Bisphosphonate squalene synthetase inhibitors and method
First Claim
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1. A compound having the structure ##STR86## wherein R1, R2, R3 and R4 are the same or different and are H, lower alkyl, a metal ion or a prodrug ester;
- R5 is H, halogen or lower alkyl;
Z is alkenyl group contains at least 7 carbon atoms in the chain and from 1 to 4 double bonds;
aklynyl containing 1 to 4 triple bonds;
mixed alkenyl-alkynyl containing 1 to 3 double bonds and 1 to 3 triple bonds, and wherien alkenyl and/or alkynyl may be substituted or unsubstituted; and
wherein alkenyl and/or alkynyl may optionally include a (CH2)x group, wherein x is 1 to 15, which is linked to the carbon joining the two phosphorus moieties; and
wherein stubsituted alkenyl and substituted alkynyl refer to such groups substituted with alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, alkenyloxy, alkynyloxy, aryl and/or cycloalkyl, provided that if Z is an alkenyl group and contains only one carbon-carbon double bond, then it must be substituted with at least one group other than an alkyl group;
or a group of the structure ##STR87## wherein (CH2)p contains from 1 to 15 carbons in the chain and may include 0, 1, 2 or 3 triple bonds in the normal chain and/or may include 0, 1, 2 or 3 substituents which are alkyl, alkenyl, alkoxy, alkynyl, hydroxy and/or halogen; and
R6, R7 and R8 are the same or different and are H, alkyl containing 1 to 40 carbons, alkoxy containing 1 to 40 carbons, alkenyl containing 2 to 40 carbons, alkenyloxy containg 2 to 40 carbons, alkynyl containing 2 to 40 carbons, alkynyloxy, aryloxy, hydroxy, halogen, nitro, amino, thiol, alkylthio, arylthio, arylsulfinyl, alkylsulfinyl, arylsulfonyl, alkylsulfonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyl, arylcarbonylamino or alkylcarbonylamino, at least one or R6, R7 and R8 being alkenyl, alkenyloxy, alkynyl or alkynyloxy, and wherein the total number of carbons in ##STR88## exceeds 10 carbons, wherein the prodrug ester is (1-alkanoyloxy)-alkyl, ##STR89## wherein R14 is H, CH3, C6 H5 ;
or R1 and R2, and/or R3 and R4 can be taken together as in ##STR90## wherein R11 and R12 are H, alkyl, aryl, or arylalkyl and n is 0 to 3.
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Abstract
Compounds which are inhibitors of cholesterol biosynthesis (by inhibiting de novo squalene biosynthesis), and thus are useful as hypocholesterolemic agents and antiatherosclerotic agents are provided which have the structure ##STR1## and analogs thereof, wherein R1, R2, R3 and R4 are the same or different and are H, lower alkyl, a metal ion or a prodrug ester;
R5 is H, halogen or lower alkyl;
Zq is substituted alkenyl, substituted alkynyl, mixed alkenyl-alkynyl or substituted phenylalkyl or, phenylalkenyl or phenylalkynyl, or alkyl, including all stereoisomers thereof.
New methods for using such compounds to inhibit cholesterol biosynthesis are also provided.
134 Citations
24 Claims
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1. A compound having the structure ##STR86## wherein R1, R2, R3 and R4 are the same or different and are H, lower alkyl, a metal ion or a prodrug ester;
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R5 is H, halogen or lower alkyl; Z is alkenyl group contains at least 7 carbon atoms in the chain and from 1 to 4 double bonds;
aklynyl containing 1 to 4 triple bonds;
mixed alkenyl-alkynyl containing 1 to 3 double bonds and 1 to 3 triple bonds, and wherien alkenyl and/or alkynyl may be substituted or unsubstituted; and
wherein alkenyl and/or alkynyl may optionally include a (CH2)x group, wherein x is 1 to 15, which is linked to the carbon joining the two phosphorus moieties; and
wherein stubsituted alkenyl and substituted alkynyl refer to such groups substituted with alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, alkenyloxy, alkynyloxy, aryl and/or cycloalkyl, provided that if Z is an alkenyl group and contains only one carbon-carbon double bond, then it must be substituted with at least one group other than an alkyl group;
or a group of the structure ##STR87## wherein (CH2)p contains from 1 to 15 carbons in the chain and may include 0, 1, 2 or 3 triple bonds in the normal chain and/or may include 0, 1, 2 or 3 substituents which are alkyl, alkenyl, alkoxy, alkynyl, hydroxy and/or halogen; and
R6, R7 and R8 are the same or different and are H, alkyl containing 1 to 40 carbons, alkoxy containing 1 to 40 carbons, alkenyl containing 2 to 40 carbons, alkenyloxy containg 2 to 40 carbons, alkynyl containing 2 to 40 carbons, alkynyloxy, aryloxy, hydroxy, halogen, nitro, amino, thiol, alkylthio, arylthio, arylsulfinyl, alkylsulfinyl, arylsulfonyl, alkylsulfonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyl, arylcarbonylamino or alkylcarbonylamino, at least one or R6, R7 and R8 being alkenyl, alkenyloxy, alkynyl or alkynyloxy, and wherein the total number of carbons in ##STR88## exceeds 10 carbons, wherein the prodrug ester is (1-alkanoyloxy)-alkyl, ##STR89## wherein R14 is H, CH3, C6 H5 ;
or R1 and R2, and/or R3 and R4 can be taken together as in ##STR90## wherein R11 and R12 are H, alkyl, aryl, or arylalkyl and n is 0 to 3. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)
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Current AssigneeE R Squibb & Sons Incorporated
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Original AssigneeE R Squibb & Sons Incorporated
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InventorsMagnin, David R., Biller, Scott A.
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Primary Examiner(s)Lee, Mary C.
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Assistant Examiner(s)AMBROSE, MICHAEL GEORGE
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Application NumberUS07/699,429Time in Patent Office526 DaysField of Search558/155, 558/161, 514/107, 514/108, 562/21US Class Current514/107CPC Class CodesA61P 3/06 AntihyperlipidemicsA61P 9/10 for treating ischaemic or a...C07F 9/3839 Polyphosphonic acidsC07F 9/4025 Esters of poly(thio)phospho...
