Claims for Patent: 6,211,233

Summary for Patent: 6,211,233

Title:	Prostaglandin pharmaceutical compositions
Abstract:	Compounds of the general formula A—X1—NO2, or their pharmaceutical compositions, wherein A contains a prostaglandin residue, X1 is a bivalent connecting bridge.
Inventor(s):	Piero del Soldato
Assignee:	Nicox SA
Application Number:	US09/423,286
Patent Claims:	1. Compounds of the formula A—X1—NO2 (I) wherein A is R(CRaRbO)u(COX)t (II) wherein t and u are integers and are equal to 0 or 1; X═O, NH, NR1c wherein R1c is a linear or branched alkyl having form 1 to 10 carbon atoms; Ra and Rb are equal to or different from each other and are H, or a C1-C3 alkyl radical and R is a radical having the following formula: wherein m0 is an integer having a value of 0 or 1; and when t=1, u=0 and m0=1: R1=H; an alkyl having from 1 to 6 carbon atoms or a free valance; R2=OH, O— such as to form with R1 when R1 is a free valance, and with the carbon atom at position 15 a C═O group; R3 and R4 are equal to or different from one another and are equal to R1 or one of them is a bond O—, and the other is a free valance so that with the carbon atom C6 they form a C═O group; R5 and R6 are equal to or different from one another, and are equal to R1 when both R5 and R3 are each a free valence, R5 and R3 form a double bond between C5 and C6; R7, R8, R9, and R10 are equal to or different from each other, and have the same meaning as R1; when R7 or R9, and at the same time R8 or R10 are each a free valence, there is a double bond between C13 and C14; R11=R1; R12=R11 or OH; R13, R14, R15, and R16 are equal to or different from each other, and are equal to R1; when R13 or R15, and at the same time R14 or R16, are each a free valence, there is a double bond between C3 and C2; R17 and R18 are equal to or different from each other and are equal to R1; R19 and R20 are equal to or different from each other and are equal to R1; when R6 or R5 is a free valence, and R19 or R20 is a free valence, there is a double bond between C4 and C5; R21, R22, R23, and R24 are equal to or different from each other and are equal to R1; R25 and R26 are equal to or different from each other and are equal to R1, but both R25 and R26 cannot be a free valence, R27 is a linear or branched alkyl having one to six carbon atoms; B is equal to the group O— (a keto group with the carbon atom at position 9 of the prostaglandin molecule) or is OH or —O—; when no aliphatic chain C7-C2 is at position 8, there is in its place an alkylaromatic residue: which is bound to formula (III) (B=—O—) in the following way: wherein m1 is an integer from 1 to 6, Ra and Rb are equal to or different from each other, and are as defined above, when t=0, u=1, and m0=1 the meanings of the various substituents are as defined above, when t=1, u=0, and m0=0 the meanings of the various substituents are as defined above and C16 is bound, optionally by a bridging group —O—, to an aromatic radical or an alkyl-aryl radical, where the aryl can be substituted, said aryl radical can also contain heteroatoms, such as O or N; the alkyl of the alkyl-aryl radical is an aliphatic chain from 1 to 3 carbon atoms; X1 of formula A—X1—NO2 is a bivalent connecting bridge, chosen from the following: —Y where Y is a linear or whenever possible branched C1-C20 alkylene oxygen terminated, or is a C5-C7 cycloalkylene oxygen terminated optionally substituted; where n3 is an integer from 0 to 3; where nf′ is an integer from 1 to 6; and where R1f=H or CH3, and nf is an integer from 1 to 6. 2. Compounds according to claim 1 wherein the prostaglandin residues R are the following: when in formula (II) t=1 u=0 and in formula (III) m0=1: B is O═ (keto group with C9); R7, R8, R9 and R10 are such as to given a double bond between C13 and C14; R2 is OH; R27 is CH3; the substituents of the carbon atoms of the C2-C7 and C16-C19 aliphatic chains are H; R thus defined is known as the residue of Prostaglandin E1; or, by putting in the formula of Prostaglandin E1, R1=CH3 and R3, R4, R5, R6 such as to give a double bond between C5 and C6; R thus defined is known as the residue of Arbaprostil; or, by putting in the formula of Arbaprostil R7=R8=R9=R10=H; R1 and R2 are such as to form the group C═O with C15; B is OH; R27=C3H7; R thus defined is known as the residue of Unoprostone; or, by putting in the formula of Arbaprostil R11=R12=CH3, R1=H, R thus defined s known as the residue of Trimoprostil; or, when in the formula of Arbaprostil B is OH; R1=H; R thus defined is known as the residue of Prostaglandin F2α; or, when in the formula of Prostaglandin F2α B is O═ (keto group with C9); R thus defined is known as the residue of Prostaglandin R2; or, when in the formula of Arbaprostil B is OH; R thus defined is known as the residue of Carboprost; or, by putting in the formula of Arbaprostil R1=H; R17=H; R19=CH3; R3=R4=R5=R6=H; R27=C2H5; R13=R16=H and R14=R15 being free valences such as to form a double bond between C2 and C3; R thus defined is known as the residue of Limaprost; or, by putting in the formula of Trimoprostil R3=R4=R5=R6=H, and positioning the double bond between C2 and C3 instead that between C5 and C6; R thus defined is known as the residue of Gemeprost; or, by putting in the formula of Arbaprostil R1=R2=H; R12=OH; R11=CH3, R3=R5=R4=R6=H; R thus defined is known as the residue of Misoprost; or, by putting in the formula of Arbaprostil R1=H; R18=CH3; R27=C2H5; R3 and R4 are such that one of them is a free valence and the other is a single bond with an oxygen atom so that together with the carbon atom C6 form a keto group C═O; R5=R6=H, R thus defined is known as the residue of Ornoprostil; or, as in Arbaprostil, without the C7-C2 aliphatic chain and the carbon atoms C9-C8 linked to the group of formula (IV) as shown in (V); R1=H; R11=CH3; R21, R22, R23, R24 being each a free valence to form a triple bond between C18 and C19; R thus defined is known as the residue of Beraprost; when t=0; u=1 and m0=1: Ra=Rb=H and R is the residue of Misoprostol, R thus defined is known as the residue of Rioprostil, when t=1, u=0 and m0=0: when R is the residue of Arbaprostil except that R1=H; R19 or R20 is a free valence or H, so that between C4 and C5 there is a double bond; C16 is linked to a group —O—Ar wherein Ar=phenyl; R thus defined is known as the residue of Enprostil; when R is the residue of Arbaprostil except that B is OH; R1=H; C16 is linked to a group —CH2—Ar where Ar is phenyl; it is defined a radical known as the residue of Latanaprost; when in the formula of Enprostil R20=R19=H; it is defined a radical known as the residue of Sulprostone. 3. A compound according to claim 1 where R is the residue of Prostaglandin E1. 4. A method for treating cerebrovascular and cardiovascular disorders, glaucoma, and peptic ulcer disorders, and a method for inducing abortion, comprising administering to a patient an effective amount of a compound of claim 1. 5. Pharmaceutical compositions containing as the active ingredient compounds of claim 1 and a pharmaceutically acceptable carrier. 6. A method for treating impotence comprising administering to a patient an effective amount of a compound of the formula: A—X1—X—X1—NO2 (I) wherein A is R(CRaRbO)u(COX)t (II) wherein t and u are integers and are equal to 0 or 1; X═O, NH, NR1c wherein R1c is a linear or branched alkyl having form 1 to 10 carbon atoms; Ra and Rb are equal to or different from each other and are H, or a C1-C3 alkyl radical and R is a radical having the following formula: wherein m0 is an integer having a value of 0 or 1; and when t=1, u=0 and m0=1: R1=H; an alkyl having from 1 to 6 carbon atoms or a free valance; R2=OH, O— such as to form with R1 when R1 is a free valance, and with the carbon atom at position 15 a C═O group; R3 and R4 are equal to or different from one another and are equal to R1 or one of them is a bond O—, and the other is a free valance so that with the carbon atom C6 they form a C═O group; R5 and R6 are equal to or different from one another, and are equal to R1 when both R5 and R3 are each a free valence, R5 and R3 form a double bond between C5 and C6; R7, R8, R9, and R10 are equal to or different from each other, and have the same meaning as R1; when R7 or R9, and at the same time R8 or R10 are each a free valence, there is a double bond between C13 and C14; R11=R1; R12=R11 or OH; R13, R14, R15, and R16 are equal to or different from each other, and are equal to R1; when R13 or R15, and at the same time R14 or R16, are each a free valence, there is a double bond between C3 and C2; R17 and R18 are equal to or different from each other and are equal to R1; R19 and R20 are equal to or different from each other and are equal to R1; when R6 or R5 is a free valence, and R19 or R20 is a free valence, there is a double bond between C4 and C5; R21, R22, R23, and R24 are equal to or different from each other and are equal to R1; R25 and R26 are equal to or different from each other and are equal to R1, but both R25 and R26 cannot be a free valence, R27 is a linear or branched alkyl having one to six carbon atoms; B is equal to the group O═ (a keto group with the carbon atom at position 9 of the prostaglandin molecule) or is OH or —O—; when no aliphatic chain C7-C2 is at position 8, there is in its place an alkylaromatic residue: which is bound to formula III (B=—O—) in the following way: wherein m1 is an integer from 1 to 6, Ra and Rb, are equal to or different from each other, and are as defined above, when t=0, u=1, and m0=1 the meanings of the various substituents are as defined above, when t=1, u=0, and m0=0 the meanings of the various substituents are as defined above and C16 is bound, optionally by a bridging group —O—, to an aromatic radical or an alkyl-aryl radical, where the aryl can be substituted, said aryl radical can also contain heteroatoms, such as O or N; the alkyl of the alkyl-aryl radical is an aliphatic chain from 1 to 3 carbon atoms; X1 of formula A—X1—NO2 is a bivalent connecting bridge, chosen from the following: —Y where Y is a linear or whenever possible branched C1-C20 alkylene oxygen terminated, or is a C5-C7 cycloalkylene oxygen terminated optionally substituted; where n3 is an integer from 0 to 3; where nf′ is an integer from 1 to 6; and where R1f=H or CH3, and nf is an integer from 1 to 6.