WO1996034010A3 - Inhibitors of farnesyl-protein transferase - Google Patents

Inhibitors of farnesyl-protein transferase Download PDF

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Publication number
WO1996034010A3
WO1996034010A3 PCT/US1996/003975 US9603975W WO9634010A3 WO 1996034010 A3 WO1996034010 A3 WO 1996034010A3 US 9603975 W US9603975 W US 9603975W WO 9634010 A3 WO9634010 A3 WO 9634010A3
Authority
WO
WIPO (PCT)
Prior art keywords
farnesyl
ca1a2x
inhibitors
thiol
analogs
Prior art date
Application number
PCT/US1996/003975
Other languages
French (fr)
Other versions
WO1996034010A2 (en
Inventor
S Jane Desolms
Original Assignee
Merck & Co Inc
S Jane Desolms
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck & Co Inc, S Jane Desolms filed Critical Merck & Co Inc
Priority to EP96929648A priority Critical patent/EP0837875A4/en
Priority to JP8528692A priority patent/JPH11502822A/en
Priority to AU68950/96A priority patent/AU708620B2/en
Publication of WO1996034010A2 publication Critical patent/WO1996034010A2/en
Publication of WO1996034010A3 publication Critical patent/WO1996034010A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Abstract

The present invention comprises analogs of the CA1A2X motif of the protein Ras that is modified by farnesylation in vivo. These CA1A2X analogs inhibit the farnesyl-protein transferase and the farnesylation of certain proteins. Furthermore, these CA1A2X analogs differ from those previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. The compounds of the instant invention also incorporate a cyclic amine moiety in the A2 position of the motif. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.
PCT/US1996/003975 1995-03-29 1996-03-25 Inhibitors of farnesyl-protein transferase WO1996034010A2 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP96929648A EP0837875A4 (en) 1995-03-29 1996-03-25 Inhibitors of farnesyl-protein transferase
JP8528692A JPH11502822A (en) 1995-03-29 1996-03-25 Farnesyl-protein transferase inhibitors
AU68950/96A AU708620B2 (en) 1995-03-29 1996-03-25 Inhibitors of farnesyl-protein transferase

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US41262695A 1995-03-29 1995-03-29
US41282895A 1995-03-29 1995-03-29
US441995P 1995-09-27 1995-09-27
US60/004,419 1995-09-27
US08/412,626 1996-02-13
US08/412,828 1996-02-13

Publications (2)

Publication Number Publication Date
WO1996034010A2 WO1996034010A2 (en) 1996-10-31
WO1996034010A3 true WO1996034010A3 (en) 1996-12-12

Family

ID=56289685

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/003975 WO1996034010A2 (en) 1995-03-29 1996-03-25 Inhibitors of farnesyl-protein transferase

Country Status (1)

Country Link
WO (1) WO1996034010A2 (en)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5703241A (en) * 1995-10-16 1997-12-30 Merck & Co., Inc. Inhibitor of farnesyl-protein transferase
CA2249617A1 (en) * 1996-04-03 1997-10-09 S. Jane Desolms Inhibitors of farnesyl-protein transferase
ES2579832T3 (en) 2011-10-14 2016-08-17 Bristol-Myers Squibb Company Substituted tetrahydroisoquinoline compounds as factor XIa inhibitors
SI2766346T1 (en) 2011-10-14 2017-05-31 Bristol-Myers Squibb Company Substituted tetrahydroisoquinoline compounds as factor xia inhibitors
WO2013055984A1 (en) 2011-10-14 2013-04-18 Bristol-Myers Squibb Company Substituted tetrahydroisoquinoline compounds as factor xia inhibitors
WO2014059214A1 (en) 2012-10-12 2014-04-17 Bristol-Myers Squibb Company Guanidine and amine substituted tetrahydroisoquinoline compounds as factor xia inhibitors
SI2906551T1 (en) 2012-10-12 2018-05-31 Bristol-Myers Squibb Company Crystalline forms of a factor xia inhibitor
US9315519B2 (en) 2012-10-12 2016-04-19 Bristol-Myers Squibb Company Guanidine substituted tetrahydroisoquinoline compounds as factor XIa inhibitors
WO2014160668A1 (en) 2013-03-25 2014-10-02 Bristol-Myers Squibb Company Tetrahydroisoquinolines containing substituted azoles as factor xia inhibitors
JP6464176B2 (en) 2014-01-31 2019-02-06 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Macrocycles as factor XIA inhibitors with aromatic P2 'groups
NO2760821T3 (en) 2014-01-31 2018-03-10
JP6526796B2 (en) 2014-09-04 2019-06-05 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Diamide macrocycles that are FXIA inhibitors
US9453018B2 (en) 2014-10-01 2016-09-27 Bristol-Myers Squibb Company Pyrimidinones as factor XIa inhibitors

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5238922A (en) * 1991-09-30 1993-08-24 Merck & Co., Inc. Inhibitors of farnesyl protein transferase
US5326773A (en) * 1992-10-29 1994-07-05 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US5340828A (en) * 1991-09-30 1994-08-23 Merck & Co., Inc. Inhibitors of farnesyl protein transferase
US5504212A (en) * 1992-10-29 1996-04-02 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5238922A (en) * 1991-09-30 1993-08-24 Merck & Co., Inc. Inhibitors of farnesyl protein transferase
US5340828A (en) * 1991-09-30 1994-08-23 Merck & Co., Inc. Inhibitors of farnesyl protein transferase
US5326773A (en) * 1992-10-29 1994-07-05 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US5504212A (en) * 1992-10-29 1996-04-02 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CANCER RESEARCH, September 1989, Volume 49, BOS, "Ras Oncogenes in Human Cancer: A Review", pages 4682-4689. *
NATURAL MEDICINE, August 1995, Vol. 1, No. 8, KOHL et al., "Inhibition of Farnesyltransferase Induces Regression of Mammary and Salivary Carcinomas in Ras Transgenic Mice", pages 792-797. *
See also references of EP0837875A4 *

Also Published As

Publication number Publication date
WO1996034010A2 (en) 1996-10-31

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