PLATINUM COMPLEX ANTI-NEOPLASTIC AGENTS COMPRISING A

C ANNABIN OID LIGAND

[01] Each reference cited in this disclosure is incorporated herein in its entirety.

TECHNICAL FIELD

[02] This disclosure relates generally to the treatment of neoplasms.

DETAILED DESCRIPTION

[03] Platinum complexes comprise a central platinum atom complexed to leaving and non leaving ligands. Platinum complexes with four ligands have an oxidation state of +2 (“Pt(II) complexes”), and those with six ligands have an oxidation state of +4 (“Pt(IV) complexes”).

[04] The general structures of Pt(II) and Pt(IV) complexes are shown below. leaving ligand component non-leaving ligand component axial ligand +4 leaving ligand component non-leaving ligand component axial ligand

[05] The “non-leaving ligand component” can be a single (bidentate or tridentate) non-leaving ligand or can be two or three individual non-leaving ligands. The “leaving ligand component” can be one or two individual ligands or can be a bidentate leaving ligand.

[06] Both Pt(II) and Pt(IV) complex anti-neoplastic agents are well known in the art. Agents in commercial use include cisplatin, carboplatin, oxaliplatin, eptaplatin, lobaplatin, nedaplatin, and satraplatin. As illustrated below, these agents work by alkylating DNA at the expense of the bond between one or two leaving ligands (circled) and the central platinum atom.

Overview

[07] The platinum complex anti-neoplastic agents (“PCAN agents”) described in this disclosure comprise at least one cannabinoid ligand as either a leaving ligand or an axial ligand. After the agent enters the cell, the cannabinoid ligand is released as a cannabinoid, where the cannabinoid can then provide additional therapeutic benefits. These benefits include, but are not limited to, anti-tumor activity (Massi etal ., J. Pharmacol. Exp. Ther. 308, 838-45, e-pub 2003; Guindon & Hohmann, Br. J. Pharmacol. 163, 1447-63, 2011; Borrelli etal., Carcinogenesis 35, 2787-97, 2014; McAllister etal., J. Neuroimmune Pharmacol. 10, 255-67, 2015) and inhibition of tumor progression (Velasco et al., Nat. Rev. Cancer 12, 436-44, 2012).

[08] As described in more detail below, a cannabinoid can be attached to a central platinum atom as a leaving ligand or, for Pt(IV) complexes, as an axial ligand. In various embodiments, a Pt(II) PCAN agent can incorporate a cannabinoid in place of one leaving ligand or in place of each of two leaving ligands. In various embodiments, a Pt(IV) PCAN agent can incorporate a cannabinoid in place of one axial ligand or in place of each of two axial ligands. In addition, a Pt(IV) PCAN agent can incorporate a cannabinoid in place of one leaving ligand or in place of each of two leaving ligands. Thus, a Pt(II) PCAN agent can incorporate and release one or two cannabinoids; and a Pt(IV) PCAN agent can incorporate and release one, two, three, or four cannabinoids. In any particular PCAN agent that incorporates two or more cannabinoids, the cannabinoids can be the same or different.

[09] In the description that follows, wherever a leaving ligand, a non-leaving ligand component, or an axial ligand is unspecified in an embodiment of a PCAN agent, such ligands can be the ligands of any platinum complex anti -neoplastic agent. See , e.g ., Kozubik etal ., 2008; Johnstone etal., 2016; Intini etal., 2017; Neumann et al., 2014; Tolan etal., 2018; Jia etal., 2019; Zhou et al., 2018; Li et al., 2018; Ndagi et al., 2017; Monroe et al., 2018; U.S. Patent 7,268,244; U.S. Patent 7,759,488; U.S. Patent 9,227,991; U.S. Patent 9,593,139; U.S. Patent 9,771,387; U.S. Patent 10,053,478.

[10] For simplicity, PCAN agents are depicted in this disclosure without indicating any stereochemistry. It is well known, however, that both cannabinoids and platinum complexes exhibit a variety of stereochemistries. In this disclosure, unless otherwise indicated, any particular PCAN agent structure includes all possible isomers, including isomers of the cannabinoid ligands incorporated into the PCAN agent.

[11] In addition, the use of any particular leaving ligand, non-leaving ligand, or cannabinoid ligand in the structural examples below is for simplicity and is not intended to limit any of the ligands of the disclosed PCAN agents.

Cannabinoid Ligand

[12] A “cannabinoid ligand” as used in this disclosure is that portion of a cannabinoid that is present in a PCAN agent in place of a leaving ligand or an axial ligand. Illustrations are shown in the examples below.

[13] A cannabinoid ligand, either a cannabinoid leaving ligand or a cannabinoid axial ligand, can be provided by any cannabinoid that contains a hydroxy group (aromatic or aliphatic) or a carboxyl group by which the cannabinoid can be attached to the central platinum atom, either directly or via a linker.

[14] The cannabinoid can be a naturally occurring molecule, either isolated or synthesized, or a modified version of a naturally occurring molecule. See, for example, Morales etal ., Frontiers in Pharmacology June 2017 review, 1-18.

[15] Examples of cannabinoids include, but are not limited to, cannabigerols, cannabichromenes, cannabidiols, tetrahydrocannabinol s, cannabicyclols, cannabielsoins, cannabinols, cannabinodiols, cannabitriols, dehydrocannabifurans, cannabifurans, cannabichromanons, and cannabiripsols.

[16] Examples of cannabigerols include cannabigerolic acid (CBGA), cannabigerolic acid monomethylether (CBGAM), cannabigerol (CBG), cannabigerol monomethyleither (CBGM), cannabigerovarinic acid (CBGVA), and cannabigerovarin (CBGV).

[17] Examples of cannabichromenes include cannabichromenic acid (CBC), cannabichromene (CBC), cannabichromevarinic acid (CBCVA), and cannabichromevarin (CBCV).

[18] Examples of cannabidiols include cannabidiolic acid (CBDA), cannabidiol (CBD), cannabidiol monomethylether (CBDM), cannabidiol-C4 (CBD-C4), cannabidivarinic acid (CBDVA), cannabidivarin (CBDV), and cannabidiorcol (CBD-Ci).

[19] Examples of tetrahydrocannabinol s include D-9-tetrahydrocannabinolic acid A (THCA- A), D-9-tetrahydrocannabinolic acid B (THCA-B), D-9-tetrahydrocannabinol (THC), D-9- tetrahydrocannabinolic acid-C4 (THCA-C4), A-9-tetrahydrocannabinol-C4 (THC-C4), D-9- tetrahydrocannabivarinic acid (THCVA), D-9-tetrahydrocannabivarin (THCV), D-9- tetrahydrocannabiorcolic acid (THCA-Ci), D-9-tetrahydrocannabiorcol (THC-Ci), D-7 -cis- tetrahydrocannabivarin, D-8-tetrahydrocannabinolic acid (A ^X -THCA), and D-8- tetrahydrocannabinol (A ^X -THC).

[20] Examples of cannabicyclols include cannabicyclolic acid (CBLA), cannabicyclol (CBL), and cannabicyclovarin (CBLV).

[21] Examples of cannabielsoins include cannabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEA-B), and cannabielsoin (CBE).

[22] Examples of cannabinols and cannabinodiols include cannabinolic acid (CBNA), cannabinol (CBN), cannabinol-C4 (CBN-C4), cannabivarin (CBV), cannabinol-C2 (CBN-C2), cannabiorcol (CBN-Ci), cannabinodiol (CBND), and cannabinodivarin (CBVD).

[23] Examples of cannabitriols include cannabitriol (CBT), 10-ethoxy-9-hydroxy-A-6a- tetrahydrocannabinol, cannabitriolvarin (CBTV), and ethoxy-cannabitriolvarin (CBTVE).

[24] Cannabifurans include dehydrocannabifuran (DCBF) and cannabifuran (CBF). [25] Examples of other cannabinoids include cannabichromanon (CBCN), 10-oxo-A-6a- tetrahydrocannabinol (OTHC), cannabiripsol (CBR), and trihydroxy-A-9-tetrahydrocannabinol (triOH-THC).

[26] In some embodiments, the cannabinoid ligand is provided by cannabidiol.

Platinum Complex Anti-Neoplastic Agents Comprising a Cannabinoid Leaving Ligand

[27] In some embodiments, a PCAN agent comprises (a) a central platinum atom; (b) a non leaving ligand component; and (c) a leaving ligand component, which comprises a first cannabinoid leaving ligand attached to the central platinum atom via an oxygen atom of (i) a first hydroxy group of the first cannabinoid ligand or of (ii) a first carboxyl group of the first cannabinoid ligand. Non-limiting examples are shown below.

[28] In some embodiments, the leaving ligand component comprises a second cannabinoid ligand (“second cannabinoid leaving ligand”). The first and second cannabinoid leaving ligands can be the same or different. Non-limiting examples are shown below.

[29] In some embodiments, the cannabinoid ligand component is a bidentate cannabinoid ligand (“bidentate cannabinoid leaving ligand”). A non-limiting example is shown below.

[30] In some embodiments, the PCAN agent further comprises (d) a first axial ligand and a second axial ligand. Non-limiting examples of these embodiments are shown below, in which · represents an axial ligand.

[31] In some embodiments, a cannabinoid leaving ligand is attached to the central platinum atom by a linker. In the linkers described below, * is the point of attachment of a cannabinoid leaving ligand and ** is the point of attachment to the central platinum atom. In some embodiments, a first cannabinoid leaving ligand is connected to the central platinum atom by a linker. In some embodiments, a first and a second cannabinoid leaving ligand are connected to the central platinum atom by a linker. The linkers, which can be the same or different, are described below.

[32] In some embodiments,

(a) Ri, R2, R3, and R4 independently are selected from the group consisting of:

(a) H;

(b) C1-C8 linear or branched alkyl, optionally substituted with

(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and/or

(2) 1, 2, or 3 substituents independently selected from the Group One Substituents;

(c) C1-C8 linear or branched heteroalkyl containing 1, 2, or 3 heteroatoms independently selected from O, N, and S and optionally substituted with

(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and/or

(2) 1, 2, or 3 substituents independently selected from the Group One Substituents;

(d) phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

(1) C1-C6 linear or branched alkyl, optionally substituted with

(i) 1, 2, 3, 4, 5, or 6 fluorine atoms; and/or

(ii) 1 or 2 substituents independently selected from the Group Two Substituents; and

(2) C1-C6 linear or branched heteroalkyl containing 1 or 2 heteroatoms independently selected from O, N, and S and optionally substituted with

(i) 1, 2, 3, 4, 5, or 6 fluorine atoms; and/or

(ii) 1 or 2 substituents independently selected from the Group One

Substituents;

(e) a 6- to 10-membered aromatic, optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: (1) phenyl;

(2) halide;

(3) cyano;

(4) C1-C6 linear or branched alkyl, optionally substituted with

(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and/or

(ii) 1, 2, or 3 substituents independently selected from the Group Two Substituents, and

(5) C1-C6 linear or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S and optionally substituted with

(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and/or

(ii) 1, 2, or 3 substituents independently selected from the Group Two Substituents;

(f) 5- to 10-membered heteroaromatic comprising 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S and optionally substituted with 1, 2, 3, or 4 substituents independently selected from

(1) phenyl;

(2) halide;

(3) cyano;

(4) trifluoromethyl;

(5) C1-C6 linear or branched alkyl optionally substituted with

(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and/or

(ii) 1, 2, or 3 substituents independently selected from the Group Two Substituents; and

(6) C1-C6 linear or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S and optionally substituted with

(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and/or

(ii) 1, 2, or 3 substituents independently selected from the Group Two Substituents; (g) optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

(1) C1-C6 linear or branched alkyl, optionally substituted with

(i) 1, 2, 3, 4, 5, or 6 fluorine atoms; and/or

(ii) 1, 2, or 3 substituents independently selected from the Group Two Substituents;

(h) 3- to 9-membered cycloheteroalkyl having 1, 2, or 3 heteroatoms independently selected from O, N, and S and optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

(1) C1-C6 linear or branched alkyl, optionally substituted with

(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and/or

(ii) 1, 2, or 3 substituents independently selected from the Group Two Substituents,

(2) C1-C6 linear or branched heteroalkyl, optionally substituted with

(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms and/or

(ii) 1, 2, or 3 substituents independently selected from the Group Two Substituents,

(3) phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the Group Two Substituents, and

(4) 5- to 10-membered heteroaromatic, optionally substituted with 1, 2, or 3 substituents independently selected from the Group Two Substituents; and

(i) C3-C6 cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from:

(1) C1-C6 linear or branched alkyl, optionally substituted with

(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and/or

(ii) 1, 2, or 3 substituents independently selected from the Group Two Substituents,

(2) C1-C6 linear or branched heteroalkyl, optionally substituted with (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and/or

(ii) 1, 2, or 3 substituents independently selected from the Group Two Substituents,

(3) phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from Group Two Substituents; and

(4) 5- to 10-membered heteroaromatic, optionally substituted with 1, 2, or 3 substituents independently selected from the Group Two Substituents

OR

(b) when any two of Ri, R2, R3, and R4, independently are (i) C1-C6 linear or branched alkyl or (ii) C1-C6 linear or branched heteroalkyl having 1, 2, or 3 heteroatoms independently selected from O, S, and N, then the two of Ri, R2, R3, and R4, together with the carbons to which they are attached, form a 3-6-membered ring.

[33] “Group One Substituents” is a group of substituents consisting of:

(a) -OH;

(b) -NH2;

(c) =0;

(d) =S;

(e) =NR7, where R7 is H or is C1-C3 linear or branched alkyl or C1-C3 linear or branched heteroalkyl comprising an O, N, or S atom;

(f) -C(0)0R4, wherein R4 is H or C1-C3 linear or branched alkyl;

(g) -C(0)NR5R6, wherein R5 and R6 independently are H or C1-C6 linear or branched alkyl;

(h) halide;

(i) C1-C6 linear or branched alkoxyl;

(j) C1-C6 linear or branched alkylamino;

(k) C1-C6 linear or branched dialkylamino;

(l) 6- to 10-membered aromatic, optionally substituted with 1, 2, 3, or 4 substituents independently selected from

(i) phenyl;

(ii) halide;

(iii) cyano;

(iv) C1-C6 linear or branched alkyl, optionally substituted with

(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and/or (2) 1, 2, or 3 substituents independently selected from the Group Two Substituents; and

(v) C1-C6 linear or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S and optionally substituted with

(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and/or

(2) 1, 2, or 3 substituents independently selected from the Group Two Substituents;

(m) 5- to 10-membered heteroaromatic, optionally substituted with 1, 2, 3, or 4 substituents independently selected from

(i) phenyl;

(ii) halide;

(iii) cyano;

(iv) C1-C6 linear or branched alkyl, optionally substituted with

(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and/or

(2) 1, 2, or 3 substituents independently selected from the Group Two Substituents; and

(v) C1-C6 linear or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S and optionally substituted with

(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and/or

(2) 1, 2, or 3 substituents independently selected from the Group Two Substituents;

(n) 3- to 9-membered cycloheteroalkyl having 1, 2, or 3 heteroatoms independently selected from O, N, and S, optionally substituted with 1, 2, 3, or 4 substituents independently selected from

(i) phenyl;

(ii) halide;

(iii) cyano;

(iv) C1-C6 linear or branched alkyl, optionally substituted with

(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and/or

(2) 1, 2, or 3 substituents independently selected from the Group Two Substituents; and

(v) C1-C6 linear or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S and optionally substituted with

(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and/or

(2) 1, 2, or 3 substituents independently selected from the Group Two Substituents; and

(o) C3-C6 cycloalkyl, optionally substituted with 1, 2, 3, or 4 substituents independently selected from

(i) phenyl; (ii) halide;

(iii) cyano;

(iv) C1-C6 linear or branched alkyl, optionally substituted with

(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and/or

(2) 1, 2, or 3 substituents independently selected from the Group Two Substituents; and

(v) C1-C6 linear or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S and optionally substituted with

(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms; and/or

(2) 1, 2, or 3 substituents independently selected from the

Group Two Substituents.

[34] “Group Two Substituents” is a group of substituents consisting of: linear or branched alkyl or C1-C3 linear or branched heteroalkyl comprising an O, N, or S atom;

(f) -C(0)0R4, wherein R4 is H or C1-C3 linear or branched alkyl;

(g) -C(0)NR5R6, wherein R5 and R6 independently are H or C1-C6 linear or branched alkyl;

(h) halide;

(i) cyano;

(j) trifluorom ethyl;

(k) C1-C6 linear or branched alkoxyl;

(l) C1-C6 linear or branched alkylamino;

(m) C1-C6 linear or branched dialkylamino;

(n) 6- to 10-membered aromatic; and

(o) 5- to 10-membered heteroaromatic comprising 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S

[35] In some embodiments, which Ri, R2, R3, and R4 are as defined above.

[36] Non-limiting examples are shown below.

Platinum Complex Anti-Neoplastic Agents Comprising a Cannabinoid Axial Ligand

[37] In some embodiments, a PCAN agent comprises (a) a central platinum atom; (b) a non leaving ligand component; (c) a leaving ligand component; and (d) a first axial ligand and a second axial ligand. In these embodiments, at least the first axial ligand is a first cannabinoid ligand (“first cannabinoid axial ligand”) attached to the central platinum atom via an oxygen atom of (i) a first hydroxy group of the first cannabinoid ligand or (ii) a first carboxyl group of the first cannabinoid ligand. In some embodiments, the first and second axial ligand are independently chosen cannabinoid ligands attached to the central platinum atom via an oxygen atom of (i) a hydroxy group of the first or second cannabinoid ligand or (ii) a carboxyl group of the first or second cannabinoid ligand. In some embodiments, one or both of the leaving ligands is a cannabinoid leaving ligand, as described above. In some embodiments, the leaving ligand component is a bidentate leaving ligand.

[38] In the non-limiting examples below, for simplicity each cannabinoid axial ligand is a cannabidiol axial ligand. B and each represents a cannabinoid leaving ligand, which can be the same or different.

[39] In some embodiments, an axial cannabinoid ligand is attached to the central platinum atom by a linker. In the linkers described below, * is the point of attachment of a cannabinoid axial ligand and ** is the point of attachment to the central platinum atom. In some embodiments, a first cannabinoid axial ligand is connected to the central platinum atom by a linker. In some embodiments, a first and a second cannabinoid axial ligand are connected to the central platinum atom by a linker. The linkers, which can be the same or different, are described below.

[40] In some embodiments, the linker is , in which Ri, R2, R3, and R4 are as defined above.

[41] In some embodiments, the linker is

[42] In some embodiments, the linker i which Ri, R2, R3, and R4 are as defined above.

[43] In some embodiments, the linker is

Ri

\/ ^R 2 /**

[44] In some embodiments, the linker is ⁰ , in which Ri and R2 are as defined above.

[45] In the non-limiting examples below, for simplicity each cannabinoid axial ligand is a cannabidiol axial ligand. B and ® each represents a cannabinoid leaving ligand, which can be the same or different.

Non-Leaving Ligand Component

[46] In some embodiments, the non-leaving ligand component is (i) a first non-leaving ligand and a second non-leaving ligand, as illustrated, for example, by cisplatin, carboplatin, and nedaplatin: carboplatin cisplatin nedaplatin

[47] In some embodiments, the non-leaving ligand component of a PCAN agent is a first non leaving ligand, a second non-leaving ligand, and a third non-leaving ligand, as illustrated, for example, by pyriplatin and phenanthriplatin: pyriplatin phenanthriplatin

[48] In some embodiments, the non-leaving ligand component is a bidentate non-leaving ligand, as illustrated, for example, by oxaliplatin, lobaplatin, heptaplatin, and eptaplatin: [49] In some embodiments, the non-leaving ligand component of a PCAN agent is a tridentate ligand, as illustrated, for example, by [Pt(dien)Cl] ⁺ and [Pt(Et2dien)Cl] ⁺ :

Modified Ligands

[50] In some embodiments, a non-leaving ligand or an axial ligand is modified to comprise a bioactive moiety, for example to alter the pharmacokinetic properties of a PCAN agent, to provide a targeting function, or to provide an additional therapeutic effect. Bioactive moieties include, but are not limited to, targeting ligands such as steroid units, carbohydrates, bile acids, peptides ( e.g ., netropsin, distamycin), and folate units; histone deacetylase inhibitors, p53 agonists, alkylating agents, nonsteroidal anti-inflammatory complexes, and adamantylamine.

See , e.g., Johnstone et al., 2016; Li etal., 2018; Kozubik etal., 2008.

Isomers

[51] As mentioned above, platinum complexes exhibit various forms of stereoisomerism. In some embodiments, a PCAN agent is a cis isomer. In some embodiments, a PCAN agent is a trans isomer. In some embodiments, a PCAN agent is a l stereoisomer. In some embodiments, a PCAN agent is a d stereoisomer.

Pharmaceutically Acceptable Salts

[52] The disclosed PCAN agents can form salts. “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual. Such salts, for example, include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Further examples of pharmaceutically acceptable salts include those listed in Berge et al, Pharmaceutical Salts, J. Pharm. Sci. 1977 Jan; 66(1): 1-19.

Methods of Synthesis

[53] The disclosed PCAN agents can be synthesized using methods well known in the art. Examples of such methods are provided in the working examples, below.

Pharmaceutical Compositions

[54] Pharmaceutical compositions comprise one or more of the PCAN agents described above, or a pharmaceutically acceptable salt of the PCAN agent, together with a pharmaceutically acceptable vehicle, such as water, or a buffered aqueous solution. Pharmaceutical compositions can be provided as lyophilized powders containing, e.g ., sodium chloride and mannitol, to be reconstituted using water for injection.

[55] In some embodiments, a pharmaceutical composition comprises both cis and trans isomers. In some embodiments, a pharmaceutical composition comprises substantially only cis isomers or substantially only trans isomers. A pharmaceutical composition comprises “substantially only” cis isomers or substantially only trans isomers when the relevant isomer is below a detectable level as measured by a conventional analytical method such as spectroscopy or chromatography.

[56] In some embodiments, a pharmaceutical composition comprises both l and d stereoisomers. In some embodiments, a pharmaceutical composition comprises substantially only l stereoisomers or substantially only d stereoisomers. A pharmaceutical composition comprises “substantially only” l stereoisomers or substantially only d stereoisomers when the relevant stereoisomer is below a detectable level as measured by a conventional analytical method such as spectroscopy or chromatography.

Delivery Vehicles

[57] In some embodiments, a pharmaceutical composition includes a delivery vehicle for the PCAN agent. Delivery vehicles include, but are not limited to, a carbon nanotube, a carbon nanoparticle, a PEGylated nanosized graphene oxide, a gold nanoparticle, a nanosized metal- organic framework, a nanoparticle comprising polysiloxane, a polymeric micellar nanoparticle, a block copolymer micelle nanoparticle, and a liposome. See , e.g ., Johnstone e/a/., 2016

Therapeutic Methods

[58] The disclosed PCAN agents are useful for treating neoplastic disorders, including cancer. “Treat” as used in this disclosure means reducing or inhibiting the progression of one or more symptoms of the disorder or disease for which a PCAN agent is administered, such as inflammation or pain.

[59] For example, treatment of cancer may include inhibiting the progression of a cancer, for example, by reducing proliferation of neoplastic or pre-neoplastic cells; destroying neoplastic or pre-neoplastic cells; or inhibiting metastasis or decreasing the size of a tumor. Cancers that can be treated include, but are not limited to, multiple myeloma (including systemic light chain amyloidosis and Waldenstrom’s macroglobulinemia/lymphoplasmocytic lymphoma), myelodysplastic syndromes, myeloproliferative neoplasms, gastrointestinal malignancies (e.g, esophageal, esophagogastric junction, gallbladder, gastric, colon, pancreatic, hepatobiliary, anal, and rectal cancers), leukemias (e.g, acute myeloid, acute myelogenous, chronic myeloid, chronic myelogenous, acute lymphocytic, acute lymphoblastic, chronic lymphocytic, and hairy cell leukemia), Hodgkin lymphoma, non-Hodgkin’s lymphomas (e.g, B-cell lymphoma, hairy cell leukemia, primary cutaneous B-cell lymphoma, and T-cell lymphoma), lung cancer (e.g, small cell and non-small cell lung cancers), basal cell carcinoma, plasmacytoma, breast cancer, bladder cancer, kidney cancer, neuroendocrine tumors, adrenal tumors, bone cancer, soft tissue sarcoma, head and neck cancer, thymoma, thymic carcinoma, cervical cancer, uterine cancers, ovarian cancer (e.g, Fallopian tube and primary peritoneal cancers), vaginal cancer, vulvar cancer, penile cancer, testicular cancer, prostate cancer, melanoma (e.g, cutaneous and uveal melanomas), non melanoma skin cancers (e.g, basal cell skin cancer, dermatofibrosarcoma protuberans, Merkel cell carcinoma, and squamous cell skin cancer), malignant pleural mesothelioma, central nervous system (CNS) cancers (e.g, astrocytoma, oligodendroglioma, anaplastic glioma, glioblastoma, intra-cranial ependymoma, spinal ependymoma, medulloblastoma, CNS lymphoma, spinal cord tumor, meningioma, brain metastases, leptomeningeal metastases, metastatic spine tumors), and occult primary cancers (i.e., cancers of unknown origin).

[60] In some embodiments, a PCAN agent can be administered in conjunction with one or more other cancer therapies such as chemotherapies, immunotherapies, tumor-treating fields (TTF; e.g, OPTUNE ^® system), radiation therapies (XRT), and other therapies (e.g, hormones, autologous bone marrow transplants, stem cell reinfusions). “In conjunction with” includes administration together with, before, or after administration of the one or more other cancer therapies.

[61] Chemotherapies include, but are not limited to, FOLFOX (leucovorin calcium, fluorouracil, oxaliplatin), FOLFIRI (leucovorin calcium, fluorouracil, irinotecan), FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan, oxaliplatin), irinotecan ( e.g ., CAMPTOSAR ^@) , capecitabine (e.g., XELODA ^® ), gemcitabine (e.g., GEMZAR ^® ), paclitaxel (e.g.,

ABRAXANE ^® ), dexamethasone, lenalidomide (e.g, REVLIMID ^® ), pomalidomide (e.g, POMALYST ^® ), cyclophosphamide, regorafenib (e.g., STIVARGA ^® ), erlotinib (e.g., TARCEVA ^® ), ixazomib (e.g., NINLARO ^® ), bevacizumab (e.g., AVASTIN ^® ), bortezomib (e.g., VELCADE ^® , NEOMIB ^® ), cetuximab (e.g, ERBITUX ^® ), daratumumab (e.g, DARZALEX ^® ), elotumumab (e.g., EMPLICITI™), carfilzomib (e.g., KYPROLIS ^® ), palbociclib (e.g., IBRANCE ^® ), fulvestrant (e.g, FASLODEX ^® ), carboplatin, cisplatin, taxol, nab paclitaxel (e.g, ABRAXANE ^® ), 5 -fluorouracil, RVD (lenalidomide, bortezomib, dexamethasone), pomolidamide (e.g, POMALYST ^® ), temozolomide (e.g, TEMODAR ^® ), PCV (procarbazine, lomustine, vincristine), methotrexate (e.g., TREXALL ^® , RASUVO ^® , XATMEP ^® ), carmustine (e.g, BICNU ^® , GLIADEL WAFER ^® ), etoposide (e.g, ETOPOPHOS ^® , TOPOSAR ^® ), sunitinib (e.g, SUTENT ^® ), everolimus (e.g, ZORTRESS ^® , AFINITOR ^® ), rituximab (e.g, RITUXAN ^® , MABTHERA ^® ), R-MPV (vincristine, procarbazine, rituximab), cytarabine (e.g, DEPOCYT ^® , CYTOSAR-U ^® ), thiotepa (e.g, TEPADINA ^® ), busulfan (e.g, BUSULFEX ^® , MYLERAN ^® ), TBC (thiotepa, busulfan, cyclophosphamide), ibrutinib (e.g, IMBRUVICA ^® ), topotecan (e.g, HYCAMTIN ^® ), pemetrexed (e.g, ALIMTA ^® ), vemurafenib (e.g, ZELBORAF ^® ), cobimetinib (e.g, COTELLIC ^® ), dabrafenib (e.g, TAFINLAR ^® ), trametinib (e.g, MEKINIST ^® ), alectinib (e.g, ALECENSA ^® ), lapatinib (e.g, TYKERB ^® ), neratinib (e.g, NERLYNX ^® ), ceritinib (e.g, ZYKADIA ^® ), brigatinib (e.g, ALUNBRIG ^® ), afatinib (e.g, GILOTRIF ^® , GIOTRIF ^® ), gefitinib (e.g, IRES S A ^® ), osimertinib (e.g, TAGRISSO ^® , TAGRIX ^® ), and crizotinib (e.g, XALKORI ^® ).

[62] Immunotherapies include, but are not limited to, checkpoint inhibitors, including monoclonal antibodies such as ipilimumab (e.g, YERVOY ^® ), nivolumab (e.g, OPDIVO ^® ), pembrolizumab (e.g, KEYTRUDA ^® ); cytokines; cancer vaccines; and adoptive cell transfer.

[63] In some embodiments, one or more PCAN agents described above are administered to a patient with a cancer, including any of those cancers listed above. In some embodiments, as described below, the patient has colon cancer, rectal cancer, pancreatic cancer, multiple myeloma, or glioblastoma multiforme and the platinum complexes(s) are administered in conjunction with an additional therapy appropriate for the particular cancer.

[64] The disclosed platinum complexes can be used to treat these and other disorders in the same way a platinum complex anti -neoplastic agent is used, and these methods are well known. An advantage of platinum complexes, however, is that the cannabinoid can be delivered at or near the site of action of the therapeutic agent, where the released cannabinoid can provide further therapeutic benefits.

[65] Suitable administration routes include, but are not limited to, intravenous, intraperitoneal, intratumoral, intra-arterial, intra-arterial with blood brain barrier disruption, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, intranasal, subcutaneous, and intrapleural. The dose of a PC AN agent can be based on the doses typically used for other platinum complex anti -neoplastic agents. These doses are well known in the art.

Example 1. Synthesis of Compound 1

[66] Compound 1 can be synthesized as follows.

[67] Ortho-dihydroxybenzenes are connected to platinum in the presence of AgNCb (Faming Zhuanli Shenqing, 101177435, 14 May 2008, Faming Zhuanli Shenqing, 101177434, 14 May 2008). Connection of one or two (as shown) phenolic groups, in this case from a cannabinoid (CBD in this example) are connected in a similar fashion. Example 2. Synthesis of Compounds 2a, 2b, and 2c

[68] Compound 2a can be synthesized as follows.

15 - -

[69] Compound 2b can be synthesized as follows.

[70] Compound 2c can be synthesized as follows. cannabidiolic acid

62928-11-4

Example 3. Synthesis of Compounds 3a and 3b

[71] Compound 3a can be synthesized as follows.

[72] Compound 3b can be synthesized as follows.

Example 4. Synthesis of Compound 4

[73] Compound 4 can be synthesized as follows. Related Pt dicarbonates (129551-82-2, 129551-94-6, 160953-30-0, Inorganic Chemistry (1995), 34(5), 1015-2, EP 328274 A1 19890816) have been made from [62928-11-4] and pyrocarbonates. Acylation of OH groups on Pt ⁴⁺ is well known. Accordingly, reaction of CBD and [62928-11-4] with phosgene or an appropriate surrogate reagent system forms the carbonate link between the cannabinoid and platinum. Alternatively, Pt ⁴⁺ OH groups can react with alkyl carbonates to form new alkyl carbonates; thus, it may also be possible to generate the reagent where both X groups are CBD and react it with the Pt reagent.

Example 5. Synthesis of Compounds 5a and 5b [74] Compound 5a can be synthesized as follows.

[75] Alternatively, cannabidiol can be acylated with succinic anhydride to form the cannabidiol propionic acid derivative shown in the synthesis of Compound 5b, below. Reaction of this intermediate with [62928-11-4] under esterification conditions yields compound 5a. [76] Compound 5b can be synthesized as follows.

Example 6. Synthesis of Compound 6

[77] Compound 6 can be synthesized as follows.

[78] Phenols can be converted to the corresponding vinyl ether as shown in the reference in the Scheme below. Reaction of the vinyl ether with isocyanic acid [75-13-8] (JOC, 28(8), 2082- 5; 1963) generates the isocyanate. The isocyanate then reacts with [62928-11-4] (Inorganic Chemistry (1995), 34(5), 1015-2; EP 328274 A1 19890816) to form Example 6. CBD dibromoethane, KOtBu

Journal of Molecular Catalysis A: Chemical, 226(1), 141-147; 2005

Example 7. Synthesis of Compound 7

[79] Compound 7 can be synthesized as follows.

CBD

References

Intini et al., “Novel Antitumor Platinum(II) Conjugates Containing the Nonsteroidal Anti inflammatory Agent Diclofenac: Synthesis and Dual Mechanisms of Antiproliferative Effects,” Inorg. Chem. 56, 1483-97, 2017

Jia et al., “Elucidation of the Mechanism of Action for Metal Based Anticancer Drugs by Mass Spectrometry-Based Quantitative Proteomics,” Molecules 24, 581, 2019, 17 pages

Johnstone et al., “The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs,” Chem. Rev. 116, 3436-86, 2016

Kozubik et al., “Novel Anticancer Platinum(IV) Complexes with Adamantylamine: Their Efficiency and Innovative Chemotherapy Strategies Modifying Lipid Metabolism,” Metal- Based Drugs, Volume 2008, Article ID 417897, 15 pages

Li et al., “Current Developments in Pt(IV) Prodrugs Conjugated with Bioactive Ligands,” Bioinorganic Chemistry and Applications Volume 2018, Article ID 8276139, 18 pages

Monroe et al., “Anti-cancer characteristics and ototoxicity of platinum(II) amine complexes with only one leaving ligand,” PLoS ONE 13, 30192505, 2018, 21 pages

Ndagi et al., “Metal complexes in cancer therapy— an update from drug design perspective,” Drug Design, Development and Therapy 11, 599-616, 2017

Neumann et al., “Conjugates of Cisplatin and Cyclooxygenase Inhibitors as Potent Antitumor Agents Overcoming Cisplatin Resistance,” (No Suggestions) 9, 1150-53, 2014 2014

Tolan et al., “Anti-tumor platinum (IV) complexes bearing the anti-inflammatory drug naproxen in the axial position,” Appl. Organometal Chem. 33:e4763, 2019, 12 pages

Zhou et al., “The effect of geometric isomerism on the anticancer activity of the monofunctional platinum complex trans-[Pt(NH3)2(phenanthridine)ClN03,” Chem. Commun. 54, 2788- 91, 2018.