US3352866A - 4-alkanoyl-1-piperazinealkanamides - Google Patents

4-alkanoyl-1-piperazinealkanamides Download PDF

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US3352866A
US3352866A US55908666A US3352866A US 3352866 A US3352866 A US 3352866A US 55908666 A US55908666 A US 55908666A US 3352866 A US3352866 A US 3352866A
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Clinton A Dornfeld
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GD Searle LLC
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D295/00Heterocyclic 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
    • C07D295/16Heterocyclic 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
    • C07D295/18Heterocyclic 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 carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182Radicals derived from carboxylic acids
    • C07D295/185Radicals derived from carboxylic acids from aliphatic carboxylic acids

Description

United States Patent 3,352,866 4-ALKANOYL-l-PIPERAZTNEALKANAES Clinton A. Dornfeld, Glenview, 11]., assignor to G. l). Searle & (10., (Ihicago, 111., a corporation of Delaware No Drawing. Filed June 21, 1966, Ser. No. 559,086 8 Claims. (Cl. 260-268) The present invention relates to a group of compounds which are 4-alkanoyl derivatives of l-piperazinealkanamides. In particular, it relates to a group of compounds having the following general formula RI! (CHa)m wherein m is a whole number between 0 and 4 inclusive; Alk is lower alkylene; R is an aliphatic hydrocarbon group containing from 1 to 29 carbon atoms; and R and R" are each selected from the group consisting of hydrogen, lower alkyl, phenyl, and substituted phenyl. R and R can further be combined to give, with the connecting nitrogen, a cyclic amine.

The lower alkylene radicals referred to above contain up to six carbon atoms and can be exemplified by groups such as methylene, ethylene, propylene, and trimethylene. Particularly preferred are those compounds in which lower alkylene is ethylene.

Since R is an aliphatic hydrocarbon group containing up to 29 carbon atoms, RCO- represents an acyl radical containing up to 30 carbon atoms. The hydrocarbon portion of this acyl radical can be a straight-chain saturated hydrocarbon group so that examples of acyl would then be acetyl, propionyl, butyryl, hexanoyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, and similar straight-chain alkanoyl groups containing up to 30 carbon atoms. R can also be a branched-chain alkyl radical; examples of acyl radicals involving this type of group are Z-ethylbutyryl and Z-heptyloctanoyl. R can further contain 1 or more double or triple bonds. This would give acyl radicals such as oleoyl, 2-octynoyl, and 10-undecynoyl.

The lower alkyl radicals referred to above as values for R and R" contain up to 6 carbon atoms. Examples of such groups are methyl, ethyl, propyl, isopropyl, and the like. When R and R are substituted phenyl, the substituents can be 1 or more methyl, halogen, or alkoxy radicals. In this case, halogen includes fluorine, chlorine,'bromine, and iodine. Examples of alkoxy would include methoxy and ethoxy. Thus, examples of substituted phenyl groups are tolyl, xylyl, fluorophenyl, chlorophenyl, methoxyphenyl, and ethoxyphenyl. R and R" can further be combined with the connecting nitrogen atom to give a cyclic amine. In this case, NRR" would be a cyclic amino group such a l-pyrrolidinyl, piperidino, and morpholino.

Although the formula presented above shows the compounds only as substituted piperazines, the present invention also encompasses the corresponding homopiperazines. That is, the present invention also includes those compounds in which a homopiperazine ring replaces the piperazine ring of the general formula.

The organic "bases of this invention form pharmaceutically acceptable, non-toxic, acid addition salts with a variety of organic and inorganic acids. Such salts are formed with acids such as sulfuric, phosphoric, hydrochloric, hydrobromic, hydriodic, sulfamic, citric, lactic, maleic, malic, oxalic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, ascorbic, and related acids.

The compounds of the present invention are useful because of their pharmacological properties. In particular, they are useful because of theiraanti-ulcer activity. This "Ice is demonstrated by the fact that they decrease acid secretion and inhibit ulceration in the Shay rat. However, they are not ganglion blocking agents. Furthermore, the present compounds inhibit corticoid-induced ulcers and, in particular, ulcers induced by prednisolone.

The present compounds also possess anti-inflammatory activity which is demonstrated by a phenylbutazone-like effect on edematous conditions. They also possess antibiotic activity against a variety of organisms. Thus, they inhibit the growth of bacteria such as Diplo'co ccus pneumoniae, protoza such as Tetrahymena gelleii, and algae such as Chlorella vulgaris. They also inhibit germination of seeds of Trifolium.

Two approaches are available for the synthesis of compounds of the present invention. Thus, a piperazinealkanamide of the formula wherein m, Alk, R, and R" are defined as above is reacted with an appropriate acid chloride or anhydride to give the desired disubstituted piperazine. The reaction is carried out, with heating, in an inert solvent such as acetone or Z-butanone. Optionally, a tertiary amine such as triethylamine can be present in the reaction mixture to react with hydrogen chloride formed in the reaction.

In an alternate procedure, a monoacylpiperazine of the formula wherein m and R are defined as above is reacted with a haloalkanamide of the formula Halogeu-Alk- C O N wherein Alk, R, and R" are defined as above and halogen is preferably chlorine. This reaction is carried out with some heating in an inert solvent such as dimethylfor-rnamide. An inorganic base such as sodium bicarbonate can further be present in the reaction mixture to react with the hydrogen chloride formed. For those compounds in which Alk is ethylene, an appropriate acrylamide can be used in place of the halopropionamide. In this case, the acrylamide is refluxed with monosubstituted piperazine to give the desired compound.

The following examples are presented to further illustrate the present invention; they should not be construed as limiting it in spirit or in scope. In these examples, quantities are indicated in parts by weight unless parts by volume are specified and temperatures are indicated in degrees centigrade C.). The relationship between parts by weight and parts by volume is the same as that between grams and milliliters.

Example 1 To a solution of 86.0 parts of piperazine in 240 parts of ethanol there are added 71.1 parts of acrylamide as a slurry in 240 parts of ethanol. This addition is carried out over a period of 15 minutes. Some precipitate is present at the end of the addition, but the mixture is stirred and heated at 85 C. for an additional 20 hours. The hot mixture is filtered to remove the solid and the filtrate is cooled and then filtered to remove additional precipitate. The resultant filtrate is then concentrated under reduced pressure and the residual solid concentrate is heated at C. under high vacuum to sublime out unreacted piperazine. The remaining residue is then purified by sublimation at 100 C. under reduced pressure. The product obtained in this way is l-piperazinepropionamide and it melts at about 125 C.

Example 2 A solution of 25.6 parts of l-acetylpiperazine and 15.6 parts of acrylamide in 480 parts of ethanol is heated at reflux for 18 hours. The resultant mixture is treated with charcoal and filtered hot and the solvent is evaporated from the filtrate under reduced pressure. 20 parts of the resultant crude product are mixed with 80 parts of 2- butanone and heated and then 17 parts by volume of 6 N hydrogen chloride in 2-propanol is added. Then, 160 parts of 2-propanol is added to the boiling mixture. Heating is continued for an additional 2 hours while ethanol is added until complete solution is obtained. The solution is then treated with charcoal and filtered and the filtrate is concentrated and cooled. The solid which forms is separated by filtration and dried at 50 C. under reduced pressure to give 4-acetyl-1-piperazinepropionamide hydrochloride melting at about 172173 C.

Example 3 A solution of 10.9 parts of lauroyl chloride in 80 parts of Z-butanone is added to a hot mixture of 7.9 parts of 1-piperazinepropionamide in 80 parts of 2-butanone. The resultant mixture is heated for about .5 minutes and then allowed to stand at room temperature for 4 hours. The mixture is then filtered to separate the precipiate which is then washed with 2-butanone and dried under vacuum. 15.7 parts of this solid are heated with 240 parts of 2-propanol and filtered, and the funnel is washed with hot 2-propanol. The resultant filtrate is reheated and then filtered again and the new filtrate is concentrated to about one half the original volume. The precipitate which forms on standing is separated by filtration and redissolved in 320 parts of 2-propanol. The resultant mixture is filtered and the filtrate is concentrated. The concentrate is allowed to stand at room temperature and the precipitate which forms is separated by filtration and dried at 80 C. under vacuum. The product obtained in this way is 4-lauroyl-l-piperazinepropionamide hydrochloride melting at about 198.l99 C. The free base of this compound has the following formula Example 4 To a solution of 5.6 parts of l-piperazinepropionamide in 40 parts of propanol there is added a solution of 9.7 parts of palmitoyl chloride in 80 parts of 2-butanone. A precipitate forms immediately but the mixture is first stirred and heated to boiling before it is allowed to cool to room temperature and then filtered. The resultant precipitate is then heated with 400 parts of 2-propanol and the hot mixture is filtered to. remove some solid. The filtrate is then concentrated to about one fifth the original volume and it is allowed to stand at room temperature. The solid which forms is separated by filtration and dried at 80 C. under reduced pressure. The product thus obtained is 4-palmitoyl-l-piperazinepropionamide hydrochloride melting at about 194-196 C.

Example 5 A mixture of 16.3 parts of octanoyl chloride, 15.7 parts of 1-piperazinepropionamide, parts of triethylamine, and 400 parts of acetone is stirred and refluxed for 14 hours. The hot mixture is then filtered and the solvent is evaporated from the filtrate under reduced pressure. The resultant residue is warmed with water and the mixture obtained is extracted with methylene chloride. The methylene chloride solution is dried with potassium carbonate and filtered and the solvent is evaporated under reduced pressure. The solid residue is dissolved in parts of warm Z-butanone and 10 parts by volume of 6.7 N hydrogen chloride in 2-propanol is added. The precipitate which forms is separated and recrystallized from 2-propanol to give 4-octanoyl-l-piperaziuepropionamide hydrochloride melting at about 195 C.

Example 6 A mixture of 30.3 parts of stearoyl chloride, 15.7 parts of 1-piperazinepropionamide, and 10 parts of triethylamine in 400 parts of acetone is stirred and refluxed for 16 hours. The resultant mixture is allowed to cool and 10 parts by volume of 50% sodium hydroxide solution is added. The solvent is then evaporated under reduced pressureand the residual solid is mixed with 640 parts of methylene chloride and filtered. The filtrate is washed twice with water and dried over potassium carbonate, and the solvent is evaporated under reduced pressure. The resultant solid is recrystallized from Z-butanone and then dried under reduced pressure at 80 C. to give 4- stearoyl-1-piperazinepropionamide melting at about 97- 98 C.

Example 7 A mixture of 30.5 parts of l-lauroylpiperazine, 10.6 parts of e-chloroacetamide, and 10 parts of sodium bicarbonate in 240 parts of dimethylformamide is stirred and refluxed for 5 hours. The mixture is filtered hot and the solvent is evaporated from the filtrate under reduced pressure. The solid residue is then stirred with 160 parts of boiling 2-propanol and the resultant hot mixture is filtered. The filtrate is concentrated to about one half the original volume and cooled and the precipitate which forms is separated by filtration and dried under reduced pressure. The product obtained in this way is 4-lauroyl lpiperazineacetamide melting at about 124 C. This compound has the following formula Example 8 A mixture of 26 parts of l-lauroylpiperazine, 9.2 parts of a-chloro-N-methylacetamide, and 10 parts of sodium bicarbonate in 380 parts of dimethylformamide is stirred and refluxed for 4 hours. The resultant mixture is filtered hot and the solvent is evaporated from the filtrate under reduced pressure. The residual oil solidifies on standing and is dissolved in 110 parts of ethyl acetate. This solution is treated with charcoal; a crystalline solid forms in the resulting solution and is separated by filtration and then dried under reduced pressure at 80 C. The product obtained in this way is 4-lauroyl-N-methyl-l-piperazineacetamide melting at about -86 C. This compound has the following formula Example 9 8.5 parts of a-chloroacetanilide, 15.2 parts of 1-lauroylpiperazine, and 5 parts of sodium bicarbonate in 380 parts of dimethylformamide are stirred and heated slowly to about 147 C. The mixture is then allowed. to cool to room temperature and then filtered. The solvent is evaporated from the filtrate under reduced pressure and the residual oil is dissolved in 330 parts of methylene chloride. The resultant solution is washed twice with water and dried over potassium carbonate, and the solvent is evaporated from the filtrate under reduced pressure. The resultant residue is crystallized from ethyl acetate and the solid product obtained is dried under reduced pressure to give 4-lauroyl-N-phenyl-l-piperazineacetamide melting at about 64 C.

Example A mixture of 10.7 parts of a-chloro-4-ethoxyacetanilide, 15.2 parts of l-lauroylpiperazine, and 5 parts of sodium bicarbonate in 380 parts of dimethylformamide is stirred and heated at reflux for 4 hours. The hot mixture is filtered and the solvent is evaporated from the filtrate under reduced pressure. The resultant residue is recrystallized from ethyl acetate and then dried to give 4-lauroyl-N-(4- ethoxyphenyl)-1-piperazineacetamide melting at about 94 C.

Example 11 The procedure of Example 10 is repeated using 30.5 parts of l-lauroylpiperazine, 12.2 parts of a-chloro-N- ethylacetamide, 10 parts of sodium bicarbonate and 240 parts of dimethylformamide. The product obtained is 4-lauroyl-N-ethyl-1-piperazineacetamide melting at about 61 C.

Likewise, the reaction of l-lauroylpiperazine with occhloro-3-methylacetanilide, ot-chloro 4 methoxyacetanilide, and a-chloro-4-fluoroacetanilide according to the procedure described in Example 10 gives the corresponding piperazineacetamide in each instance.

Example 12 Example 13 A mixture of 9.9 parts of oz-chloro-2,6-dimethylacetanilide, 13.4 parts of l-laurolypiperazine, and 5 parts of sodium bicarbonate in 240 parts of dimethylformamide is stirred and refluxed for 2 hours. The hot mixture is filtered and the solvent is evaporated from the filtrate under reduced pressure. The residual oil is dissolved in 180 parts of hot ethyl acetate and filtered to remove some inorganic materials. The solution is concentrated to about one half the original volume and diluted with 65 parts of n-hexane. 8 parts by volume of 6.7 N hydrogen chloride in 2-propanol are added and a precipitate forms immediately. It is separated by filtration and heated with 120 parts of 2-butanone. The hot mixture is filtered and the insoluble solid is dried under reduced pressure to give 4 lauroyl N-(2,6-dimethylphenyl)-1-piperazineacetamide hydrochloride melting at about 170 C.

Example 14 To a mixture of 15.7 parts of 1 piperazinepropionamide in 40 0 parts of 2-butanone there are added, portionwise, 13.5 parts of 2-ethylbutyryl chloride. After about 1 hour of heating, 400 parts of methanol are added portionwise to the mixture to bring about almost complete solution of any solid. The hot mixture is then filtered and cooled and the cooled mixture is filtered again. The filtrate is then concentrated under reduced pressure and the concentrate is diluted with Z-butanone. The solid which forms is separated by filtration and then heated with 320 parts of ethanol. A slight excess of isopropanolic hydrogen chloride is added to the hot mixture which is then filtered. The filtrate is then diluted with 320 parts of 2- propanol and filtered hot. The resultant precipitate is dried under reduced pressure to give 4-(2-ethylbutyryl)- original volume,

6 1--piperazinepropionamide hydrochloride melting at about 240 C.

Example 15 8.9 parts of 2-heptyloctanoic acid and 20 parts by volume of thionyl chloride in 175 parts of toluene are heated at reflux for 4 hours. Low boiling materials are removed under reduced pressure. The residual acid chloride is then dissolved in 40 parts of Z-butanone and added to a solution of N,N-dimethyl-l-piperazineacetamide in 40 parts of 2-butanone. A precipitate forms, but the mixture is stirred and heated before it is again cooled and filtered. The filtrate is then concentrated under reduced pressure to give a residual syrup which is dissolved in 300 parts of warm water and treated with charcoal. The filtered solution is then made alkaline with sodium hydroxide solution and extracted with methylene chloride. The methylene chloride extract is dried with potassium carbonate and then concentrated to give a residual oil. This oil is dissolved in Z-butanone and mixed with a slight excess of hydrogen chloride in 2-propanol. The solvent is evaporated from the resultant solution and the residual solid is heated with 55 parts of ethyl acetate and then filtered. A crystalline solid forms in the filtrate and it is separated and dried at C. under reduced pressure. The product obtained in this way is 4-(2-heptyloctanoyl)- N,N-dimethyl-l-piperazineacetamide hydrochloride.

Example 16 A mixture of 15.0 parts of oleoyl chloride, 7.9 parts of 1-piperazinepropionamide, and 200 parts of 2- butanone is heated to reflux with stirring. The mixture is cooled to room temperature and then filtered and the separated precipitate is sucked as dry as possible, washed with Z-butanone, and finally dried under reduced pressure. The resultant solid is heated with 480 parts of ethanol and the solution is cooled to room temperature and filtered to remove some insoluble solids. Hydrochloric acid is then added to the filtrate which is treated with charcoal, concentrated to about one third the and cooled. The precipitate which forms is separated by filtration and dried under reduced pressure to give 4-oleoyl-l-piperazinepropionamide hydrochloride.

What is claimed is:

1. A compound of the formula wherein Alkyl contains up to 17 carbon atoms and Alk is lower alkylene.

3. A compound according to claim 1 which has the formula l O Alkyl-U N N-C H2O HIT-(I5 NH2 wherein Alkyl contains up to 17 carbon atoms.

7 s 4. A compound according to claim 1 which is 4-0c- 8. A compound according to .claim 1 which is 4- tanoyl-l-piperazinepropionamide. 1auroy1-N-pheny1-l-piperazineacetamide.

5. t 1 1 h' h 4- A compound according o calm W 10 1s References Cited lauroyl-1-piperazinepropionamide.

6. A compoundaccording to claim 1 which is 4- 5 UNITED STATES PATENTS palmitoyl-l-piperazinepropionamide. 3 244 71 4/19 B- 1 26O 268 7. A compound according to claim 1 which is 4- 1e lauroyl-N-methyl-l-piperazineacetamide. HENRY R. JILES, Primary Examiner.

Claims (1)

1. A COMPOUND OF THE FORMULA
US3352866A 1966-06-21 1966-06-21 4-alkanoyl-1-piperazinealkanamides Expired - Lifetime US3352866A (en)

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4585774A (en) * 1981-05-08 1986-04-29 Otsuka Pharmaceutical Co., Ltd. Aniline derivatives and cardiotonic composition
US4935419A (en) * 1983-08-10 1990-06-19 Bjoerk Anders K K Novel 1-piperazinecarboxamide derivatives
WO1994029296A1 (en) * 1993-06-04 1994-12-22 Henkel Corporation Polymerizable compounds
US5565567A (en) * 1993-06-04 1996-10-15 Henkel Corporation. Polymerizable N,N'-substituted piperazine acrylamide compounds
US5756742A (en) * 1995-12-22 1998-05-26 Henkel Corporation Polymerizable compounds
US5922820A (en) * 1993-06-04 1999-07-13 Henkel Corporation Polymerizable compounds
US6063794A (en) * 1996-10-11 2000-05-16 Cor Therapeutics Inc. Selective factor Xa inhibitors
WO2000051612A1 (en) * 1999-03-03 2000-09-08 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
US6133256A (en) * 1997-04-14 2000-10-17 Cor Therapeutics Inc Selective factor Xa inhibitors
US6194435B1 (en) 1996-10-11 2001-02-27 Cor Therapeutics, Inc. Lactams as selective factor Xa inhibitors
US6204268B1 (en) 1997-04-14 2001-03-20 Cor Therapeutics, Inc Selective factor Xa inhibitors
US6211183B1 (en) * 1997-04-14 2001-04-03 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6218382B1 (en) 1997-08-11 2001-04-17 Cor Therapeutics, Inc Selective factor Xa inhibitors
US6228854B1 (en) 1997-08-11 2001-05-08 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6262047B1 (en) 1996-10-11 2001-07-17 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6333321B1 (en) 1997-08-11 2001-12-25 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6369080B2 (en) 1996-10-11 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6369063B1 (en) 1997-04-14 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3244718A (en) * 1964-02-17 1966-04-05 Biel John Hans Piperazine derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3244718A (en) * 1964-02-17 1966-04-05 Biel John Hans Piperazine derivatives

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4585774A (en) * 1981-05-08 1986-04-29 Otsuka Pharmaceutical Co., Ltd. Aniline derivatives and cardiotonic composition
US4935419A (en) * 1983-08-10 1990-06-19 Bjoerk Anders K K Novel 1-piperazinecarboxamide derivatives
WO1994029296A1 (en) * 1993-06-04 1994-12-22 Henkel Corporation Polymerizable compounds
US5565567A (en) * 1993-06-04 1996-10-15 Henkel Corporation. Polymerizable N,N'-substituted piperazine acrylamide compounds
US5922820A (en) * 1993-06-04 1999-07-13 Henkel Corporation Polymerizable compounds
US5756742A (en) * 1995-12-22 1998-05-26 Henkel Corporation Polymerizable compounds
US6063794A (en) * 1996-10-11 2000-05-16 Cor Therapeutics Inc. Selective factor Xa inhibitors
US6369080B2 (en) 1996-10-11 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6262047B1 (en) 1996-10-11 2001-07-17 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6194435B1 (en) 1996-10-11 2001-02-27 Cor Therapeutics, Inc. Lactams as selective factor Xa inhibitors
US6525076B1 (en) 1996-10-11 2003-02-25 Millennium Pharmaceuticals, Inc. Selective factor Xa inhibitors
US6211183B1 (en) * 1997-04-14 2001-04-03 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6369063B1 (en) 1997-04-14 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6204268B1 (en) 1997-04-14 2001-03-20 Cor Therapeutics, Inc Selective factor Xa inhibitors
US6133256A (en) * 1997-04-14 2000-10-17 Cor Therapeutics Inc Selective factor Xa inhibitors
US6333321B1 (en) 1997-08-11 2001-12-25 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6218382B1 (en) 1997-08-11 2001-04-17 Cor Therapeutics, Inc Selective factor Xa inhibitors
US6228854B1 (en) 1997-08-11 2001-05-08 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6355643B1 (en) 1999-03-03 2002-03-12 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
WO2000051612A1 (en) * 1999-03-03 2000-09-08 Merck & Co., Inc. Inhibitors of prenyl-protein transferase

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