Anticoagulant agents
| Title: | Anticoagulant agents |
|---|---|
| Patent Number: | 6,200,967 |
| Publication Date: | March 13, 2001 |
| Appl. No: | 09/202,626 |
| Application Filed: | December 17, 1998 |
| Abstract: | This invention relates to a compound of the Formula I [equation included] (wherein X, Y, G and R have the values defined in the description), or a pharmaceutically acceptable salt thereof, processes and intermediates for the preparation of such a compound or salt, pharmaceutical compositions comprising such a compound or salt and methods of their use as thrombin inhibitors, coagulation inhibitors and agents for the treatment of thromboembolic disorders. |
| Inventors: | Klimkowski, Valentine J (Carmel, IN); Schacht, Aaron L (Plainfield, IN); Wiley, Michael R (Indianapolis, IN) |
| Assignees: | Eli Lilly and Company (Indianapolis, IN) |
| Claim: | What is claimed is |
| Claim: | 1. A compound having the Formula I [equation included] |
| Claim: | wherein |
| Claim: | X--C(O)-- is ##STR37## |
| Claim: | in which |
| Claim: | T is (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.1 -C.sub.8)alkyl, ##STR38## |
| Claim: | a is 0, 1 or 2; and |
| Claim: | Q is --NH--A; |
| Claim: | A is R"SO.sub.2 --; |
| Claim: | R' is hydrogen or (C.sub.1 -C.sub.4 )alkyl; |
| Claim: | R" is (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)fluoroalkyl bearing one to five fluoros, --(CH.sub.2).sub.d --R.sup.m, or unsubstituted or substituted aryl, where aryl is phenyl or naphthyl; |
| Claim: | R.sup.m is --COOR.sup.b, --SO.sub.2 (C.sub.1 -C.sub.4 alkyl), --SO.sub.3 H, --P(O)(OR.sup.b).sub.2 or tetrazol-5-yl; |
| Claim: | each R.sup.b is independently hydrogen or (C.sub.1 -C.sub.4)alkyl; |
| Claim: | d is 1, 2, or 3; and |
| Claim: | Z is hydrogen, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4 )alkoxy, hydroxy, halo or (C.sub.1 -C.sub.4)alkylsulfonylamino; |
| Claim: | --Y--G-- is ##STR39## |
| Claim: | r is 0, 1 or 2; |
| Claim: | R.sup.g is (C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.8)cycloalkyl, or --(CH.sub.2).sub.p --L--(CH.sub.2).sub.q --T'; |
| Claim: | R.sup.P is (C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.8)cycloalkyl, or --(CH.sub.2).sub.p --L--(CH.sub.2).sub.q --T'; |
| Claim: | where p is 0, 1, 2, 3, or 4; L is a bond, --O--, --S--, or --NH--; q is 0, 1, 2 or 3; and T' is (C.sub.1 -C.sub.4)alkyl, (C.sub.3 -C.sub.8)cycloalkyl, --COOH, --CONH.sub.2, or Ar, where Ar is unsubstituted or substituted aryl, where aryl is phenyl, naphthyl, a 5- or 6-membered unsubstituted or substituted aromatic heterocyclic ring, having one or two heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen, or a 9- or 10-membered unsubstituted or substituted fused bicyclic aromatic heterocyclic group having one or two heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen; |
| Claim: | R.sup.y is --CH.sub.2 --, --O--, --S--, or --NH--; and |
| Claim: | R.sup.z is a bond or, when taken with R.sup.y and the three adjoining carbon atoms, forms a saturated carbocyclic ring of 5-8 atoms, one atom of which may be --O--, --S--, or --NH--; |
| Claim: | --G--R is --C(O)--NH--(CH.sub.2).sub.s --R, --CH.sub.2 --NH--(CH.sub.2).sub.s --R, --CH.sub.2 --NH--C(O)--R or --(CH.sub.2).sub.t --O--R in which s is 1 or 2 and t is 1, 2 or 3; and |
| Claim: | R is a 4-amidino-3-hydroxyphenyl group bearing 0, 1, 2 or 3 fluoro substituents; |
| Claim: | or a pharmaceutically acceptable salt thereof. |
| Claim: | 2. A compound as claimed in claim 1 wherein halo is fluoro, chloro, bromo or iodo; a (C.sub.1 -C.sub.4)alkyl group, a (C.sub.1 -C.sub.6)alkyl group, or a (C.sub.1 -C.sub.8)alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl; a (C.sub.1 -C.sub.4)alkoxy group is methoxy, ethoxy, propoxy, isopropoxy, or t-butyloxy; a (C.sub.3 -C.sub.8)cycloalkyl group is cyclopropyl, cyclopentyl or cyclohexyl; a (C.sub.1 -C.sub.4)fluoroalkyl group is trifluoromethyl or 2,2,2-trifluoroethyl; and aryl is phenyl, naphthyl, furyl, thienyl, pyridyl, indolyl, quinolinyl or isoquinolinyl. |
| Claim: | 3. A compound as claimed in claim 2 in which |
| Claim: | X--C(O)-- is ##STR40## |
| Claim: | in which T is cyclohexyl or phenyl; a is 0 or 1; and A is (C.sub.1 -C.sub.4 alkyl)sulfonyl; and |
| Claim: | --Y--G-- is --NR.sup.g --CH.sub.2 --G--, ##STR41## |
| Claim: | in which R.sup.g is (C.sub.1 -C.sub.6)alkyl, --(CH.sub.2).sub.q --(C.sub.3 -C.sub.8)cycloalkyl or --(CH.sub.2).sub.q --phenyl; q is 0, 1, 2 or 3; and r is 0, 1, or 2; |
| Claim: | 4. A compound as claimed in claim 3 in which |
| Claim: | X--C(O)-- is ##STR42## |
| Claim: | wherein T is cyclohexyl; a is 1; and A is ethylsulfonyl; and |
| Claim: | --Y--G-- is ##STR43## |
| Claim: | in which r is 0 or 1; |
| Claim: | 5. A compound as claimed in any one of claims 1, 2, 3 and 4 in which --G--R is --C(O)--NH--(CH.sub.2).sub.s --R, or a pharmaceutically acceptable salt thereof. |
| Claim: | 6. A compound as claimed in claim 5 in which s is 1, or a pharmaceutically acceptable salt thereof. |
| Claim: | 7. A compound as claimed in claim 6 in which R is 4-amidino-3-hydroxyphenyl or 4-amidino-3-hydroxy-2,5,6-trifluorophenyl, or a pharmaceutically acceptable salt thereof. |
| Claim: | 8. A compound as claimed in claim 7 in which R is 4-amidino-3-hydroxyphenyl, or a pharmaceutically acceptable salt thereof. |
| Claim: | 9. A compound as claimed in claim 1 selected from |
| Claim: | (a) N-ethylsulfonyl-D-cyclohexylalanyl-N-[[4-(amino-iminomethyl)-3-hydroxyphen yl]methyl]-L-prolinamide |
| Claim: | (b) 1-[N-ethylsulfonyl-D-phenylalanyl]-N-[[4-(amino-iminomethyl)-3-hydroxyphen yl]methyl]-S-azetidine-2-carboxamide |
| Claim: | (c) 1-[N-ethylsulfonyl-D-cyclohexylalanyl]-N-[[4-(amino-iminomethyl)-3-hydroxy phenyl]methyl]-S-azetidine-2-carbox-amide, and |
| Claim: | (d) N-ethylsulfonyl-D-phenylalanyl-N-[[4-(aminoiminomethyl)-3-hydroxyphenyl]me thyl]-L-prolinamide; |
| Claim: | 10. A compound as claimed in claim 9 which is N-ethylsulfonyl-D-cyclohexylalanyl-N-[[4-(aminoiminomethyl)-3-hydroxypheny l]methyl]-L-prolinamide; |
| Claim: | 11. A pharmaceutically acceptable salt of a compound of Formula I as claimed in claim 1 which salt is an acid addition salt with an acid affording a physiologically acceptable counterion or, for a compound of Formula I in which X or Y bears an acidic moiety, a salt made with a base which affords a pharmaceutically acceptable cation selected from alkali metal salts, alkaline earth metal salts, aluminum salts and ammonium salts, and salts made from physiologically acceptable organic bases. |
| Claim: | 12. A pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 in association with a pharmaceutically acceptable carrier, diluent or excipient. |
| Claim: | 13. A method of inhibiting thrombin comprising administering to a mammal in need of treatment, a thrombin inhibiting dose of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as claimed in claim 1. |
| Claim: | 14. A method of inhibiting thrombosis in a mammal comprising administering to a mammal in need of treatment, an antithrombotic dose of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as claimed in claim 1. |
| Claim: | 15. A method of inhibiting coagulation in a mammal comprising administering to a mammal in need of treatment an effective dose of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as claimed in claim 1. |
| Claim: | 16. A process for preparing a compound of Formula I, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 which comprises |
| Claim: | (A) for a compound of Formula I in which --G--R is --C(O)--NH--(CH.sub.2).sub.s --R, coupling an acid of Formula II, [equation included] |
| Claim: | or an activated derivative thereof, with an amine of Formula III; [equation included] |
| Claim: | (B) coupling an acid of Formula IV, [equation included] |
| Claim: | or an activated derivative thereof, with an amine of Formula V; [equation included] |
| Claim: | or |
| Claim: | (C) hydrogenolyzing the N--O bond of a corresponding compound of Formula VI ##STR44## |
| Claim: | in which f is 0, 1, 2 or 3; |
| Claim: | whereafter, for any of the above procedures, when a functional group is protected using a protecting group, removing the protecting group; and |
| Claim: | whereafter, for any of the above procedures, when a pharmaceutically acceptable salt of a compound of Formula I is required, it is obtained by reacting the acidic or basic form of such a compound of Formula I with a base or an acid affording a physiologically acceptable counterion or by any other conventional procedure; |
| Claim: | and wherein, unless otherwise specified, the groups X, Y, G and R and their components have any of the values defined in claim 1. |
| Current U.S. Class: | 514/183; 215/300; 215/412; 215/423; 215/601; 215/604; 215/605; 540/480; 540/521; 546/113; 548/452; 548/453; 548/480; 564/91; 564/98; 564/99 |
| Current International Class: | C07D22500; C07D40300; C07D47102; A61K 3133; B65D 3900 |
| Patent References Cited: | 596797 January 1898 Tauber 3189649 June 1965 Rosiger et al. 3632593 January 1972 Gautier et al. 4244865 January 1981 Ali et al. 4322429 March 1982 Burow, Jr. et al. 4346078 August 1982 Bajusz et al. 4661522 April 1987 Beetz 5385927 January 1995 Michel et al. 5455348 October 1995 Austel et al. 5489583 February 1996 Mack et al. 5498779 March 1996 Neises et al. 5561146 October 1996 Kim et al. 5583146 December 1996 Kimball et al. 5602253 February 1997 Antonsson et al. 5618843 April 1997 Fisher et al. 5629321 May 1997 Okumura et al. |
| Other References: | Geratz, J. D., "Inhibition of Thrombin, Plasmin, and Plasminogen Activation by Amidino Compounds," Thromb. Diath. Haemorrh., 23, 486-499, (1970). Asghar, S. S., et al., "Inhibition of Cir, Cis and Generation of Cis by Amidino Compounds," Biochimica et Biophysica Acta, 317, 539-548, (1973). Asghar, S. S., et al., "Human Plasma Kallikreins and Their Inhibition by Amidino Compounds," Biochimica et Biophysica Acta, 438, 250-264, (1976). Bajusz, S., "Interaction of Trypsin-like Enzymes wth Small Inhibitors," Symposia Biologica Hungarica, 25, 277-298, (1984). Shutske G. M., et al., "A Novel Synthesis of 3-Amino-1,2-Benzisoxazoles --an Entry into the Isoxazolo[3,4,5-ef] [1,4] benzoxazepine Ring System," J. Heterocyclic Chem., 26, 1293-1298, (1989). Reguera, R., et al., "Putrescine Uptake Inhibition by Aromatic Diamidines in Leishmania Infantum Promastigotes", Biochem. Pharm., 47, 1859-1866, (1994). Misra, Raj N., et al., "Argatroban Analogs: Synthesis Thrombin Inhibitory Activity and Cell Permeability of Aminoheterocyclic Guanidine Surrogates," Bioorg. & Med. Chem. Letters, 4, 2165-2170, (1994). Scarborough, R. M., "Anticoagulant Strategies Targeting Thrombin and Factor Xa," Annual Reports in Medical Chemistry, 30, 71-80, (1995). Edmunds, J. J., et al., "Thrombin and Factor Xa Inhibition, "Annual Reports in Medical Chemistry, 31, 51-60, (1996). Hilpert, K., et al., "Design and Synthesis of Potent and Highly Selective Thrombin Inhibitors," J. Med. Chem., 37, 3889-3901, (1994). Handin et al., Bleeding and Thrombosis, Harrison's Principles of Internal Medicine, Thirteenth Edition, pp. 317-322, 1994. |
| Primary Examiner: | Shah, Mukund J. |
| Assistant Examiner: | McKenzie, Thomas |
| Attorney, Agent or Firm: | Jackson, Thomas E. |
| Accession Number: | edspgr.06200967 |
| Database: | USPTO Patent Grants |
| Language: | English |
|---|