Pharmaceutical compositions and methods of transporting compounds across biological membrane
First Claim
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1. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective amount of a compound having the formula:
- ##STR25## wherein A is O, OH, OR6, NR7 R8, N3, NHCOR7, OCOAr, O--CO--OR9, OCOR9, NHCH2 C6 H5, and in which Ar is phenyl or phenyl substituted with 1-3 groups selected from the group consisting of halogen, C1 -C12 alkyl or C1 -C3 alkoxy;
"a" is a single bond in the alpha or beta configuration with the proviso that when A=0, "a" is a double bond;
R5 is CO2 R10, CH2 OR9, CONH2, CONHR7, CONR7 R8, CO--S--R10, CH2 S(O)p --S--R10, CH2 NH2, CH2 NHR7, CH2 NR7 R8, CH2 --SO(O)p --S--R10 ;
R6 is a glycosyl moiety comprising 1-10 monosaccharide units in which the glycosidic linkage at the anomeric carbon of each monosaccharide unit is independently alpha or beta;
R7 and R8, independently are H, C1 -C4 alkyl, C3 -C7 cycloalkyl,C4 -C10 alkylcycloalkyl, phenyl, benzyl, or, taken together are (CH2)f, where f=3-6;
R9 is H, or C1 -C3 alkyl;
R10 is H, C1 -C10 alkyl, C1 -C10 alkenyl, C1 -C10 alkynyl, C6 H5 or CH2 C6 H5 ;
p is 0, 1 or 2;
n is 0, 1 or 2;
or a pharmaceutically suitable salt thereof.
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Abstract
Novel glycosylated steroid derivatives for facilitating the transport of compounds across biological membranes are disclosed. A novel process for efficient synthesis of these glycosylated steroid derivatives, using activated glycosyl sulfoxide intermediates is also provided.
111 Citations
73 Claims
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1. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective amount of a compound having the formula:
- ##STR25## wherein A is O, OH, OR6, NR7 R8, N3, NHCOR7, OCOAr, O--CO--OR9, OCOR9, NHCH2 C6 H5, and in which Ar is phenyl or phenyl substituted with 1-3 groups selected from the group consisting of halogen, C1 -C12 alkyl or C1 -C3 alkoxy;
"a" is a single bond in the alpha or beta configuration with the proviso that when A=0, "a" is a double bond; R5 is CO2 R10, CH2 OR9, CONH2, CONHR7, CONR7 R8, CO--S--R10, CH2 S(O)p --S--R10, CH2 NH2, CH2 NHR7, CH2 NR7 R8, CH2 --SO(O)p --S--R10 ; R6 is a glycosyl moiety comprising 1-10 monosaccharide units in which the glycosidic linkage at the anomeric carbon of each monosaccharide unit is independently alpha or beta; R7 and R8, independently are H, C1 -C4 alkyl, C3 -C7 cycloalkyl, C4 -C10 alkylcycloalkyl, phenyl, benzyl, or, taken together are (CH2)f, where f=3-6; R9 is H, or C1 -C3 alkyl; R10 is H, C1 -C10 alkyl, C1 -C10 alkenyl, C1 -C10 alkynyl, C6 H5 or CH2 C6 H5 ; p is 0, 1 or 2; n is 0, 1 or 2; or a pharmaceutically suitable salt thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 32)
- ##STR25## wherein A is O, OH, OR6, NR7 R8, N3, NHCOR7, OCOAr, O--CO--OR9, OCOR9, NHCH2 C6 H5, and in which Ar is phenyl or phenyl substituted with 1-3 groups selected from the group consisting of halogen, C1 -C12 alkyl or C1 -C3 alkoxy;
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15. A method of transporting a therapeutically significant compound across a biological membrane comprising contacting a biological membrane with a therapeutically significant compound in the presence of an effective amount of a second compound of the formula:
- ##STR26## in which A is O, OH, OR6, NR7 R8, N3, NHCOR7, OCOAr, O--CO--OR9, OCOR9, NHCH2 C6H5, and in which Ar is phenyl or phenyl substituted with 1-3 groups selected from the group consisting of halogen, C1 -C12 alkyl or C1 -C3 alkoxy;
"a" is a single bond in the alpha or beta configuration with the proviso that when A=0, "a" is a double bond; R5 is CO2 R10, CH2 OR9, CONH2, CONHR7, CONR7 R8, CO--S--R10, CH2 S(O)p --S--R10, CH2 NH2, CH2 NHR7, CH2 NR7 R8, CH2 --SO(O)p --S--R10 ; R6 is a glycosyl moiety comprising 1-10 monosaccharide units in which the glycosidic linkage at the anomeric carbon of each monosaccharide unit is independently alpha or beta; R7 and R8, independently are H, C1 -C4 alkyl, C3 -C7 cycloalkyl, C4 -C10 alkylcycloalkyl, phenyl, benzyl, or, taken together are (CH2)f, where f=3-6; R9 is H, or C1 -C3 alkyl; R10 is H, C1 -C10 alkyl, C1 -C10 alkenyl, C1 -C10 alkynyl, C6 H5 or CH2 C6 H5 ; p is 0, 1 or 2; n is 0, 1 or 2; or a pharmaceutically suitable salt thereof. - View Dependent Claims (16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 66, 67, 68, 69, 70, 71, 72, 73)
- ##STR26## in which A is O, OH, OR6, NR7 R8, N3, NHCOR7, OCOAr, O--CO--OR9, OCOR9, NHCH2 C6H5, and in which Ar is phenyl or phenyl substituted with 1-3 groups selected from the group consisting of halogen, C1 -C12 alkyl or C1 -C3 alkoxy;
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29. A pharmaceutical composition comprising:
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a) an effective amount of a compound of the formula;
##STR27## in which A is O, OH, OR6, NR7 R8, N3, NHCOR7, OCOAr, O--CO--OR9, OCOR9, NHCH2 C6 H5, and in which Ar is phenyl or phenyl substituted with 1-3 groups selected from the group consisting of halogen, C1 -C12 alkyl or C1 -C3 alkoxy;"a" is a single bond in the alpha or beta configuration with the proviso that when A=0, "a" is a double bond; R5 is CO2 R10, CH2 OR9, CONH2, CONHR7, CONR7 R8, CO--S--R10, CH2 S(O)p --S--R10, CH2 NH2, CH2 NHR7, CH2 NR7 R8, CH2 --SO(O)p --S--R10 ; R6 is a glycosyl moiety comprising 1-10 monosaccharide units in which the glycosidic linkage at the anomeric carbon of each monosaccharide unit is independently alpha or beta; R7 and R8, independently are H, C1 -C4 alkyl, C3 -C7 cycloalkyl, C4 -C10 alkylcycloalkyl, phenyl, benzyl, or, taken together are (CH2)f, where f=3-6; R9 is H, or C1 -C3 alkyl; R10 is H, C1 -C10 alkyl, C1 -C10 alkenyl, C1 -C10 alkynyl, C6 H5 or CH2 C6 H5 ; p is 0, 1 or 2; n is 0, 1 or 2; or a pharmaceutically suitable salt thereof; b) an effective amount of a therapeutically significant compound; and c) a pharmaceutically acceptable carrier. - View Dependent Claims (30, 31, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65)
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Current AssigneeThe Trustees of Princeton University (Princeton University)
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Original AssigneeThe Trustees of Princeton University (Princeton University)
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InventorsKahne, Daniel E., Kahne, Suzanne W.
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Primary Examiner(s)GRIFFIN, RONALD
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Application NumberUS08/224,862Time in Patent Office543 DaysField of Search536/5, 540/106, 514/26, 514/178, 514/182, 514/885, 424/451, 424/455, 424/456, 424/464US Class Current536/5CPC Class CodesA61K 31/575 substituted in position 17 ...A61K 31/70 Carbohydrates; Sugars; Deri...A61K 47/54 the modifying agent being a...A61K 47/549 Sugars, nucleosides, nucleo...A61P 31/04 Antibacterial agentsC07J 17/005 GlycosidesC07J 31/006 not covered by C07J31/003C07J 41/0005 the nitrogen atom being dir...C07J 41/0011 Unsubstituted amino radicalsC07J 41/0027 AzidesC07J 41/0061 one of the carbon atoms bei...C07J 43/003 not condensedC07J 51/00 Normal steroids with unmodi...C07J 9/005 containing a carboxylic fun...
