US 5,631,401 AGranted

Inhibitors of protein farnesyltransferase and squalene synthase

AssigneeAbbott Laboratories

InventorsHerman H. Stein, William R. Baker, Anthony K. L. Fung, Saul H. Rosenberg, Todd W. Rockway, Stephen A. Fakhoury, David S. Garvey, B. Gregory Donner, William J. McClellan, Stephen J. O'Connor, Rajnandan Prasad, Wang Shen, Gerard M. Sullivan

Life of this patent

Estimating the term…

patentgrep

Loading patent…

Abstract

The present invention provides a compound of the formula ##STR1## or a pharmaceutically acceptable salt thereof, which are useful in inhibiting protein farnesyltransferase and the farnesylation of the oncogene protein Ras or inhibiting de novo squalene production resulting in the inhibition of cholesterol biosynthesis, processes for the preparation of the compounds of the invention in addition to intermediates useful in these processes, a pharmaceutical composition, and to methods of using such compounds.

Claims14

Dependent claims

A compound of the formula ##STR49## wherein A.sub.1 and A.sub.2 are independently --C(O)NR.sub.1 R.sub.2 wherein

R.sub.1 at each occurrence is independently selected from
(i) hydrogen,
(ii) loweralkyl,
(iii) cycloalkyl,
(iv) cycloalkylalkyl,
(v) aryl,
(vi) arylalkyl,
(vii) alkenyl,
(viii) alkynyl,
(ix) carboxyalkyl,
(x) heterocyclicalkyl,
(xi) aryloxyarylalkyl,
(xii) aryloxyalkyl,
(xiii) arylalkyl substituted arlyalkyl,
(xiv) arylalkoxyarylalkyl,
(xv) arylalkoxyaryl, and
R.sub.2 at each occurrence is independently selected from
(i) aryl,
(ii) arylalkyl,
(iii) alkenyl,
(iv) alkynyl,
(v) arylalkenyl,
(vi) arylalkynyl,
(vii) heterocyclicalkyl,
(viii) aryloxyalkyl,
(ix) arylalkyl wherein the alkyl group is substituted with --OR.sub.10 wherein R.sub.10 is hydrogen or alkanoyl and
(x) aryl, arylalkyl or heterocyclicalkyl wherein the aryl group, the aryl part of the arylalkyl group or the heterocyclic part of the heterocyclicalkyl group is substituted with --Y--R.sub.3 wherein at each occurrence Y is independently selected from
(a) a covalent bond,
(b) --C(O)--,
(c) --CH.sub.2 --,
(d) --O--,
(e) --S--,
(f) --NH--,
(g) --CH.sub.2 O--,
and at each occurrence R.sub.3 is independently selected from
(a) aryl,
(b) arylalkyl,
(c) cycloalkyl,
(d) cycloalkylalkyl,
(e) heterocyclic and
(f) (heterocyclic)alkyl,
or R.sub.1 and R.sub.2 taken together with the nitrogen atom to which they are attached form a nitrogen-containing heterocycle;
B.sub.1 and B.sub.2 are independently --C(O)--OR.sub.7 wherein at each occurrence R.sub.7 is independently selected from hydrogen and a carboxy protecting group;
or a pharmaceutically acceptable salt thereof.

41 more elements

A compound of the formula ##STR50## wherein A.sub.1 and A.sub.2 are independently--C(O)NR.sub.1 R.sub.2 wherein

R.sub.1 at each occurrence is independently selected from
(i) hydrogen,
(ii) loweralkyl,
(iii) cycloalkyl,
(iv) cycloalkylalkyl,
(v) aryl,
(vi) arylalkyl,
(vii) alkenyl,
(viii) alkynyl,
(ix) carboxyalkyl,
(x) heterocyclicalkyl,
(xii) aryloxyarylalkyl,
(xiii) arylalkyl substituted arylalkyl,
(xiv) aryloxyaryl,
(xv) arylalkoxyarylalkyl,
(xvi) arylalkoxyaryl, and
R.sub.2 at each occurrence is independently selected from
(i) aryl,
(ii) arylalkyl,
(iii) alkenyl,
(iv) alkynyl,
(v) arylalkenyl,
(vi) arylalkynyl,
(vii) heterocyclicalkyl,
(viii) aryloxyalkyl,
(ix) arylalkyl wherein the alkyl group is substituted with --OR.sub.10 wherein R.sub.10 is hydrogen or alkanoyl and (x) aryl, arylalkyl or heterocyclicalkyl wherein the aryl group, the aryl part of the arylalkyl group or the heterocyclic part of the heterocyclicalkyl group is substituted with --Y--R.sub.3 wherein at each occurrence Y is independently selected from
(a) a covalent bond,
(b) --C(O)--,
(c) --CH.sub.2 --,
(d) --O--,
(e) --S--,
(f) --NH--,
(g) --CH.sub.2 O--, and
at each occurrence R.sub.3 is independently selected from
(a) aryl,
(b) arylalkyl,
(c) cycloalkyl,
(d) cycloalkylalkyl,
(e) heterocyclic and
(f) (heterocyclic)alkyl, or
R.sub.1 and R.sub.2 taken together with the nitrogen atom to which they are attached form a nitrogen-containing heterocycle;
B.sub.1 and B.sub.2 are independently --C(O)--OR.sub.7 wherein at each occurrence
R.sub.7 is independently selected from hydrogen and a carboxy protecting group;
or a pharmaceutically acceptable salt thereof.

41 more elements

A compound selected from the group consisting of:

(1.alpha.,2.beta.,3.beta.,4.alpha.)-1,3-Di[N-benzyl-N-(4-phenoxybenzyl)-ami nocarbonyl]cyclobutane-2,4-dicarboxylic acid;
(1.alpha.,2.beta.,3.beta.,4.alpha.)-1,3-Di[N-ethyl-N-(4-phenoxybenzyl)-amin ocarbonyl]cyclobutane-2,4-dicarboxylic acid;
(1.alpha.,2.beta.,3.beta.,4.alpha.)-1,3-Di[N-methyl-N-(3-phenoxybenzyl)-ami nocarbonyl]cyclobutane-2,4-dicarboxylic acid;
(1.alpha.,2.beta.,3.beta.,4.alpha.)-1,3-Di[N-methyl-N-(3-(4-fluorophenoxy)b enzyl)-aminocarbonyl]cyclobutane-2,4-dicarboxylic acid;
(1.alpha.,2.beta.,3.beta.,4.alpha.)-1,3-Di[N-propyl-N-(4-benzylbenzyl)-amin ocarbonyl]cyclobutane-2,4-dicarboxylic acid;
(1.alpha.,2.beta.,3.beta.,4.alpha.)-1,3-Di[N-(n-butyl)-N-(4-phenoxybenzyl)- aminocarbonyl]cyclobutane-2,4-dicarboxylic acid;
(1.alpha.,2.beta.,3.beta.,4.alpha.)-1,3-Di[N-cyclopropyl-N-(4-phenoxybenzyl )-aminocarbonyl]cyclobutane-2,4-dicarboxylic acid;
(1.alpha.,2.beta.,3.beta.,4.alpha.)-1,3-Di[N,N-dibenzylaminocarbonyl]cyclob utane-2,4-dicarboxylic acid;
(1.alpha.,2.beta.,3.beta.,4.alpha.)-1,3-Di[N-propyl-N-(5-phenylpentyl)-amin ocarbonyl]cyclobutane-2,4-dicarboxylic acid;
(1.alpha.,2.beta.,3.beta.,4.alpha.)-1-[N-Propyl-N-(4-phenoxybenzyl)-aminoca rbonyl]-3-[N-benzyl-N-(4-phenoxybenzyl)aminocarbonyl]cyclobutane-2,4-dicarb oxylic acid;
(1.alpha.,2.beta.,3.beta.,4.alpha.)-1,3-Di[N-carboxymethyl-N-(4-phenoxybenz yl)-aminocarbonyl]cyclobutane-2,4-dicarboxylic acid;
(1.alpha.,2.beta.,3.beta.,4.alpha.)-1,3-Di[N-propyl-N-(4-phenoxymethylbenzy l)-aminocarbonyl]-2,4-cyclobutanedicarboxylic acid;
(1.alpha.,2.beta.,3.beta.,4.alpha.)-1,3-Di[N-(furan-2-ylmethyl)-N-(4-phenox ybenzyl)-aminocarbonyl]cyclobutane-2,4-dicarboxylic acid;
(1.alpha.,2.beta.,3.beta.,4.alpha.)-1,3-Di[N-(thien-2-ylmethyl)-N-(4-phenox ybenzyl)-aminocarbonyl]cyclobutane-2,4-dicarboxylic acid;
(1.alpha.,2.beta.,3.beta.,4.alpha.)-1,3-Di [N-benzyl-N-{syn-(4-acetoxy-5-methyl)-6-phenylhexyl}aminocarbonyl]cyclobut ane-2,4-dicarboxylic acid;
(1.alpha.,2.beta.,3.beta.,4.alpha.)-1,3-Di[N-benzyl-N-((2R)-5-phenyl-2-meth ylpentyl)-aminocarbonyl]cyclobutane-2,4-dicarboxylic acid;
(1.alpha.,2.beta.,3.beta.,4.alpha.)-1,3-Di [N-benzyl-N-{(E)-(2R)-2-methyl-5-phenyl-4-pentenyl}aminocarbonyl]cyclobuta ne-2,4-dicarboxylic acid;
(1.alpha.,2.beta.,3.beta.,4.alpha.)-1,3-Di[N-(S)-.alpha.-Methylbenzyl-N-(4- phenoxybenzyl)-aminocarbonyl]cyclobutane-2,4-dicarboxylic acid;
(1.alpha.,2.beta.,3.beta.,4.alpha.)-1,3-Di[4-(4-phenoxyphenyl)-1,2,3,6-tetr ahydropyridin-1-ylcarbonyl]cyclobutane-2,4-dicarboxylic acid;
and
(1.alpha.,2.beta.,3.beta.,4.alpha.)-1,3-Di[N-(4-fluorobenzyl)-N-(4-phenoxyb enzyl)-aminocarbonyl]cyclobutane-2,4-dicarboxylic acid;
or a pharmaceutically acceptable salt thereof.

19 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/378,334Filed 24 Jan 1995 · continuation in part
Priority: 9 Feb 1994
Granted: 20 May 1997
Term ends: Not estimatedThe source records don’t support an estimate.

Classification23 codes

C07D 295/135
Substituted by singly or doubly bound nitrogen atoms: with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic…
C07C 233/58
Having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings: having the nitrogen atoms of the…
C07C 233/59
Having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings: having the nitrogen atom of at…
C07C 233/60
Having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings: having the nitrogen atom of at…