You’re using a public version of DrugPatentWatch with 5 free searches available | Register to unlock more free searches. CREATE FREE ACCOUNT

Last Updated: March 28, 2024

Details for Patent: 5,631,365


✉ Email this page to a colleague

« Back to Dashboard


Title: Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
Abstract:A process for preparing compounds of the formula ##STR1## wherein R and R.sup.2 are independently --OH, --O(lower alkyl) or --0-benzyl and the remaining variables are as defined in the specification, comprising (a) treating with a strong base in an anhydrous organic solvent a lactone of the formula ##STR2## respectively, wherein Ar.sup.10 is Ar.sup.1 or a suitably protected hydroxy- or amino-substituted aryl, and R' and R.sup.2' are R and R.sup.2 as defined above or are suitably protected hydroxy groups; (b) reacting a product of step (a) with an imine of the formula ##STR3## wherein Ar.sup.20 and Ar.sup.30 are Ar.sup.2 or Ar.sup.3 or suitably protected hydroxy- or amino-substituted aryl; c) quenching the reaction with an acid; and d) removing protecting groups as necssary.
Inventor(s): Rosenblum; Stuart B. (West Orange, NJ), Dugar; Sundeep (Bridgewater, NJ), Burnett; Duane A. (Fanwood, NJ), Clader; John W. (Cranford, NJ), McKittrick; Brian A. (Bloomfield, NJ)
Assignee: Schering Corporation (Kenilworth, NJ)
Filing Date:Jun 09, 1994
Application Number:08/257,593
Claims:1. A process for preparing a compound of the formula ##STR69## wherein: Ar.sup.1 and Ar.sup.2 are independently selected from the group consisting of aryl and R.sup.4 -substituted aryl;

Ar.sup.3 is aryl or R.sup.5 -substituted aryl;

X, Y and Z are independently selected from the group consisting of --CH.sub.2 --, --CH(lower alkyl)- and --C(dilower alkyl)-;

R is --OH, --O(lower alkyl) or --O-- benzyl:

R.sup.1 and R.sup.3 are independently selected from the group consisitng of hydrogen, lower alkyl and aryl;

q is 0 or 1; m and n are independently 0, 1, 2, 3 or 4, and p is 0, 1, 2, 3 or 4; provided that the sum of m, n, p and q is 1, 2, 3, 4, 5 or 6;

R.sup.4 is 1-5 substituents independently selected from the group consisting of lower alkyl, --OH, --O(lower alkyl), --O-benzyl, --NR .sup.6 R.sup.7, --COOR.sup.6, --CONR.sup.6 R.sup.7, --COR.sup.6, --SO.sub.2 NR.sup.6 R.sup.7, S(O).sub.0-2 R.sup.9, -(lower alkylene)COOR.sup.6, --CH.dbd.CH--COOR.sup.6, --CF.sub.3, --CN, --NO.sub.2 and halogen;

R.sup.5 is is 1-5 substituents independently selected from the group consisting of --OH, --O(lower alkyl), --O-benzyl, --NR.sup.6 R.sup.7, --COOR.sup.6, --CONR.sup.6 R.sup.7, --COR.sup.6, --SO.sub.2 NR.sup.6 R.sup.7, S(O).sub.0-2 R.sup.9, -(lower alkylene)-COOR.sup.6 and --CH.dbd.CH--COOR.sup.6 ;

R.sup.5, R.sup.7 and R.sup.8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and

R.sup.9 is lower alkyl, aryl or aryl-substituted lower alkyl, comprising:

(a) treating with a strong base in an anhydrous organic solvent a lactone of the formula ##STR70## wherein X, Y, Z, R', R.sup.3, m, n, p and q are as defined above, R' is R as defined above or a suitably protected hydroxy group, and Ar.sup.10 is Ar.sup.1 as defined above, a suitably protected hydroxy-substituted aryl or a suitably protected amino-substituted aryl;

(b) reacting the product of step (a) with an Imine of the formula ##STR71## wherein Ar.sup.20 is Ar.sup.2, a suitably protected hydroxy-substituted aryl or a suitably protected amino-substituted aryl, and Ar.sup.30 is Ar.sup.3, a suitably protected hydroxy-substituted aryl or a suitably protected amino-substituted aryl;

c) quenching the reaction with an acid; and

d) removing as necessary a protecting group from any of substituents R', Ar.sup.10, Ar.sup.20 and Ar.sup.30 to obtain a compound wherein R, Ar.sup.1, Ar.sup.2 and Ar.sup.3 are as defined above.

2. The process of claim 1 further comprising converting a compound as defined in claim 1 having a hydroxy substituent at R, or a hydroxy or amino substituent at any of Ar.sup.1, Ar.sup.2 and Ar.sup.3, to another compound of claim 1 wherein a hydroxy at R and at the carbon to which the R.sup.3 substituent is attached is converted to a --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9 or --O(CO)NR.sup.6 R.sup.7 group: or a hydroxy group at Ar.sup.1, Ar.sup.2 or Ar.sup.3 is converted to a --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9, --O(CH.sub.2).sub.1-5 OR.sup.6, --O(CO)NR.sup.6 R.sup.7, --O(CH.sub.2).sub.1-10 --COOR.sup.6 or --O(CH.sub.2).sub.1-10 CONR.sup.6 R.sup.7 group: or an amino group at Ar.sup.1, Ar.sup.2 or Ar.sup.3 is converted to a --NR.sup.6 R.sup.7, --NR.sup.6 (CO)R.sup.7, --NR.sup.6 (CO)OR.sup.9, --NR.sup.6 (CO)NR.sup.7 R.sup.8 or --NR.sup.6 SO.sub.2 R.sup.9 group.

3. A process for preparing a compound of the formula ##STR72## wherein: Ar.sup.1 and Ar.sup.2 are independently selected from the group consisting of aryl and R.sup.4 -substituted aryl:

Ar.sup.3 is aryl or R.sup.5 -substituted aryl;

X, Y and Z are independently selected from the group consisting of --CH.sub.2 --, --CH(lower alkyl)- and --C(dilower alkyl)-;

R.sup.2 is --OH, --O(lower alkyl) or --O-benzyl:

R.sup.1 and R.sup.3 are independently selected from the group consisitng of hydrogen, lower alkyl and aryl; Pl r is 0 or 1; m, n and p are independently 0, 1, 2, 3 or 4; provided that the sum of m, n. p and r is 1, 2, 3, 4, 5 or 6, and further provided that when r and n are each zero, p is 1, 2, 3 or 4;

R.sup.4 is 1-5 substituents independently selected from the group consisting of lower alkyl, --OH. --O(lower alkyl), --O-benzyl, --NR.sup.6 R.sup.7, --COOR.sup.6, --CONR.sup.6 R.sup.7, --COR.sup.6, --SO.sub.2 NR.sup.6 R.sup.7, S(O).sub.0-2 R.sup.9, -(lower alkylene)COOR.sup.6, --CH.dbd.CH--COOR.sup.6, --CF.sub.3, --CN, --NO.sub.2 and halogen;

R.sup.5 is is 1-5 substituents independently selected from the group consisting of --OH, --O(Iower alkyl), --O-benzyl --NR.sup.6 R.sup.7, --COOR.sup.6, --CONR.sup.6 R.sup.7, --COR.sup.6, --SO.sub.2 NR.sup.6 R.sup.7, S(O).sub.0-2 R.sup.9, -(lower alkylene)-COOR.sup.6 and --CH.dbd.CH--COOR.sup.6 ;

R.sup.6, R.sup.7 and R.sup.8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and

R.sup.9 is lower alkyl, aryl or aryl-substituted lower alkyl, comprising:

(a) treating with a strong base in an anhydrous organic solvent a lactone of the formula ##STR73## wherein X, Y, Z, R.sup.1, R.sup.3, m, n, r and p are as defined above, with the further proviso that if n and r are each zero, p is 1, 2, 3 or 4; Ar.sup.10 is Ar.sup.1 as defined above, a suitably protected hydroxy-substituted aryl or a suitably protected amino-substituted aryl; and R.sup.2' is R.sup.2 as defined above or a suitably protected hydroxy group;

(b) reacting the product of step (a) with an imine of the formula ##STR74## wherein Ar.sup.20 is Ar.sup.2, a suitably protected hydroxy-substituted aryl or a suitably protected amino-substituted aryl, and Ar.sup.30 is Ar.sup.3, a suitably protected hydroxy-substituted aryl or a suitably protected amino-substituted aryl;

c) quenching the reaction with an acid; and

d) removing as necessary a protecting group from any of substituents R.sup.2', Ar.sup.10, Ar.sup.20 and Ar.sup.30 to obtain a compound wherein R, Ar.sup.1, Ar.sup.2 and Ar.sup.3 are as defined above.

4. The process of claim 3 further comprising converting a compound as defined in claim 3 having a hydroxy substituent at R.sup.2, or a hydroxy or amino substituent at any of Ar.sup.1, Ar.sup.2 and Ar.sup.3, to another compound of claim 1 wherein a hydroxy at R.sup.2 and at the carbon to which the R.sup.1 substituent is attached is converted to a --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9 or --O(CO)NR.sup.6 R.sup.7 group; or a hydroxy group at Ar.sup.1, Ar.sup.2 or Ar.sup.3 is converted to a --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9, --O(CH.sub.2).sub.1-5 OR.sup.6, --O(CO)NR.sup.6 R.sup.7, --O(CH.sub.2).sub.1-10 --COOR.sup.6 or --O(CH.sub.2).sub.1-10CONR.sup.6 R.sup.7 group; or an amino group at Ar.sup.1, Ar.sup.2 Ar.sup.3 is converted to a --NR.sup.6 R.sup.7, --NR.sup.6 (CO)R.sup.7, --NR.sup.6 (CO)OR.sup.9, --NR.sup.6 (CO)NR.sup.7 R.sup.8 or --NR.sup.6 SO.sub.2 R.sup.9 group.

Make Better Decisions: Try a trial or see plans & pricing

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.