Antidiabetic alpha-substituted phosphonates
First Claim
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1. A compound selected from those of the formula:
- ##STR107## wherein A is selected from the group consisting of C1 -C4 alkylene and C2 to C4 hydroxyalkylene;
B is selected from the group consisting of C1 to C4 alkylene and C2 to C4 hydroxyalkylene in which the carbon atom of the alkylene moiety or the hydroxyalkylene moiety which is adjacent to the phosphorous atom is mono- or disubstituted with a substituent selected from the group consisting of halogen, hydroxy, and C1 to C4 alkoxy;
R1 is selected from the group consisting of hydrogen, C1 to C4 alkyl, C1 to C4 hydroxyalkyl, C2 to C4 dihydroxyalkyl, C3 or C4 trihydroxyalkyl and C4 tetrahydroxyalkyl;
R'"'"', R", R"'"'"' and R"" are selected independently from the group consisting of hydrogen, C1 to C18 alkyl, C3 to C6 cycloalkyl, phenyl, C3 to C8 isoalkyl, Cl3 CCH2 --, CH2 CH═
CH2 --, ZCH2 CHh2 -- [where Z is SO2 R2, SR2, OR2, or Si(R2)3, and R2 is C1 to C3 alkyl], ##STR108## [where R3 is C1 to C3 alkyl and R3 -R3 is alkylene or acetal], ##STR109## (where R4 is hydrogen or methyl), ##STR110## [where, when R5 ═
R6, they are both hydrogen, fluoro or C1 -C4 alkyl, R5 is hydrogen, R6 is fluoro, oxy or OR7 [where R7 is C1 to C6 alkyl, C3 to C6 cycloalkyl or aryl]], ##STR111## [where R8 is hydrogen or C1 to C18 alkyl], ##STR112## phenylmethyl, substituted phenylmethyl wherein the substituents are selected from C1 to C18 alkyl, C1 to C6 alkoxy, NO2 and halogen, and mono- and disubstituted phenyl wherein the substituents are selected from C1 to C18 alkyl, C1 to C6 alkoxy, NO2 and halogen; and
, when any one or more of R'"'"', R", R"'"'"' or R"" are hydrogen, the pharmacologically acceptable salts thereof.
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Abstract
Alpha-substituted phosphonates are disclosed which stimulate the enzyme fructose-1,6-bisphosphatase and inhibit the enzyme 6-phosphofructo-1-kinase, thereby lowering glucose levels in mammals. These alpha-substituted phosphonates may thus be used to treat hyperglycemia and/or diabetes. Processes for the synthesis of the alpha-substituted phosphonates are also disclosed.
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Citations
29 Claims
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1. A compound selected from those of the formula:
- ##STR107## wherein A is selected from the group consisting of C1 -C4 alkylene and C2 to C4 hydroxyalkylene;
B is selected from the group consisting of C1 to C4 alkylene and C2 to C4 hydroxyalkylene in which the carbon atom of the alkylene moiety or the hydroxyalkylene moiety which is adjacent to the phosphorous atom is mono- or disubstituted with a substituent selected from the group consisting of halogen, hydroxy, and C1 to C4 alkoxy;
R1 is selected from the group consisting of hydrogen, C1 to C4 alkyl, C1 to C4 hydroxyalkyl, C2 to C4 dihydroxyalkyl, C3 or C4 trihydroxyalkyl and C4 tetrahydroxyalkyl;
R'"'"', R", R"'"'"' and R"" are selected independently from the group consisting of hydrogen, C1 to C18 alkyl, C3 to C6 cycloalkyl, phenyl, C3 to C8 isoalkyl, Cl3 CCH2 --, CH2 CH═
CH2 --, ZCH2 CHh2 -- [where Z is SO2 R2, SR2, OR2, or Si(R2)3, and R2 is C1 to C3 alkyl], ##STR108## [where R3 is C1 to C3 alkyl and R3 -R3 is alkylene or acetal], ##STR109## (where R4 is hydrogen or methyl), ##STR110## [where, when R5 ═
R6, they are both hydrogen, fluoro or C1 -C4 alkyl, R5 is hydrogen, R6 is fluoro, oxy or OR7 [where R7 is C1 to C6 alkyl, C3 to C6 cycloalkyl or aryl]], ##STR111## [where R8 is hydrogen or C1 to C18 alkyl], ##STR112## phenylmethyl, substituted phenylmethyl wherein the substituents are selected from C1 to C18 alkyl, C1 to C6 alkoxy, NO2 and halogen, and mono- and disubstituted phenyl wherein the substituents are selected from C1 to C18 alkyl, C1 to C6 alkoxy, NO2 and halogen; and
, when any one or more of R'"'"', R", R"'"'"' or R"" are hydrogen, the pharmacologically acceptable salts thereof. - 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, 26, 27, 28, 29)
- ##STR107## wherein A is selected from the group consisting of C1 -C4 alkylene and C2 to C4 hydroxyalkylene;
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25. A compound selected from those of the formula:
- ##STR113## wherein A is selected from the group consisting of C1 to C4 alkylene and C2 to C4 hydroxyalkylene;
R'"'"', R", R"'"'"' and R"" are selected independently from the group consisting of hydrogen, C1 to C18 alkyl, C3 to C6 cycloalkyl, phenyl, C3 to C8 isoalkyl, Cl3 CCH2 --, CH2 CH═
CH2 --, ZCH2 CH2 --, [where Z is SO2 R2, SR2, OR2, or Si(R2)3,and R2 is C1 -C3 alkyl], ##STR114## [where R3 is C1 to C3 alkyl and R3 -R3 is alkylene or acetal], ##STR115## (where R4 is hydrogen or methyl), ##STR116## [where, when R5 ═
R6 they are both hydrogen, fluoro or C1 -C4 alkyl, R5 is hydrogen, R6 is fluoro, hydroxy or OR7 [where R7 is C1 -C6 alkyl, C3 to C6 cycloalkyl or aryl]], ##STR117## [where R8 is hydrogen or C1 to C18 alkyl], ##STR118## phenylmethyl, substituted phenylmethyl wherein the substituents are selected from C1 to C18 alkyl, C1 to C6 alkoxy, NO2 and halogen and mono- and disubstituted phenyl wherein the substituents are selected from C1 to C18 alkyl, C1 to C6 alkoxy, NO2 and halogen;
X and Y are selected independently from the group consisting of hydrogen, halogen, hydroxy and C1 to C4 alkoxy; and
, when any one or more of R'"'"', R", R"'"'"' or R"" are hydrogen, the pharmacologically acceptable salts thereof.
- ##STR113## wherein A is selected from the group consisting of C1 to C4 alkylene and C2 to C4 hydroxyalkylene;
Specification
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Current AssigneeAmerican Cyanamid Co (Pfizer Inc.)
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Original AssigneeAmerican Cyanamid Co (Pfizer Inc.)
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InventorsAyral-Kaloustian, Semiramis, Floyd, Middleton B. Jr., Claus, Thomas H., DeVries, Vern G.
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Primary Examiner(s)Griffin, Ronald W.
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Application NumberUS07/232,331Time in Patent Office711 DaysField of Search536/117, 514/24, 514/25US Class Current536/117CPC Class CodesA61P 3/08 for glucose homeostasis pan...A61P 3/10 for hyperglycaemia, e.g. an...A61P 43/00 Drugs for specific purposes...C07F 9/65515 the oxygen atom being part ...C07H 11/04 Phosphates; Phosphites; Pol...
