Claims
- 1. A compound of Formula (I): wherein:R1 is —X(CH2)nAr′, dihydrobenzofuranyl, benzodioxanyl, cyclohexyl or C1-4alkyl, wherein Ar′ is a moiety of formula (a) or (b); wherein A is C═O, or (C(R6)2)m; and B is —CH2— or —O—; R2 is a moiety of fornula (a) or (b); P1 is —X(CH2)nRg; P2 is hydrogen or C1-4alkyl, R6 is independently hydrogen or C1-10alkyl; R7 is independently hydrogen, C1-4alkyl, C2-10alkenyl or C2-8alkynyl, all of which may be unsubstituted or substituted by one or morc OH, N(R6)2, CO2R12, Br, Cl, F, I, or XC1-5alkyl; or R7 is (CH2)nAr; R8 is hydrogen, R11, CO2R7, CO2C(R11)2O(CO)XR7, PO3(R7)2, SO2NR7R11, N7SO2R11,CONR7SO2R11, SO3R7, SO2RR7, P(O)(OR7)R7, CN, —CO2(CH2)mC(O)N(R6)2, C(R11)2N(R7)2, C(O)N(R6)2, tetrazole or OR6; R9 is a bond, C1-10alkylene, C2-10alkenylene, C1-10alkylidene, C2-10aldkynylene, all of which may be linear or branched, or R9 is phenylene, all of which may be unsubstituted or substituted by one or more OH, N(R6)2, COOH or halogen; R10 is hydrogen; R11 is hydrogen, Ar, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, all of whiich may be unsubstituted or substituted by one or more OH, CH2OH, N(R6)2′Br, Cl, I, or F; R12 is hydrogen, C1-6alkyl, C2-6alkenyl or C2-7alkynyl; R13 is divalent Ar, C1-10alkylene, C1-10alkylidene, C2-10alkenylene, C2-10alkynylene, all of which may be unsubstltuted or substituted by one or two OH, CH2OH, N(R6)2 Br, Cl, I, or F; X is (CH2)n or O; Y is CH3 or X(CH2)nAr; Ar is naplthyl, indolyl, pyridyl, thienyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyll imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, prolyl, or pyrimidyl; all of which may be unsubstituted or substituted by one or two OH, C1-5alkoxy, I, Br, F, Cl, —OC1-4alkylphenyl, R13CO2R7, C1-4alkyl, —N(R)6)2, —NH(CO)CH3, —X(CH2)nRg, —X—R9—Y, pyridyl, phenyl or S(O)qCl5alkyl, provided that when R13, R8 pr Y are Ar, the Ar is not substituted by another Ar which is further substituted by an yet another Ar; Z1, Z2 and Z3 are independently hydrogen, OH, C1-8alkoxy, S(O)qC1-8alkyl, N(R6)2, Br, F, I, Cl, NHCOR6, —X—R9—Y, —X(CH2)nR8; or Z1 and Z2 together may be —O—A—O— on contiguous carbons; q is zero, onc or two; n is an integer from 0 to six; m is 1, 2 or 3; or a pharmaceutically acceptable salt thereof; provided that when Z1, Z2, or Z3 is X(CH2)nR8, n is not 0 when X is oxygcn and R8 is OR6 or CO2H; and P1 is not CO2H, C(R6)2COOH or tetrazole wien P2 is hydrogen and Ar is pyridyl.
- 2. A compound of claim 1 wherein Ar is substituted by —X(CH2)nR8 or R13CO2R7, Z1 and Z3 are hydrogen and Z2 is hydrogen, OH, C1l5alkoxy, Br, Cl, F, I, X(CH2)nR8, NH2, benzyl, or NH(CO)CH3, or Z1 and Z2 together may be O—A—O on contiguous carbons.
- 3. A compound of claim 1 wherein R1 is a moiety of formula (b); A is CH2, B is —O—; R1 and XR2 are trans to P1; Z2 is hydrogen, OH, or C1-5alkoxy, Z1 is hydrogen; Ar is substituted by XAr, X(CH2)nCO2H, X(CH2)nCONR7SO2R11, X(CH2))OR6or CH═CHCO2H, and P1 is CO2H or CH2CO2H.
- 4. A compound of claim 1 wherein R1 is (b) and R2 is (a); A is CH2, B is —O—; R1 and XR2 are trans to P1; X is a bond; Z1 and Z3 are hydrogen; Z2 is hydrogen, OH, or C1-5alkoxy; Ar is substituted by X(CH2)nCONR7SO2R11, OAr or OCH2Ar (where Ar is (a), (b) or pyridyl and A is CH2 and B is —O— and Ar may be substituted by CO2H, O(CH2)11-3CO2H, —O(CH2)1-3CONHSO2R11, (CH2)0-4CO2H, (CH2)0-3CONH—SO2R11, O((CR6)2)2-4OH or C1-2alkoxy, and P1 is CO2H or CH2CO2H.
- 5. A process for the preparation of a comporid of formula (I) of claim 1 or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (II) wherein Z1, Z2, Z3 and R1 are as described in claim 1 or a group convertible thereto, and X is alkyl, with an organomargnesiumn compound of formula (III)R2—(CH2)n—MgBr (III) wherein R2 is as described in claim 1 or a group convertible thereto, in a suitable solvent to provide a compound of formula (IV) which is reduced and thereafter, when desired or necessary undergoes,a) alkylation or acylation to give compounds wherein P1 is other than CO2H; and/or b) conversion R1, R2, Z1, Z2 and Z3; to afford a compound of formula (I).
Parent Case Info
This is a divisional of application Ser. No. 09/099,373, filed Jun. 18, 1998, now U.S. Pat. No. 6,087,389; which is a divisional of application Ser. No. 08/336,444, filed Nov. 9, 1994, now U.S. Pat. No. 5,817,693; which is a continuation-in-part of International Application PCT/US94/04603, filed, Apr. 26, 1994; which is a continuation-in-part of application Ser. No. 08/066,818, filed Apr. 27, 1993 (now abandoned); which is a continuation-in-part of International Application PCT/US92/09427, filed Oct. 29, 1992; which is a continuation-in-part of Ser. No. 07/854,195 filed Mar. 20, 1992 (now abandoned), which is a continuation-in-part of Ser. No. 07/787,870 filed Nov. 5, 1991 (now abandoned).
US Referenced Citations (3)
| Number |
Name |
Date |
Kind |
|
3642785 |
Shen et al. |
Feb 1972 |
|
|
3737455 |
Shen et al. |
Jun 1973 |
|
|
5817693 |
Cousins et al. |
Oct 1998 |
|
Foreign Referenced Citations (2)
| Number |
Date |
Country |
| 206241 |
Dec 1986 |
EP |
| WO 9308799 |
May 1993 |
WO |
Non-Patent Literature Citations (5)
| Entry |
| Yamamara et al., Bull. Chem. Soc. Japan, 59, 3699 (1986). |
| Komendantov et al., C.A., 88:190,677p (1978). |
| Ihara et al., Biochem & Biophys Res. Comm., 178(1), 132-137 (1991). |
| Miyata et al., Journal of Antibiotics, 45(7), 1041-1046 (1992). |
| Koelsch, J. Org. Chem, 25, 2088 (1960). |
Continuation in Parts (5)
|
Number |
Date |
Country |
| Parent |
PCT/US94/04603 |
Apr 1994 |
US |
| Child |
08/336444 |
|
US |
| Parent |
08/066818 |
Apr 1993 |
US |
| Child |
PCT/US94/04603 |
|
US |
| Parent |
PCT/US92/09427 |
Oct 1992 |
US |
| Child |
08/066818 |
|
US |
| Parent |
07/854195 |
Mar 1992 |
US |
| Child |
PCT/US92/09427 |
|
US |
| Parent |
07/787870 |
Nov 1991 |
US |
| Child |
07/854195 |
|
US |
Patent Grant
6274737
