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US 8,338,454 B2Granted
Nitrile derivatives and their pharmaceutical use and compositions
AssigneeCellceutix Corporation
InventorKrishna Menon
Life of this patent
Estimating the term…
Abstract
Disclosed are nitrile derivatives and pharmaceutical compositions comprising nitrile derivatives. The pharmaceutical compositions comprise compounds of the formula I and the pharmaceutically acceptable salts of such compounds. Also disclosed are processes for the preparation of such compounds, intermediates used in the preparation of such compounds, and the uses of such compounds in treating hyperproliferative diseases, inflammatory diseases and viral and bacterial infections and inducing apoptosis in cancer cells.
Claims48
A pharmaceutical composition for treating hyperproliferative diseases, inflammatory diseases, viral infections or bacterial infections in mammals comprising an antihyperproliferative disease, anti-inflammatory, antiviral or antibacterial effective amount of a compound of formula I
- wherein, Z is selected from sulphur, copper, silver, gold and platinum, or Z is a halogen-containing moiety selected from ClO2, BrO2, and IO2;
- wherein n is zero or an integer from 1 to 8 and m is zero or an integer from 1 to 8;
- R1, R2 and R3 are independently selected from hydrogen, —CH2-cyclohexyl, C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl, wherein the alkyl moieties of said alkyl, alkenyl and alkynyl groups may be linear, branched and cyclic and combinations of linear, branched and cyclic alkyl, alkenyl and alkynyl moieties and said groups may be substituted with groups selected from methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, methoxy, ethoxy, O-n-propyl, O-isopropyl, O-n-butyl, and O-t-butyl;
- or
- R1 and R2, taken together with the nitrogens to which they are directly attached and the carbon which is attached to the nitrogens, form a five or more membered ring, wherein p is an integer from 1 to 7 as shown below
- wherein the broken line represents an optional double bond, with the proviso that when there is such a double bond, R3 is absent and the CH2 group adjacent to the double bond has one hydrogen rather than two hydrogens,
- or R2 and R3 taken together with the nitrogen to which they are attached form a three or more membered ring, wherein p is an integer from 1 to 7, as shown below
- W is absent or W is selected from
- —CH2—, —CH2—CH2—, trans —CH═CH—, cis —CH═CH—, —C≡≡C—, or —CHR4—CHR5—, trans —C R4═C R5—, cis —CR4═CR5—, wherein R4, and R5 are independently selected from —CH2-cyclohexyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkyl ether (also referred to as C1-C6 alkyl —O—);
- or
- W is a disubstituted moiety, wherein the term disubstituted is used to indicate how W is attached to the groups (CH2)m and (CH2)n, selected from the group of disubstituted moieties consisting of
- (a) a 1,2-, 1,3-, or 1,4-disubstituted six membered ring which may be saturated or unsaturated with one, two or three double bonds;
- a 1,2-, or 1,3-disubstituted five membered ring which may be saturated or unsaturated with one or two double bonds;
- a 1,2-, or 1,3-disubstituted four membered ring which may be saturated or unsaturated with one or two double bonds;
- or a 1,2-disubstituted three membered ring which may be saturated and unsaturated with a double bond as shown by the following formulas, wherein the substituents on said disubstituted rings are the groups attached to W in formula I
- wherein the broken lines indicate optional double bonds;
- (b) a 1,2-, 1,3-, or 1,4-disubstituted six membered ring which may be saturated or unsaturated with one, two or three double bonds;
- a 1,2-, or 1,3-disubstituted five membered ring which may be saturated or unsaturated with one or two double bonds;
- a 1,2-, or 1,3-disubstituted four membered ring which may be saturated or unsaturated with one or two double bonds;
- or a 1,2-disubstituted three membered ring which may be saturated and unsaturated with a double bond as shown by the following formulas, wherein the substituents on said disubstituted rings are the groups attached to W in formula I, and said disubstituted rings may have additional substituents R6, R7, R8, and R9 as shown in the following formulas
- wherein the broken lines indicate optional double bonds;
- wherein R6, R7, R8 and R9 are independently selected from hydrogen, —CH2-cyclohexyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkyl ether;
- the six membered ring may be saturated or have one, two or three double bonds, the five and four membered rings may be saturated or have one or two double bonds and the three membered ring may be saturated or have one double bond;
- wherein Y is nitrogen, oxygen, or sulphur;
- (c) a ring selected from 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, or 1,7-disubstituted saturated and unsaturated 9-membered rings with one or more double bonds, with ring positions numbered as shown in the first ring set forth below, said ring selected from the second to the thirteenth rings set forth below, wherein the substituents on said disubstituted rings are the groups attached to W in formula I, and said disubstituted rings may have additional substituents R6, R7, R8, R9 and R10 as shown in the following formulas
- wherein the broken lines indicate optional double bonds;
- wherein R6, R7, R8, R9, and R10 are independently selected from hydrogen, —CH2-cyclohexyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkyl ether;
- wherein Y is nitrogen, oxygen, or sulphur;
- (d) a ring selected from 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, or 1,8-disubstituted saturated and unsaturated naphthalene rings with one or more double bonds, with ring positions numbered as shown in the first ring set forth below, said rings selected from the second to sixth rings set forth below, wherein the substituents on said disubstituted rings are the groups attached to W in formula I, and said disubstituted rings may have additional substituents R6, R7, R8, R9, R10 and R11 as shown in the following formulas
- wherein the broken lines indicate optional double bonds;
- wherein R6, R7, R8, R9, R10 and R11 are independently selected from hydrogen, —CH2-cyclohexyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkyl ether;
- wherein Y is nitrogen, oxygen, or sulphur;
- and
- (e) a ring selected from 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 1,9-, 1,10-, 2,5-, 3,5-, 4,5-, or 5,10-disubstituted saturated and unsaturated anthracene rings with one or more double bonds, with ring positions numbered as shown in the first ring set forth below, said ring selected from the second to ninth rings set forth below, wherein the substituents on said disubstituted rings are the groups attached to W in formula I, and said disubstituted rings may have additional substituents R6, R7, R8, R9, R10, R11, R12 and R13 as shown in the following formulas
- wherein the broken lines indicate optional double bonds;
- wherein R6, R7, R8, R9, R10, R11, R12, and R13 are independently selected from hydrogen, —CH2-cyclohexyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkyl ether;
- wherein Y is nitrogen, oxygen, or sulphur;
- or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
35 more elements
A method of treating hyperproliferative diseases, inflammatory diseases, viral infections or bacterial infections comprising administering to a patient in need of such treatment an antihyperproliferative disease, anti-inflammatory, antiviral or antibacterial effective amount of a compound of formula I
- wherein, Z is selected from sulphur, copper, silver, gold and platinum, or Z is a halogen-containing moiety selected from ClO2, BrO2, and IO2;
- wherein n is zero or an integer from 1 to 8 and m is zero or an integer from 1 to 8;
- R1, R2 and R3 are independently selected from hydrogen, —CH2-cyclohexyl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein the alkyl moieties of said alkyl, alkenyl and alkynyl groups may be linear, branched and cyclic and combinations of linear, branched and cyclic alkyl, alkenyl and alkynyl moieties and said groups may be substituted with groups selected from methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, methoxy, ethoxy, O-n-propyl, O-isopropyl, O-n-butyl, and O-t-butyl;
- or
- R1 and R2, taken together with the nitrogens to which they are directly attached and the carbon which is attached to the nitrogens, form a five or more membered ring, wherein p is an integer from 1 to 7 as shown below
- wherein the broken line represents an optional double bond, with the proviso that when there is such a double bond, R3 is absent and the CH2 group adjacent to the double bond has one hydrogen rather than two hydrogens,
- or R2 and R3 taken together with the nitrogen to which they are attached form a three or more membered ring, wherein p is an integer from 1 to 7, as shown below
- W is absent or W is selected from
- —CH2—, —CH2—CH2—, trans —CH═CH—, cis —CH═CH—, —C≡≡C—, or —CHR4—CHR3—, trans —C R4═C R5—, cis —CR4═CR5—, wherein R4, and R5 are independently selected from —CH2-cyclohexyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkyl ether (also referred to as C1-C6 alkyl —O—);
- or
- W is a disubstituted moiety, wherein the term disubstituted is used to indicate how W is attached to the groups (CH2)m and (CH2)n, selected from the group of disubstituted moieties consisting of
- (a) a 1,2-, 1,3-, or 1,4-disubstituted six membered ring which may be saturated or unsaturated with one, two or three double bonds;
- a 1,2-, or 1,3-disubstituted five membered ring which may be saturated or unsaturated with one or two double bonds;
- a 1,2-, or 1,3-disubstituted four membered ring which may be saturated or unsaturated with one or two double bonds;
- or a 1,2-disubstituted three membered ring which may be saturated and unsaturated with a double bond as shown by the following formulas, wherein the substituents on said disubstituted rings are the groups attached to W in formula I
- wherein the broken lines indicate optional double bonds;
- (b) a 1,2-, 1,3-, or 1,4-disubstituted six membered ring which may be saturated or unsaturated with one, two or three double bonds;
- a 1,2-, or 1,3-disubstituted five membered ring which may be saturated or unsaturated with one or two double bonds;
- a 1,2-, or 1,3-disubstituted four membered ring which may be saturated or unsaturated with one or two double bonds;
- or a 1,2-disubstituted three membered ring which may be saturated and unsaturated with a double bond as shown by the following formulas, wherein the substituents on said disubstituted rings are the groups attached to W in formula I, and said disubstituted rings may have additional substituents R6, R7, R8, and R9 as shown in the following formulas
- wherein the broken lines indicate optional double bonds;
- wherein R6, R7, R8 and R9 are independently selected from hydrogen, —CH2-cyclohexyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkyl ether;
- the six membered ring may be saturated or have one, two or three double bonds, the five and four membered rings may be saturated or have one or two double bonds and the three membered ring may be saturated or have one double bond;
- wherein Y is nitrogen, oxygen, or sulphur;
- (c) a ring selected from 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, or 1,7-disubstituted saturated and unsaturated 9-membered rings with one or more double bonds, with ring positions numbered as shown in the first ring set forth below, said ring selected from the second to the thirteenth rings set forth below, wherein the substituents on said disubstituted rings are the groups attached to W in formula I, and said disubstituted rings may have additional substituents R6, R7, R8, R9 and R10 as shown in the following formulas
- wherein the broken lines indicate optional double bonds;
- wherein R6, R7, R8, R9, and R10 are independently selected from hydrogen, —CH2-cyclohexyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkyl ether;
- wherein Y is nitrogen, oxygen, or sulphur;
- (d) a ring selected from 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, or 1,8-disubstituted saturated and unsaturated naphthalene rings with one or more double bonds, with ring positions numbered as shown in the first ring set forth below, said rings selected from the second to sixth rings set forth below, wherein the substituents on said disubstituted rings are the groups attached to W in formula I, and said disubstituted rings may have additional substituents R6, R7, R6, R9, R10 and R11 as shown in the following formulas
- wherein the broken lines indicate optional double bonds;
- wherein R6, R7, R8, R9, R10 and R11 are independently selected from hydrogen, —CH2-cyclohexyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkyl ether;
- wherein Y is nitrogen, oxygen, or sulphur;
- and
- (e) a ring selected from 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 1,9-, 1,10-, 2,5-, 3,5-, 4,5-, or 5,10-disubstituted saturated and unsaturated anthracene rings with one or more double bonds, with ring positions numbered as shown in the first ring set forth below, said ring selected from the second to ninth rings set forth below, wherein the substituents on said disubstituted rings are the groups attached to W in formula I, and said disubstituted rings may have additional substituents R6, R7, R8, R9, R10, R11, R12 and R13 as shown in the following formulas
- wherein the broken lines indicate optional double bonds;
- wherein R6, R7, R8, R9, R10, R11, R12, and R13 are independently selected from hydrogen, —CH2— cyclohexyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkyl ether;
- wherein Y is nitrogen, oxygen, or sulphur;
- or a pharmaceutically acceptable salt thereof.
35 more elements
A compound of formula I
- wherein, Z is selected from sulphur, copper, silver, gold and platinum, or Z is a halogen-containing moiety selected from ClO2, BrO2, and IO2;
- wherein n is zero or an integer from 1 to 8 and m is zero or an integer from 1 to 8;
- R1, R2 and R3 are independently selected from hydrogen, —CH2-cyclohexyl, C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl, wherein the alkyl moieties of said alkyl, alkenyl and alkynyl groups may be linear, branched and cyclic and combinations of linear, branched and cyclic alkyl, alkenyl and alkynyl moieties and said groups may be substituted with groups selected from methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, methoxy, ethoxy, O-n-propyl, O-isopropyl, O-n-butyl, and O-t-butyl;
- or
- R1 and R2, taken together with the nitrogens to which they are directly attached and the carbon which is attached to the nitrogens, form a five or more membered ring, wherein p is an integer from 1 to 7 as shown below
- wherein the broken line represents an optional double bond, with the proviso that when there is such a double bond, R3 is absent and the CH2 group adjacent to the double bond has one hydrogen rather than two hydrogens,
- or R2 and R3 taken together with the nitrogen to which they are attached form a three or more membered ring, wherein p is an integer from 1 to 7, as shown below
- W is absent or W is selected from
- —CH2—, —CH2—CH2—, trans —CH═CH—, cis —CH═CH—, —C≡≡C—, or —CHR4—CHR5—, trans —C R4═C R5—, cis —CR4═CR5—, wherein R4, and R5 are independently selected from —CH2-cyclohexyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkyl ether (also referred to as C1-C6 alkyl —O—);
- or
- W is a disubstituted moiety, wherein the term disubstituted is used to indicate how W is attached to the groups (CH2)m and (CH2)n, selected from the group of disubstituted moieties consisting of,
- (a) a 1,2-, 1,3-, or 1,4-disubstituted six membered ring which may be saturated or unsaturated with one, two or three double bonds;
- a 1,2-, or 1,3-disubstituted five membered ring which may be saturated or unsaturated with one or two double bonds;
- a 1,2-, or 1,3-disubstituted four membered ring which may be saturated or unsaturated with one or two double bonds;
- or a 1,2-disubstituted three membered ring which may be saturated and unsaturated with a double bond as shown by the following formulas, wherein the substituents on said disubstituted rings are the groups attached to W in formula I
- wherein the broken lines indicate optional double bonds;
- (b) a 1,2-, 1,3-, or 1,4-disubstituted six membered ring which may be saturated or unsaturated with one, two or three double bonds;
- a 1,2-, or 1,3-disubstituted five membered ring which may be saturated or unsaturated with one or two double bonds;
- a 1,2-, or 1,3-disubstituted four membered ring which may be saturated or unsaturated with one or two double bonds;
- or a 1,2-disubstituted three membered ring which may be saturated and unsaturated with a double bond as shown by the following formulas, wherein the substituents on said disubstituted rings are the groups attached to W in formula I, and said disubstituted rings may have additional substituents R6, R7, R8, and R9 as shown in the following formulas
- wherein the broken lines indicate optional double bonds;
- wherein R8, R7, R8 and R9 are independently selected from hydrogen, —CH2-cyclohexyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkyl ether;
- the six membered ring may be saturated or have one, two or three double bonds, the five and four membered rings may be saturated or have one or two double bonds and the three membered ring may be saturated or have one double bond;
- wherein Y is nitrogen, oxygen, or sulphur;
- (c) a ring selected from 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, or 1,7-disubstituted saturated and unsaturated 9-membered rings with one or more double bonds, with ring positions numbered as shown in the first ring set forth below, said ring selected from the second to the thirteenth rings set forth below, wherein the substituents on said disubstituted rings are the groups attached to W in formula I, and said disubstituted rings may have additional substituents R6, R7, R8, R9 and R10 as shown in the following formulas
- wherein the broken lines indicate optional double bonds;
- wherein R6, R7, R8, R9, and R10 are independently selected from hydrogen, —CH2-cyclohexyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkyl ether;
- wherein Y is nitrogen, oxygen, or sulphur;
- (d) a ring selected from 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, or 1,8-disubstituted saturated and unsaturated naphthalene rings with one or more double bonds, with ring positions numbered as shown in the first ring set forth below, said rings selected from the second to sixth rings set forth below, wherein the substituents on said disubstituted rings are the groups attached to W in formula I, and said disubstituted rings may have additional substituents R6, R7, R8, R9, R10 and R11 as shown in the following formulas
- wherein the broken lines indicate optional double bonds;
- wherein R6, R7, R8, R9, R10 and R11 are independently selected from hydrogen, —CH2-cyclohexyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkyl ether;
- wherein Y is nitrogen, oxygen, or sulphur;
- and
- (e) a ring selected from 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 1,9-, 1,10-, 2,5-, 3,5-, 4,5-, or 5,10-disubstituted saturated and unsaturated anthracene rings with one or more double bonds, with ring positions numbered as shown in the first ring set forth below, said ring selected from the second to ninth rings set forth below, wherein the substituents on said disubstituted rings are the groups attached to W in formula I, and said disubstituted rings may have additional substituents R6, R7, R8, R9, R10, R11, R12 and R13 as shown in the following formulas
- wherein the broken lines indicate optional double bonds;
- wherein R6, R7, R8, R9, R10, R11, R12, and R13 are independently selected from hydrogen, —CH2-cyclohexyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkyl ether;
- wherein Y is nitrogen, oxygen, or sulphur;
- or a pharmaceutically acceptable salt thereof with the proviso that the compound is not S-(cyanomethyl)isothiourea HCl, S-(cyanomethyl)isothiourea HBr, S-(2-cyanoethyl)isothiourea HCl, S-(2-cyanoethyl)isothiourea HBr, S-(2-cyanoethyl)isothiourea p-toluenesulfonate, S-(3-cyanopropyl)isothiourea HCl, S-(3-cyanopropyl)isothiourea picrate, or S-para-cyanobenzylisothiourea HCl.
35 more elements
Dependencies are inferred from the claim text.