved in EtOAc (10 mL), cooled to -78°C and saturated with HC1 gas, warmed to 0°C for 1 hour and concentrated to give 5-8 as a white solid.
Rf(9:1:1 EtOH/H20/NH40H)=0.67.
1H NMR (400 MHz, D20 NaOD) 5 7.71 1H), 7.70 1H), 7.2 (s, 1H), 7.06 1H), 7.05 1H), 6.9 2H), 4.0 2H), 3.83 2H), 3.15 4H), 2.85 7H).
WO 98/00144 PCT/US97/11037 -56tBuO 0 0 N
O
H -Q
\-CO
2 Et 5-9
NO
2 Ethyl -dimethylethoxycarbonyl)piperazin- 1vl)phenylcarbonvlamino)-2'-nitrophenoxy)acetate (5-9) A solution of 5-2 (0.3 g, 0.88 mmol) was dissolved in EtOAc (10 mL), cooled to -78 0 C and saturated with HC1 gas, warmed to 0°C for 1 hour and concentrated to give ethyl 2-(2-nitro-4aminophenoxy)acetic acid as a white solid that was coupled immediately (0.26 g, 0.88 mmol) to 1-5 (0.29 g, 0.95 mmol) as described for 5-5 to give 5-9 as a yellow solid after chromatography in a gradient of 40 to 100% EtOAc/hexanes.
EtOAc/hexanes)=0.22 HN N- O H 0 CO 2
H
5-10 NO 2 2-(4-(4-(Piperazin-1-yl)phenylcarbonylamino)-2'-nitrophenoxy)acetic acid (5-10) A solution of 5-9 (0.186 g, 0.352 mmol) in EtOAc was treated first with HC1 gas then with LiOH*H20 as described for 5-6 to give 5-10 as a yellow solid after chromatography in 18:1:1 EtOH/H20/NH40H).
Rf(18:1:1 EtOH/H20/NH40H)=0.47 1 H NMR (400 MHz, D20) 8.0 1H), 7.68 (2s, 2H), 7.52 1H), 2H), 3.12 (bs, 4H), 2.85 (bs, 4H).
I III I I I WO 98/00144 WO 9800144PCTIUS97/1 1037 57 tBuO4~ N' 0 H -Q
-CO
2 Et 5-11 NHO Ethyl (3 -pyridylsulfonylamino-4-( 1,1 -dimethylethoxycarbonyl) aminop~henoxy)acetate (5-11) A solution of 5-.2 (2 g, 5.88 mmol) in EtOAc (25 mL) was treated with 10% Pd/C and 3-pyridylsulfonyl chloride (JOC, 1989, 54, 389-393) as described for 5-3 to give 5-1 1 after chromatography in a gradient of 30 to 50% EtOAc/hexanes as a white solid.
Rf(40% EtOAc/hexanes) 0. 11 IH NMR (400 MHz, CDCI3) 8 9.02 1H), 8.71 1H), 8.1 (in, 2H), 7.4 1H), 7.33 (in, 2H), 6.69 IH), 6.58 1H), 4.4 2H), 4.23 2H), 1.5 9H), 1.25 3H).
tBuO YN
N--
0 H C0E 5-13 NHS0 2 Ethyl 1-dimethylethoxycarbonyl)piperazin- 1-yl)phenylcarbonylamino)-2'-(3 -pyridylsulfonvlamino)p2henoxy)acetate (5-13) A solution of 5-11 (0.318 g, ,0.704 mmol) in Et:OAc ml-) was treated with HCl gas as described for 5-4 to give 5-12 as a white solid that was coupled directly with 1-5 as described for 5-5 to WO 98/00144 WO 9800144PCTfUS97/1 1037 58 give 5-13 as a oiiy yellow solid after chromatography in a gradient of to 40% acetone/hexanes.
EtOAc/hexanes) 0.41 IH NMR (400 MHz, CDCl3) 8 NN-0O H
-COH
5-14 NHS0 2 I N N 0O H -Q
\-COOH
NHS0 2 (Piperazin- 1 -yl)phenylcarbonylamino)-2' -pyridylsulfonylamino)p2henoxy)acetate (5-1 4) A solution of 5-13 (0.047 g, 0.087 mmol) in EtOAc was treated first with HCl gas then with LiOH*H20 as described for 5-6 to give 5-14 as a yellow solid after chromatography in 18:1:1 EtOHIH2OINH4OH).
Rf(18:1:1 EtOHIH2OIN1-40H) 0.38 1 H NMR (400 MHz, D20 NaOD) 6 8.76 1H1), 8.5 (in, 1H), 8.13 (mn, 1H), 7.7 (mn, 2H), 7.45 (mn, 1H), 7.12 11H), 7.08 (in, 2H), 6.84 (mn, 1H), 6.67 1H1), 4.13 2H), 3.25 (mn, 4H), 2.87 (in, 4H).
WO 98/00144 PCT/US97/11037 -59- 0NO
CO
2 Et 2 OgN -OCH 3 5-15 Ethyl (2-methoxv-4-nitrophenoxv)acetic acid (5-15) 2-Methoxy-4-nitrophenol (Aldrich) (1.0 g, 5.9 mmol) was treated with cesium carbonate and ethylbromoacetate as described for 2 to give crude 5-15 after removal of DMF. The crude material was partitioned between water and EtOAc, the organic layer was dried with brine and MgSO4, filtered and evaporated to give 5-15 as a yellow solid.
EtOAc/hexanes)=0.54 1 H NMR (400 MHz, CDC13) 8 7.8 1H), 7.76 1H), 6.75 1H); 4.71 2H), 4.2 2H), 3.9 3H), 1.21 3H).
O CO 2 Et
H
2 N
OCH
3 5-16 Ethyl 2 -methoxy-4-aminophenoxy)acetic acid (5-16) A solution of 5-15 (0.7 g, 2.7 mmol) in EtOH (10 mL) was treated with 10% Pd/C (0.14 g) and hydrogenated at balloon pressure.
The solution was filtered through Solka-Floc and evaporated to give 16 as a tan oil.
1 H NMR (400 MHz, CDC13) 6 6.78 1H), 6.33 1H), 6.21 1H), 4.59 2H), 4.21 2H), 3.8 3H), 3.45 (bs, 2H), 1.28 3H).
WO 98/00144 WO 9800144PCTIUS97/1 1037 tBuIO>N-/ N 0 H COEt 5-17 00H 3 Ethyl 1,1-dimethylethoxycarbonyl)piperazin- 1vl)phenylcarbonylamino)-2'-(2-methoxy)phenoxy)acetate (5-17) Acid 1-5 and amine 5-16 were coup led as described for to give 5-17 as brown solid after chromatography in EtOAc/hexanes.
EtOAc/hexanes) 0.13 IH NMR (400 MHz, CDCl3) 8 7.8 2H), 7.6 1H), 6.92 2H), 6.86 (in, 2H), 4.64 2H), 4.24 2H), 3.9 3H), 3.6 (in, 4H), 3.3 (in, 4H), 1.5 9H), 1.25 3H).
HN N/\0 N 05-18 H -C0 2
H
OCH
3 2-(4-(4-(4-Piperazin- 1 -yl)phenylcarbonylamino)-2'- (2-methoxy) p2henoxy)acetate (5-18) Compound 5-17 was treated with LIOH and HCI gas as described for 5-6 to give 5-18 as a white solid after chromatography in 10:1:1 EtOHIH2O/N1-40H.
Rf (10: 1: 1 EtOH/H20/NH4OH)=0. 1 H NMR (400 MHz, D20) 8 7.7 8 2H), 7.15 1iH), 7.08 2H), 6.9 (in, 1H), 6.78 1H), 4.4 2H), 3.8 3H), 3.18 (bs, 4H), 2.88 (bs, 4H).
WO 98/00144 WO 9800144PCTIUS97/11037 61 SCHEME 6 HN I H 6-1 B0C 2 0 tBuO N yI N6- 0H 1. CH 3 MgBr 2. t-BuLi 3. C0 2 0 tBuO N I OH 4al-N 0H 6-3 WO 98/00144 WO 9800144PCTIUS97/1 1037 62 PYCLU H 2 -0 OI--OO 2
E
HCI. O H 3 3-4 tBu ON I N 0 CO 2 Et yN H
I/
0 H H 3 6-4 1 .HCI/EtOAc 0 HN, ,C09H r
OH
3 WO 98/00144 WO 9800144PCT/US97/1 1037 63 0 tBuO Na OH NilN PYCLU I -HCI
H
3 C
NH
2 4-2 IH
OH
3 BuO-7-Na N N 0 H 0 0 I HI/EtOAc HCI -HN~ L H 6-7 WO 98/00144 PCT/US97/11037 -64tBuO N I "Y
N
O
H
2-(1,1 -Dimethylethoxycarbonyl)-7-bromo 1,2,3,4-tetrahydro-9Hpyridor3.4-Blindole (6-2) A suspension of 6-1, prepared by the method of Rinehard 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.
1 H NMR (400 MHz, CDC13) 8 8.0-7.6 1H), 7.46 1H), 7.33 (d, 1H), 7.2 1H), 4.6 (bs, 2H), 3.78 (bs, 2H), 2.76 (bs, 2H), 1.5 9H).
0 0
H
O
2-(1,1 -Dimethylethoxycarbonyl)- 1,2,3,4-tetrahydro-9H-pyrido- 3,4-B]indol-7-vl carboxylic acid (6-3) A solution of 6-2 (0.26 g, 0.734 mmol) in THF (10 mL) 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 minutes the solution was cooled to -78C and treated with tBuLi (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 10 minutes. Saturated NH4C1, 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, acidified to pH 7 and extracted with EtOAc, the EtOAc layer WO 98/00144 WO 9800144PCTIUS97/1 1037 65 was dried (Na2SO4) filtered and concentrated to give as an offwhite solid.
Rf(75:25: 1 CHCI3/MeOHIHOAc)=0.48 I H NMR (400 MHz, DMSO-d6) 8 12.0 bs, I1H), 11.2 I1H), 7.93 (s, 1H), 7.6 1H), 7.45 1H), 4.6 2H), 3.68 (in, 2H), 2.7 (in, 2H), 1.4 9H).
tBuO N N 0 OC0 2 Et 6- 0H
CH
3 Ethyl (3-methyl-4-(9-H-2-( 1,1-dimethylethoxycarbonyl- 1,2,3,4tetrahydro-9H-pyrido [3 ,4-B]indol-7-y1-carboxamido)phenoxy)acetic acid (6-4) A solution of 6- (0.078 g, 0.25 mmol) and 3-4 (0.303 g, 1.23 inmol) in CH2C12 were treated with diisopropylamnine and PYCLU as described for 5-5 to give 6-4 as a white solid after chromatography in a gradient of 40 to 60% EtOAc/hexanes.
Rf (40% EtOAclhexanes)=0. 11I IH NMR (400 MHz, CDC13) 5 8.5-8.2 (mn, IH), 8.0 1H), 7.75 (d, 1H), 7.63 1H), 7.52 2H), 6.83 1H), 6.80 1H), 4.7 (bs, 2H), 4.6 2H), 4.28 2H), 3.8 (bs, 2H), 2.83 (bs, 2H), 2.82 3H), 9H), 1.3 3H).
WO 98/00144 WO 9800144PCTIUS97/11037 66 0 HN IN 0\CO 2 H 6- H
OH
3 (3 -Methyl-4-( 1,2,3 ,4-tetrahydro-9H-pyrido [3,4-B ]indol-7 -ylcarboxamido)p2henoxy)acetic acid A solution of 6-4 (0.082 g, 0.16 mmol) in EtOAc (10 mnL) was treated first with HCl gas, then with LiOH*H20 as described for 5-6 to give 6-5 as a white solid after chromatography in 18: 1:1 EtOHIH2O/NH4OH.
Rf (18:1:1 EtOH/H2OINH4OH)=0.48 I H NMR (400 MHz, D20) 5 7.9 IR), 7.54 (in, 2H), 7.13 1H), 6.84 1H), 6.75 1H), 4.40 2H), 3.8 2H), 3.0 (mn, 2H), 2.7 (in, 2H), 2.15 3H).
0 tBuC N N0, 6-6
N
H OH 3 (3-Methyl-4-(9-H-2-( 1,1 -dimethylethoxycarbonyl)- 1,2,3 ,4-tetrahydro- 9H-pyrido[3,4-Blindol-7-yl-carboxamido)phenoxy)ethanoI (6-6) A solution of 6- (0.068 g, 0.214 mmol) and 4-2 (0.213 g, 1.04 nimol) in CH2CI2 (5 mL) were treated with diisopropylamine and PYCLU as described for 2-5 to give 6-6 as a white solid after chromatography in 100% EtOAc.
Rf (100% EtOAc)=0.33 IH NMR (400 MHz, CD3OD) 8 7.98 lH), 7.65 lH), 7.5 1H), 7.2 1H), 6.9 1H), 6.82 1H), 5.5 IH), 4.66 2H), 4.05 (in, 2H), 3.87 (mn, 2H), 3.8 (mn, 2H), 2.7 (mn, 2H-) 2.3 3H), 1.5 9H).
I
WO 98/00144 WO 98/0 144PCT/US97/11037 67 6-7
OH
3 2-(3-Methyl-4-( 1,2,3 ,4-tetrahydro-9H-pyrido [3,4-B ]indol-7-ylcarboxamido)p2henoxv)ethanol (6-7) A suspension of 6-6 in dioxane was treated with HCl gas as described for 5-8 to give 6-7 as a yellow solid after chromatography in 18:1:1 EtOHIH2OINH4OH.
Rf(1 8:1:1 EtOH/H2OINH4OH)=0.5 I H NMR (400 MHz, D20) 6 7.95 I1H), 7.6 (in, 2H), 7.15 I1H), 6.93 1H), 6.84 1H), 4.44 4.1 (in, 2H), 3.85 (in, 2H), 3.55 (in, 2H), 3.05 (in, 2H), 2.18 3H).
HCI. HN N OCO 2 Et 6-8
CH
3 Ethyl (3 -Methyl-4- 1,2,3 ,4-tetrahydro-9H-pyrido [3 ,4-Blindol-7-ylcarboxamido)p2henoxy)acetate hydrochloride (6-8) A suspension of 6-4 in EtOAc was treated with HC1 gas as described for 5-8 to give 6-8 as a yellow solid.
I H NMR (400 MHz, DMSO-d6) 6 11.2 1H), 9.85 1H), 9.5 (bs, 1H), 8.05 1H), 7.7 1H), 7.57 1H), 6.85 iH), 6.75 111), 4.78 2H), 4.4 (bs, 2H), 4.18 2H), 3.45 (mn, 2H), 2.2 3H), 1.23 3H).
WO 98/00144 WO 9800144PCT/US97/1 1037 68 SCHEME 7 t-BuO
J
N ~OH H
H
3 0 N BS/TH F t-BuO Br N ~OH H
H:
3 C Br 7-1 0S 2 00 3 /BrC H 2
CO
2 Et 0 Br t-BuO
N
H
-CO
2 Et
H
3 C Br 7-2 HO /EtOAc WO 98/00144 WO 9800144PCT/US97111037 69 SCHEME 7 (CONT'D) Br HCI H 2 N 0
-CO
2 Et
H
3 C Br tBuO 0 0 N a OH t-BuO N \/N 7-4
CO
2 Et
H
3 0 t-BuO 0 7-4a
\CO
2 Et WO 98/00144 WO 9800144PCTfUS97/I 1037 70 SCHEME 7 (CONT'D' 7-4 7-4a I LOH L~i'.J Br N N-0 H ~'C0 2
H
EtOAc H 3 0 Br HN N-aBr HN0 7-6
H
3 C Br \C2 t-BuO Br O -0 -0 OH H,0 Br HCI -HN Br
HN
1 0 OH 7-8
H
3 C Br WO 98/00144 WO 98/0 144PCT/JS97/1 1037 71 0 Br t-BuO N /J N- 70 H1 H -7-
H
3 C Br 2,6-Dibromo-3-methyl-4-(, 1, -dimethylethoxycarbonyl)aminophenol (7-1) A solution of 3-2 (1.0 g, 450 mmol) in 20 mL THF under argon was treated with N-Bromosuccinimide (1.6 g, 9 mmnol) for 2 hr.
The solution was concentrated and the residue was resuspended in carbontetrachioride and filtered. The filtrate was concentrated and chromatographed (15% EtOAc/hexanes) to give 7-1 as a white solid.
EtOAclhexanes)=0.56 IH NMR (400 MHz, CDC13) 6 7.79 (bs, IH), 6.08 (bs, 1H), 5.8 lH), 2.33 3H), 1.43 9H).
0 Br t-BuO
N
H \-COEt
H
3 0 Br 7-2 Ethyl 2-(2,6-dibromo-3-methyl-4-( 1,1-dimethylethoxycarbonyl)aminop~henoxy) acetic acid (7-2) A solution of 7-1 (0.6 g, 1.57 mmol) in DMF was treated with cesium carbonate and ethyl bromo acetate as described for 3-3 to give 7-2 as a tan solid EtOAc/hexanes)=O.56 1 H NMR (400 MHz, CDCl3) 8 8.0 (bs, IlH), 6.21 (bs, I1H), 4.56 2H), 4.3 2H),-2.35 3H), 1.5 9H), 1.33 3H).
WO 98/00144 PCT/US97/1 1037 72 Br
H
2 N 0 C0 2 Et
H
3 0 Br7- Ethyl 2 6 -dibromo-3-methvI-4-aminop~henoxy) acetic acid (7-3 A solution of 7-2 (0.6 g, 1.29 mmol) in EtOAc (10 mE) was cooled to -78'C, Saturated with HCI gas, warmed to 0 0 C and stirred for 1 hour, then concentrated at ambient temperature to give 7- as a tan solid.
IH NMR (400 MHz, DMSO) 8 7.0 1H), 4.8-4.4 4.41 2H), 4.2 2H), 2.18 3H), 1.2 3H).
t-BtO N0 Br 0 N-0
H
\-COEt 74H 3 C Br Ethyl (2,6-dibromo -3 -methyl-4-(4-(N-( 1,1-dimethylethoxycarbonvl)piperazin-4-vl)phenylcarboxamide)phenoxy) acetic acid (7-4) A solution of 1-3. (0.520 g, 1.29 mmol) and 1-5 (0.395 g, 1.29 mrnol) in CH2Cl2 was treated with chloro-N,N,N'N',-bis(pentamethylene)formamidmnium hexafluorophosphate (0.504 g, 0.1.4 mmol) and diisopropylethyl amine (0.9 mL, 5.16 mmol) and stirred at room temperature for 24 hours. The solution was diluted with EtOAc and washed with H20, 10% KHSO4, saturated NaHCO3 and brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed (silica gel 30% EtOAc/hexanes) to give a mixture of 7-4 and 7-4a.
Rf7 a(50% EtOAclhexanes)=0.45 1 H NMR (400 MHz, CDCI3) 6 8.0 (in, 2H), 7.8 2H), 7.5 IlH), 6.93 2H), 6.85 1H), 4.6 2H), 4.3 2H), 3.6 (bs, 8H), 3.35 (mn, 8H), 2.4 3H), 1.45 9H), 1.35 3H).
WO 98/00144 WO 9800144PCTIUS97/11037 73 Rf2A4(50% EtOAclhexanes)=0.37 I H NMR (400 MHz, CDC13) 8 7.6 2H), 6.7 2H), 4.6 2H), 4.3 2H), 3.55 (bs, 4H), 3.3 (bs, 4H), 2.38 3H), 1.45 9H), 1.33 (t, 3H).
t-BuO 0 Br 0/ N-C N 0 7-
H
3 C Br 2-(2,6-Dibromo-3-methyl-4-(4-(N..(, 1, -dimethylethoxycarbonyl)pip~erazin-4-vl)phenylcarboxamide)p2henoxy) acetic acid A solution of 7-4 and 7-4a (0.3 g) in 1: 1: 1 was treated with LIOH (0.084 g, 2 mmol) at 60'C. After 1 hour the reaction was diluted with EtOAc and 10% KHS04 and the layers were separated. The organic layer was washed with H20, brine, dried with MgSO4, filtered and evaporated to give 7-5 as a clear oil after chromatography in 9:0.5:0.5 CH2C12/MeOH/HOAc.
Rf(9:O.5:0.5 CHCI3/MeOH/l-OAc)=0.6 I H NMR (400 MHz, CD3OD) 8 7.90 2H), 7.6 2H), 7.05 2H), 4.55 2H), 3.6 (bs, 4H), 3.3 (bs, 4H), 2.35 3H), 1.5 9H).
HNN/\0 Br H N N0 7-6 *HCI '-COH
H
3 C Br (2,6-Dibromo-3 -methyl- 4 -(4-piperazin.4.yl)phenylcarbox.
amide)phenoxv) acetic acid hdrochloride (7-6) A slurry of the intermediate acid (0.4 g, 0.6 mmol) in EtOAc was cooled to -78'C and saturated with HCl gas. The reaction WO 98/00144 PCT/US97/11037 -74was warmed to 0°C, then concentrated in vacuo to give 7-6 as the HCI salt.
Rf(10:0.5:0.5 EtOH/H20/NH40H)=0.18 1 H NMR (400 MHz, D20) 5 7.73 2H), 7.23 1H), 7.02 2H), 4.3 2H), 3.1 (bs, 4H), 2.82 (bs, 4H), 2.1 3H).
t-BuO N Br N N Br 0 HN 7-7
H
3 C Br
OH
2-(2,6-Dibromo-3-methyl-4-(4-(N-(1, 1 -dimethylethoxycarbonyl)piperazin- 4 -vl)phenylcarboxamide)phenoxv) ethanol (7-7) A solution of 7-4 (0.2 g, 0.32 mmol) in THF (5 mL) was cooled to 0°C and treated with Borane (1M in THF, 3.2 mL, 3.2 mmol) and stirred at room temperature for 48 hours. An additional 3.2 mL of Borane solution was added and after 15 minutes the reaction was quenched with MeOH, stirred for 0.5 hour, concentrate, the residue was dissolved in EtOAc and washed with 10% KHSO4, brine, dried over MgSO4, filtered and evaporated to give 7-7 as a white solid.
EtOAc/hexanes)=0.42 1H NMR (400 MHz, CDC13) 5 7.8 2H), 7.5 1H), 6.94 2H), 4.2 2H), 4.0 2H), 3.6 4H), 3.3 4H), 2.4 3H), 1.45 (s, 9H).
WO 98/00144 WO 9800144PCTIUS97/1 1037 75 HN 0 Br HN\- -0 H -00 OH 7-8
HCI-
H
3 0 Br 2-(2,6-Dibromo-3 -methyl-4-( 4 -(piperazin-4-yl)phenylcarboxamide)phenoxv') ethanol hydrochloride (7-9) A solution of 7-7 (0.15 g, 0.24 mmnol) in dioxane was treated with HCl gas as described for 7-5 to give 7-8 as a white solid.
Rf(l0% MeOH/CHCl3 saturated with NH3)=0.31 I H NMR (400 MHz, CD3OD) 8 7.85 2H), 7.59 lH), 7.02 I1H), 4.1 (in, 2H), 3.95 (mn, 2H), 3.0 (mn, 4H), 2.54 3H).
WO 98/00144 PCT/US97/11037 76 SCHEME 8
N&-CI
NMM,
NMP
1100 H Na
CO
2Et N\ /-NOD-CO 2 Et 8-1 /-NaC0 2
H
8-2 PYCLU, iPr 2 NEt,
DMF
H
2 N-Q
OH
H
3
C
WO 98/00144 PCT/US97/11037 -77- SCHEME 8 (CONT'D) H OH
H
a
C
Ethyl 4 -yr ieridlpipridin-4-vlcarboxylate (8-1) Ethyl isonipecotate (6.0g, 38.66 mmol), 4 -chloropyridine hydrochloride (5.9g, 38.66 mmol) and N-methylmorpholine 9 .3g mL, 85.00 mmol), were dissolved in N-methylpyrrolidine (50 mL) and the resulting solution was heated at 100oC for 48h. The solution was concentrated in vacuo and the residue was dissolved in EtOAc and washed with water and brine (2 x 100 mL), then dried (Na2SO4) and evaporated. The resulting residue was purified by flash chromatography MeOH CHC13) to afford 8-1 as a crystalline solid.
1H NMR (CDC1 3 8 8.21 j= 6.8 Hz, 2H), 6.78 j= 6.8 Hz, 2H), 4.18 j= 7.0 Hz, 2H), 3.85 2H), 3.10 2H), 2.61 1H), 2.05 2H), 1.85 2H), 1.23 j= 7.0 Hz, 3H).
4 -Pyridylpiperidin-4-ylcarboxvlic acid (8-2) A solution of 8-1 (10g, 42.7 mmol) in THF (50 mL) was teated with IN LiOH (47 mL, 47.0 mmol) and water (50 mL). The resulting solution was stirred at ambient temperature for 12h. The solution was concentrated and the aqueous residue was cooled to o0C, then adjusted to pH 6 with 1N HC1. The resulting solid was collected by filtration and dried in vacuo to afford 8-1 as a white solid.
H NMR (D 2 0) 8 7.95 (d j=6.8 Hz, 2H), 6.73 j=6.8 Hz, 2H), 3.76 j=12.8 Hz, 2H), 2.81 2H), 2.20 1H), 1.85 j=12.9 Hz, 2H), 1.55 2H).
WO 98/00144 WO 9800144PCT[US97/1 1037 78 N-(4-Pyridyl)piperidin-4-carbonylamino-3-methylphenoxyethanol A solution of 2-(3-methyl-4-aminophenoxy)ethanol (2:4) (0.29 g, 1.41 mmol), 4-(pyridyl)(piperidin)-4-carboxylic acid (0.30 g, 1.41 mmol), chloro-N, N, N'-bis(pentamethylene)formamidinium hexafluorophosphate (0.50 g, 1.41 mmol), and dilsopropylamnine (0.25 mL, 1.41 mmol) in dimethylformamide (15 mL) was stirred at ambient temperature for 48 h and the solvent removed in vacuo to give an oil.
This material was chromatographed on silica gel using 5:95 methanolammonia saturated chloroform as eluant to give 8-3 as an off-white solid.
I H NMR (CD3OD): 8 8. 10 j=6.6 Hz, 2H), 7.11 j=8.6 Hz, 2H), 6.87 j=6.6 Hz, 2H), 6.83 lH), 6.77 j=8.6 Hz, 2H), 4. 10 (d, j=13.4 Hz, 2H), 4.02 j=4.6 Hz, 2H), 3.85 j=4-9 Hz, 2H), 3.01 (t, j=12.5 Hz, 2H), 2.72 (in, 1H), 2.20 3H), 1.98 j 13.2 Hz, 2H), 1.84 (in, 211).
WO 98/00144 PCT/US97/11037 -79- EXAMPLE 9 Tablet Preparation Tablets containing 25.0, 50.0, and 100.0 mg., respectively, of the prodrug 2-(3-Methyl-4-(4-( -piperazinyl)phenylcarbonylamino)phenoxy)-ethanol hydrochloride are prepared as illustrated below: TABLE FOR DOSES CONTAINING FROM 25-100MG OF THE PRODRUG Prodrug Microcrystalline cellulose Modified food corn starch Magnesium stearate 25.0 37.25 37.25 0.50 Amount-mg 50.0 100.0 4.25 0.75 100.0 200.0 All of the active compound, cellulose, and a portion of the corn starch are mixed and granulated to 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 25.0, 50.0, and 100.0 mg, respectively, of active ingredient per tablet.
WO 98/00144 PCT/US97/11037 EXAMPLE Intravenous formulations An intravenous dosage form of the above-indicated prodrug is prepared as follows: Prodrug 0.5-10.0mg Sodium Citrate 5-50mg Citric Acid 1-15mg Sodium Chloride 1-8mg Water for Injection (USP) q.s. to 1 L Utilizing the above quantities, the active compound is dissolved at room temperature in a previously prepared solution of sodium chloride, citric acid, and sodium citrate in Water for Injection (USP, see page 1636 of United States Pharmacopeia/National Formulary for 1995, published by United States Pharmacopeial Convention, Inc.
(Rockville, Maryland, copyright 1994).
EXAMPLE 11 Intravenous formulation A pharmaceutical composition was prepared at room temperature using 2-(3-Methyl-4-(4-(1-piperazinyl)phenylcarbonylamino)phenoxy)-ethanol hydrochloride, a citrate buffer, and sodium chloride, to obtain a concentration of of 0.25 mg/ml.
800 grams of water was introduced into a standard pharmaceutical mixing vessel. 0.25 grams of 2-(3-Methyl-4-(4-(1piperazinyl)phenylcarbonylamino)phenoxy)-ethanol hydrochloride was dissolved in the water. 2.7 grams sodium citrate and 0.16 grams citric acid were added to obtain a finished citrate concentration of 10 mM. 8 grams of sodium chloride was added. 200 grams of water was then WO 98/00144 PCT/US97/11037 -81 added to achieve the desired final concentrations of ingredients. The resulting aqueous formulation had the following concentrations: Ingredient Amount 2-(3-Methyl-4-(4-(1 -piperazinyl)phenylcarbonylamino)phenoxy)-ethanol hydrochloride 0.25 mg/ml citrate buffer 10 mM sodium chloride 8 mg/ml The finished concentrated formulation is stored in a standard USP Type I borosilicate glass container at 30-40 degrees C.
Prior to compound administration, the concentrated formulation is diluted in a 4:1 ratio resulting in a finished concentration of 0.05 mg/ml and transfered to an infusion bag.
Diborane Reduction Additional alcohol prodrugs of the present invention can be prepared according to the procedure whereby diborane is used to reduce the acid to the corresponding alcohol: R -O COOH B2H"THF R--O
OH
A
B
According to the procedure, 1 mmol of acid A and 50 mL of distilled dry THF is added to an oven dried round bottomed flask with a stirring bar, septum, condenser and argon inlet to form a solution. This solution is cooled in an ice bath and one molar equivalent of borane-THF comple as a 1M solution in THF is added with a syringe over 5 min. The cooling bath is allowed to expire and the mixture is stirred at ambient temperature until the reduction is complete. The WO 98/00144 PCT/US97/11037 -82reaction is quenched with methanol and the resulting mixture is stirred one hour. The solvents are removed in vacuo and the residue is chromatographed on silica gel to provide the desired alcohol B.
Exemplary starting materials for the diborane reaction are shown in the following table: WO 98/00144 WO 9800144PCTIUS97/11037 83
H
2 N l l- C O O H EP 381 033 EP 381 033 US 5,256,812 EP 381 033
H
2
N
0 COOH WO 98/00144 PCTIUS97/1 1037 84 0 "a
O,,COOH
N H H EP 632 019
H
2 N N\ -N 0 WO 94/22834 0
H
N'
NH
H H
H
2 N 0 0 COOH EP 632 016
COOH
EP 632 020
NH
/r-C0OH 0 WO 94/22835
COOH
WO 98/00144 PCTIUS97/11037 85 Source
HN
H
2
N
/pCOOH EP 503 548 HN
/~-,-COOH
H
2 N
N
pvf-COI EP 503 548 EP 531 883 WO 98/00144 WO 9800144PCT/US97/1 1037 86
H
3
C-N.
OCH
3 EP 659743 EP 659743 EP 659743
,'-COOH
.0 H3C-N OCH3 OCH3 X COOH 0 0
H
COOH EP 659743 .4 WO 98/00144 PCTIUS97I1 1037 87
.O~COOH
H
2
N.
JP 7138221 JP 7179407 WO 98/00144 WO 9800144PCTIUS97/1 1037 88 WO 94/14775 WO 94/1 4775
COGH
COOH
H
2
N
WO 94/15913 WO 94/22440 .0O-%COOH
COOH
WO 98/00144 WO 9800144PCTIUS97/11037 89 Source EP 623615 WO 94121599
'-GOGH
COOH
WO 94/21 599
\-COOH
.0 w
\-COOH
0O 94/21599 0 0 WO 98/00144 PCTIUS97/11037 90 Source EP 0 505 868
NH
H
2 N 0Q9H EP 0 505 868 NCHAN2O EP 0 635 492 OCHqCOqH WO 98/00144 PTU9/13 PCTIUS97/11037 91
A
HND -(CH 2 2 -N YN 00CH 2 00 2 H EP 0
OH
3 NA N OCH 2 00 2 H EP
H
0 -N H ND OCH 2 C0 2
H
0 Source o0587 134 O0612 741 o0632 016 2 N U
EP
NcO N NC 2OCH 2 C O2 WO 94/22835 WO 98/00144 PCT/US97/11037 -92- Therapeutic Treatment Compounds of the invention may be administered to patients where inhibition of human or mammalian platelet aggregation or adhesion is desired.
Compounds of the invention are useful in inhibiting platelet aggregation and thus, they may find utility in surgery on peripheral arteries (arterial grafts, carotid endaterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interation of platelets with artificial surfaces, leads to platelet aggregation and consumption. The aggregated platelets may form thrombi and thromboemboli. Compounds of the invention may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.
Claims (4)
1. A compound having the formula X'-A-B and pharmaceutically acceptable salts, wherein X' is a moiety, comprising between 8 and 11 contiguous atoms selected from carbon and nitrogen, terminating at the non-A bond end in an amino, aliphatic amino, aromatic amino, amidino, or guanidino substituent having a pKa of between about 5-14, wherein the atom attached to A is selected from carbon and nitrogen; A is a 5 or 6 membered aromatic ring, having 0, 1, 2 or 3 heteroatoms selected from N, 0, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R 5 disubstituted on carbon and nitrogen atoms with R 5 and R 6 or trisubstituted on carbon and nitrogen with R 5 R 6 and R 9 where R 5 R 6 and R 9 are independently selected from the group consisting of hydrogen, halogen, C1-10 alkyl, C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, amino, amino C1-8 alkyl, C1-3 acylamino, C1-3 acylamino C1-8 alkyl, C1-6 alkylamino, C1-6 alkylamino C1-8 alkyl, WO 98/00144 PCTIUS97/1 1037 94 CI -6 dialkylamino, C 1 -6 dialkylamino C 1 -8 alkyl, C 1-6 alkoxy, C 1.-6 alkoxy C 1-6 alkyl, aryl C 1 -6 alkyloxy, aryl C 1-6 alkyloxy C 1-6 alkyl, carboxy C 1 6 alkyl, Ci-.3 alkoxycarbonyl, C1 -3 alkoxycarbonyl Ci1 -6 alkyl, carboxy, carboxy CI -6 alkyloxy, hydroxy, and hydroxy CI-6 aikyl, or a 9 or 10 membered fused aromatic ring, having 0, 1, 2 or 3 heteroatoms selected from N, 0, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R 5 9 disubstituted on carbon and nitrogen atoms with R 5 and R 6 or trisubstituted on carbon and nitrogen with R 5 R 6 and R 9 where R 5 R 6 and R 9 are independently selected from the group consisting of hydrogen, halogen, CI1..1 alkyl, C3-8 cycloalkyl, aryl, aryl C1..8 alkyl, amino, amino CI-8 alkyl, C 1-3 acylamino, C 1-3 acylamino C 1-8 alkyl, C 1 6 alkylamino, C1-6 alkylamino alkyl, CI -6 dialkylamino, WO 98/00144 PCT/US97/1103 7 95 Cl1 6 dialkylamino C 1-8 alkyl, CI1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, aryl CI -6 alkyloxy, aryl C 1-6 alkyloxy CI1 -6 alkyl, carboxy C 1-6 alkyl, CI -3 alkoxycarbonyl, Ci -3 alkoxycarbonyl Cj -6 alkyl, carboxy, carboxy C1-6 alkyloxy, hydroxy, and hydroxy C1-6 alkyl; and B is -0 (CH 2 )nCH 2 oR", -CH 2 (CH 2 )mCH 2 0R 8 o -CH(CH 2 )mCH 2 OR8 F1 wherein n is I or 2, and m is 0, 1, or 2; R 7 is selected from the group consisting of hydrogen, halogen, Ci-lo alkyl, C3-8. cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino C 1-8 alkyl, Ci -3 acylamino, Cl1-3 acylamino C 1-8 alkyl, Cp-6 alkylamino, Cl-6 alkylamino CI-8 alkyl, Cp-6 dialkylamnino, WO 98/00144 PCT/US97/1103 7 96 C 1 -6 dialkylamino C 1 -8 alkyl, Ci1 -6 alkoxy, C 1 6 alkoxy C 1-6 alkyl, aryl Cl1 -6 alkyloxy, aryl CI1-6 alkyloxy Cl1 6 alkyl, carboxy, carboxy C 1 -6 alkyl, Ci-.3 alkoxycarbonyl, CI -3 alkoxycarbonyl Cj -6 alkyl, carboxy, carboxy Ci -6 alkyloxy, hydroxy, and hydroxy CI -6 alkyl; R8 is selected from the group consisting of hydrogen, -C(O)-Ci -8alkyl, -C(O)-C3 -8cycloalkyl, -C(O)-aryl, and 1 -3alkylaryl.
2. A compound of claim I having the formula X-Y-Z-A-B and pharmaceutically acceptable salts, wherein X is a 5, 6 or 7 membered aromatic or nonaromatic ring, having 1, 2 or 3 heteroatoms selected from N, 0, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R I or disubstituted with R I and R 2 where R I and R 2 are independently selected from the group consisting of hydrogen, WO 98/00144 PCT/US97/1 1037 97 halogen, ailkyl, C3-.8 cycloalkyl, aryl, aryl CI-8 alkyl, amino, amino CI..8 alkyl, C 1 -3 acylamino, C1-3 acylamino Cp.8 alkyl, Cp- alkylamino, CI-.6 alkylamino C 1-8 alkyl, Ci1 -6 dialkylamino, C1..6 dialkylamino Cl-8 alkyl, C 1 -6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, aryl C1-6 alkyloxy, aryl C 1-6 alkyloxy C 1.-6 alkyl, carboxy CI-.6 alkyl, CI .3 alkoxycarbonyl, Cj-3 alkoxycarbonyl CI-6 alkyl, carboxy, carboxy CI-6 alkyloxy, hydroxy, and hydroxy Ci -6 alkyl, or a 9 or 10 membered fused aromatic or nonaromatic ring, having 1, 2 or 3 heteroatoms selected from N, 0, and S, and either Unsubstituted or monosubstituted on carbon and nitrogen atoms with R I or disubstituted with R I and R 2 where R I and R 2 are independently selected from the group consisting of hydrogen, halogen, C1i alkyl, C3-8 cycloallcyl, WO 98/00144 PCTIUS97/110 3 7
98- aryl, aryl CI-8 alkyl, amino, amino C 1-8 alkyl, Cu.3 acylamino, CI1-3 acylatnino CIl-8 alkyl, C 1 -6 alkylamino, C1-6 alkylamino C1-8 alkyl, Ci1 -6 dialkylamino, CI -6 dialkylamino CI..-8 alkyl, C 1 -6 alkoxy, CI-6 alkoxy C1..6 alkyl, aryl Cj -6 alkyloxy, aryl C 1-6 alkyloxy CI -6 alkyl, carboxy CI..6 alkyl, Ci -3 alkoxycarbonyl, Ci1 -3 alkoxycarbonyl Ci1 -6 alkyl, carboxy, carboxy CI-6 alkyloxy, hydroxy, and hydroxy CI..6 alkyl; Y is a 5 or 6 membered aromatic or nonaromatic ring, having 0, 1, 2 or 3 heteroatoms selected from N, 0, and S, and either unsubstituted or substituted on carbon and nitrogen atoms with R 3 selected from the group consisting of halogen, CI11 alkyl, C3-8 cycloalkyl, aryl, aryl CI-8 alkyl, amino, amino Ci1 -8 alkyl, WO 98/00144 PCT/US97/1 1037 99 Ci -3 acylamino, C 1-3 acylamino Ci1 -8 alkyl, Ci1 -6 alkylamino, Ci1 -6 alkylamino C I 9 alkyl, C 1-6 dialkylamino, Ci -6 dialkylamino CI -8 alkyl, C 1 -6 alkoxy, Ci1 6 alkoxy C 1 -6 alkyl, aryl Ci -6 alkyloxy, aryl Ci -6 alkyloxy Ci -6 alkyl, carboxy Ci-6 alkyl, C 1 -3 alkoxycarbonyl, Ci1 -3 alkoxycarbonyl Ci1 -6 alkyl, carboxy, carboxy CI-6 alkyloxy, hydroxy, and hydroxy C 1 -6 alkyl; or X and Y combined together form the structure RIN Ni 0,7 ZDor R'N, WO 98/00144 PCT/US97/1 1037 100 Z is 0 R 4 -0-N- R 4 0 1 11 -N-C- CH 2 CH 2 -OH=OH- 0H 2 -O- -0-OH 2 0 11 -C-OH 2 0 11 -CH 2 NR 4 -NR 4 OH 2 OH -OH-OH 2 OH OCH 2 0UH or Z represents a bond; R 4 is selected from the group consisting of hydrogen, WO 98/00144 PCTIUS97/1 1 0 3 7
101- halogen, alkyl, C3-8 cycloalkyl, aryl, aryl CI-8 alkyl, amino, amino C1-8 alkyl, CI -3 acylamino, C1.3 acylammno CI..8 alkyl, C1-6 alkylamino, CI-6 alkylamino C1..8 alkyl, C 1 -6 dialkylamino, C 1-6 dialkylamino C 1-8 alkyl, Ci1 -4 alkoxy, C 1 4 alkoxy C 1-6 alkyl, carboxy, carboxy 1-6 alkyl, Cj 1 -3 alkoxycarbonyl, C 1 3 alkoxycarbonyl C 1 6 alkyl, carboxy CI-6 alkyloxy, hydroxy, and hydroxy Ci1 -6 alkyl; A is a 5 or 6 membered aromatic ring, having 0, 1, 2 or 3 heteroatoms selected from N, 0, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R 5 disubstituted on carbon and nitrogen atoms with R 5 and R 6 or trisubstituted on carbon and nitrogen with R 5 R 6 and R 9 where R 5 R 6 and R 9 are independently selected from the group consisting of hydrogen, halogen, CP.1o alkyl, WO 98/00144 PCT/US97/1 1037 -102 C3-8 cycloalkyl, aryl, aryl C1-8 alkyl, amino, amino C 1-9 alkyl, C 1 -3 acylamino, C 1-3 acylamino C1 -8 alkyl, C 1-6 alkylamino, Cb.6 alkylamino C1..8 alkyl, CI-6 dialkylamino, CI-6 dialkylamino Cp.8 alkyl, Ci1 -6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, aryl CI -6 alkyloxy, aryl C 1.-6 alkyloxy C 1 6 alkyl, carboxy Ci -6 alkyl, Ci -3 alkoxycarbonyl, Ci -3 alkoxycarbonyl Cj -6 alkyl, carboxy, carboxy Ci -6 alkyloxy, hydroxy, and hydroxy Cj -6 alkyl, or a 9 or 10 membered fused aromatic ring, having 0, 1, 2 or 3 heteroatoms selected from N, 0, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R 5 disubstituted on carbon and nitrogen atoms with R 5 and R 6 or trisubstituted on carbon and nitrogen with R 5 R 6 and R 9 where R 5 R 6 and R 9 are independently selected from the group consisting of hydrogen, halogen, CI-1o alkyl, C3-8 cycloalkyl, WO 98/00144 PCTJUS97/1 1037 -103 aryl, aryl CI-8 alkyl, amino, amino CI-8 alkyl, C.13 acylamnino, C.3 acylamino Cp-8 alkyl, C 1 6 alkylamino, C1-6 alkylamino C1-8 alkyl, Ci -6 dialkylamino, CI-6 dialkylamino CI-8 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1 6 alkyl, aryl CI -6 alkyloxy, aryl C 1-6 alkyloxy C 1-6 alkyl, carboxy CI-6 alkyl, CI -3 alkoxycarbonyl, CI -3 alkoxycarbonyl CI -6 alkyl, carboxy, carboxy Ci -6 alkyloxy, hydroxy, and hydroxy C.1-6 alkyl; B is 0 (CH 2 )nCH 2 oR 8 -CH 2 (CH 2 )mCH 2 0R 8 or CH(CH 2 )mCH 2 ORB wherein nis I or 2, and mis 0, 1, or 2; R 7 is selected from the group consisting of hydrogen, halogen, C3-8 cycloalkyl, WO 98/00144 PCTIUS97/1 1037 104 aryl, aryl C 1-8 alkyl, amino, amino C1-8 alkyl, CI-3 acylamino, C 1-3 acylamino C I -8 alkyl, C 1-6 alkylamino, C1-6 alkylamino C1..8 alkyl, C 1.-6 dialkylamino, C.1-6 dialkylamino C.1-8 alkyl, C1 -6 alkoxy, CI-6 aikoxy C1-6 alkyl, aryl C1-6 alkyloxy, aryl C1-6 alkyloxy CI-.6 alkyl, carboxy, carboxy CI-6 alkyl, CI-.3 alkoxycarbonyl, CI-3 alkoxycarbonyl Cl..6 alkyl, carboxy, carboxy Ci -6 alkyloxy, hydroxy, and hydroxy C 1 -6 alkyl; R 8 is selected from the group consisting of hydrogen, -C(O)-CI -8alkyl, -C(O)-C3 -8cycloalkyl, -C(O)-aryl, and I -3alkylaryl. I WO 98/00144 PCT/US97/11037 -105- 3. A compound of claim 2 having the formula 0 X-Y-C-NH-A-OCH 2 and pharmaceutically acceptable salts, wherein X is a 6 -membered aromatic or nonaromatic ring having 1, 2 or 3 nitrogen atoms; Y is a 6 -membered aromatic or nonaromatic ring having 0, 1, 2 or 3 nitrogen atoms; A is a 6 -membered aromatic ring unsubstituted, mono- substituted with a moiety selected from the group consisting of halogen, C1-3alkyl, and CI-3alkylsulfonylamino, disubstituted with one or more moieties, same or different, selected from the group consisting of halogen, C1-3alkyl, and C1-3alkylsulfonylamino or trisubstituted with one or more moieties, same or different, selected from the group consisting of halogen, C1-3alkyl, and Cl- 3alkylsulfonylamino. 4. A compound of claim 3 having the formula O II X-Y-C-NH-A-OCH 2 CH 2 0H and pharmaceutically acceptable salts, wherein X is a 6 -membered aromatic or nonaromatic ring having 1 or 2 nitrogen atoms; Y is a 6 -membered aromatic or nonaromatic ring having 0 or 1 nitrogen atoms; WO 98/00144 PCT/US97/11037 -106- A is a 6 -membered aromatic ring unsubstituted, mono- substituted with a moiety selected from the group consisting of Br, CH3, and NHSO2CH3, disubstituted with one or more moieties, same or different, selected from the group consisting of Br, CH3, and NHSO2CH3, or trisubstituted with one or more moieties, same or different, selected from the group consisting of Br, CH3, and NHSO2CH3. A compound of claim 4 having the formula O II X-Y-C-NH-A-OCH 2 CH 2 OH and pharmaceutically acceptable salts, wherein X is HN N- Y is or or and and O- A is Br II H 3 C H o H 3 C Br or 6. A compound of claim 5 selected from the group consisting of 2-(4-(4-(1-piperazinyl)phenylcarbonylamino)phenoxy)ethanol, 2 3 -methyl-4-(4-(1-piperazinyl)phenylcarbonylamino)phenoxy)-ethanol 2 4 4 -(4-piperazin-1-yl)phenylcarbonylamino)-2-methanesulfonyl-aminophenoxy)ethanol 2-(3-methyl-4-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-7-yl-carboxamido)phenoxy)ethanol, 2-(2,6-dibromo-3-methyl-4-(4-(piperizin-4-yl)phenylcarbox-amide)phenoxy) ethanol, and N-( 4 -pyridyl)piperidin-4-carbonylamino-3-methylphenoxyethanol, S 10 and pharmaceutically acceptable salts thereof. 7. A fibrinogen receptor antagonist, substantially as hereinbefore described with reference to any one of the examples. 8. A composition comprising a compound of any one of claims 1 to 7 and a pharmaceutically acceptable carrier. 15 9. A composition of claim 8, further comprising an efficacious amount of one or more agents selected from a thrombolytic agent, an anticoagulant agent, and an antiplatelet agent and a pharmaceutically acceptable carrier. A method for the treatment or prophylaxis of thrombus formation in a mammal requiring said treatment or prophylaxis, which method includes or consists of administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 7, or of a composition according to claim 8. 11. A compound according to any one of claims 1 to 7 or a composition according to claim 8 when used in the treatment or prophylaxis of thrombus formation. 12. The use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment or prophylaxis of thrombus formation. S 13. A method for the treatment or prophylaxis of embolus formation in a mammal requiring said treatment or prophylaxis, which method includes or consists of administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 7, or of a composition according to claim 8. 14. A compound according to any one of claims 1 to 7 or a composition according to claim 8 when used in the treatment or prophylaxis of embolus formation. The use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment or prophylaxis of embolus formation. 16. A method for inhibiting the binding of fibrinogen to blood platelets in a mammal requiring said treatment or prophylaxis, which method includes or consists of administering to said mammal an C00191 effective amount of at least one compound according to any one of claims 1 to 7, or of a composition according to claim 8. 17. A compound according to any one of claims 1 to 7 or a composition according to claim 8 when used in inhibiting the binding of fibrinogen to blood platelets. 18. The use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for inhibiting the binding of fibrinogen to blood platelets. 19. A method for inhibiting the aggregation of blood platelets in a mammal requiring said treatment or prophylaxis, which method includes or consists of administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 7, or of a composition lo according to claim 8. A compound according to any one of claims 1 to 7 or a composition according to claim 8 when used in inhibiting the aggregation of blood platelets. 20. The use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for inhibiting the aggregation of blood platelets. 22. A method for inhibiting osteoclast mediated bone resorption in a mammal requiring said treatment or prophylaxis, which method includes or consists of administering to said mammal an S effective amount of at least one compound according to any one of claims 1 to 7, or of a composition according to claim 8. 23. A compound according to any one of claims 1 to 7 or a composition according to claim 8 S 20 when used in inhibiting osteoclast mediated bone resorption. 24. The use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for inhibiting osteoclast mediated bone resorption. A method for inhibiting angiogenesis in a mammal requiring said treatment or 04 prophylaxis, which method includes or consists of administering to said mammal an effective amount S 25 of at least one compound according to any one of claims 1 to 7, or of a composition according to claim 0.:t 8. 26. A compound according to any one of claims 1 to 7 or a composition according to claim 8 when used in inhibiting angiogenesis. 27. The use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for inhibiting angiogenesis. 28. A method for inhibiting tumour growth in a mammal requiring said treatment or prophylaxis, which method includes or consists of administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 7, or of a composition according to claim 8. 29. A compound according to any one of claims 1 to 7 or a composition according to claim 8 when used in inhibiting tumour growth. The use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for inhibiting tumour growth. 31. A method for preventing platelet thrombosis in a mammal requiring said treatment or prophylaxis, which method includes or consists of administering to said mammal an effective amount Coo191 COO 19 1 of at least one compound according to any one of claims 1 to 7, or of a composition according to claim 8. 32. A compound according to any one of claims 1 to 7 or a composition according to claim 8 when used in preventing platelet thrombosis. 33. The use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for preventing platelet thrombosis. 34. A method for preventing thromboembolism in a mammal requiring said treatment or prophylaxis, which method includes or consists of administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 7, or of a composition according to claim 8. A compound according to any one of claims 1 to 7 or a composition according to claim 8 when used in preventing thromboembolism. 36. The use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for preventing thromboembolism. S 15 is 37. A method for preventing reocclusion in a mammal requiring said treatment or prophylaxis, which method includes or consists of administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 7, or of a composition according to claim 8. 38. A compound according to any one of claims 1 to 7 or a composition according to claim 8 when used in preventing reocclusion. 39. The use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for preventing reocclusion. 40. A method for inhibiting the aggregation of blood platelets by blocking fibrinogen from acting at its receptor site in a mammal requiring said treatment or prophylaxis, which method includes S 25 or consists of administering to said mammal an effective amount of at least one compound according .o to any one of claims 1 to 7 in combination with one or more agents selected from a thrombolytic agent, an anticoagulant agent, and an antiplatelet agent, or of a composition according to claim 9. 41. A compound according to any one of claims 1 to 7 in combination with one or more agents selected from a thrombolytic agent, an anticoagulant agent, and an antiplatelet agent or a composition according to claim 9 when used in inhibiting the aggregation of blood platelets by blocking fibrinogen from acting at its receptor site. 42. The use of a compound according to any one of claims 1 to 7 in combination with one or more agents selected from a thrombolytic agent, an anticoagulant agent, and an antiplatelet agent for the manufacture of a medicament for inhibiting the aggregation of blood platelets by blocking fibrinogen from acting at its receptor site. 43. A method for inhibiting the binding of fibrinogen to blood platelets by blocking fibrinogen from acting at its receptor site in a mammal requiring said treatment or prophylaxis, which method includes or consists of administering to said mammal an effective amount of at least one compound a-cording to any one of claims 1 to 7 in combination with one or more agents selected from a C00191 C019 thrombolytic agent, an anticoagulant agent, and an antiplatelet agent, or of a composition according to claim 9. 44. A compound according to any one of claims 1 to 7 in combination with one or more agents selected from a thrombolytic agent, an anticoagulant agent, and an antiplatelet agent or a composition according to claim 9 when used in inhibiting the binding of fibrinogen to blood platelets by blocking fibrinogen from acting at its receptor site. The use of a compound according to any one of claims 1 to 7 in combination with one or more agents selected from a thrombolytic agent, an anticoagulant agent, and an antiplatelet agent for the manufacture of a medicament for inhibiting the binding of fibrinogen to blood platelets by blocking fibrinogen from acting at its receptor site. Dated 5 February 1999 MERCK Co., INC. Patent Attorneys for the Applicant/Nominated Person SPRUSON&FERGUSON S* S S** 00 S 0* S 0 0 C00191 coolgi
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2097696P | 1996-06-28 | 1996-06-28 | |
| US60/020976 | 1996-06-28 | ||
| GBGB9617983.3A GB9617983D0 (en) | 1996-08-28 | 1996-08-28 | Fibrinogen receptor antagonist prodrugs |
| GB9617983 | 1996-08-28 | ||
| PCT/US1997/011037 WO1998000144A1 (en) | 1996-06-28 | 1997-06-25 | Fibrinogen receptor antagonist prodrugs |
Publications (2)
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| AU3503397A AU3503397A (en) | 1998-01-21 |
| AU709631B2 true AU709631B2 (en) | 1999-09-02 |
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| AU35033/97A Ceased AU709631B2 (en) | 1996-06-28 | 1997-06-25 | Fibrinogen receptor antagonist prodrugs |
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| EP (1) | EP0912182A4 (en) |
| JP (1) | JP2000514427A (en) |
| AU (1) | AU709631B2 (en) |
| CA (1) | CA2257937A1 (en) |
| WO (1) | WO1998000144A1 (en) |
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| EP0912175A4 (en) * | 1996-06-28 | 1999-09-08 | Merck & Co Inc | Fibrinogen receptor antagonists |
| NL1006179C2 (en) * | 1997-05-30 | 1998-12-01 | Alcoa Nederland Bv | Method for processing material from aluminum and plastic. |
| GB0319150D0 (en) * | 2003-08-14 | 2003-09-17 | Glaxo Group Ltd | Novel compounds |
| GB0421908D0 (en) * | 2004-10-01 | 2004-11-03 | Angeletti P Ist Richerche Bio | New uses |
| WO2006131452A1 (en) * | 2005-06-06 | 2006-12-14 | F. Hoffmann-La Roche Ag | SULFONAMIDE DERIVATIVES USEFUL AS LIVER CARNITINE PALMITOYL TRANSFERASE (L-CPTl) INHIBITORS |
| AU2007221207A1 (en) | 2006-02-28 | 2007-09-07 | Merck Sharp & Dohme Corp. | Inhibitors of histone deacetylase |
| SG11201405328SA (en) | 2012-03-16 | 2014-11-27 | Vitae Pharmaceuticals Inc | Liver x receptor modulators |
| ME02660B (en) | 2012-03-16 | 2017-06-20 | Vitae Pharmaceuticals Inc | Liver x receptor modulators |
| CN107501202A (en) * | 2017-09-26 | 2017-12-22 | 杨文浪 | Microwave method prepares the synthesis technique of 1,4 benzoxazinones |
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| US5256812A (en) * | 1989-01-31 | 1993-10-26 | Hoffmann-La Roche Inc. | Carboxamides and sulfonamides |
| WO1994022835A2 (en) * | 1993-03-29 | 1994-10-13 | Zeneca Limited | Heterocyclic compounds as platelet aggregation inhibitors |
| NZ262941A (en) * | 1993-03-29 | 1997-07-27 | Zeneca Ltd | Pyridine derivatives and medicaments |
| US5547671A (en) * | 1995-09-20 | 1996-08-20 | Duthinh; Phu | Anti-intoxication composition |
-
1997
- 1997-06-25 WO PCT/US1997/011037 patent/WO1998000144A1/en not_active Application Discontinuation
- 1997-06-25 CA CA 2257937 patent/CA2257937A1/en not_active Abandoned
- 1997-06-25 AU AU35033/97A patent/AU709631B2/en not_active Ceased
- 1997-06-25 JP JP10504262A patent/JP2000514427A/en active Pending
- 1997-06-25 EP EP97931396A patent/EP0912182A4/en not_active Withdrawn
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| Publication number | Publication date |
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| AU3503397A (en) | 1998-01-21 |
| CA2257937A1 (en) | 1998-01-08 |
| JP2000514427A (en) | 2000-10-31 |
| EP0912182A4 (en) | 1999-12-29 |
| EP0912182A1 (en) | 1999-05-06 |
| WO1998000144A1 (en) | 1998-01-08 |
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