KR20160045668A - Lipid-based platinum compounds and nanoparticles - Google Patents

Abstract

The present invention relates to the field of nanotechnology and cancer therapy. In particular, the present invention relates to platinum-based compounds comprising platinum moieties, linker moieties, and lipid moieties and their corresponding nanoparticles. The present invention further relates to the synthesis of the platinum-based compounds, the synthesis of nanoparticles, and the synthesis of compositions comprising the platinum-based compounds / nanoparticles. The present invention also relates to a method of managing cancer by using the above-mentioned carbene compounds, platinum-based compounds, nanoparticles and compositions thereof.

Description

LIPID-BASED PLATINUM COMPOUNDS AND NANOPARTICLES < RTI ID = 0.0 >

Related application

This application claims the benefit of U.S. Patent Application No. 1781 / DEL / 2013 filed on June 14, 2013, the contents of which are incorporated herein by reference in their entirety. Benefits are claimed under one or more of § 119 (a) -119 (d).

The present invention relates to the field of nanotechnology and cancer therapy. In particular, the present invention relates to platinum-based compounds comprising platinum moieties, linker moieties, and lipid moieties and their corresponding nanoparticles. The present invention further relates to the synthesis of the platinum-based compounds, the synthesis of nanoparticles, and the synthesis of compositions comprising the platinum-based compounds / nanoparticles. The present invention also relates to a method of managing cancer by using the above-mentioned platinum-based compounds, nanoparticles and compositions.

The use of nanotechnology in cancer is emerging worldwide. There are several reports of nanoparticles in cancer therapy, but they all have various drawbacks such as toxicity, low kinetics of drug release, and low circulation stability.

Complexes such as lipidic nanoparticles (e.g., Doxil, pegylated liposomal formulation of doxorubicin hydrochloride) and albumin-complexes (e.g., Abraxane, paclitaxel-albumin complexes) Particles have been used in humans and have been proven to have an improved systemic toxicity profile and have helped to solve certain difficulties in formulation (Ferrari M, Nature Rev. Cancer, 2005, 5: 161 ]). Platinum-based chemotherapeutic agents are used as first-line therapy in excess of 70% of all cancers. Cisplatin (cisplatin) is a cis _{- [Pt (NH 3) 2} Cl (OH 2)] + and cis _{- [Pt (NH 3) 2} (OH 2)] undergoes the rapid formation of ^2+, and as a result nephrotoxicity (nephrotoxicity ). In addition, the acquisition of both carboplatin and oxaliplatin is significantly slower, resulting in reduced potency. In recent years, considerable progress has been made by Dhar et al. (PNAS, 2008, 105, 17356), which discloses a platinum (IV) complex (c, t) sufficiently hydrophobic to encapsulate into PLGA-b- , c - [Pt (NH ₃ ) ₂ (O ₂ CCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ) ₂ Cl ₂ ]). However, the prodrug in such cases must be intracellularly processed into cisplatin. Moreover, an alternative strategy based on conjugation of platinum to the polymer (e.g., polyamidoamine dendrimer-platinum complex) was reduced by 200 to 550 times in comparison to free cisplatin in cytotoxicity. This was the result of a strong bond formed between the polymer and the platinum (J Pharm Sci, 2009, 98, 2299). Another example is AP5280, a less potent N- (2-hydroxypropyl) methacrylamide copolymer-bonded platinum than carboplatin. Here, the platinum is retained by an aminomalonic acid chelating agent coupled to the COOH-terminal glycine of the tetrapeptide spacer (Clin Can Res, 2004, 10, 3386); Eur J Can, 2004, 40, 291 ]).

In addition, International Patent Application Publication WO 2010/091192 A2 (Sengupta et al.) Discloses a biosensor comprising a copolymer backbone, a plurality of side chains covalently bonded to the backbone, and a plurality of platinum compounds releasably bonded to the backbone Conjugated polymer nanoparticles. The disclosure also relates to a dicarbonyl-lipid compound wherein the platinum compound is releasably bound to the dicarbonyl compound.

However, various drawbacks are associated with currently used nanoparticles. The present invention aims to overcome the shortcomings of the prior art and to provide a nano-platinate which is stable, powerful and safer in cancer chemotherapy.

In one aspect, the present invention provides a process for the preparation of (a) a platinum moiety; And (b) a lipid linked to the platinum moiety. In some embodiments, the present compounds have formula VIII:

(VIII)

Q-linker-lipid

In this formula,

Q is a platinum containing moiety, and the linker has at least one bond to the platinum atom.

The present invention also provides a method of obtaining the Pt-lipid molecules disclosed herein. Thus, in one aspect, the present invention provides a method of obtaining a compound comprising (a) a platinum moiety, and a lipid linked to the platinum moiety, wherein the method is a method of obtaining a compound comprising contacting the lipid with a platinum moiety ≪ / RTI > to yield the compound.

The present invention also provides particles, such as nanoparticles, comprising one or more of the Pt-lipid molecules disclosed herein. Thus, in one aspect, the present invention provides particles comprising platinum-based compounds, such as, but not limited to, nanoparticles, wherein the platinum-based compound comprises (a) a platinum moiety; And (b) a lipid linked to the platinum moiety.

The present invention also relates to pharmaceutical compositions comprising a compound as described above or a nanoparticle as described above or a combination thereof, together with a pharmaceutically acceptable excipient, and a pharmaceutical composition as described above, The present invention provides a method for managing or treating cancer, comprising administering to a subject in need of such treatment or treatment a cancer or a composition as described above.

In order that the present invention may be readily understood and practiced, reference will now be made to the exemplary embodiments as illustrated with reference to the accompanying drawings. These drawings, which are incorporated in and constitute a part of this specification, form a part hereof, together with further description of the invention, serve to further illustrate the embodiments and to explain various principles and advantages thereof.
Figures 1a to 1c is a carbamoyl cholesterol having mate bond depicts the synthetic procedure of oxaliplatin compound (formula I) (compounds 1, 2 and 3). Reagents and conditions: a) Ethylenediamine (20 eq), dry DCM, 0 ° C to room temperature (RT), 24 hours; b) succinic anhydride, DCM, pyridine, RT, 24 h; c) Malonic acid monoethyl ester, DCM, EDCI, HOBt, RT, 24 h; d, d ') LiOH, THF , H 2 O, 3 sigan, RT; e) oxalic acid monoethyl ester, DCM, EDCI, HOBt, RT, 24 h; f) AgNO ₃ , H ₂ O, RT, 24 h; g, g ', g ") DMF, H 2 O, RT, 24 hours.
Figures 2a to 2c depict the synthetic procedure of cholesterol-oxaliplatin compounds (Formula I) (compounds 6, 4 and 5) having an ether linkage. Reagents and conditions: a) TsCl, dry DCM, pyridine, RT, 6 hours; b) ethylene glycol, dioxane, reflux, 4 h; c) TsCl, DCM, pyridine, RT, 6 h; d) NaN ₃ , DMF, 3 h, RT; e) PPh ₃ , THF, H ₂ O, RT, 4 h; f) succinic anhydride, DCM, pyridine, RT, 24 h; g) malonic acid monoethyl ester, DCM, EDCI, HOBt, RT, 24h; h, h ') LiOH, THF , H 2 O, 3 sigan, RT; i) Oxalic acid monoethyl ester, DCM, EDCI, HOBt, RT, 24 h; j) AgNO ₃ , H ₂ O, RT, 24 h; k, k ', k ") DMF, H 2 O, RT, 24 hours.
Figure 3a to 3e shows the synthetic procedure of the compound of formula III. Figure 3a shows the synthesis of compound 32, where R = cholesterol or other lipids. Figure 3b shows the synthesis of compound 33, where R = cholesterol or other lipids. Figure 3c shows the synthesis of compound 34, where R = cholesterol or other lipids. Figure 3d shows the synthesis of compound 35, where R = cholesterol or other lipids. Figure 3e shows the synthesis of compound 36, where R = cholesterol or other lipids.
Figure 4a to Figure 4e depicts a synthetic process of the compound of formula (II). Figure 4a demonstrates the synthesis of compound 38. Figure 4b shows the synthesis of compound 39. Figure 4c shows the synthesis of compound 40. Figure 4d shows the synthesis of compound 41. Figure 4e shows the synthesis of compound 42.
Figure 5 depicts the physicochemical characterization of nanoparticles. A DLS chart showing the distribution of particle sizes is shown.
Figure 6a to Figure 6c is synthesized cholesterol - depicts the in vitro (in-vitro) Characterization of oxaliplatin nanoparticle composition. These graphs of as measured using the MTT test 4T1 (breast cancer cell line) (Fig. 6a), HeLa (cervical cancer cell line) (Fig. 6b) and LLC (lung cancer cell line) (Fig. 6c) different for a cell viability of cancer cells (Concentration-effect of cholesterol-oxaliplatin nanoparticle composition and oxaliplatin (control). The x-axis describes the equivalent concentration of platinum.
Figures 7a-7f show the MTT test results for some exemplary compounds disclosed herein. Graphical representation of MTT assays for the activity of exemplary compounds investigated for various human cancer cell lines. The MTT assay showed a decrease in cell viability for the various exemplary compounds tested. The IC ₅₀ values of the compound / oxaliplatin tested in the cell line are listed together next to the corresponding color as the cell viability curve.
8 shows the cell uptake of the platinum compound. Cells were incubated with platinum compounds at a concentration of 50 [mu] M for 5 hours. The amount of platinum accumulated in the cells was measured by AAS and expressed as ng of platinum accumulated per 10 ⁵ cells.
Figure 9 shows the platinum distribution in the tumor. The total platinum content in the tumor was measured by AAS and expressed as ng of platinum accumulated per mg of tumor.

In some embodiments, a platinum-based compound is disclosed, wherein the platinum-based compound comprises (a) a platinum moiety; (b) at least one linker connected to the platinum moiety; And (c) a lipid connected to the linker.

In the compounds disclosed herein, the platinum moiety is attached to the lipid molecule either directly or through a linker molecule. In some embodiments, the platinum moiety is linked to the lipid molecule through a linker molecule. For example, the presence of a linker can provide a carbamate and / or ether linkage linking a dicarbonyl molecule (for linking with a platinum moiety) to a lipid molecule. In some other embodiments of the invention, the platinum moiety is directly linked to the lipid molecule. All possible linker molecules that provide carbamate and / or ether linkages form part of the present invention.

In some embodiments, the platinum-based compound disclosed herein is a compound of formula VIII:

(VII)

Q-linker-lipid

In this formula,

Q is a platinum containing moiety, and the linker has at least one bond to the platinum atom.

이며, 여기서 X₃은 (CH₂)_n, CH₂-NH 및 C₄H₈을 포함하는 군으로부터 선택되고; X₄는 CO 또는 -CH-CH₃이고; Z는 백금 함유 화합물이며, 여기서 백금은 고리의 일부를 형성하고; n은 0, 1, 또는 2이다.In some embodiments of the various embodiments described herein, Q is

, Wherein X ₃ is selected from the group comprising (CH ₂ ) _n , CH ₂ -NH and C ₄ H ₈ ; X ₄ is CH-CO or -CH _3, and; Z is a platinum containing compound wherein platinum forms part of a ring; n is 0, 1, or 2;

이며, 여기서 X는 NH 또는 N(CH₂COO^-)이고; Z는 백금 함유 화합물이며, 여기서 백금은 고리의 일부를 형성한다.In some embodiments of the various embodiments described herein, Q is

, Where X is NH or N (CH ₂ COO ^-) and; Z is a platinum-containing compound, wherein platinum forms part of the ring.

이며, 여기서 X는 S⁺, C, S⁺=O, N⁺H 및 P=O를 포함하는 군으로부터 선택되고; X₁은 -CH, -CH₂ 및 -CH₂O를 포함하는 군으로부터 선택되고; X₂는 C=O이고; Z는 백금 함유 화합물이며, 여기서 백금은 고리의 일부를 형성한다.In some embodiments of the various embodiments described herein, Q is

, Wherein X is selected from the group comprising S ⁺ , C, S ⁺ = O, N ⁺ H and P = O; X ₁ is selected from the group comprising -CH, -CH _2, and -CH ₂ O; X ₂ is C = O; Z is a platinum-containing compound, wherein platinum forms part of the ring.

이며, 여기서 X₁은 (CH₂)_n이고; X₂는 C=O이고; Z는 백금 함유 화합물이며, 여기서 백금은 고리의 일부를 형성하고; n은 0, 1, 또는 2이다.In some embodiments of the various embodiments described herein, Q is

, Where X ₁ is (CH _{2) n} a; X ₂ is C = O; Z is a platinum containing compound wherein platinum forms part of a ring; n is 0, 1, or 2;

In some embodiments of the various embodiments disclosed herein, the platinum is coordinated to a leaving group through a native O-Pt monocarboxylate covalent bond and ═O → Pt coordination bond. Additionally, the present invention also discloses a platinum-based compound wherein the platinum is coordinated to the leaving group through an O-Pt monocarboxylate or dicarboxylate covalent bond (s).

In some embodiments of the various embodiments disclosed herein, the platinum moiety is a platinum (II) or platinum (IV) compound. In some embodiments, the platinum (II) compound is selected from the group comprising DACH-platinum, cisplatin, oxaliplatin, carboplatin, paraplatin, sartaplatin, and various combinations thereof. In some embodiments, the platinum-containing compound is a Pt (II) compound, a Pt (IV) compound, or a halide-containing platinum compound. In a preferred embodiment, the platinum compound is oxaliplatin.

이며, 여기서 R₁ 및 R₂는 독립적으로 할로겐, 알킬, 아미노, 알킬아미노, 디알킬아미노, 하이드록실, 알콕시, 티올, 티오알킬, O-아실, 또는 이들의 임의의 조합이다. 일부 실시 형태에서, R₁과 R₂는 Pt 원자와 함께, 선택적으로 치환된 사이클릴 또는 헤테로사이클릴을 형성한다. 일부 실시 형태에서, Z는

이며, 여기서 p is 0, 1, 2, 또는 3이다. 일 실시 형태에서, p는 2이다.In some embodiments, Z is

Wherein R ₁ and R ₂ are independently halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, O-acyl, or any combination thereof. In some embodiments, R ₁ and R ₂ together with the Pt atom form an optionally substituted cyclic or heterocyclyl. In some embodiments, Z is

, Where p is 0, 1, 2, or 3. In one embodiment, p is 2.

이며, 여기서 R¹, R² 및 R³은 독립적으로 할로겐, 알킬, 아미노, 알킬아미노, 디알킬아미노, 하이드록실, 알콕시, 티올, 티오알킬, O-아실, -링커-지질, 또는 이들의 임의의 조합이다. 일부 실시 형태에서, R₁과 R₂는 Pt 원자와 함께 또는 R₂와 R₃은 Pt 원자와 함께, 선택적으로 치환된 사이클릴 또는 헤테로사이클릴을 형성한다. 일 실시 형태에서, R₁과 R₂는 Pt 원자와 함께 그리고 R₂와 R₃은 Pt 원자와 함께, 선택적으로 치환된 사이클릴 또는 헤테로사이클릴을 형성한다.In some embodiments, Z is

Wherein R ¹ , R ² and R ³ are independently selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, O-acyl, . In some embodiments, R ₁ and R ₂ together with the Pt atom or R ₂ and R ₃ together with the Pt atom form an optionally substituted cyclic or heterocyclyl. In one embodiment, R ₁ and R ₂ together with the Pt atom and R ₂ and R ₃ together with the Pt atom form an optionally substituted cyclic or heterocyclyl.

이고, R₁은 할로겐, 알킬, 아미노, 알킬아미노, 디알킬아미노, 하이드록실, 알콕시, 티올, 티오알킬, O-아실, 또는 이들의 임의의 조합이고; p는 0, 1, 2, 또는 3이다. 이의 일부 추가 실시 형태에서, R₁은 할로겐 -Cl, -NCS, -O=S(CH₃)₂, -SCH₃, 또는 -링커-지질이다. 일 실시 형태에서, p는 2이다. In some embodiments, Z is

And R ₁ is halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, O-acyl, or any combination thereof; p is 0, 1, 2, or 3; In some further embodiments thereof, R ₁ is halogen-Cl, -NCS, -O = S (CH ₃ ) ₂ , -SCH ₃ , or a linker-lipid. In one embodiment, p is 2.

이다.In some embodiments, Z is

to be.

이며, 여기서 R₁, R₂, R₃, R₄ 및 R₅는 독립적으로 할로겐, 알킬, 아미노, 알킬아미노, 디알킬아미노, 하이드록실, 알콕시, 티올, 티오알킬, O-아실, -링커-지질, 또는 이들의 임의의 조합이다. 일부 실시 형태에서, R₁과 R₂는 Pt 원자와 함께, 선택적으로 치환된 사이클릴 또는 헤테로사이클릴을 형성한다. 일부 실시 형태에서, R₁과 R₂는 Pt 원자와 함께, 선택적으로 치환된 사이클릴 또는 헤테로사이클릴을 형성한다. 일 실시 형태에서, R₁과 R₂는 Pt 원자와 함께, 선택적으로 치환된 사이클릴 또는 헤테로사이클릴을 형성하고, R₃과 R₄는 Pt 원자와 함께, 선택적으로 치환된 사이클릴 또는 헤테로사이클릴을 형성한다. 일부 실시 형태에서, R₅는 OH, OC(O)CH₃, 또는 OC(O)-페닐이다.In some embodiments, Z is

Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are independently selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, Lipids, or any combination thereof. In some embodiments, R ₁ and R ₂ together with the Pt atom form an optionally substituted cyclic or heterocyclyl. In some embodiments, R ₁ and R ₂ together with the Pt atom form an optionally substituted cyclic or heterocyclyl. In one embodiment, R ₁ and R ₂ together with the Pt atom form an optionally substituted cyclic or heterocyclyl, R ₃ and R ₄ together with the Pt atom form an optionally substituted cyclic or heterocyclic Thereby forming a reel. In some embodiments, R ₅ is OH, OC (O) CH ₃ , or OC (O) -phenyl.

이며, 여기서 p 및 q는 독립적으로 0, 1, 2, 또는 3이다. 일부 실시 형태에서, p는 2이다. 일부 실시 형태에서, q는 2이다. 일 실시 형태에서, p 및 q는 둘 모두 2이다.In some embodiments, Z is

, Wherein p and q are independently 0, 1, 2, or 3. In some embodiments, p is 2. In some embodiments, q is 2. In one embodiment, p and q are both 2.

이며, 여기서 p 및 q는 둘 모두 2이고; R₅는 OH, OC(O)CH₃, 또는 OC(O)-페닐이다.In one embodiment, Z is

, Wherein p and q are both 2; R ₅ is OH, OC (O) CH ₃ , or OC (O) -phenyl.

In some embodiments, the platinum (II) compound comprises at least two nitrogen atoms, and the nitrogen atoms are directly connected to the platinum. In a further embodiment, the two nitrogen atoms are connected to one another via an optionally substituted linker, such as an acyclic or cyclic linker. The cyclic linker means a linking moiety comprising at least one ring structure. The cyclic linker may be aryl, heteroaryl, cyclic or heterocyclyl.

이며, 여기서 R₁ 및 R₂는 독립적으로 할로겐, 알킬, 아미노, 알킬아미노, 디알킬아미노, 하이드록실, 알콕시, 티올, 티오알킬, O-아실, 또는 이들의 임의의 조합이다. 일부 실시 형태에서, R₁과 R₂는 Pt 원자와 함께, 선택적으로 치환된 사이클릴 또는 헤테로사이클릴을 형성한다. 일부 실시 형태에서, Q는

이며, 여기서 p is 0, 1, 2, 또는 3이다. 일 실시 형태에서, p는 2이다.In some embodiments, Q is

Wherein R ₁ and R ₂ are independently halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, O-acyl, or any combination thereof. In some embodiments, R ₁ and R ₂ together with the Pt atom form an optionally substituted cyclic or heterocyclyl. In some embodiments, Q is

, Where p is 0, 1, 2, or 3. In one embodiment, p is 2.

이며, 여기서 R¹, R² 및 R³은 독립적으로 할로겐, 알킬, 아미노, 알킬아미노, 디알킬아미노, 하이드록실, 알콕시, 티올, 티오알킬, O-아실, 또는 이들의 임의의 조합이다. 일부 실시 형태에서, R₁과 R₂는 Pt 원자와 함께 또는 R₂와 R₃은 Pt 원자와 함께, 선택적으로 치환된 사이클릴 또는 헤테로사이클릴을 형성한다. 일 실시 형태에서, R₁과 R₂는 Pt 원자와 함께 그리고 R₂와 R₃은 Pt 원자와 함께, 선택적으로 치환된 사이클릴 또는 헤테로사이클릴을 형성한다.In some embodiments, Q is

Wherein R ¹ , R ² and R ³ are independently halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, O-acyl, or any combination thereof. In some embodiments, R ₁ and R ₂ together with the Pt atom or R ₂ and R ₃ together with the Pt atom form an optionally substituted cyclic or heterocyclyl. In one embodiment, R ₁ and R ₂ together with the Pt atom and R ₂ and R ₃ together with the Pt atom form an optionally substituted cyclic or heterocyclyl.

이고, R₁은 할로겐, 알킬, 아미노, 알킬아미노, 디알킬아미노, 하이드록실, 알콕시, 티올, 티오알킬, O-아실, 또는 이들의 임의의 조합이고; p는 0, 1, 2, 또는 3이다. 이의 일부 추가 실시 형태에서, R₁은 할로겐 -Cl, -NCS, -O=S(CH₃)₂, -SCH₃, 또는 -링커-지질이다. 일 실시 형태에서, p는 2이다.In some embodiments, Q is

And R ₁ is halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, O-acyl, or any combination thereof; p is 0, 1, 2, or 3; In some further embodiments thereof, R ₁ is halogen-Cl, -NCS, -O = S (CH ₃ ) ₂ , -SCH ₃ , or a linker-lipid. In one embodiment, p is 2.

이다.In some embodiments, Q is

to be.

이며, 여기서 R₁, R₂, R₃, R₄ 및 R₅는 독립적으로 할로겐, 알킬, 아미노, 알킬아미노, 디알킬아미노, 하이드록실, 알콕시, 티올, 티오알킬, O-아실, 또는 이들의 임의의 조합이다. 일부 실시 형태에서, R₁과 R₂는 Pt 원자와 함께, 선택적으로 치환된 사이클릴 또는 헤테로사이클릴을 형성한다. 일부 실시 형태에서, R₁과 R₂는 Pt 원자와 함께, 선택적으로 치환된 사이클릴 또는 헤테로사이클릴을 형성한다. 일 실시 형태에서, R₁과 R₂는 Pt 원자와 함께, 선택적으로 치환된 사이클릴 또는 헤테로사이클릴을 형성하고, R₃과 R₄는 Pt 원자와 함께, 선택적으로 치환된 사이클릴 또는 헤테로사이클릴을 형성한다. 일부 실시 형태에서, R₅는 OH, OC(O)CH₃, 또는 OC(O)-페닐이다.In some embodiments, Q is

Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are independently selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, Any combination. In some embodiments, R ₁ and R ₂ together with the Pt atom form an optionally substituted cyclic or heterocyclyl. In some embodiments, R ₁ and R ₂ together with the Pt atom form an optionally substituted cyclic or heterocyclyl. In one embodiment, R ₁ and R ₂ together with the Pt atom form an optionally substituted cyclic or heterocyclyl, R ₃ and R ₄ together with the Pt atom form an optionally substituted cyclic or heterocyclic Thereby forming a reel. In some embodiments, R ₅ is OH, OC (O) CH ₃ , or OC (O) -phenyl.

이며, 여기서 p 및 q는 독립적으로 0, 1, 2, 또는 3이다. 일부 실시 형태에서, p는 2이다. 일부 실시 형태에서, q는 2이다. 일 실시 형태에서, p 및 q는 둘 모두 2이다.In some embodiments, Q is

, Wherein p and q are independently 0, 1, 2, or 3. In some embodiments, p is 2. In some embodiments, q is 2. In one embodiment, p and q are both 2.

이며, 여기서 p 및 q는 둘 모두 2이고; R₅는 OH, OC(O)CH₃, 또는 OC(O)-페닐이다.In one embodiment, Q is

, Wherein p and q are both 2; R ₅ is OH, OC (O) CH ₃ , or OC (O) -phenyl.

The term "lipid" is used in its ordinary sense and includes compounds having chain lengths varying from about 2 carbon atoms to as long as about 28 carbon atoms in short. Additionally, the compound may be saturated or unsaturated and may be in the form of a linear or branched chain, or in the form of a non-fused or fused ring structure. Exemplary lipids include, but are not limited to, fats, waxes, sterols, steroids, bile acids, fat-soluble vitamins (e.g., A, D, E and K), monoglycerides, diglycerides, phospholipids, glycolipids, But are not limited to, lipids such as chromolipids (lipochromes), sugar phospholipids, sphingolipids, prenol lipids, saccharose lipids, polyketides, and fatty acids.

Without limitation, the lipid may be selected from the group consisting of sterol lipids, fatty acids, fatty alcohols, glycolipids (e.g., monoglycerides, diglycerides, and triglycerides), phospholipids, glycerophospholipids, sphingolipids, prenol lipids, Polyesters, polyesters, polyesters, polyesters, polyesters, polyesters, polyesters, polyesters, Lipids can be polyunsaturated fatty acids or fatty alcohols. As used herein, the term " polyunsaturated fatty acid "or" polyunsaturated fatty alcohol "means a fatty acid or fatty alcohol having two or more carbon-carbon double bonds in the hydrocarbon chain. Lipids can also be highly unsaturated fatty acids or fatty alcohols. As used herein, the term "highly polyunsaturated fatty acid" or "highly polyunsaturated fatty alcohol" means a fatty acid or fatty alcohol having at least 18 carbon atoms and at least three double bonds. Lipids can be omega-3 fatty acids. As used herein, the term "omega-3 fatty acid" refers to polyunsaturated fatty acids in which the first double bond occurs at the third carbon-carbon bond from the opposite end of the acid group.

In some embodiments, the lipid may be selected from the group consisting of: 1,3-propanediol dicaprylate / dicaprate; 10-undecenoic acid; 1-ditriacontanol; 1-heptacanoic acid; 1-nonanoic acid; 2-ethylhexanol; Androstane; Arachidic acid; Arachidonic acid; Arachidyl alcohol; Behenic acid; Behenyl alcohol; Capmul MCM C10; Capric acid; Capric alcohol; Caprylic alcohol; Caprylic acid; Caprylic acid / capric acid esters of saturated fatty alcohols C12-C18; Caprylic / capric acid triglyceride; Caprylic / carraic acid triglyceride; Ceramide phosphorylcholine (sphingomyelin, SPH); Ceramide phosphorylethanolamine (Sphingomyelin, Cer-PE); Ceramide phosphoryl glycerol; Cerplastic acid; Lt; / RTI >Lt; / RTI > Ceryl alcohol; Cetearyl alcohol; Ceteth-10; Cetyl alcohol; Cholan; Cholestane; cholesterol; Cis-11-eicosanoic acid; Cis-11-octadecenoic acid; Cis-13-docosanoic acid; Allyl alcohol; Coenzyme Q10 (CoQ10); Dihomo-gamma-linolenic acid; Docosahexaenoic acid; Egg lecithin; Eicosapentaenoic acid, eicosanic acid, elaidic acid, elaidorinolenyl alcohol; Elaidorinol rail alcohol; Elaidil alcohol; Erucic acid; Ethersyl alcohol; Estran; Ethylene glycol distearate (EGDS); Ged Mountain; Aldehydes; Glycerol distearate (Type I) EP (Precirol ATO 5); Glycerol tricaprylate / caprate; Glycerol tricaprylate / caprate (CAPTEX® 355 EP / NF); Glyceryl monocaprylate (Capmul MCM C8 EP); Glyceryl triacetate; Glyceryl tricaprylate; Glyceryl tricaprylate / caprate / laurate; Glyceryl tricaprylate / tricaprate; Glyceryl tripalmitate (tripalmitin); Henatriacontylic acid; Hexecosyl alcohol; Hexecosylic acid; Heptacosylic acid; Heptadecanoic acid; Heptadecyl alcohol; Hexatriacontylic acid; Isostearic acid; Isostearyl alcohol; Lacceroic acid; Lauric acid; Lauryl alcohol; Lignoceric acid; Lignoceryl alcohol; Linoleic acid; Linoleic acid; Linolenyl alcohol; Linoleyl alcohol; Margaric acid; Mead; Melissic acid; Melissyl alcohol; Montanic acid; Montanyl alcohol; Myristyl alcohol; Myristic acid; Myristoleic acid; Myristyl alcohol; Neodecanoic acid; Neoheptanoic acid; Neononanoic acid; Norbornic acid; Nonacosylic acid; Nonadecyl alcohol; Nonadecylic acid; Nonadecylic acid; Oleic acid; Oleyl alcohol; Palmitic acid; Palmitoleic acid; Pallitolyl alcohol; Pelargonic acid; Pelargonic alcohol; Pentacosylic acid; Pentadecyl alcohol; Pentadecylic acid; POSPATIDAYSAN (POSPATAYATE, PA); Phosphatidylcholine (lecithin, PC); Phosphatidylethanolamine (cephalin, PE); Phosphatidylinositol (PI); Phosphatidylinositol bisphosphate (PIP2); Phosphatidylinositol phosphate (PIP); Phosphatidylinositol triphosphate (PIP3); Phosphatidylserine (PS); Polyglyceryl-6-distearate; Prone; Propylene glycol dicaprate; Propylene glycol dicaprylroccaprate; Propylene glycol dicaprylroccaprate; Fumic acid; Ricinoleic acid; Ricinole rail alcohol; Sapienic acid; Soy lecithin; Stearic acid; Stearidic acid; Stearyl alcohol; Tricosylic acid; Tridecyl alcohol; Tridecylic acid; Triolein; Undecyl alcohol; Undecylenic acid; Undecylic acid; Park, Sung - San; ? -linolenic acid; ? -linolenic acid; Octadecenoic acid, cis-13-octadecenoic acid, cis-11-octadecenoic acid, cis-13-octadecenoic acid, But are not limited to, docosahexaenoic acid, docosahexaenoic acid, eicosapentaenoic acid, elaidic acid, erucic acid, heneicosic acid, heptacosic acid, heptadecanoic acid, isostearic acid, lauric acid, lignoceric acid, Butanedioic acid, neodecanoic acid, neodecanoic acid, nonadecanoic acid, oleic acid, palmitic acid, palmitoleic acid, pelargonic acid, pentacosylic acid, Stearic acid, tricosylic acid, tridecylic acid, undecylenic acid, undecylic acid, valeric acid, valeric acid, alpha-linolenic acid, gamma-linolenic acid, gamma-linolenic acid - fatty acid salts of linolenic acid; And any combination thereof.

In some embodiments, the lipid is cholesterol or alpha tocopherol.

As used herein, the term "linker " means an organic moiety that links two parts of a compound. The linker is typically a direct bond or atoms, such as oxygen or sulfur, a unit such as ^{NR 1, C (O),} C (O) NH, C (O) O, NHC (O) O, OC (O) O, SO , SO _2, SO ₂ NH or a chain of atoms, such as substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl , Heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylaryl Alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylarylalkenyl, Alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, < RTI ID = 0.0 > Alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylheterocyclylalkynyl, alkenylheterocyclylalkynyl, alkenylheteroarylalkynyl, alkynylheteroarylalkynyl, Alkylaryl, alkenylaryl, alkynylaryl, alkynylarylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkenyl, alkyl, heteroaryl, alkenyl includes a heteroaryl, alkynylene-heteroaryl, wherein at least one methylene is O, S, S (O) , SO 2, NR 1, C (O), C (O) NH, C ( O) O, NHC (O) O, OC (O) O, SO 2 NH, cutting connectable group, a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring by Or they can be intervened; Wherein R < ¹ > is hydrogen, acyl, aliphatic or substituted aliphatic.

In some embodiments, the linker is a branched linker. The branch point of the branched linker may be at least 3, but may be a 4, 5 or 6 membered atom, or a group that presents such a multivalent valence. In some embodiments, the branching point is selected from the group consisting of -N, -N (Q) -C, -OC, -SC, -SS-C, ) -C (O) -N (Q) C (O) -C or -N (Q) C Wherein Q is independently for each occurrence H or an optionally substituted alkyl. In some embodiments, the branching point is glycerol or a derivative thereof.

A cleavable linker is sufficiently stable outside the cell, but is cleaved upon entry into the target cell, releasing the two portions that the linker is holding together. In a preferred embodiment, the cleavable linker is attached to the target cell (s) in a target cell rather than under the second reference condition (e.g., which may be selected to mimic or exhibit conditions found in blood or serum) Or at least 10 times, preferably at least 100 times faster under the first reference condition (which may be selected, for example, to mimic or represent intracellular conditions).

A cleavable linker is desired to be affected by the presence of cleavage agents, such as pH, redox potential or degradable molecules. Generally, the cleavage factor is found or predominates to a higher level or activity within the cell than in serum or blood. Examples of such degradative agents include: redox agents that are selected for a particular substrate or that do not have substrate specificity (e.g., those that are present in cells capable of degrading a redox cleavable linkage group by reduction A reducing agent such as a mercaptan, or an oxidizing or reducing enzyme); Esterase; Amidase; Endosomes or agents capable of producing an acidic environment, such as those producing a pH of 5 or less; Enzymes capable of hydrolyzing or decomposing an acid cleavable linkage by acting as a general acid, peptidases and proteases (which may be substrate specific), and phosphatases.

The linker may comprise a cleavable linker that is cleavable by a particular enzyme. The type of cleavable linker incorporated into the linker may depend on the cell to be targeted. For example, the liver ligand may be linked to a cationic lipid via a linker comprising an ester group. The liver cells are enriched with esters, so that the linker will be cleaved more efficiently in liver cells than in cell types that are not enriched with esters. Other cell-types enriched for esters include the lung, kidney cortex, and testicular cells. Linkers containing peptide bonds can be used to target peptidase-rich cell types, such as liver and synovial cells.

In some embodiments, the cleavable linker is compared to blood or serum (or under in vitro conditions selected to mimic the extracellular conditions), and is expressed in the cell (or under in vitro conditions selected to mimic intracellular conditions) ) At least 1.25, 1.5, 1.75, 2, 3, 4, 5, 10, 25, 50, or 100 times faster. In some embodiments, the cleavable linker is 90%, 80% or more in blood (or in vitro conditions selected to mimic the extracellular conditions) compared to the cell (or under in vitro conditions selected to mimic intracellular conditions) , 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, or 1%.

Exemplary cleavable linkers include, but are not limited to, a redox cleavable linker (e.g., -SS- and -C (R) ₂ -SS-, wherein R is H or C ₁ -C ₆ alkyl, at least one R is C ₁ -C ₆ alkyl, such as CH ₃ or CH ₂ CH ₃ Im); (S) (SR) -O-, -SP (O) -O-, -OP (S) (OR) -S-, -SP (O) (OR) -S-, -SP (O) -S (R) -O-, -OP (O) (R) -O-, -OP (S) -O (O) (R) -S-, -OP (S) (R) -S-, -OP -O-, -OP (S) (SH) -O-, -SP (O) (OH) -OP (S) (OH) -S-, -SP (S) (OH) -O-, -OP (O) (H) -O-, -SP (S) (H) -O-, -SP is optionally substituted linear or branched C ₁ -C ₁₀ alkyl) replaced by; cuttable acid linking group (e.g., a hydrazone, ester of ester and amino acid, -C = NN-, and -OC (O) (For example, -C (O) O-), a peptide-based cleavable linkage group (for example, a linking group which is cleaved by an enzyme such as a peptidase and a protease in a cell, , for example, ^{-NHCHR a C (O) NHCHR B} C (O) -, wherein R ^a and R ^B is the two adjacent amino R giim of the mountains). Peptide-based cutting connectable groups include two or more amino acids and in some embodiments, peptide-based cutting coupling comprises a substrate, an amino acid sequence for a peptidase or protease that is found in the cell.

In some embodiments, the acid cleavable linker is present in an acidic environment with a pH of less than or equal to about 6.5 (e.g., about 6.5, 6.0, 5.5, 5.0, or less), or in an agent such as an enzyme .

Linkers in accordance with the present invention include moieties that include two or more carbon molecules, such as ethylenediamine, ethylene glycol, glycine, beta-alanine, and polyethylene glycol (PEG) having a molecular weight of about 44 to about 200 kD. It should also be understood from the present invention that platinum moieties and / or lipids can be modified to include functional groups for linking to linker molecules.

In some embodiments of the various embodiments disclosed herein, the linker is -X-CH ₂ -X ₂ -X ₁ -, wherein X is NH; X ₁ is C (O) O, C (O) NH, O (CH ₂ ) -O, NH, or O; X ₂ is (CH ₂ ) _n or C (O); n is 0, 1, 2, 3, 4, or 5.

In some other embodiments, the linker is _{- (CH 2) n O-,} - (CH 2) n NHC (O) O-, - (CH 2) n OC (O) NH-, - (CH 2) n C _{(O) NH (CH 2)} m O-, - (CH 2) n O (CH 2) m O-, - (CH 2) n O (O) -, - (CH 2) n NHC (O) ( CH ₂ ) _m O-, or - (CH ₂ ) _n C (O) O-, where n and m are independently 0, 1, 2, 3, 4,

In yet some other embodiments, the linker _{-X 3 -X 4 X 5 -X 6} - , where X ₃ is CH, CH _2, or O; X ₄ , X ₅ and X ₆ are independently the same or different and are -CH ₂ O- or O.

In still other embodiments, the linker is -CH ₂ O-.

In some embodiments, the linker is selected from the group consisting of _{bond, -O-, NHCH 2 CH 2 NHC} (O) -, -NHCH 2 CH 2 NHC (O) O-, -NHCH 2 CH 2 -, _{-NHCH 2 CH 2 O-, -NHCH 2} C (O) -, -NHCH 2 C (O) O-, -NHCH 2 C (O) OCH 2 CH 2 CH 2 -, -NHCH 2 C (O) OCH _{2 CH 2 CH 2 O-, -NHCH} 2 C (O) NH-, -CH 2 CH 2 -, -CH 2 CH 2 O-, -CH 2 CH 2 NHC (O) -, -CH 2 CH 2 NHC _{(O) O-, -CH 2 CH} 2 O-, -CH 2 C (O) NHCH 2 CH 2 -, -CH 2 C (O) NHCH 2 CH 2 O-, -CH 2 CH 2 OCH 2 CH 2 _{-, -CH 2 CH 2 OCH 2} CH 2 O-, -CH 2 C (O) -, -CH 2 C (O) O-, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 O _{-, = CHCH = CH 2 -} , = CHCH = CHCH 2 O-, -CH = CHCH 2 -, -CH = CHCH 2 O-, -OCH 2 CH 2 O-, -CH 2 -, - _{CH 2 O-, -NHC (O)} CH 2 -, -NHC (O) CH 2 O-, -C (O) CH 2 -, -C (O) CH 2 O-, -OC (O) CH 2 _{-, -OC (O) CH 2} O-, -C (O) CH 2 CH 2 C (O) NHCH 2 CH 2 -, -OC (O) CH 2 CH 2 C (O) NHCH 2 CH 2 -, _{-C (O) CH 2 CH 2} C (O) NHCH 2 CH 2 O-, -OC (O) CH 2 CH 2 C (O) NHCH 2 CH 2 O-, -C (O) CH 2 CH 2 C _{(O) NHCH 2 CH 2 NHC} (O) -, -OC (O) CH 2 CH 2 C (O) NHCH 2 CH 2 NHC (O) -, -C (O) CH 2 CH 2 C (O) NHCH ₂ CH ₂ NHC (O) O-, -OC (O) CH ₂ CH ₂ C (O) NHCH ₂ CH ₂ NHC (O) O-, and any combination thereof.

In some embodiments, the platinum-based compounds disclosed herein are represented by Formula I:

(I)

In this formula,

X is NH;

X ₁ is selected from the group comprising COOH, CONH ₂ , O- (CH ₂ ) _n -OH, NH ₂ and OH;

X ₂ is (CH ₂ ) _n or CO;

X ₃ is selected from the group comprising (CH ₂ ) _n , CH ₂ -NH and C ₄ H ₈ ;

X ₄ is CH-CO or -CH _3, and;

Z is a platinum-containing compound, wherein platinum forms part of the ring of formula (I);

N is 0, 1, or 2.

In some other embodiments, the platinum-based compounds disclosed herein are represented by formula II:

≪ RTI ID = 0.0 &

In this formula,

X is NH or N-CH ₂ COO ^-, and;

X ₁ is _{- (CH 2) n OH,} - (CH 2) n NHCOOH, - (CH 2) n CONH (CH 2) n OH, (CH 2) n O (CH 2) n OH, (CH 2) _n C = O, - (CH ₂ ) _n NHCO (CH ₂ ) _n OH and (CH ₂ ) _n -COOH;

Z is a platinum-containing compound wherein platinum forms part of a ring of formula II;

N is 0, 1, or 2.

In some embodiments, the platinum-based compounds disclosed herein are represented by formula III:

(III)

In this formula,

X is selected from the group comprising S ⁺ , C, S ⁺ = O, N ⁺ H and P = O;

X ₁ is selected from the group comprising -CH, -CH _2, and -CH ₂ O;

X ₂ is C = O;

X ₃ is selected from CH, CH ₂ or O;

X ₄ , X ₅ , X ₆ is selected from -CH ₂ O or O;

Z is a platinum-containing compound, wherein platinum forms part of a ring of formula III.

In some embodiments, the platinum-based compounds disclosed herein are represented by Formula IV:

(IV)

In this formula,

X is CH ₂ OH;

X ₁ is (CH _{2) n} a;

X ₂ is C = O;

Z is a platinum containing compound wherein platinum forms part of a ring of formula (IV);

N is 0, 1, or 2.

Exemplary compounds of formula I include, but are not limited to, the following compounds:

Exemplary compounds of formula (II) include, but are not limited to, the following compounds:

Exemplary compounds of formula (II) include, but are not limited to, the following compounds:

Exemplary compounds of formula (III) include, but are not limited to, the following compounds:

Exemplary compounds of formula (IV) include, but are not limited to, the following compounds:

Compound 22

The present invention also provides the following compounds:

In some embodiments, the platinum moiety of the platinum complex of the present invention is a platinum (IV) compound. The complex with the platinum (IV) compound is shown as follows:

Compound 96

Compound 97

Compound 98

Compound 99

Compound 100

In some embodiments of the various embodiments disclosed herein, the present invention provides platinum (II) compounds of formula V:

(V)

In this formula,

Wherein X ₁ , X ₂ , X ₃ and X ₄ are independently selected from O, P, S, Se, Cl, N, C, OA, OB, DACH, halide and chelated or non-chelated dicarboxylate bond Groups, and any combination thereof;

Wherein A and B are independently selected from the group consisting of C, P, S, N, and any combination thereof;

X ₄ is optional.

In some embodiments of the various embodiments disclosed herein, the platinum (II) compound of formula (V) is selected from the group comprising compounds 43 to 65 and compounds 73 to 85 and compound 95. In a preferred embodiment, the Pt (II) compound is DACH-Pt.

In the compound, a, R ^1, unless otherwise defined is-lipid, n is 1-linker.

In another embodiment, a platinum (II) compound [compound 95] is also provided by the present invention.

The synthesis of some exemplary compounds of formula (V) is described in the Examples section.

Without wishing to be bound by theory, the compounds disclosed herein have a higher uptake of platinum in cancer cells than cisplatin and oxaliplatin. As shown in Figure 8 , the uptake of cisplatin and oxaliplatin is similar in MDA-MB-231 cells. However, all of the exemplary compounds tested showed higher absorption (about 7 to 20 times). These results indicate that when the platinum equivalent concentration is administered, the uptake of an exemplary compound is significantly higher in cancer cells compared to cisplatin or oxaliplatin. In some embodiments, the compounds disclosed herein are about 25%, about 50%, about 75%, about 1-fold, about 5-fold, about 10-fold, about 15-fold , About 20 times, about 25 times or more platinum absorption.

In addition, the compounds disclosed herein also have a higher accumulation of platinum in tissues such as, but not limited to, cisplatin and oxaliplatin, when administered in equivalent doses. For example, the compounds disclosed herein, when administered at equivalent doses, may be administered at a dose of about 25%, about 50%, about 75%, about 1-fold, about 5-fold, about 10-fold, about 15-fold relative to cisplatin or oxaliplatin , About 20 times, about 25 times or more platinum accumulation structure.

The present invention relates to the synthesis of a series of platinum-based nanoparticles, wherein the diaminocyclohexyl-Pt (DACH-Pt) has a monocarboxylated covalent bond through a carboxylic acid and a coordination bond with the amide oxygen. Dicarbonyl molecules (dicarboxylic acids) such as succinic acid, malonic acid and oxalic acid are used, which eventually form 7, 6 and 5-membered rings with platinum (II), respectively. The linker between the platinum ring and the cholesterol helps to form a bond selected from the group comprising carbamate bonds (compounds 1, 2, 3), ether linkages (compounds 6, 4, 5), etc. or any combination thereof . Accordingly, some of the embodiments of the present invention are directed to compounds represented by the general structure: lipid-linker-dicarbonyl. These molecules are used in complex platinum compounds such as DACH-Pt, oxaliplatin, cisplatin, platinum-containing carbenes or other platinates and platinum compounds via covalent and / or coordination bonds.

In one embodiment of the present invention, several modifications of platinum-based compounds are also provided (e. G., Compounds 1-6), such as racemates, diastereomers, and the like.

In one embodiment of the invention, any molecule having two carbonyl groups may be used. In one embodiment, the dicarbonyl molecule is a dicarboxylic acid, such as succinic acid, malonic acid or oxalic acid.

The present invention also provides particles comprising at least one of the platinum-based compounds described herein. Generally, the particles disclosed herein may be in any shape or form, for example, spherical, rod-shaped, elliptical, cylindrical, encapsulated, or disc-shaped; These particles may be part of a network or agglomerate.

In some embodiments, the particles are microparticles or nanoparticles. As used herein, the term "microparticles" refers to particles having a particle size of from about 1 [mu] m to about 1000 [mu] m. As used herein, the term "nanoparticle" refers to a particle having a particle size from about 0.1 nm to about 1000 nm. Generally, the particles have an arbitrary size ranging from nm to millimeters. In some embodiments, the particles may have a size ranging from about 5 nm to about 5000 nm. In some embodiments, the particles have an average diameter of about 50 nm to about 2500 nm. In some embodiments, the particles have an average diameter of about 100 nm to about 2000 nm. In some embodiments, the particles have an average diameter of about 150 nm to about 1700 nm. In some embodiments, the particles have an average diameter from about 200 nm to about 1500 nm. In some embodiments, the particles have an average diameter of about 260 nm. In one embodiment, the particles have an average diameter of about 30 nm to about 150 nm. In some embodiments, the particles have an average diameter from about 100 nm to about 1000 nm, from about 200 nm to about 800 nm, from about 200 nm to about 700 nm, or from about 300 nm to about 700 nm.

In some embodiments, the particles have an average size of from about 50 to about 1000 nm. In a further embodiment, the nanoparticles of the present invention range from about 50 to about 500 nm. In yet another embodiment, the nanoparticles of the present invention range from about 50 to about 500 nm ( Figure 5 ). In one embodiment, the particles have a size of about 500 nm.

It will be appreciated by those skilled in the art that particles typically denote a distribution of particle sizes around the indicated "size ". Unless otherwise stated, as used herein, the term "particle size" refers to the mode of size distribution of particles, i.e., the most frequently occurring value in the size distribution. Methods for measuring particle size are known to those skilled in the art and include, for example, dynamic light scattering (e.g., photocorrelation spectroscopy, laser diffraction, low-angle laser light scattering (LALLS) Such as medium-angle laser light scattering (MALLS), light obscuration methods (e.g., Coulter analysis methods), or other techniques such as rheology and optical or electron microscopy The "substantially spherical" means that the ratio of the length of the longest perpendicular axis to the length of the shortest perpendicular axis of the particle cross section is less than or equal to about 1.5. The spheres do not need a line of symmetry. The particles can also have surface texturing, e.g., small lines or indentations or protrusions when compared to the total size of the particles. In some embodiments, the ratio of the length between the longest and shortest axes of the particles is less than or equal to about 1.5, less than or equal to about 1.45, less than or equal to about 1.4, less than or equal to about 1.35, less than or equal to about 1.30, 1.25 or less, about 1.20 or less, about 1.15 or less, about 1.1 or less. Without wishing to be bound by theory, surface contact is minimized in substantially spherical particles, which causes undesirable agglomeration of particles during storage. Many crystals or flakes have a flat surface that can enable a large surface contact area where aggregation can occur by ionic or nonionic interactions Spheres can be contacted over a much smaller area Allow.

In some embodiments, the particles have substantially the same particle size. Particles with a wide size distribution in which both relatively large and relatively small particles are present allow smaller particles to fill in the gap between larger particles thereby creating a new contact surface. Extensive size distribution can result in larger spheres by creating many contact opportunities for aggregate bonding. The particles described herein are within a narrow size distribution, thereby minimizing the opportunity for clumping contact. By "narrow size distribution" is meant a particle size distribution wherein the ratio of the volume diameter of 90% of the small spherical particles to the volume diameter of 10% is less than or equal to 5. In some embodiments, 90% of the small spherical particles have a volume diameter of less than or equal to 4.5%, less than 4, less than 3.5, less than 3, less than 2.5, less than 2, less than 1.5, less than 1.45, less than 1.40, less than 1.35 , 1.3 or less, 1.25 or less, 1.20 or less, 1.15 or less, or 1.1 or less.

The Geometric Standard Deviation (GSD) can also be used to represent a narrow size distribution. The GSD calculation involved determining the effective cutoff diameter (ECD) at cumulative percentages of less than 15.9% and 84.1%. GSD is equal to the square root of the ratio of ECD less than 84.17% to ECD less than 15.9%. The GSD has a narrow size distribution when the GSD is less than 2.5. In some embodiments, the GSD is less than 2, less than 1.75, or less than 1.5. In one embodiment, the GSD is less than 1.8.

In addition to the platinum compounds disclosed herein, the particles can include co-lipids and / or stabilizers. Additional lipids may be included in the particles for various purposes, for example to prevent lipid oxidation, to stabilize the bilayer, to reduce aggregation during formation, or to attach the ligand to the particle surface. Any of a number of additional lipids and / or other ingredients may be present, including amphiphilic, neutral, cationic, anionic lipids, and programmable fusion lipids. Such lipids and / or components may be used alone or in combination. One or more components of the particle may comprise a ligand, e. G., A target ligand.

In some embodiments, the particle further comprises a phospholipid. Without limitation, the phospholipid may be of natural origin, such as yolk or soybean phospholipids, or of synthetic or semisynthetic origin. The phospholipid is selected from the group consisting of phosphatidyl choline, phosphatidyl choline having a defined acyl group with 6 to 22 carbon atoms, phosphatidyl ethanolamine, phosphatidyl inositol, phosphatidic acid, phosphatidylserine, sphingomyelin or phosphatidylglycerol, Purified or fractionated. Suitable phospholipids include, but are not limited to, phosphatidylcholine, phosphatidylglycerol, lecithin,?,? - dipalmitoyl-alpha-lecithin, sphingomyelin, phosphatidylserine, phosphatidic acid, N- (9- (Z) -octadecenyloxy)) - prop-1-yl-N, N, N-trimethylammonium chloride, phosphatidylethanolamine, lysolecithin, lysophosphatidylethanolamine, phosphatidylinositol, Phosphatidylcholine, di-stearoyl-phosphatidylcholine, di-stearoyl-phosphatidylcholine, di-stearoyl-phosphatidylcholine, di-stearoyl-phosphatidylcholine, stearoyl-phosphatidylcholine, Phosphatidylethanolamine, di-stearoyl-phosphatidylethanolamine, di-myristoyl-phosphatidylserine, di-palmitoyl-phosphatidylethanolamine, (DOPE), palmitoyl oleoyl phosphatidylcholine (POPC), egg phosphatidylcholine (EPC), distearoylphosphatidylcholine (DSPC), diol leuco phosphatidylcholine (DMPC), diol leuylphosphatidylethanolamine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioloylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), phosphatidylethanolamine (POPE), diolaurylphosphatidylethanolamine 4- Maleimidomethyl) -cyclohexane-1-carboxylate (DOPE-mal), 1-stearoyl-2-oleoylphosphatidylcholine (SOPC), 1,2- distearoyl-sn- 3-phosphoethanolamine (DSPE), and any combination thereof. Phosphorus-free lipids may also be used. These include, for example, stearylamine, dodecylamine, acetyl palmitate, fatty acid amides, and the like. Other phosphorus-deficient compounds such as sphingolipids, glycophenol family, diacylglycerol, and? -Acyloxysaccharides can also be used.

In some embodiments, the phospholipid in the particle is selected from the group consisting of: 1,2-didecanoyl- sn -glycero-3-phosphocholine; 1,2-dienylcoyl- sn -glycero-3-phosphate (sodium salt); 1,2-dienylcoyl- sn -glycero-3-phosphocholine; 1,2-dienylcoyl- sn -glycero-3-phosphoethanolamine; 1,2-dienylcoyl- sn -glycero-3 [phospho-rac- (1-glycerol) (sodium salt); 1,2-dirinoleoyl- sn -glycero-3-phosphocholine; Sodium 1,2-dilauryl- sn -glycero-3-phosphate (sodium salt); 1,2-dilauroyl- sn -glycero-3-phosphocholine; 1,2-dilauryl- sn -glycero-3-phosphoethanolamine; 1,2-dilauryl- sn -glycero-3 [phospho-rac- (1-glycerol) (sodium salt); Di-lauroyl- sn -glycero-3 [phospho-rac- (1-glycerol) (ammonium salt); 1,2-dilauryl- sn -glycero-3-phosphocerine (sodium salt); 1,2- dimyristoyl - sn -glycero-3-phosphate (sodium salt); 1,2- dimyristoyl - sn -glycero-3-phosphocholine; 1,2- dimyristoyl - sn -glycero-3-phosphoethanolamine; 1,2- dimyristoyl - sn -glycero-3 [phospho-rac- (1-glycerol) (sodium salt); 1,2- dimyristoyl - sn -glycero-3 [phospho-rac- (1-glycerol) (ammonium salt); 1,2- dimyristoyl - sn -glycero-3 [phospho-rac- (1-glycerol) (sodium / ammonium salt); 1,2- dimyristoyl - sn -glycero-3-phosphocerine (sodium salt); 1,2- diolureo - sn -glycero-3-phosphate (sodium salt); 1,2- diolureo - sn -glycero-3-phosphocholine; 1,2- diolureo - sn -glycero-3-phosphoethanolamine; 1,2- diolureo - sn -glycero-3 [phospho-rac- (1-glycerol) (sodium salt); 1,2- diolureo - sn -glycero-3-phosphocerine (sodium salt); 1,2-dipalmitoyl- sn -glycero-3-phosphate (sodium salt); 1,2-dipalmitoyl- sn -glycero-3-phosphocholine; 1,2-dipalmitoyl- sn -glycero-3-phosphoethanolamine; 1,2-dipalmitoyl- sn -glycero-3 [phospho-rac- (1-glycerol) (sodium salt); 1,2-dipalmitoyl- sn -glycero-3 [phospho-rac- (1-glycerol) (ammonium salt); 1,2-dipalmitoyl- sn -glycero-3-phosphocerine (sodium salt); 1,2-distearoyl- sn -glycero-3-phosphate (sodium salt); 1,2-distearoyl- sn -glycero-3-phosphocholine; 1,2-distearoyl- sn -glycero-3-phosphoethanolamine; 1,2-distearoyl- sn -glycero-3 [phospho-rac- (1-glycerol) (sodium salt); 1,2-distearoyl- sn -glycero-3 [phospho-rac- (1-glycerol) (ammonium salt); 1,2-distearoyl- sn -glycero-3-phosphocerine (sodium salt); Egg-PC; Hydrogenated egg PC; Hydrogenated soybean PC; 1-myristoyl- sn -glycero-3-phosphocholine; 1-palmitoyl- sn -glycero-3-phosphocholine; 1-stearoyl- sn -glycero-3-phosphocholine; 1-myristoyl-2-palmitoyl- sn -glycero 3-phosphocholine; 1-myristoyl-2-stearoyl- sn -glycero-3-phosphocholine; 1-palmitoyl-2-myristoyl- sn -glycero-3-phosphocholine; 1-palmitoyl-2-oleoyl- sn -glycero-3-phosphocholine; 1-palmitoyl-2-oleoyl- sn -glycero-3-phosphoethanolamine; 1-palmitoyl-2-oleoyl- sn -glycero-3 [phospho-rac- (1-glycerol)] (sodium salt); 1-palmitoyl-2-stearoyl- sn -glycero-3-phosphocholine; 1-stearoyl-2-myristoyl- sn -glycero-3-phosphocholine; 1-stearoyl-2-oleoyl- sn -glycero-3-phosphocholine; And 1-stearoyl-2-palmitoyl- sn -glycero-3-phosphocholine. In some embodiments, the phospholipid is SPOC, Egg PC, or hydrogenated soybean PC (HSPC). In one, the phospholipid in the composition is HSPC.

In some embodiments, the particles further comprise polyethylene glycol (PEG). The PEC can be incorporated alone or in combination with the components present in the particles and contained within the particles. For example, PEG can be conjugated to a co-lipid / stabilizer component of the particle or a platinum-based compound. In some embodiments, the PEG is conjugated to the co-lipid component of the particle. Without limitation, PEG can be conjugated to any co-lipid. For example, PEG conjugated co-lipids include PEG conjugated diacyl glycerol and dialkyl glycerol, PEG-conjugated phosphatidylethanolamine, PEG conjugated phosphatidic acid, PEG conjugated ceramide 5,885,613), PEG conjugated dialkylamines, PEG conjugated 1,2-diacyloxypropan-3-amine, and PEG conjugated 1,2-distearoyl-sn- - phosphoethanolamine (DSPE), and any combination thereof. In some embodiments, the PEG conjugated lipid is 1,2-distearoyl-sn-glycem-3-phosphoethanolamine-N- [amino (polyethylene glycol) -2000] (DSPE-PEG2000).

In some embodiments, the particles further comprise a surfactant. Surfactants are widely used in formulations, such as emulsions (including microemulsions) and liposomes. The most common method of classifying and grading many different types of properties of both natural and synthetic surfactants is by the use of a hydrophile / lipophile balance (HLB). The nature of hydrophilic groups (also known as "heads") provides the most useful means for categorizing the different surfactants used in formulations (Rieger, in Pharmaceutical Dosage Forms, Marcel Dekker, Inc., New York , NY, 1988, p. 285).

When the surfactant molecule is not ionized, it is classified as a nonionic surfactant. Nonionic surfactants are widely used in pharmaceuticals and cosmetics and can be used over a wide range of pH values. In general, their HLB values range from 2 to about 18, depending on their structure. Nonionic surfactants include nonionic esters such as ethylene glycol esters, propylene glycol esters, glyceryl esters, polyglyceryl esters, sorbitan esters, sucrose esters, and ethoxylated esters. Nonionic alkanolamides and ethers such as fatty alcohol ethoxylates, propoxylated alcohols, and ethoxylated / propoxylated block polymers are also included in this class. Polyoxyethylene surfactants are the most prominent members of the class of nonionic surfactants.

When a surfactant molecule is dissolved or dispersed in water and it retains a negative charge, the surfactant is classified as anionic. Anionic surfactants include carboxylates such as soaps, acyl lactates, acyl amides of amino acids, esters of sulfuric acid such as alkyl sulfates and ethoxylated alkyl sulfates, sulfonates such as alkyl benzene sulfonates, acyl isethionates, And sulfosuccinates, and phosphates. The most important members of the anionic surfactant class are alkyl sulphate and soap.

When the surfactant molecule is dissolved or dispersed in water and it retains a positive charge, the surfactant is classified as cationic. Cationic surfactants include quaternary ammonium salts and ethoxylated amines. Quaternary ammonium salts are the most used members of this class.

If the surfactant molecule has the ability to retain either a positive charge or a negative charge, the surfactant is classified as amphoteric. Amphoteric surfactants include acrylic acid derivatives, substituted alkyl amides, N-alkyl betaines and phosphatides.

The use of surfactants in drug products, formulations and emulsions has been reviewed (Rieger, in Pharmaceutical Dosage Forms, Marcel Dekker, Inc., New York, N.Y., 1988, p. 285).

In some embodiments, the particles may further comprise a cationic lipid. Exemplary cationic lipids include, but are not limited to, N, N-dioleyl-N, N-dimethylammonium chloride (DODAC), N, N-distearyl-N, N-dimethylammonium bromide ), N- (1- (2,3-dioloyloxy) propyl) -N, N, N-trimethylammonium chloride (DOTAP) N, N, N-trimethylammonium chloride (DOTMA), N, N-dimethyl-2,3-dioleyloxy) propylamine (DODMA), 1,2-dirinoleyloxy- DLinDMA), 1,2-dynlinolyloxy-N, N-dimethylaminopropane (DLenDMA), 1,2-dirinoleylcarbamoyloxy-3-dimethylaminopropane (DLin- 2-dirinoleyloxy-3- (dimethylamino) acetoxypropane (DLin-DAC), 1,2-dirinoleyloxy-3-morpholinopropane (DLin-MA) (DLinDAP), 1,2-dirinoleylthio-3-dimethylaminopropane (DLin-S-DMA), 1-linoleoyl-2-linoleyl (DLin-2-DMAP), 1,2-dirinoleyloxy-3-trimethylaminopropane chloride salt (DLin-TMA.C1), 1,2-dirinoleoyl- (DLin-TAP.C1), 1,2-dirinoleyloxy-3- (N-methylpiperazino) propane (DLin-MPZ) Amino) -1,2-propanediol (DLinAP), 3- (N, N-dioleylamino) -1,2-propanedio (DOAP), 1,2- , N-dimethylamino) ethoxypropane (DLin-EG-DMA), 1,2 -dinolenyloxy-N, N-dimethylaminopropane (DLinDMA), 2,2- - [1,3] -dioxolane (DLin-K-DMA) or analogs thereof, (3aR, 5s, 6aS) -N, N-dimethyl- (6Z, 9Z, 28Z, 31Z) -heptatriaconta-6,9,9-dienyl) tetrahydro-3aH-cyclopenta [ , 28,31-tetraen-19-yl 4- (dimethylamino) butanoate (MC3), 1,1 '- (2- (4- (2- Attempt decyl) amino) ethyl) (2-hydroxy-dodecyl) amino) ethyl) piperazin-1-yl) ethyl O grass yl) Titus decan-2-ol (Tech Gi), or mixtures thereof.

In some embodiments, the particles further comprise non-cationic lipids. Non-cationic lipids may be anionic lipids or neutral lipids, including but not limited to: distearoylphosphatidylcholine (DSPC), dioloylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC Phosphatidylethanolamine (DOPE), palmitoyl oleoyl phosphatidylcholine (POPC), palmitoyl oleoyl phosphatidyl ethanolamine (POPE), phosphatidyl choline chloride , Dioleoyl-phosphatidylethanolamine 4- (N-maleimidomethyl) -cyclohexane-1-carboxylate (DOPE-mal), dipalmitoylphosphatidylethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoylphosphatidyl-ethanolamine (DSPE), 16-O-monomethyl PE, 16-O-dimethyl PE, 18-1- trans PE, 1-stearoyl- Phosphatidylethanolamine (SOPE), cholesterol, and A mixture thereof.

Conjugated lipids that inhibit aggregation of particles may also be included within the particles disclosed herein. Such lipids include, but are not limited to, polyethylene glycol (PEG) -lipids, including but not limited to PEG-diacylglycerol (DAG), PEG-dialkyloxypropyl (DAA), PEG-phospholipids, PEG- Cer), or mixtures thereof. The PEG-DAA conjugate can be, for example, PEG-dilauryloxypropyl (C ₁₂ ), PEG-dimyristyloxypropyl (C ₁₄ ), PEG-dipalmityloxypropyl (C ₁₆ ), or PEG- Lt; RTI ID = 0.0 > ( _C18 ). ≪ / RTI > Conjugated lipids that prevent aggregation of the particles can be from about 0.01 mole percent to about 20 mole percent or about 2 mole percent of the total lipid present in the particles.

In some embodiments, the particles may be in the form of liposomes, vesicles, or emulsions. As used herein, the term "liposome" encompasses any compartment surrounded by a lipid layer. Liposomes can have one or more lipid membranes. Liposomes can be characterized by membrane type and by size. Small unilamellar vesicles (SUV) have a single membrane and typically range in diameter from 0.02 to 0.05 mu m; Large unilamellar vesicles (LUV) are typically greater than 0.05 microns. The oligolamellar large vesicles and the multi-lamellar vesicles typically have a plurality of concentric membrane layers and are typically greater than 0.1 microns. Liposomes with several non-concentric membranes, i.e. several smaller vesicles contained in larger vesicles, are referred to as multi-vesicular vesicles.

To form liposomes, lipid molecules include elongated non-polar (hydrophobic) and polar (hydrophilic) moieties. The hydrophobic and hydrophilic moieties of the molecule are preferably located at two ends of the elongate molecular structure. When such lipids are dispersed in water, they voluntarily form bilayer membranes, referred to as lamellas. Lamellas consist of two monolayer sheets of lipid molecules, where their nonpolar (hydrophobic) surfaces face each other and their polar (hydrophilic) surfaces face an aqueous medium. The membrane formed by the lipids surrounds a portion of the aqueous phase in a manner similar to the way the cell membrane encloses the cell contents. Thus, the bilayer of liposomes has similarity to the cell membrane without protein components present in the cell membrane.

Liposome compositions can be prepared by a variety of methods known in the art. For example, U.S. Patent Nos. 4,235,871, 4,897,355, and 5,171,678; International Patent Application Publication Nos. WO 96/14057 and WO 96/37194; Felgner, PL et al ., Proc . Natl. Acad . Sci . , USA (1987) 8: 7413-7417], Bangham, et al . M. Mol . Biol. (1965) 23: 238], Olson, et al . Biochim . Biophys . Acta (1979) 557: 9], Szoka, et al . Proc . Natl . Acad . Sci . (1978) 75: 4194, Mayhew, et al . Biochim . Biophys . Acta (1984) 775: 169, Kim, et al . Biochim . Biophys. Acta (1983) 728: 339, and Fukunaga, et al . Endocrinol . (1984) 115: 757, the contents of both of which are incorporated herein by reference in their entirety.

Liposomes can be made to have a substantially homogeneous size within a selected size range. One effective sizing method involves extruding an aqueous suspension of liposomes through a series of polycarbonate membranes having a selected uniform pore size; The pore size of the membrane will generally correspond to the maximum size of the liposome produced by extrusion through such a membrane. See, for example, U.S. Patent No. 4,737,323, the content of which is incorporated herein by reference in its entirety.

The particles may also be in the form of an emulsion. Emulsions are heterogeneous systems in which one liquid is typically dispersed in the form of droplets in another liquid (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker New York, NY, Volume 1, p. 199); Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, New York, NY, volume 2, p. 335; Higuchi et < RTI ID = 0.0 > et al., & al., Remington ' s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1985, p. Frequently, emulsions are biphasic systems that include two immiscible liquid phases that are intimately mixed and dispersed with one another. Generally, the emulsion may be one of water-in-oil (w / o) or oil-in-water (o / w) When the aqueous phase is finely divided into small droplets and dispersed into a bulk oily phase, the resulting composition is referred to as a water-in-oil (w / o) emulsion. Alternatively, when the oil phase is finely divided into minute droplets and dispersed into the bulk aqueous phase, the resulting composition is referred to as an oil-in-water (o / w) emulsion. The emulsion may contain additional components in addition to the dispersed phase, and the conjugates disclosed herein may be present as a solution in the aqueous phase or the oil phase, or may be present as separate phases themselves. Pharmaceutical excipients such as emulsifiers, stabilizers, dyes, and antioxidants may also be present in the emulsion if desired. The pharmaceutical emulsion may also be multiple emulsions composed of more than two phases, as in the case of, for example, water-in-oil heavy oil (o / w / o) and water in oil water (w / o / w) emulsions. Such complex formulations often provide certain advantages that are not possible with simple two-phase emulsions. Multiple emulsions in which the individual oil droplets of the o / w emulsion surround small water droplets constitute the w / o / w emulsion. Likewise, a system of oil droplets enclosed within a globule of water stabilized in an oil continuous phase provides an o / w / o emulsion.

Emulsions are characterized by thermodynamic stability with little or no effect. Often, the dispersed or discontinuous phase of the emulsion is well dispersed in the external or continuous phase and is maintained in this form either through the use of emulsifiers or through the viscosity of the formulation. Either of the phases of the emulsion may be semisolid or solid, as is the case with emulsion-style ointment bases and creams. Other means of stabilizing the emulsion involve the use of emulsifiers that can be incorporated into any phase of the emulsion. Emulsifiers can be broadly categorized into four categories: synthetic surfactants, naturally occurring emulsifiers, absorption bases, and finely dispersed solids (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker , 1988, Marcel Dekker, Inc., New York, NY, volume 1, p. 199).

Synthetic surfactants, also known as surface active agents, have shown wide applicability in the formulation of emulsions and have been reviewed in the literature (Rieger, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker , Ed., Marcel Dekker, Inc., New York, NY, 1988, volume 1, p. 285; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker 1, p. 199). Surfactants are typically amphiphilic and include hydrophilic and hydrophobic moieties. The ratio of hydrophilic to hydrophobic nature of the surfactant has been referred to as the hydrophilic / lipophilic balance (HLB) and is a useful means to categorize and select surfactants in the formulation. Surfactants can be classified into different classes based on the nature of the hydrophilic group: nonionic, anionic, cationic and amphoteric (Rieger, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds. , Marcel Dekker, Inc., New York, NY, volume 1, p.

Naturally occurring emulsifiers used in emulsion formulations include lanolin, beeswax, phosphatide, lecithin and acacia. The absorption base possesses hydrophilic properties to absorb water to maintain its semi-solid consistency while forming a w / o emulsion, such as anhydrous lanolin and hydrophilic petrolatum. The finely divided solids have also been used as excellent emulsifiers, especially in combination with surfactants and in viscous preparations. These include, but are not limited to, polar inorganic solids such as heavy metal hydroxides, nonswelling clays such as bentonite, adapulgite, hectorite, kaolin, montmorillonite, colloidal aluminum silicate and magnesium colloidal aluminum silicate, pigments and non- Or glyceryl tristearate.

A wide variety of non-emulsifiable materials can also be included in the emulsion formulation and contribute to the properties of the emulsion. These include but are not limited to fats, oils, waxes, fatty acids, fatty alcohols, fatty esters, wetting agents, hydrophilic colloids, preservatives and antioxidants (Block, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds. , 1988, Marcel Dekker, Inc., New York, NY, volume 1, p. 335; Marcel Dekker, Inc., 1988; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker York, NY, volume 1, p. 199).

Hydrophilic colloids or hydrocolloids include natural gums and synthetic polymers such as polysaccharides (e.g., acacia, agar, alginic acid, carrageenan, guar gum, karaya gum, and tragacanth), cellulose derivatives , Carboxymethylcellulose and carboxypropylcellulose), and synthetic polymers (e.g., carbomers, cellulose ethers, and carboxyvinyl polymers). They disperse or swell in water to form a colloidal solution which stabilizes the emulsion by forming a strong interfacial film around the dispersed droplets and by increasing the viscosity on the external surface.

These formulations often contain preservatives, since often emulsions contain a number of components such as carbohydrates, proteins, sterols and phosphatides that can readily support the growth of microorganisms. Commonly used preservatives included in the emulsion formulations include methyl paraben, propyl paraben, quaternary ammonium salts, benzalkonium chloride, esters of p-hydroxybenzoic acid, and boric acid. Antioxidants are also generally added to the emulsion formulations to prevent deterioration of the formulations. The antioxidant used may be a free radical scavenger such as tocopherol, alkyl gallate, butylated hydroxyanisole, butylated hydroxytoluene or a reducing agent such as ascorbic acid and sodium metabisulfite, and antioxidant, such as citric acid, Tartaric acid, and lecithin.

Application of emulsion formulations via dermatological, oral and parenteral routes and methods for their preparation have been reviewed in the literature (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc New York, NY, volume 1, p. 199). Emulsion formulations for oral delivery have been very widely used because of their ease of formulation as well as their efficacy from the point of view of absorption and bioavailability (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds. , 1988, Marcel Dekker, Inc., New York, NY, volume 1, p. 245; Marcel Dekker, Inc., 1988; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker York, NY, volume 1, p. 199).

Exemplary surfactants for inclusion in the particles disclosed herein include ionic surfactants, nonionic surfactants, Brij 96, polyoxyethylene oleyl ether, polyglycerol fatty acid esters, tetraglycerol monolaurate (ml 310) (PO400), hexaglycerol pentaoleate (PO500), decaglycerol monocaprate (MCA750), decaglycerol monooleate (MO750), decaglycerol sesquiole (MO310), tetraglycerol monooleate (SO750), decaglycerol decaoleate (DAO750), but are not limited thereto, either alone or in combination with a co-surfactant. Co-surfactants that are typically short-chain alcohols such as ethanol, 1-propanol, and 1-butanol penetrate into the surfactant film and consequently increase the interfacial fluidity by producing disordered films due to the void space created between the surfactant molecules It plays a role. However, microemulsions can be prepared without the use of co-surfactants, and non-alcohol self-emulsifying microemulsion systems are known in the art. The aqueous phase is typically, but not limited to, water, an aqueous solution of the drug, glycerol, PEG 300, PEG 400, polyglycerol, propylene glycol, and derivatives of ethylene glycol. The oil phase may be selected from the group consisting of Captex 300, Captex 355, Capmul MCM, fatty acid esters, heavy chain (C8-C12) mono, di and tri-glycerides, polyoxyethylated glyceryl fatty acid esters, fatty alcohols, polyglycated glycerides, But are not limited to, materials such as glycolated C8-C10 glycerides, vegetable oils, and silicone oils.

Microemulsions are of particular interest in terms of drug stabilization and improved drug absorption. Lipid-based microemulsions (both o / w and w / o) have been proposed to improve oral bioavailability of drugs including peptides (see, for example, U.S. Patent Nos. 6,191,105; 7,063,860; 7,070,802 ; 7,157,099; Constantinides et al., Pharmaceutical Research, 1994, 11, 1385-1390; Ritschel, Meth. Find. Exp. Clin. Pharmacol., 1993, 13, 205). The microemulsions are characterized by improved drug stabilization, protection of the drug from enzymatic hydrolysis, possible enhancement of drug absorption due to surfactant-induced changes in membrane fluidity and permeability, ease of manufacture, ease of oral administration compared to solid dosage forms , Constantinides et al., Pharmaceutical Research, 1994, < RTI ID = 0.0 > 11, 1385; Ho et al., J. Pharm. Sci., 1996, 85, 138-143). Often microemulsions can form spontaneously when combining their components at ambient temperature. This may be particularly advantageous when formulating heat labile drugs. Microemulsions were also effective in transdermal delivery of the active ingredients in both cosmetic and pharmaceutical applications. The microemulsion compositions and formulations of the present invention are expected to not only promote increased systemic absorption of platinum-based compounds from the gastrointestinal tract, but also improve the local cell uptake of the platinum-based compounds disclosed herein.

Without wishing to be bound by theory, the nanoparticles disclosed herein have a higher uptake of platinum in cancer cells than cisplatin and oxaliplatin. In some embodiments, the nanoparticles disclosed herein exhibit at least about 25%, about 50%, about 75%, about 1-fold, about 5-fold, about 10-fold, or about 15-fold greater activity in cancer cells than equivalent doses of cisplatin or oxaliplatin Fold, about 20 times, about 25 times or more platinum absorption.

In addition, the nanoparticles disclosed herein also have a higher accumulation of platinum in tissues such as, but not limited to, tumors, when administered in equivalent, compared to cisplatin and oxaliplatin. For example, the nanoparticles disclosed herein can be present in an amount of about 25%, about 50%, about 75%, about 1-fold, about 5-fold, about 10-fold, about 15- Fold, about 20 times, about 25 times or more platinum accumulation structure.

The design and synthesis of oxaliplatin nanoparticles is based on its structure-activity relationship. The present invention describes the synthesis of various platinum-based amphipathic materials by functional group interchange chemistry. In a specific embodiment, to obtain a carbamate bond, cholesteryl chloroformate is used as a starting material, and ethylenediamine (a) (linker) is added thereto to obtain ethylenediamine conjugated cholesterol, In the diamine conjugated cholesterol, one amine group of ethylenediamine forms a carbamate bond with the cholesterol and the other amines are free ( FIG. 1A ). In the next step, the free amine reacts with one of the carboxyl groups of the succinic anhydride (b) (dicarbonyl derivative capable of forming a 7-membered ring molecule) to form an amide bond, and the other free carboxylic acid group ( Fig. 1A ). Dichloro-diamino-platinum (II) [RR isomer] to obtain a oxaliplatin hydrated and hydrated overnight silver nitrate (Fig. 1b), which through the formation of monocarboxylic reyito covalent bond and amide another coordination bond of the oxygen (Fig. To form adducts with intermediates II / III / IV (as depicted in 1a ) ( FIG. 1c ).

Similarly, in another embodiment, the synthesis of an ether-linked platinum amphoteric material is summarized in FIG. 2 , wherein the cholesterol molecule is initially converted to intermediate I by functional exchange ( FIG. 2a ). This intermediate I is converted to the intermediate II, which in turn leads to the final adduct by reaction steps analogous to those used for the synthesis of the carbamate bond as described above. Similarly, for the synthesis of the six- and five-membered ring molecules as described above, the monoethyl esters of malonic acid and oxalic acid were used for the synthesis of both carbamate linked and ether linked platinum amphoteric materials , respectively 1a and Fig. 2a ), followed by ethyl ester deprotection.

After synthesis, the final platinum adduct is formulated into nanoparticles using different co-lipids selected from soybean-PC, DOPE, DOPC, and the like and different stabilizers selected from DSPE-PEG-OMe and the like. Furthermore, the characterization of all the intermediates is carried out by ¹ HNMR, the final oxaliplatin characterization of amphiphilic molecules is carried out by using ¹ HNMR and MALDI-TOF, respectively.

[Table 1] Classification of platinum (II) compounds (including compounds of formula (III)) based on coordination environment:

Without wishing to be bound by theory, the nanoparticle composition of the present invention exhibits significant cancer cell killing efficacy. Exemplary nanoparticles were tested in different cancer cell lines and these compounds are significantly better than comparable compounds such as oxaliplatin, cisplatin, oxaliplatin, carboplatin, paraplatin and sartraplatin, which are known platinum drugs, Efficacy. ≪ / RTI >

Thus, in another aspect, a method of treating cancer is described herein. Generally, the methods comprise administering a therapeutically effective amount of a platinum-based compound described herein to a subject in need of treatment of cancer.

As used herein, the phrase "therapeutically effective amount" refers to an amount of a compound, or a pharmaceutically acceptable salt thereof, effective to produce any desired therapeutic effect, at least with a reasonable benefit / risk ratio applicable to any medical treatment, Material, or composition of matter of the present invention. Determination of a therapeutically effective amount is well within the capability of those skilled in the art. In general, the therapeutically effective amount will vary depending on the subject's age, condition, sex, as well as the severity and type of medical condition in the subject, and the administration of other agents to alleviate the disease or disorder to be treated have.

Usually, the amount of the active compound is 0.1 to 95% by weight of the preparation, preferably 0.2 to 20% by weight in the formulation for parenteral use, and preferably 1 to 50% by weight in the formulation for oral administration.

Toxicity and therapeutic efficacy may be determined by standard pharmaceuticals in cell cultures or laboratory animals to determine, for example, LD50 (lethal dose for 50% of the population) and ED50 (therapeutically effective dose in 50% of the population) Can be determined by the procedure. The dose ratio between toxic and therapeutic effects is a rheumatic index, which can be expressed as the LD50 / ED50 ratio. Compositions exhibiting a large therapeutic index are preferred. As used herein, the term ED refers to an effective dose and is used in connection with animal models. The term EC represents the effective concentration and is used in connection with the in vitro model.

Data obtained from cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations, including ED50, with little or no toxicity. The dosage may vary within this range depending on the dosage form employed and the route of administration utilized.

Therapeutically effective doses can be estimated initially from cell culture assays. Capacity can be formulated in animal models to achieve a range of circulating plasma concentrations, including IC50 (i.e., the concentration of therapeutic agent that achieves half-maximal inhibition of symptoms) as determined in cell culture. Plasma levels can be measured, for example, by high performance liquid chromatography. The effect of any particular dose can be monitored by a suitable bioassay.

The dose is determined by the physician and, if necessary, can be adjusted to suit the observed effect of the treatment. Generally, the composition will contain the active agent in an amount ranging from 1 ug / kg to 150 mg / kg, 1 ug / kg to 100 mg / kg, 1 ug / kg to 50 mg / kg, 1 ug / kg to 20 mg / kg to 10 mg / kg, 1 μg / kg to 1 mg / kg, 100 μg / kg to 100 mg / kg, 100 μg / kg to 50 mg / kg, 100 μg / kg to 20 mg / To 10 mg / kg, 100 μg / kg to 1 mg / kg, 1 mg / kg to 100 mg / kg, 1 mg / kg to 50 mg / kg, 1 mg / kg to 20 mg / 10 mg / kg, 10 mg / kg to 100 mg / kg, 10 mg / kg to 50 mg / kg, or 10 mg / kg to 20 mg / kg. It is to be understood that the ranges provided herein are intended to encompass all intermediate ranges, such as from 1 mg / kg to 2 mg / kg, 1 mg / kg to 3 mg / kg, 1 mg / kg to 4 mg / kg, 1 mg / kg to 5 mg / kg, 1 mg / kg to 6 mg / kg, 1 mg / kg to 9 mg / kg, 2 mg / kg to 10 mg / kg, 3 mg / kg to 10 mg / kg, 4 mg / kg to 10 mg / kg, 6 mg / kg to 10 mg / kg, 7 mg / kg to 10 mg / kg, 8 mg / kg to 10 mg / kg, 9 mg / kg to 10 mg / kg and the like. 2 mg / kg to 8 mg / kg, 3 mg / kg to 7 mg / kg, 4 mg / kg to 5 mg / kg in the intermediate ranges, for example in the range of 1 mg / kg to 10 mg / kg to 6 mg / kg, and the like, are also within the scope of the present invention.

In some embodiments, the composition is administered at a dose of 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, Less than 100 nM, less than 50 nM, less than 25 nM, less than 20 nM, less than 100 nM, less than 50 nM, less than 25 nM, less than 100 nM, ( In vivo ) concentration of less than 10 nM, less than 5 nM, less than 1 nM, less than 0.5 nM, less than 0.1 nM, less than 0.05, less than 0.01 nM, less than 0.005 nM, less than 0.001 nM .

With regard to duration and frequency of treatment, the skilled clinician will be able to determine when the treatment is providing a therapeutic benefit and to determine whether the dose is increased or decreased, whether the dose is increased or decreased, It is typical to monitor the subject to determine whether to stop, whether to resume treatment, or whether to make other changes to the treatment regimen. The dosing schedule can vary from once a week to every day, depending on the sensitivity of the subject to a number of clinical factors, such as polypeptides. The desired dose may be administered daily or every 3 days, every 4 days, every 5 days, or every 6 days. The desired dose may be administered all at once or divided into sub-doses, e.g., two to four sub-doses, and administered over a period of time, e. G., At appropriate intervals throughout the day, or other appropriate schedule. Such lower doses may be administered in unit dosage forms. In some embodiments of the aspects described herein, the administration is chronic administration, for example, administration of one or more doses daily over a period of several weeks or months. Examples of dosing schedules are daily, twice daily, three times daily for periods of 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or more Or four times per day or more.

In some embodiments, the platinum-based compound may be administered to a subject in combination with a pharmaceutically active agent, for example, a second therapeutic agent. Exemplary pharmaceutically active compounds are to be found in [Harrison's Principles of Internal Medicine, 13 th Edition, Eds. TR Harrison et al. McGraw-Hill NY, NY]; Physicians Desk Reference, 50 ^th Edition, 1997, Oradell New Jersey, Medical Economics Co.; Pharmacological Basis of Therapeutics, 8 ^th Edition, Goodman and Gilman, 1990; And the United States Pharmacopeia, The National Formulary, USP XII NF XVII, 1990, the entire contents of both of which are incorporated herein by reference. The platinum-based compound and the second therapeutic agent can be administered to the same pharmaceutical composition or to the subject with different pharmaceutical compositions (at the same time or at different times).

As used herein, the term "administering " refers to placement into a subject by a route or pathway leading to at least partial localization of the composition at the desired site to produce the desired effect. The compounds or compositions described herein may be administered by any suitable route known in the art and include oral or parenteral routes such as intravenous, intramuscular, subcutaneous, transdermal, aerosol, lung, But are not limited to, nasal, rectal, and topical (including buccal and sublingual) administration.

Exemplary modes of administration include, but are not limited to, injection, infusion, instillation, inhalation, or ingestion. "Injection" includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracerebral, intraarticular, orbital, intracardiac, intraperitoneal, intraperitoneal, intracapsular, subcutaneous, subcutaneous, intraarticular, , Subarachnoidal, spinal, intraepithelial, and intrasternal injection and infusion. In some embodiments, the composition is administered by intravenous infusion or injection.

As used herein, the term "cancer" refers to uncontrolled growth of cells that may interfere with normal function of the body organs and system. Cancer from the original location and sown on vital organs can ultimately lead to death by dysfunction of the affected organ. Metastasis is a group of cancer cells or cancer cells distinct from the primary tumor location, which is due to the sowing of cancer cells from primary tumors to other parts of the body. At the time of diagnosis of the primary tumor mass, the subject can be monitored for the presence of cancer cells in transit, e.g., in the process of sowing, during transport. As used herein, the term cancer includes, but is not limited to, the following types of cancer: breast cancer, biliary cancer, bladder cancer, brain cancer (including glioblastomas and marrow embryos); Cervical cancer; Chorionic villus carcinoma; Colon cancer; Endometrial cancer; Esophagus cancer; Gastric cancer; Hematologic neoplasm (acute lymphocytic and myeloid leukemia, T-cell acute lymphoblastic leukemia / lymphoma, hair cell leukemia, chronic myeloid leukemia, multiple myeloma, AIDS-related leukemia and adult T-cell leukemia lymphoma, (Including Bowen's disease and Paget's disease), liver cancer, lung cancer, lymphoma (including Hodgkin's disease and lymphoid lymphoma), neuroblastoma, oral cancer (including squamous cell carcinoma Ovarian cancer (including those derived from epithelial cells, stromal cells, germ cells and mesenchymal cells), pancreatic cancer, prostate cancer, rectal cancer, sarcoma (leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, and Including but not limited to osteosarcoma), skin cancer (including melanoma, Merkel cell carcinoma, Kaposi sarcoma, basal cell carcinoma, and squamous cell carcinoma); testicular cancer (including embryonal tumors such as testicular tumors, Species (teratoma, chorionic villus (Including thyroid adenocarcinomas and watery carcinomas) and kidney cancers (including adenocarcinomas, Wilms tumors). Examples of cancers include, but are not limited to, But are not limited to, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, gastric cancer, Hodgkin's lymphoma, lymphoma, sarcoma, melanoma, sarcoma and carcinoma including leukemia. But not limited to, non-Hodgkin's lymphoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer such as liver and hepatocellular carcinoma, bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial carcinoma, salivary carcinoma, Wilms' tumor, basal cell carcinoma, melanoma, prostate cancer, vulvar cancer, thyroid cancer, testicular cancer, esophageal cancer, and various types of head and neck cancer. Other cancers will be known to those skilled in the art.

As used herein, the term "cancer" includes but is not limited to solid tumors and blood borne tumors. The term cancer refers to diseases of the skin, tissues, organs, bone, cartilage, blood and blood vessels. The term "cancer" further encompasses primary and metastatic cancers. Examples of cancers that may be treated with the compounds of the present invention include, but are not limited to, carcinoma (bladder carcinoma, breast carcinoma, colon carcinoma, renal carcinoma, lung carcinoma, ovarian carcinoma, pancreatic carcinoma, gastric carcinoma, Carcinomas, thyroid carcinomas, and skin carcinomas, including squamous cell carcinomas); Hematopoietic tumor of the lymphoid lineage (leukemia, acute lymphocytic leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin lymphoma, Cell lymphoma, and Burkitt lymphoma); Hematopoietic tumors of the myeloid lineage including, but not limited to acute and chronic myelogenous leukemia and promyelocytic leukemia; Tumors of mesenchymal origin, including but not limited to fibrosarcoma, rhabdomyosarcoma, and osteosarcoma; Other tumors (including melanoma, testicular, teratoma, neuroblastoma, and glioma); Tumors of the central and peripheral nervous system (including, but not limited to, astrocytomas, neuroblastomas, gliomas, and schwannomas); And other tumors including, but not limited to, pigment epitheliosis, keratocyte sarcoma, thyroid follicular cancer, and malignant carcinoma. The methods disclosed herein are useful for treating patients who have not previously received cancer treatment as well as patients who have previously received cancer treatment. Indeed, the methods and compositions of the present invention can be used in the treatment of cancer in both the first line and the second line.

As used herein, the term "precancerous condition" means its usual meaning, i.e., uncontrolled growth without metastasis, and includes various forms of hyperplasia and benign hyperplasia. Thus, "precancerous conditions" are diseases, syndromes, or findings that, if left untreated, can lead to cancer. This is a generalized condition associated with a significantly increased risk of cancer. Pre-cancerous lesions are morphologically altered tissues, where cancer is more likely to occur than apparently normal counterparts. Examples of pre-cancerous conditions include, but are not limited to, oral mildew, keratosis, atopic dermatitis, atopic dermatitis, atopic dermatitis, But are not limited to, hyperkeratotic cancer syndrome (HNPCC), Barrett's esophagus, bladder dysplasia, precancerous conditions of the cervix, and cervical dysplasia.

In some embodiments, the cancer is breast cancer; Ovarian cancer; Gypsum; Gastrointestinal cancer; Prostate cancer; Carcinoma, lung carcinoma, hepatocellular carcinoma, testicular cancer; Cervical cancer; Endometrial cancer; Bladder cancer; Head and neck cancer; Lung cancer; Stomach cancer, gastric-esophageal cancer, and gynecological cancer.

In some embodiments, the methods described herein relate to treating a subject having or diagnosed with having cancer. A subject with cancer can be identified by a physician using current cancer diagnostic methods. Symptoms and / or complications of cancer that characterize these conditions and aid in diagnosis are well known in the art and include, but are not limited to, tumor growth, impaired function of the organs or tissues where cancer cells lurk, and the like. Tests that may be helpful in diagnosing, for example, in the diagnosis of cancer include, but are not limited to, tissue biopsy and histological examination. Exposure to a family history of cancer, or a risk factor for cancer (e.g., tobacco products, radiation, etc.) may also be helpful in determining whether the subject is more likely to have cancer or in making a diagnosis of cancer have.

In some embodiments, the method further comprises co-administering to the patient one or more additional anti-cancer therapies. In some embodiments, the additional therapy is selected from the group consisting of surgery, chemotherapy, radiation therapy, thermotherapy, immunotherapy, hormone therapy, laser therapy, anti-angiogenesis therapy and any combination thereof. In some embodiments, the additional therapy comprises administering an anti-cancer agent to the patient. In some embodiments, the methods comprise co-administration of a conjugate and an anti-cancer agent or chemotherapeutic agent to a subject. As used herein, the term "anti-cancer agent " refers to any compound (including analogs, derivatives, prodrugs, and pharmaceutical salts thereof) or composition that can be used to treat cancer. Anticancer compounds for use in the present invention include, but are not limited to, inhibitors of topoisomerase I and II, alkylating agents, microtubule inhibitors (e.g., taxol), and angiogenesis inhibitors. Exemplary anti-cancer compounds include, but are not limited to: paclitaxel (Taxol); Docetaxel; Gemcity bin; Aldethsky; Alemtuzumab; Alitretinoin; Allopurinol; Altretamine; Amipostin; Anastrozole; Arsenic trioxide; Asparaginase; BCG Live; Bexarotene capsules; Beckaroten gel; Bleomycin; Mounted plate (intravenous); Attached panorals; Callus teron; Capecitabine; Platinum salt; Carmustine; Carmustine and polypepoic acid transplantation; Celecoxib; Chlorambucil; Cladribine; Cyclophosphamide; Cytarabine; Cytarabine (liposomes); Dakar Basin; Dactinomycin; Actinomycin D; Darbepoetin alpha; Daunorubicin (liposomes); Daunorubicin, daunomycin; Denyylkindiptitox, dexlazolic acid; Docetaxel; Doxorubicin; Doxorubicin (liposomes); Dlromotranolone propionate; Elliott's B Solution; Epirubicin; Epoetin alfa estra mastin; Etoposide phosphate; Ethofoside (VP-16); Exemestane; Phil Grass Team; Fluoxidone (intraarterial); Fludarabine; Fluorouracil (5-FU); Full Best Land; Gemtuzumi Ozo gymnast; Goserelene acetate; Hydroxyurea; Ibritumomitic cetane; Rubicin; Iospasmide; Imatinib mesylate; Interferon alpha-2a; Interferon alpha-2b; Irinotecan; Letrozole; Leucovorin; Levamisole; Rosemastin (CCNU); Mechlorethamine (nitrogen mustard); Megestrol acetate; Melphalan (L-PAM); Mercaptopurine (6-MP); Mesna; Methotrexate; Methoxsalen; Mitomycin C; Mitotane; Mitoxantrone; Nandrolone penpropionate; Nopeptomop; LOddC; Offrelebene; Pamidronate; Pegadermase; Pegasper; Pegpilgrass team; Pentostatin; Pipobroman; Plicamycin; Mitramycin; Sodium formate; Procarbazine; Quinacrine; Rasberry; Rituximab; Sarragramos Team; Streptozocin; Decabidine (LDT); talc; Tamoxifen; Temozolomide; TenniPoside (VM-26); Testol lactone; Thioguanine (6-TG); Thiotepa; Topotecan; Toremie pen; Tositumomab; Trastuzumab; Tretinoin (ATRA); Uracil mustard; Valvicine; Valtorsine turbine (mono-foot LDC); Bin blastin; Vinorelbine; Zoledronate; And any mixture thereof. In some embodiments, the anticancer agent is a paclitaxel-carbohydrate conjugate, such as a paclitaxel-glucose conjugate as described in U.S. Patent No. 6,218,367, the contents of which are incorporated herein by reference in its entirety.

The methods of the invention are particularly useful when used in combination with chemotherapy, including administering a second drug that acts at different stages of the cell cycle.

For administration to a subject, the particles comprising the platinum-based compound and / or the platinum-based compound are provided in a pharmaceutically acceptable composition. Accordingly, the present invention also provides a pharmaceutical composition comprising a platinum-based compound or particle as disclosed herein. These pharmaceutically acceptable compositions comprise a therapeutically effective amount of one or more platinum-based compounds or particles described herein formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents. The pharmaceutical compositions of the present invention are specially formulated for administration in solid or liquid form, including those suitable for the following administration: (1) oral administration, for example, drenches (aqueous or non- Lozenges, powders, granules, tongues (such as those intended for buccal, sublingual, and systemic absorption), lozenges, powders, granules, A paste for application to a substrate; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, sterile solutions or suspensions, or sustained-release formulations; (3) application as a topical application, for example as a cream, ointment, or control-release patch or spray applied to the skin; (4) vaginal or rectal administration, for example as a pessary, cream or foam; (5) sublingual administration; (6) ocularly administration; (7) administration of contrast medium; (8) transmucosal administration; Or (9) nasal administration. Additionally, the compounds of the present invention may be injected or implanted into a patient using a drug delivery system.

As used herein, the term "pharmaceutically acceptable" is intended to include within the scope of sound medical judgment, in contact with tissues of humans and animals without undue toxicity, irritation, allergic response, or other problem or complication Refers to a compound, material, composition, and / or dosage form that is suitable for use and that meets a reasonable benefit / risk ratio.

As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutical agent that is involved in the transport or transport of a subject compound from one organ or part of the body to another organ or another part of the body (E.g., a lubricant, talc, magnesium, calcium or zinc stearate, or stearic acid), or a solvent, such as, for example, a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient, Means an encapsulating material. Each carrier should be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and is not harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) Cellulose, and derivatives thereof such as sodium carboxymethylcellulose, methylcellulose, ethylcellulose, microcrystalline cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricants such as magnesium stearate, sodium lauryl sulfate and talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol and polyethylene glycol (PEG); (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) Buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline solution; (18) Ringer's solution; (19) Ethyl alcohol; (20) pH buffer solution; (21) polyesters, polycarbonates and / or polyanhydrides; (22) Bulking agents such as polypeptides and amino acids (23) Serum components such as serum albumin, HDL and LDL; (22) C2-C12 alcohols such as ethanol; And (23) other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents, coloring agents, release agents, coatings, sweeteners, flavors, fragrances, preservatives and antioxidants may also be present in the formulations. The terms such as "excipient "," carrier ", "pharmaceutically acceptable carrier ", and the like are used interchangeably herein.

In some embodiments, the pharmaceutical composition comprising a platinum-based compound may be of a parenteral dosage form. Because administration of a parenteral dosage form typically bypasses the patient ' s natural defense of contaminants, the parenteral dosage form is preferably sterile or may be sterilized to the patient prior to administration. Examples of parenteral dosage forms include, but are not limited to, directly injectable solutions, dry products that can be dissolved or suspended directly in a pharmaceutically acceptable vehicle for injection, injectable suspensions, and emulsions. In addition, control-release parenteral dosage forms can be prepared for the administration of a patient, including, but not limited to, DUROS-type dosage forms and and dose-dumping.

Suitable vehicles which can be used to provide parenteral dosage forms of the compositions as described herein are well known to those skilled in the art. Examples include, without limitation: sterile water; Injection water USP; Saline solution; Glucose solution; Aqueous vehicles such as, without limitation, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, and lactic acid-added Ringer injection; Water-miscible vehicles, such as, without limitation, ethyl alcohol, polyethylene glycol, and propylene glycol; And non-aqueous vehicles such as, without limitation, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. Compounds that alter or modify the solubility of pharmaceutically acceptable salts may also be incorporated into the parenteral dosage forms of the invention, including conventional parenteral and controlled-release parenteral dosage forms.

The pharmaceutical composition may also be formulated for oral administration, for example, as a separate dosage form, such as tablets (including, without limitation, scored or coated tablets), pills (Eg, syrups, elixirs, aqueous liquids, non-aqueous liquids, oil-in-water emulsions, or water-in-oil emulsions or liquids), such as tablets, capsules, chewable tablets, powder packets, cachets, troche, wafers, aerosol sprays, But are not limited to, solutions or suspensions in emulsions). Such compositions contain a predetermined amount of the pharmaceutically acceptable salts of the disclosed compounds and may be prepared by the preparation methods well known to those skilled in the art. Overall, Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams, and Wilkins, Philadelphia PA. (2005).

Conventional dosage forms generally provide for rapid or immediate drug release from the formulation. Depending on the pharmacology and pharmacokinetics of the drug, the use of conventional dosage forms may lead to wide variations in the concentration of the drug in the blood and other tissues of the patient. These fluctuations can affect a number of parameters such as frequency of dosing, onset of action, duration of efficacy, maintenance of therapeutic blood levels, toxicity, side effects, and the like. Advantageously, a controlled-release formulation can be used to control the onset of action of the drug, the duration of action, the plasma level within the therapeutic window, and the peak blood level. In particular, it is desirable to minimize the potential side effects and safety problems that may arise from under-dosing (i.e., less than the minimal therapeutic level) of the drug as well as from exceeding the level of toxicity to the drug, Control- or prolonged-release dosage forms or formulations may be used to ensure efficacy is achieved. In some embodiments, the compositions as described herein can be administered in sustained-release formulations.

Controlled-release medicines have a general purpose of improving drug therapy over that achieved by its non-controlled-release counterparts. Ideally, the use of controlled-release formulations designed optimally in medical therapy is characterized by the minimal drug substance being used to cure or control the disease in a minimum amount of time. Advantages of controlled-release formulations include: 1) prolonged activity of the drug; 2) reduced dosing frequency; 3) increased patient compliance; 4) less total drug use; 5) reduction of local or systemic side effects; 6) minimization of drug accumulation; 7) reduction of blood level fluctuations; 8) improvement of therapeutic efficacy; 9) potentiation of drug activity or reduction of loss; And 10) improved control of the disease or disorder. Kim, Cherng-ju, Controlled Release Dosage Form Design, 2 (Technomic Publishing, Lancaster, Pa. 2000).

Most control-release formulations are intended to initially release the amount of drug (active ingredient) that immediately produces the desired therapeutic effect, and gradually and continuously release other amounts of the drug to provide such therapeutic or prophylactic effect, And is designed to maintain the level over an extended period of time. To maintain this constant level of drug in the body, the drug should be released from the dosage form at a rate that will replace the amount of drug metabolized and excreted in the body. Control-release of the active ingredient can be stimulated by a variety of conditions including, but not limited to, pH, ionic strength, osmotic pressure, temperature, enzymes, water, and other physiological conditions or compounds.

Various known control- or prolonged-release dosage forms, formulations, and devices may be configured for use with the salts and compositions of the present invention. Examples include U.S. Patent Nos. 3,845,770; 3,916, 899; 3,536,809; 3,598,123; 4,008, 719; 5,674,533; 5,059,595; 5,591, 767; 5,120,548; 5,073,543; 5,639,476; 5,354, 556; 5,733, 566; And 6,365,185 B1, all of which are incorporated herein by reference in their entirety; Each of which is incorporated herein by reference. These dosage forms include, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems such as OROS (Alza Corporation, Mountain View, CA) Can be used to provide sustained or controlled release of one or more active ingredients using a combination thereof to provide the desired release profile of the active ingredient.

Embodiments of the various aspects described herein may be defined in any of the following numbered paragraphs:

One.

(a) a platinum moiety; And

(b) a lipid linked to said platinum moiety.

2. The compound of paragraph 1, wherein said compound comprises a carbonyl moiety.

3. The compound of paragraph 2, wherein said carbonyl moiety is a carboxylic acid selected from the group consisting of succinic acid, malonic acid, oxalic acid, keto acid, and any combination thereof.

4. The compound of any one of paragraphs 1 to 3, wherein said platinum atom or moiety is conjugated to said lipid via a covalent bond, a coordination bond, or a combination thereof.

5. The compound of any one of paragraphs 1 to 4, wherein said compound comprises at least one linker between said platinum moiety and said lipid.

6. The compound of any one of paragraphs 1 to 5, wherein said compound has formula VIII:

(VIII)

Q-linker-lipid

In this formula,

Q is

(여기서, X는 NH 또는 N(CH₂COO^-)이고; Z는 백금 함유 화합물이며, 여기서 백금은 고리의 일부를 형성함);(i)

(Wherein X is NH or N (CH ₂ COO ^- ) and Z is a platinum containing compound, wherein the platinum forms part of a ring;

(여기서, X₃은 (CH₂)_n, CH₂-NH 및 C₄H₈을 포함하는 군으로부터 선택되고; X₄는 CO 또는 -CH-CH₃이고; Z는 백금 함유 화합물이며, 여기서 백금은 고리의 일부를 형성하고; n은 0, 1, 또는 2임);(ii)

Wherein X ₃ is selected from the group comprising (CH ₂ ) _n , CH ₂ -NH and C ₄ H ₈ , X ₄ is CO or -CH-CH ₃ , Z is a platinum- And n is 0, 1, or 2;

(여기서, X는 S⁺, C, S⁺=O, N⁺H 및 P=O를 포함하는 군으로부터 선택되고; X₁은 -CH, -CH₂ 및 -CH₂O를 포함하는 군으로부터 선택되고; X₂는 C=O이고; Z는 백금 함유 화합물이며, 여기서 백금은 고리의 일부를 형성함);(iii)

Wherein X is selected from the group comprising S ⁺ , C, S ⁺ = O, N ⁺ H and P = O; X ₁ is selected from the group comprising -CH, -CH ₂ and -CH ₂ O X ₂ is C = O and Z is a platinum-containing compound, wherein platinum forms part of a ring;

(여기서, X₁은 (CH₂)_n이고; X₂는 C=O이고; Z는 백금 함유 화합물이며, 여기서 백금은 고리의 일부를 형성하고; n은 0, 1, 또는 2임);(iv)

Wherein X ₁ is (CH ₂ ) _n , X ₂ is C═O, Z is a platinum containing compound wherein platinum forms part of a ring, and n is 0, 1, or 2;

(여기서, R¹, R² 및 R³은 독립적으로 할로겐, 알킬, 아미노, 알킬아미노, 디알킬아미노, 하이드록실, 알콕시, 티올, 티오알킬, O-아실, -링커-지질, 또는 이들의 임의의 조합이거나, 또는 R₁과 R₂는 Pt 원자와 함께 또는 R₂와 R₃은 Pt 원자와 함께, 선택적으로 치환된 사이클릴 또는 헤테로사이클릴을 형성하거나, 또는 R₁과 R₂는 Pt 원자와 함께 그리고 R₂와 R₃은 Pt 원자와 함께, 선택적으로 치환된 사이클릴 또는 헤테로사이클릴을 형성함); 또는(v)

Wherein R ¹ , R ² and R ³ are independently selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, O-acyl, Or R ₁ and R ₂ together with the Pt atom or R ₂ and R ₃ together with the Pt atom form an optionally substituted cyclic or heterocyclyl or R ₁ and R _{2 together} with the Pt atom And R < ₂ > and R < ₃ > together with the Pt atom form an optionally substituted cyclic or heterocyclyl; or

(여기서, R₁, R₂, R₃, R₄ 및 R₅는 독립적으로 할로겐, 알킬, 아미노, 알킬아미노, 디알킬아미노, 하이드록실, 알콕시, 티올, 티오알킬, O-아실, -링커-지질, 또는 이들의 임의의 조합이거나, R₁과 R₂는 Pt 원자와 함께, 선택적으로 치환된 사이클릴 또는 헤테로사이클릴을 형성하거나, 또는 R₃ 및 R₄는 Pt 원자와 함께, 선택적으로 치환된 사이클릴 또는 헤테로사이클릴을 형성함)이다.(vi)

Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are independently selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, Lipid, or any combination thereof, or R ₁ and R ₂ together with the Pt atom form an optionally substituted cyclic or heterocyclyl, or R ₃ and R ₄ together with the Pt atom are optionally substituted Lt; RTI ID = 0.0 > heterocyclyl < / RTI >

이며, 여기서 R₁ 및 R₂는 독립적으로 할로겐, 알킬, 아미노, 알킬아미노, 디알킬아미노, 하이드록실, 알콕시, 티올, 티오알킬, O-아실, 또는 이들의 임의의 조합이거나, 또는 R₁과 R₂는 Pt 원자와 함께, 선택적으로 치환된 사이클릴 또는 헤테로사이클릴을 형성하는, 단락 6의 화합물. 7. Z is

, Where the R ₁ and R ₂ are independently selected from halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, O- acyl, or is any combination of these, or R ₁ R < ₂ > together with the Pt atom form an optionally substituted cyclic or heterocyclyl.

이며, 여기서 p는 0, 1, 2, 또는 3인, 단락 7의 화합물.8. Z is

, Wherein p is 0, 1, 2, or 3.

9. The compound of paragraph 8, wherein p is 2.

10. The linker

_{(i) -X-CH 2 -X} 2 -X 1 - ( wherein, X is NH and; X ₁ is C (O) O, C ( O) NH, O (CH 2) -O, NH, or O X ₂ is (CH ₂ ) _n or C (O); and n is 0, 1, 2, 3, 4, or 5;

_{(ii) - (CH 2)} n O-, - (CH 2) n NHC (O) O-, - (CH 2) n OC (O) NH-, - (CH 2) n C (O) NH ( _{CH 2) m O-, - (} CH 2) n O (CH 2) m O-, - (CH 2) n O (O) -, - (CH 2) n NHC (O) (CH 2) m O -, or - (CH ₂ ) _n C (O) O-, wherein n and m are independently 0, 1, 2, 3, 4, or 5;

(iii) -X ₃ -X ₄ X ₅ -X ₆ -, wherein X ₃ is CH, CH ₂ or O, X ₄ , X ₅ and X ₆ are independently the same or different and -CH ₂ O- Or O; And

(iv) any combination of (i) to (iii)

Lt; RTI ID = 0.0 > 1 < / RTI > to < RTI ID = 0.0 > 9, < / RTI >

11. The linker is a bond, ethylene diamine, ethylene glycol, diethylene glycol, 1,3-propanediol, glycine, _{beta-alanine, -O-, -CH 2 O-NHCH} 2 CH 2 NHC (O) -, -NHCH _{2 CH 2 NHC (O) O-} , -NHCH 2 CH 2 -, -NHCH 2 CH 2 O-, -NHCH 2 C (O) -, -NHCH 2 C (O) O-, -NHCH 2 C (O _{) OCH 2 CH 2 CH 2 -} , -NHCH 2 C (O) OCH 2 CH 2 CH 2 O-, -NHCH 2 C (O) NH-, -CH 2 CH 2 -, -CH 2 CH 2 O-, _{-CH 2 CH 2 NHC (O)} -, -CH 2 CH 2 NHC (O) O-, -CH 2 CH 2 O-, -CH 2 C (O) NHCH 2 CH 2 -, -CH 2 C (O _{) NHCH 2 CH 2 O-, -CH} 2 CH 2 OCH 2 CH 2 -, -CH 2 CH 2 OCH 2 CH 2 O-, -CH 2 C (O) -, -CH 2 C (O) O-, _{-CH 2 CH 2 CH 2 -,} -CH 2 CH 2 CH 2 O-, = CHCH = CH 2 -, = CHCH = CHCH 2 O-, -CH = CHCH 2 -, -CH = CHCH 2 _{O-, -OCH 2 CH 2 O-,} -CH 2 -, -CH 2 O-, -NHC (O) CH 2 -, -NHC (O) CH 2 O-, -C (O) CH 2 -, _{-C (O) CH 2 O-,} -OC (O) CH 2 -, -OC (O) CH 2 O-, -C (O) CH 2 CH 2 C (O) NHCH 2 CH 2 -, -OC _{(O) CH 2 CH 2 C} (O) NHCH 2 CH 2 -, -C (O) CH 2 CH 2 C (O) NHCH 2 CH 2 O-, -OC (O) CH 2 CH 2 C (O) _{NHCH 2 CH 2 O-, -C (} O) CH 2 CH 2 C (O) NHCH 2 CH 2 NHC (O) -, -OC (O) CH 2 CH 2 C (O) NHCH 2 CH 2 NHC ( O) -, -C (O) CH 2 CH 2 C (O) NHCH 2 CH 2 NHC (O) O-, -OC (O) CH 2 CH 2 C (O) NHCH 2 CH 2 NHC (O) O -, < / RTI > and any combination thereof. ≪ RTI ID = 0.0 > 11. < / RTI >

12. The composition of claim 1, wherein the lipid is selected from the group consisting of fats, waxes, sterols, steroids, bile acids, fat-soluble vitamins, monoglycerides, diglycerides, phospholipids, glycolipids, sulfolipids, aminolipids, pigment lipids, glycerophospholipids, Which is a sterol selected from cholesterol, cholesterol, cholesterol chloroformate or derivatives thereof, and any combination thereof, selected from nanolithic, nanolithic, saccharose, polyketide and fatty acids or any combination thereof, Lt; RTI ID = 0.0 > 11 < / RTI >

13. The compound of paragraph 12, wherein said lipid is cholesterol or alpha-tocopherol.

14. The compound of any one of paragraphs 1 to 13, wherein said compound is as shown below:

(i)

(I)

(Wherein,

X is NH;

X ₁ is selected from the group comprising COOH, CONH ₂ , O- (CH ₂ ) _n -OH, NH ₂ and OH;

X ₂ is (CH ₂ ) _n or CO;

X ₃ is selected from the group comprising (CH ₂ ) _n , CH ₂ -NH and C ₄ H ₈ ;

X ₄ is CH-CO or -CH _3, and;

Z is a platinum-containing compound, wherein platinum forms part of the ring of formula (I);

n is 0, 1 or 2;

(ii)

≪ RTI ID = 0.0 &

(Wherein,

X is NH or N-CH ₂ COO ^-, and;

X ₁ is _{- (CH 2) n OH,} - (CH 2) n NHCOOH, - (CH 2) n CONH (CH 2) n OH, (CH 2) n O (CH 2) n OH, (CH 2) _n C = O, - (CH ₂ ) _n NHCO (CH ₂ ) _n OH and (CH ₂ ) _n -COOH;

Z is a platinum-containing compound wherein platinum forms part of a ring of formula II;

n is 0, 1 or 2;

(iii)

(III)

(Wherein,

X is selected from the group comprising S ⁺ , C, S ⁺ = O, N ⁺ H and P = O;

X ₁ is selected from the group comprising -CH, -CH _2, and -CH ₂ O;

X ₂ is C = O;

X ₃ is selected from CH, CH ₂ or O;

X ₄ , X ₅ , X ₆ is selected from -CH ₂ O or O;

Z is a platinum-containing compound, wherein platinum forms part of a ring of formula (III);

(iv) a compound of formula IV:

(IV)

(Wherein,

X is CH ₂ OH;

X ₁ is (CH ₂ ) _n ;

X ₂ is C = O;

Z is a platinum containing compound wherein platinum forms part of a ring of formula (IV);

n is 0, 1 or 2;

(v)

(VI)

(vi)

(VII)

15. A compound of formula V:

(V)

In this formula,

Wherein X ₁ , X ₂ , X ₃ and X ₄ are independently selected from O, P, S, Se, Cl, N, C, OA, OB, DACH, halide and chelated or non-chelated dicarboxylate bond Groups, and any combination thereof;

Wherein A and B are independently selected from the group consisting of C, P, S, N, and any combination thereof;

X ₄ is optional.

16.

Platinum moiety; And

The platinum-linked lipids

≪ RTI ID = 0.0 >

Conjugating the lipid to the platinum moiety to obtain the compound.

17.

(a) reacting the lipid with a linker to obtain a first compound;

(b) optionally reacting said first compound of step (a) with a carbonyl moiety to obtain a second compound; And

(c) conjugating said first compound of step (a) or said second compound of step (b) with said platinum moiety to obtain said compound

Lt; RTI ID = 0.0 > 16, < / RTI >

18. The process according to paragraph 16 or 17, wherein said compound is a compound of any one of paragraphs 1 to 15.

19.

(a) a platinum moiety; And

(b) a lipid linked to said lipid

≪ / RTI >

20. The nanoparticle of paragraph 19, wherein said compound is the compound of any one of paragraphs 1 to 15.

21. The nanoparticle of paragraph 19 or paragraph 20, wherein the nanoparticle further comprises co-lipid and / or stabilizer.

22. The nanoparticle of paragraph 21, wherein the ratio of said compound to co-lipid and / or stabilizer is in the range of 99: 1 to 1:99 (w / w), (mol / mol) or (vol / vol).

23. The nanoparticle comprises soy-phosphatidyl choline and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy (polyethylene glycol) -2000] as co-lipids. And wherein the ratio of the compound to the co-lipids is in the range of about 1: 1: 0.01 to about 1: 4: 3.

24. A pharmaceutical composition comprising the nanoparticles of any one of paragraphs 19 to 23.

25. A pharmaceutical composition comprising a compound of any one of paragraphs 1 to 15.

26. A pharmaceutical composition according to any one of the preceding claims, wherein the excipient is selected from the group consisting of granulating agents, binders, lubricants, disintegrants, sweeteners, glidants, anti-adherents, antistatic agents, surfactants, antioxidants, gums, coatings, The pharmaceutical composition of paragraph 24 or paragraph 25, wherein the pharmaceutical composition is selected from the group comprising plasticizers, preservatives, suspending agents, emulsifiers, plant cellulosic materials, spheronization agents, and any combination thereof.

27. The composition of any of paragraphs 24-24, wherein said composition is formulated into a dosage form selected from the group consisting of injectable, tablet, lyophilized powder, liposomal suspension, and any combination thereof. The pharmaceutical composition of any one of paragraphs 26 to 26.

28. A method of treating cancer comprising administering to a subject a therapeutically effective amount of a compound of any one of paragraphs 1 to 15, or a nanoparticle of any one of paragraphs 19 to 23, , A method of treating or managing cancer in a subject.

29. The use of the above-mentioned cancer for the treatment of breast cancer, head and neck cancer, ovarian cancer, testicular cancer, pancreatic cancer, oral-esophageal cancer, gastrointestinal cancer, liver cancer, gallbladder cancer, lung cancer, melanoma, skin cancer, sarcoma, ≪ / RTI > and any combination thereof.

30. The method of treatment or management of cancer of paragraph 28 or 29, wherein the administration is by intravenous, intraarticular, pancreaticoduodenal, peritoneal, portal, intramuscular, or any combination thereof .

31. The nanoparticle of any one of paragraphs 19 to 23, wherein said nanoparticle has an increased amount of platelets in cancer cells relative to cisplatin or oxaliplatin.

32. The nanoparticle of any of paragraphs 19 to 23 and paragraph 31, wherein the nanoparticle has a higher accumulation of platinum in the tumor relative to cisplatin or oxaliplatin in an equivalent dose amount of cisplatin or oxaliplatin.

33. The compound of any one of paragraphs 1 to 15, wherein said compound has an increased amount of platelet uptake of platinum relative to cisplatin or oxaliplatin in cancer cells.

34. The compound of any one of paragraphs 1 to 15 and 33, wherein said compound has a higher accumulation of platinum in the tumor relative to cisplatin or oxaliplatin in an equivalent dose amount of cisplatin or oxaliplatin.

35. Method for producing nanoparticles:

a. Providing a platinum compound, wherein the platinum compound comprises a platinum moiety and a lipid linked to the platinum moiety; And

b. Reacting the compound with a co-lipid in the presence of a solvent to obtain the nanoparticles.

36. The process according to paragraph 35, wherein said platinum compound is prepared according to the process of any one of paragraphs 16 to 18.

37. The method of paragraph 35 or paragraph 36, wherein said solvent is selected from the group comprising chloroform, methanol, dichloromethane, ethanol, and any combination thereof.

38. The co-lipid according to any one of the preceding claims, wherein the co-lipid is selected from the group consisting of soybean-phosphatidyl choline (fully hydrogenated), 1,2-distearoyl-sn- glycero-3-phosphoethanolamine- N- [methoxy (polyethylene glycol) (DOPC), DSPE-PEG-OMe, Dioleoylphosphatidylethanolamine (DOPE), and any combination thereof, as described in any one of paragraphs 35 to 37 Way.

39. The method of any one of paragraphs 35 to 38, wherein step (b) further comprises a drying step, an incubation step and an optional stabilizer addition step.

40. The method of paragraph 39, wherein said stabilizer is selected from the group consisting of DSPE-PEG-OMe, DSPE-PEG-NH2, PEG, inorganic salts, carbohydrates, and any combination thereof.

41. The method of paragraph 40, wherein the inorganic salt is selected from the group consisting of ammonium chloride, potassium chloride, sodium chloride, disodium hydrogen phosphate, sodium dihydrogen phosphate, and any combination thereof.

42. The method of paragraph 40 or paragraph 41, wherein said carbohydrate is selected from the group consisting of glucose, dextrose, and any combination thereof.

43. The method of paragraph 35 wherein said co-lipid is soy-phosphatidyl choline and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy (polyethylene glycol) A method according to any one of the preceding paragraphs.

44. The method of any one of paragraphs 35 to 43, wherein the ratio of the platinum compound and the co-lipids is about 1: 1: 0.01 to about 1: 4: 3.

Some Selected Definitions

For convenience, in the Detailed Description, the Examples and the appended claims, certain terms used in the specification are summarized herein. Unless otherwise stated or implied from the context, the following terms and phrases include the meanings given below. Unless expressly stated otherwise or clear from the context, the following terms and phrases do not exclude meanings obtained in the art to which the term or phrase relates. These definitions are provided to aid in describing particular embodiments and are not intended to limit the claimed invention, since the scope of the invention is limited only by the claims. Also, unless otherwise required by context, singular terms will include plural forms, and plural terms will include singular forms.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs. Although any known method, apparatus, or material may be used in the practice or testing of the present invention, the methods, apparatus, and materials associated therewith are described herein.

As used herein, the term " comprising "or" comprising "means that a composition, method, and each of its elements that are open to inclusion of an element not expressly listed, whether essential or still essential, Is used in connection with component (s).

Singular terms ("a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Similarly, the word "or" includes "and" unless the context clearly dictates otherwise.

In other respects, or where otherwise indicated, all numbers expressing the reaction conditions or amounts of ingredients used herein should be understood as being modified in all instances by the term "about ". The term "about" when used with a percentage may mean +/- 5% of the value mentioned. For example, about 100 means 95 to 105.

Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. The term " comprises "means" containing ". The abbreviation "eg" is derived from Latin exempli gratia and is used herein to illustrate non-limiting examples. Thus, the abbreviation "for example" is synonymous with the term "for example ".

The terms "reduce," " reduced, "" decrease," " decrease, "or" suppression "are all used herein to mean a decrease in a statistically significant amount. However, in order to avoid misunderstandings, "reduced", "reduced" or "reduced" or "suppressed" means a reduction of at least 10%, eg, at least about 20%, or at least about 30% Or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% , A member level as compared to a reference sample), or any reduction of 10-100% relative to a reference level.

The terms "increased "," increased ", or "enhanced" or "activated" are all used herein to denote an increase in a generally statistically significant amount; In order to avoid any misunderstanding, the terms "increased "," increased ", or "enhanced" or "activated" means an increase of at least 10%, for example at least about 20%, or at least about 30% Or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% Or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold relative to a reference level, or 2 Quot; means any increase of from 10-fold to 10-fold or more.

The term "statistically significant" or "significantly" refers to statistical significance, which generally means that at least two standard deviations (2SD) are off the reference level. This term refers to statistical evidence that there is a difference. This is defined as the probability of making a decision to reject the null hypothesis if the null hypothesis is actually true.

The term " treating ", "treating "," treating ", or "improving ", as used herein, refers to a therapeutic treatment, wherein the purpose in therapeutic treatment is to treat a disease or disorder, Relieve, ameliorate, inhibit, slow or stop the progression or severity of the associated condition. The term "treating" includes reducing or alleviating at least one side effect or symptom of a disease, disorder or disorder associated with cancer. If one or more symptoms or clinical markers are reduced, treatment is generally "effective ". Alternatively, treatment is "effective" if the progression of the disease is reduced or stopped. In other words, "treatment" includes not only the improvement of symptoms or markers, but also the progression or deterioration of symptoms, or at least deceleration, as compared to what is predicted in the absence of treatment. A beneficial or desired clinical result may include a reduction in one or more symptoms (s), a decrease in the severity of the disease, a stabilized (i.e., not worsening) condition of the disease, a delay or slowing of disease progression, (Whether partly or wholly), and / or reduced mortality, whether or not they are detectable or undetectable. The term "treatment" of a disease also includes providing relief from symptoms or side effects of the disease (including conventional treatment).

As used herein, "administering" or " administering "means preventing a disease or disorder from occurring in a subject, reducing the risk of death from a disease or disorder, delaying the onset of a disease or disorder , Partial or complete healing of the disease or disorder and / or side effects attributable to said disease or disorder, obtaining the desired pharmacological and / or biological effect, Or may be therapeutic in terms of partial or complete healing of the side effects caused by the disease or disorder and / or the disease or disorder) , Alleviating the disease or disorder (i. E., Causing the regression of the disease or disorder). In addition, the invention also contemplates treating such diseases by administering a therapeutic composition of the invention.

The terms "subject" and "subject" are used interchangeably herein and refer to a human or animal. Typically, the animal is a vertebrate animal such as a primate, rodent, livestock, or game animal. Primates include chimpanzees, cynomolgus monkeys, spider monkeys, and macaques, such as Bengal monkeys. Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters. Livestock and Prey Animal is a species of animal such as cattle, horses, pigs, deer, bison, buffalo, cats and bells such as domestic cats, nests and species such as dogs, foxes, wolves, (emu), ostriches, and fish, such as trout, catfish, and salmon. The patient or subject includes any of the foregoing, for example any of the above subsets, but excludes one or more populations or species such as humans, primates, or rodents. In certain embodiments, the subject is a mammal, such as a primate, such as a human. The terms "patient" and "subject" are used interchangeably herein. The terms "patient" and "subject" are used interchangeably herein.

Preferably, the subject is a mammal. Mammals may be humans, non-human primates, mice, rats, dogs, cats, horses, or bees, but are not limited to these examples. Non-human mammals can be advantageously used as subjects to represent animal models of cancer. In addition, the methods described herein can be used to treat domesticated animals and / or pets. The subject may be male (male) or female (female). The subject may be a person who has been previously diagnosed with cancer or who has been identified as suffering from cancer.

The description of the embodiments of the present invention is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Although specific embodiments of the invention and the embodiments thereof have been described herein for purposes of illustration, various equivalent modifications are possible within the scope of the invention, as would be recognized by those skilled in the relevant arts. For example, although method steps or functions are presented in a given order, alternative embodiments may perform the functions in a different order, or substantially simultaneously, the functions may be performed. The teachings of the present invention provided herein may be applied to other procedures or methods where appropriate. The various embodiments described herein may be combined to provide additional embodiments. Aspects of the present invention can be modified to use the compositions, functions and concepts of the above referenced and claimed applications to provide yet another further embodiment of the present invention, if desired. These and other changes may be made to the invention in light of the detailed description. All such modifications are intended to be included within the scope of the appended claims.

Specific elements of any of the above-described embodiments may be combined or replaced with elements in other embodiments. Moreover, although advantages associated with certain embodiments of the present invention are described in connection with these embodiments, it is to be understood that other embodiments may also exhibit such advantages, and all embodiments are not necessarily limited thereto This need not be the case.

Example

The following examples illustrate some embodiments and aspects of the present invention. Additions, substitutions, and so on can be made without departing from the spirit or scope of the present invention, and such variations and modifications are included within the scope of the present invention as defined in the following claims, . The following examples do not limit the invention in any way.

Example  One: Carbamate Having a bond  cholesterol- Oxaliplatin  Synthesis of Compound (I)

Cholesterol-oxaliplatin complexes containing carbamate linkages were synthesized as follows (Figure 1):

part A (Figure 1a ): ( step a) : In a 250 ml round-bottomed flask, ethylenediamine (about 22.2 ml, 30 eq) was added to about 50 ml of dry DCM (dichloromethane). The reaction flask was cooled to about 0 < 0 > C under an ice bath. Solid cholesteryl chloroformate (about 5.0 g, 11.14 mmol) was dissolved in another 50 mL of dry DCM and added dropwise to the reaction flask using a dropping funnel over a period of about 30 to about 45 minutes with vigorous stirring . The resulting solution was stirred at room temperature (25 [deg.] C) overnight (about 8 hours to 12 hours). Thereafter, the solution was poured into chloroform (about 100 mL), washed sequentially with water (3 x 50 mL) and brine (1 x 50 mL) for about one to three times. The organic layer obtained was dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by rotary evaporation. The residue at the time of purification by column chromatography with 60-120 mesh silica gel using 1% methanol-chloroform (v / v) as eluent gave 0.4.12 g (78%) of pure intermediate ( I ) Figure 1, Part A]. ( _Rf = 0.2 using 10% methanol-chloroform v / v as TLC eluting solvent).

Were performed for characterization of the intermediate (I) by proton NMR, the results are as ^{follows: 1 H NMR (500 MHz,} CDCl 3) δ 5.30 (s, 1H, -C = C H), 5.05 (s, 1H, -O-CO-N H), 4.42 (s, 1H, -C H -O-), 3.18 (s, 2H, -HN-C H 2 -CH 2 -), 2.79 (s, 2H, -O- _{CO-NH-C H 2)} , 2.35-0.60 (m, 45H, cholesterol skeletal).

(Step b) : Intermediate ( I ) (about 1.0 g, 2.12 mmol) obtained in step (a) and succinic anhydride (about 1.04 g, 10.57 eq) were dissolved together in dry DCM (about 20 mL) Stir at room temperature (25 < 0 > C) for a period ranging from about 15 minutes to about 30 minutes. Pyridine (ca. 3.41 mL, 20 eq) was added dropwise and the reaction mixture was stirred overnight (about 8 hours to 12 hours). The reaction mixture was then diluted with about 50 mL of chloroform and washed with 0.1 N HCl (3 x 100 mL) and brine (1 x 100 mL) for about 3 times. The organic layer obtained was dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by rotary evaporation, which was then purified by silica gel chromatography to give about 1.06 g (87%) of intermediate ( II ) . (R _f = 0.2 using 20% methanol-chloroform v / v as TLC evolution solvent).

The characterization of intermediate ( II ) was carried out by proton NMR and the results were as follows: ¹ H NMR (500 MHz, CDCl ₃ )? 6.72 (s, 1H, N H ), 5.32 C H), 5.09 (s, 1H, N H), 4.42 (s, 1H, C H -O-), 3.35-3.18 (m, 4H, -CO-NH-C H 2, CO 2 HC H 2 - ), 2.65 (s, 2H, -O-CO-NH-C H 2 -), 2.48 (s, 2H, -NH-CO-C H 2 -), 2.25-0.62 (m, 43H, cholesterol skeletal). ESIMS for C ₃₄ H ₅₆ N ₂ O ₅ m / z = 572 [M + 1] ⁺

(Step c): In a 50 ml 1-necked round bottom flask, about 0.15 ml (1.27 mmol) of monoethyl malonate was placed with about 185 mg (1.37 mmol) of HOBt and about 263 mg (1.37 mmol) of EDCl. About 7 mL of dry DCM was added and the reaction mixture was continuously stirred under a N ₂ atmosphere for a period of about 20 minutes to 30 minutes. At 0 < 0 > C, a solution of step (a) ( Example About 500 mg (1.06 mmol) of the intermediate ( I ) obtained in [ 1 ] was added to the reaction mixture. DIPEA (N, N-diisopropylethylamine) was added dropwise until the pH of the reaction mixture reached alkalinity. The reaction was continuously stirred at room temperature overnight (about 8 hours to 12 hours) (about 20 ° C to 25 ° C). Thereafter, the reaction mixture was washed with about 0.1 N HCl (1 x 30 mL), saturated NaHCO ₃ (1 x 50 mL) and brine (1 x 30 mL) for about 3 times. The organic layer obtained was dried over anhydrous Na ₂ SO ₄ and evaporation was carried out in a rotary evaporator. Column chromatography purification (1.5% chloroform-methanol) was performed, yielding about 530 mg (85%) of the product of the intermediate ( IIIi ) product. (R _f = 0.6; using 10% methanol-chloroform v / v as TLC evolution solvent).

By proton NMR, was carried out the characterization of the intermediate product (IIIi) obtained in the above, the results are as ^{follows: 1 H NMR (500 MHz,} CDCl 3) δ 7.34 (s, 1H, -CH2-N H -CO -), 5.30 (s, 1H , -CH2-C H = C-), 4.90 (s, 1H, -OCO-N H -CH2-), 4.42 (s, 1H, -C H -OCO-), 4.14 (m, 2H, -OC H 2 -CH3), 3.48 - 3.27 (m, 6H), 2.37 - 0.61 (m, 46H, cholesterol skeletal).

(Step d) : In a 50 ml 1-neck round bottom flask, about 1.03 g (1.75 mmol) of the intermediate obtained in step (c) [Example 1] was placed in THF: H ₂ O (15 mL: 5 mL) , And the mixture was stirred at room temperature (about 20 [deg.] C to 25 [deg.] C) for about 5 minutes. To the reaction mixture, about 146 mg (3.50 mmol) of LiOH (lithium hydroxide) was added and the mixture was stirred at room temperature (about 25 ° C) for an additional period of about 2 to 3 hours. After completion of the reaction, the mixture was diluted with chloroform (about 100 mL) and acidified with about 50 mL of dilute HCl (0.1 N). The resulting organic layer was washed with NaHCO ₃ solution (ca. 50 mL) and dried over anhydrous Na ₂ SO ₄ . Column chromatography purification (4% methanol-chloroform) gave about 631 mg (64%) of intermediate ( III ). (R _f = 0.4; using 20% methanol-chloroform v / v as TLC evolution solvent).

(Step e) : In a 50 mL 1-neck round bottom flask, about 0.12 mL (1.27 mmol) monoethyl oxalate was placed with about 185 mg (1.37 mmol) of HOBt and about 263 mg (1.37 mmol) of EDCl. About 7 ml of dry DCM was added and the reaction mixture was continuously stirred under a N ₂ atmosphere for a period of about 20 minutes to about 30 minutes. At 0 ° C, about 500 mg (1.06 mmol) of intermediate ( I ) obtained in step (a) [Example 1] dissolved in about 5 mL of dry DCM (about 20 mL) was added to the reaction mixture. DIPEA was added dropwise until the pH of the reaction mixture reached alkalinity. The reaction mixture was stirred continuously at room temperature overnight. The reaction mixture was washed with 0.1 N HCl (1 x 30 mL), saturated NaHCO ₃ (1 x 50 mL) and brine (1 x 30 mL). After drying the obtained organic layer over anhydrous Na ₂ SO _4, and it evaporated in a rotary evaporator. Column chromatography purification (1.5% methanol-chloroform) gave about 570 mg (94%) of the intermediate product ( IVi ). (R _f = 0.6; using 10% methanol-chloroform v / v as TLC evolution solvent).

By proton NMR, was carried out the characterization of the intermediate product (IVi) obtained in the above, the results are as ^{follows: 1 H NMR (500 MHz,} CDCl 3) δ 7.40 (s, 1H, -CO-N H -CH2 -), 5.28 (s, 1H , -C H = C-), 4.30 (q, J = 7.1 Hz, 2H, -OC H 2-CH3), 3.52 (d, J = 3.7 Hz, 2H, -OC H 2-CH2-), 3.46 (d , J = 4.2 Hz, 2H, -NH-C H 2-CH2-), 3.11 (t, J = 11.0 Hz, 1H, -OC H -CH2-), 2.33-0.55 (m, 47H, cholesterol skeleton).

(Step d ') : In a 50 ml 1-neck round bottom flask, about 500 mg (0.87 mmol) of the intermediate obtained in step (e) [Example 1] was dissolved in THF: H ₂ O (15 mL: 5 mL) , And the mixture was stirred at room temperature for about 5 minutes. To this reaction mixture, about 75 mg (1.75 mmol) of LiOH was added and the mixture was stirred at room temperature for an additional period of about 2 hours. After completion of the reaction, the mixture was diluted with chloroform (about 50 mL) and acidified with about 50 mL of dilute HCl (0.1 N). The organic layer was washed with NaHCO ₃ solution (50 mL) and dried over anhydrous Na ₂ SO ₄ . Column chromatography purification (4% methanol-chloroform) gave about 180 mg (38%) of intermediate ( IV ). ( _Rf = 0.2 using 10% methanol-chloroform v / v as TLC eluting solvent).

Part B (FIG. 1b) : (step f) : Dichloro (1,2-diamino-cyclohexane) platinum (II) (about 300 mg, 0.79 mmol) was partially dissolved in about 40.0 mL of H ₂ O. To this solution, silver nitrate (about 340 mg, 1.58 mmol) was added and the resulting reaction mixture was stirred at room temperature for a period of about 24 hours. When the mixture began to show milky white, silver chloride was removed by centrifugation at about 12000 rpm for about 30 minutes. Finally, hydrated oxaliplatin ( V ) was obtained by filtration through a 0.2 mu m filter.

Part C (Figure 1c): Step g: Synthesis of compound 1 : Intermediate ( II ) (about 407 mg, 0.71 mmol) obtained in step b (Example 1, part A) was dissolved in about 1.5 mL of DMF . To this solution, about 40.0 mL of hydrated oxaliplatin ( V ) (0.09 mmol) obtained in step f (Example 1, part B) was added and the reaction mixture was stirred for about 24 hours. The reaction mixture was lyophilized to give compound 1 , a cholesterol-oxaliplatin compound.

Characterization of the compound 1 (proton NMR and MALDI-TOF MS) is as ^{follows: 1 H NMR (500 MHz,} CDCl 3) δ 6.65 (s, 1H, N H), 5.30 (s, 1H, -C = C H), 5.01 (s, 1H , N H), 4.42 (s, 1H, C H -O-), 3.42 (s, 2H, Pt-NH 2 -C H -), 3.38-3.18 (m, 4H, _{-CO-NH-C H 2,} CO 2 HC H 2 -), 2.65 (s, 2H, -O-CO-NH-C H 2 -), 2.48 (s, 2H, -NH-CO-C H 2 -), 2.30-0.58 (m, 55H, cholesterol backbone and aminocyclohexane). MALDI-TOF MS for C ₄₀ H ₆₉ N ₄ O ₅ Pt = 880.4784 [M] ⁺

Step (g '): Synthesis of compound 2 : Intermediate ( III ) (about 58 mg, 0.11 mmol) obtained in step d (Example 1, part A) was dissolved in about 1.5 mL of DMF. To this solution, about 8.0 mL of hydrated oxaliphatin ( V ) (0.11 mmol) obtained in step f (Example 1, part B) was added and the reaction mixture was stirred for about 24 hours. The reaction mixture was lyophilized to give compound 2 , a cholesterol-oxaliplatin compound.

Characterization of the compound 2 (proton NMR and MALDI-TOF MS) is as ^{follows: 1 H NMR (500 MHz,} CDCl 3) δ 7.41 (s, H, -CO-N H -CH2-), 5.40 (s, 1H, -CH2-C H = C- ), 5.07 (s, 1H, -OCO-N H -CH2-), -), 4.49 (m, 1H, -C H -OCO-), 3.48 - 3.27 (m , 6H), 2.88 (s, 1H, -C H -NH2), 2.81 (s, 1H, -C H -NH2), 2.30-0.51 (m, 46H, cholesterol backbone and aminocyclohexane). MALDI-TOF MS for C ₃₉ H ₆₇ N ₄ O ₅ Pt = 886.5048 [M] ⁺

Step g '': Synthesis of Compound 3 : Intermediate ( IV ) (about 57 mg, 0.11 mmol) obtained in step d '(Example 1, Part A) was dissolved in about 1.5 mL of DMF. To this solution, about 8.0 mL of hydrated oxaliphatin ( V ) (0.11 mmol) obtained in step f (Example 1, part B) was added and the reaction mixture was stirred for about 24 hours. The reaction mixture was lyophilized to give compound 3 , a cholesterol-oxaliplatin compound.

Characterization of the compound 3 (proton NMR and MALDI-TOF MS) is as ^{follows: 1 H NMR (500 MHz,} CDCl 3) δ 7.84 (s, 1H, -O-CO-N H -CH2-), 5.31 ( s, 1H, -C H = C- ), 4.89 (s, 1H, -CO-N H -CH2-), 4.44 (s, 1H, -OC H -CH2-), 3.48-3.40 (m, 2H, -CO-NH-C H 2-) , 3.37-3.28 (m, 2H, -O-CO-NH-C H 2-), 2.91 (s, 1H, NH2-C H -CH2-), 2.83 (s , 1H, NH2-C H -CH2- ), 2.33-0.56 (m, 55H, cholesterol skeleton, and a cyclohexane ring proton). MALDI-TOF MS for C ₃₈ H ₆₅ N ₄ O ₅ Pt = 853.4823 [M] ⁺

Example  2: Ether Having a bond  cholesterol- Oxaliplatin  Synthesis of Compound (I)

The cholesterol-oxaliplatin complexes containing ether linkages were synthesized as follows ( Figure 2 ):

Part A (Figure 2a) : (steps a to e) : Synthesis of amine intermediate ( II ): Step a to step e were performed as described in example 3 (step 1 to step 5; synthesis of compound 25) .

(Step f): 100 ㎖ 1-neck round bottomed flask, steps (a) through (e) [Example 2, part A], after obtained the intermediate (II) (amine 500 mg, 1.164 mmol) for N ₂ atmosphere In DCM (about 10 mL) and stirred at room temperature for a period ranging from about 5 minutes to about 10 minutes. The reaction mixture was cooled to about 0 < 0 > C, succinic anhydride (about 570 mg, 5.82 mmol) followed by pyridine (about 1.88 mL, 23.3 mmol) was added and the reaction mixture was allowed to stir at room temperature for about 24 hours.

After completion of the stirring process (as checked by TLC), the reaction mixture was diluted with CH ₂ Cl ₂ (about 20 mL), washed with 0.1 N HCl (about 500 mL, to remove the pyridine completely) ₂ < / _RTI > SO4. The organic layer was concentrated in vacuo and purified by silica gel chromatography to give the required intermediate ( III ) in 95% yield (about 585 mg).

Were performed for characterization of the intermediates (III) by proton NMR, the results are as ^{follows: 1 H NMR (500 MHz,} CDCl 3) δ 6.18 (s, 1H, -CO-N H -CH2-), 5.28 (s , 1H, -C H = C-) , 3.49 (d, J = 4.4 Hz, 2H, -OC H 2-CH2-), 3.38 (d, J = 4.4 Hz, 2H, -NH-C H 2-CH2 -), 3.11 (t, J = 11.1 Hz, 1H, -OC H -CH1-), 2.63 (t, J = 6.4 Hz, 2H, -NH-CO-C H 2-), 2.47 (t, J = 6.4 Hz, 2H, HOOC-C H 2-), 2.31-0.55 (m, 43H, cholesterol skeletal).

(Step g): About 0.07 mL (0.64 mmol) of monoethyl malonate was placed in a 50 mL 1-neck round bottom flask with about 74 mg (0.64 mmol) of HOBt and about 134 mg (0.69 mmol) of EDCl. About 7 mL of dry DCM was added and the reaction mixture was continuously stirred under a N ₂ atmosphere for a period of about 20 minutes to 30 minutes. At about 0 ° C, about 250 mg (0.58 mmol) of intermediate ( II ) obtained after step (a) to step (e) [Example 2, part A] dissolved in about 5 mL of dry DCM (about 20 mL) ) Was added to the reaction mixture. DIPEA was added dropwise until the pH of the reaction mixture turned alkaline. The reaction mixture was stirred continuously at about room temperature overnight, and washed successively with 0.1 N HCl (1 x 30 mL), saturated NaHCO ₃ (1 x 50 mL) and brine (1 x 30 mL) Lt; / RTI > The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporation was carried out in a rotary evaporator. (R _f = 0.5; 5% methanol-chloroform v / v as TLC evolution solvent) to give about 290 mg (92% purity) of intermediate ( IVi ) Used).

By proton NMR, was carried out the characterization of the intermediate product (IVi) obtained in the above, the results are as ^{follows: 1 H NMR (500 MHz,} CDCl 3) δ 7.27 (s, 1H, -CO-N H -CH2 -), 5.28 (s, 1H , -C H = C-), 4.13 (q, J = 7.1 Hz, 2H, -OC H 2-CH3), 3.49 (d, J = 4.0 Hz, 2H, -OC H 2-CH2-), 3.40 (d , J = 4.8 Hz, 2H, -NH-C H 2-CH2-), 3.25 (s, 2H, -CO-C H 2-CO-), 3.10 (t, J = 10.9 Hz, 1H, -OC H -CH2-), 2.34-0.55 (m, 46H, cholesterol skeletal).

(Step h): In a 25 ml 1-neck round bottom flask, about 250 mg (0.46 mmol) of intermediate ( IVi ) obtained in step (g) [Example 2] was dissolved in THF: H ₂ O ) And the mixture was stirred at room temperature for about 5 minutes. To this reaction mixture, about 58 mg (1.38 mmol) of LiOH was added and the mixture was stirred at room temperature (about 20-25) for an additional period of about 3 hours. After completion of the reaction, the mixture was diluted with chloroform (about 50 mL) and acidified with about 10 mL of dilute HCl (0.1 N). The organic layer was washed with NaHCO ₃ solution (about 20 ㎖) and dried over anhydrous Na ₂ SO _4. Column chromatography purification (4% methanol-chloroform) gave about 228 mg (96%) of intermediate ( III ). (R _f = 0.4; using 20% methanol-chloroform v / v as TLC evolution solvent).

(Step i): Approximately 0.06 mL (10.64 mmol) of monoethyl oxalate was placed in a 50 mL 1-neck round bottom flask with about 74 mg (0.64 mmol) of HOBt and about 145 mg (0.76 mmol) of EDCl. About 7 ml of dry DCM was added and the reaction mixture was continuously stirred under a N ₂ atmosphere for a period of about 20 minutes to about 30 minutes. At 0 ° C, about 250 mg (0.58 mmol) of intermediate ( II ) obtained after steps (a) to (e) dissolved in about 5 mL of dry DCM (about 20 mL) was added to the reaction mixture. DIPEA was added dropwise until the pH of the reaction mixture turned alkaline. The reaction mixture was stirred continuously at room temperature overnight, and then washed successively with 0.1 N HCl (1 x 30 mL), saturated NaHCO ₃ (1 x 50 mL), and brine (1 x 30 mL). The organic layer was dried with anhydrous Na ₂ SO _4, and evaporated in a rotary evaporator. Column chromatography purification (1.5% methanol-chloroform) gave about 128 mg (41%) of intermediate ( VIi ) compound. (R _f = 0.5; using 10% methanol-chloroform v / v as TLC evolution solvent).

By proton NMR, was carried out the characterization of the intermediate product (VIi) obtained in the above, the results are as ^{follows: 1 H NMR (500 MHz,} CDCl 3) δ 7.40 (s, 1H, -CO-N H -CH2 -), 5.28 (s, 1H , -C H = C-), 4.30 (q, J = 7.1 Hz, 2H, -OC H 2-CH3), 3.52 (d, J = 3.7 Hz, 2H, -OC H 2-CH2-), 3.46 (d , J = 4.2 Hz, 2H, -NH-C H 2-CH2-), 3.11 (t, J = 11.0 Hz, 1H, -OC H -CH2-), 2.33-0.55 (m, 47H, cholesterol skeleton).

Step (h ') : In a 25 ml two-neck round bottom flask, about 128 mg (0.22 mmol) of the intermediate as obtained in step (i) [Example 1] was dissolved in THF: H ₂ O (3 ml: 1 Ml), and the mixture was stirred at room temperature for about 5 minutes. To this reaction mixture, about 18 mg (0.45 mmol) of LiOH was added and the reaction mixture was stirred at room temperature for an additional period of about 2 hours. After completion of the reaction, the reaction mixture was diluted with chloroform (about 15 mL) and then acidified with about 10 mL of diluted HCl (0.1 N). The organic layer was washed with NaHCO ₃ solution (about 20 ㎖) and dried over anhydrous Na ₂ SO _4. Column chromatography purification (4% methanol-chloroform) gave about 79 mg (66% purity) of intermediate ( V ). ( _Rf = 0.2 using 10% methanol-chloroform v / v as TLC eluting solvent).

Part B (FIG. 2b): Step (j) : Dichloro (1,2-diamino-cyclohexane) Platinum (II) (about 300 mg, 0.79 mmol) was partially dissolved in about 40.0 mL of H ₂ O. Silver nitrate (about 340 mg, 1.58 mmol) is added thereto and the resulting reaction mixture is stirred at room temperature for about 24 hours. After a milky appearance, silver chloride was removed by centrifugation at about 12000 rpm for about 30 minutes. Finally, hydrated oxaliplatin ( VI ) was obtained by filtration through a 0.2 mu m filter.

Part C (Fig. 2c): Step (k): Synthesis of Compound 4: step (f) the intermediate (III) (about 69 mg, 0.13 mmol) obtained in (Example 2, part A) of about 1.5 ㎖ DMF ≪ / RTI > Thereafter, about 10 mL of hydrated oxaliplatin ( VI ) (0.13 mmol) as obtained in step (j) (Example 2, Part B) was added and the reaction mixture was stirred for about 24 hours. The reaction mixture is lyophilized to give compound 4 , a cholesterol-oxaliplatin compound.

The characterization results of Compound 4 (proton NMR and MALDI-TOF MS) are as follows: ¹ H NMR (500 MHz, CDCl 3)? 6.12 (s, 1H, 2H), 3.13-3.35 (m, 2H, -NH-CH2-CH2-), 3.17 (t, J = 2H), 2.65 (dd, J = 7.6, 5.1 Hz), 3.05 (s, , 2H, -O-CO-CH2-CH2), 2.56-2.46 (m, 2H, -NH-CO-CH2-), 2.30-0.56 (m, 55H, cholesterol backbone, and cyclohexane ring protons). MALDI-TOF MS for C ₃₉ H ₆₈ N ₃ O ₄ Pt = 837.5227 [M] ⁺

Step (k '): Synthesis of compound 5: Intermediate ( IV ) (27 mg, 0.05 mmol) obtained in step h (Example 2, part A) was dissolved in about 1.5 mL of DMF. Thereafter, about 10 mL of hydrated oxaliplatin ( VI ) (0.05 mmol) obtained in step (j) (Example 2, Part B) was added and the reaction mixture was stirred for about 24 hours. The reaction mixture was lyophilized to give compound 5 , a cholesterol-oxaliplatin compound.

The characterization results of Compound 5 (proton NMR and MALDI-TOF MS) are as follows: ¹ H NMR (500 MHz, CDCl 3)? 6.52 (s, 1H, 2H, -O-CH2-CH2-), 3.41 (m, 2H, -NH-CH2-CH2-), 3.27 (s, , 2H, -CO-CH2-CO-), 3.17-3.02 (m, 1H, -O-CH-CH2-), 2.89 (s, 1H, NH2- -), 2.30-0.56 (m, 55H, cholesterol backbone, and cyclohexane ring protons). MALDI-TOF MS for C ₃₈ H ₆₆ N ₃ O ₄ Pt = 823.5242 [M] ⁺

Step (k "): Synthesis of Compound 6: Intermediate ( V ) (26 mg, 0.05 mmol) obtained in step h '(Example 2, Part A) was dissolved in about 1.5 mL of DMF. Then, about 5 ml of hydrated oxaliplatin ( VI ) (0.05 mmol) obtained in step e (Example 2, Part B) was added and the reaction mixture was stirred for about 24 hours. The reaction mixture was lyophilized to give compound 6 , a cholesterol-oxaliplatin compound.

Characterization of the compound 6 (proton NMR and MALDI-TOF MS) is as ^{follows: 1 H NMR (500 MHz,} CDCl 3) δ 7.96 (s, 1H, -CO-N H -CH2-), 5.28 (s, 1H, -C H = C-), 3.61 - 3.42 (m, 4H, -OC H 2-CH2-, -NH-C H 2-CH2), 3.18 - 3.02 (m, 1H, -OC H -CH2- ), 2.90 (s, 1H, NH2-C H -), 2.82 (s, 1H, NH2-C H -), 2.31-0.56 (m, 55H, cholesterol skeleton, and a cyclohexane ring proton). MALDI-TOF MS for C ₃₇ H ₆₄ N ₃ O ₄ Pt = 809.5258 [M] ⁺

Compounds 7 to 21 were prepared by using the required carboxylic acids, linker molecules, lipids and platinum moieties, analogously to the synthetic procedure described above.

Example  3: Synthesis of compound of formula (II)

Synthesis of Compound 25

Step 1 : To a ice-cold solution of cholesterol ( 1.01 ) (about 10 g, 0.026 mol) in CH ₂ Cl ₂ (about 45 mL), pyridine (about 15 mL) is added and stirred for about 15 minutes. To this solution, p-toluenesulfonyl chloride (about 9.8 g, 0.052 mol) is added and stirred for about 6 hours (h) at about 0 ° C, followed by TLC. After completion, the reaction mixture was diluted with CHCl ₃ (about 20 ㎖), washed with about 1N HCl (3 X 50 ㎖) and brine (about 20 ㎖) continuously. The organic layer was dried with anhydrous Na ₂ SO _4, and concentrated in vacuo to give the intermediate (1.02), and directly used in the subsequent reaction of the intermediate without further purification.

Step 2 : Ethylene glycol (about 15 mL) is added to a solution of tosylated cholesterol ( 1.02 ) (about 10 g, 0.018 mol) in dioxane (about 45 mL) and refluxed for about 4 hours. TLC. After completion, the reaction mixture is extracted with ethyl acetate and washed successively with water (about 3 x 50 mL) and brine (about 20 mL). The organic layer was dried with anhydrous Na ₂ SO _4, concentrated in vacuo, to yield the intermediate (1.03) column.

Step 3 : To a solution of cholesteryl ethylene glycol ( 1.03 ) (about 6.95 g, 16.13 mmol) in dichloromethane (about 15 mL) was added pyridine (about 13 mL) under nitrogen atmosphere and stirred for about 15 min do. To this solution, p-toluenesulfonyl chloride (about 3.7 g, 19.35 mmol) is added, stirred at about 0 ° C for about 5 hours, and checked by TLC. After completion, the reaction mixture was diluted with CHCl ₃ (about 20 ㎖), washed with about 1N HCl (3 X 50 ㎖) and brine (about 20 ㎖) continuously. The organic layer was dried with anhydrous Na ₂ SO _4, concentrated in vacuo and purified to give the intermediate (1.04) by silica gel chromatography.

Step 4 : In a 50 mL round bottomed flask, 1.04 (about 6 g, 10.26 mmol) was added to DMF (about 20 mL) under nitrogen atmosphere and stirred for about 30 min (warmed if necessary) . To this solution, sodium azide (about 3.4 g, 51.33 mmol) is added, stirred at room temperature (rt) for about 18 hours and checked by TLC. After completion, the reaction mixture was concentrated in vacuo to remove THF and purified by flash chromatography to give the intermediate ( 1.05 ).

Step 5 : To a solution of the azide ( 1.05 ) (about 3 g, 7.6 mmol) in dry DMF (about 15 mL), TPP (about 1.5 g, 15.2 mmol) is added under a nitrogen atmosphere. The reaction is stirred at room temperature for about 6 hours and about 2 ml of water is added to the reaction mixture. The reaction mixture is stirred for an additional period of about 6 hours and checked by TLC. After completion, the reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography using methanol / chloroform as eluent to give the amine intermediate ( 1.06 ).

Step 6 : NaH (ca. 120 mg, 2.094 mmol) was added to the ice-cold solution of the amine ( 1.06 ) (about 300 mg, 0.698 mmol) in THF (about 5 mL) by pinch over a period of about 10 min. . The resulting solution is stirred for about 20 minutes, ethyl bromoacetate is added and stirred at room temperature (rt) for a period of about 6 hours. After completion, the reaction mixture is cooled to about 0 C, quenched with water, and the compound is extracted with ethyl acetate (ca. 2 X 20 mL). Dry the organic layer over anhydrous Na ₂ SO ₄ and concentrated and purified by silica gel chromatography, to give a yield of about 52% of the diester intermediate (1.07).

Step 7 : In a 50 ml 1-neck round bottom flask, the diester compound ( 1.07 ) (about 218 mg, 0.363 mmol) is placed in THF / water (about 4 ml, at a ratio of about 3: 1) Lt; / RTI > To this cooled solution was added LiOH (ca. 34 mg, 1.45 mmol) and stirred at room temperature for a further 6 h period. After completion, the reaction mixture is concentrated under reduced pressure to remove THF and the aqueous layer is washed with ethyl acetate. The aqueous layer was lyophilized to give a solid di-lithium salt in a quantitative yield of 1.08 .

Step 8: Synthesis of DACH-Pt (H ₂ O) ₂ : Dichloro (1,2-diamino-cyclohexane) platinum ( 1.09 ) (about 200 mg, 0.526 mmol) was dissolved in a 50 ml 1-necked round bottom flask Insert the 20.0 ㎖ of H ₂ O. To this suspension, silver nitrate (about 178.7 mg, 1.052 mmol) is added and the reaction mixture is stirred at room temperature for about 24 hours. The milky solution is centrifuged and the solution is filtered through a 0.22 쨉 m syringe filter to yield DACH-Pt ( 1.10 ) hydrated to a quantitative yield (about 10 mg / ml).

Step 9 : In a 100 ml 1-neck round bottom flask, add 1.08 (about 202 mg, 0.363 mmol) of intermediate ( 1.08 ) in about 1.0 ml of water. To this solution, DACHPt (H ₂ O) ₂ (about 13.8 mL) obtained in the previous step is added and stirred for an additional 12 hours. The solid residue is filtered and washed with water (about 20 mL). The white solid residue is lyophilized and dissolved in excess methanol, filtered and concentrated under reduced pressure to yield cholesterol-oxaliplatin amphipathic compound 25 in about 85% yield.

Synthesis of Compound 26

Step 1 : To a solution of ethylenediamine (about 22.2 mL) in CH ₂ Cl ₂ (about 40 mL) was added a solution of compound 1.11 (about 5 g) in CH ₂ Cl ₂ (about 50 mL) And the reaction mixture is stirred at the same temperature for about 1 hour and further stirred at room temperature for an additional period of about 20 hours. After completion (the test by TLC), the reaction mixture was quenched with water Ken dichloromethane extract (about 4 x 50 ㎖), and the combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue is purified by column chromatography using methanol-chloroform as eluant to give intermediate ( 1.12 ).

Step 2 : In a 50 ml one-neck round bottom flask, amine ( 1.12 ) (about 300 mg, 0.634 mmol) is placed in THF (about 5 ml) under a nitrogen atmosphere. The reaction mixture is cooled to about 0 < 0 > C under an ice bath and NaH (about 130 mg, 3.17 mmol) is added over night for a period of about 10 minutes. The resulting solution is stirred for about 20 minutes and ethyl bromoacetate is added. The reaction mixture is stirred at room temperature for about 2 hours and checked by TLC. After completion, the reaction mixture was cooled to about 0 ℃ and cold water quenched (about 5 ㎖), extracted with ethyl acetate (approximately 2 X 20 ㎖), dried over anhydrous Na ₂ SO _4, and concentrated in the future. The residue is purified by column chromatography using methanol-chloroform as eluant to give intermediate ( 1.13 ).

Step 3: In a 50 ml 1-neck round bottom flask, the diester ( 1.13 ) (about 1.7 g, 2.63 mmol) is placed in THF / water (about 3: 1) (about 16 ml). The reaction mixture is cooled to about 0 < 0 > C under an ice bath and LiOH (about 130 mg, 5.27 mmol) is added to the reaction mixture. The resulting solution is stirred at room temperature for about 6 hours and checked by TLC. After completion, the reaction mixture is concentrated under reduced pressure to remove THF and diluted with water (about 5 mL). The aqueous layer was washed with successive use of ethyl acetate and CH ₂ Cl ₂ and lyophilized to yield intermediate ( 1.14 ) in quantitative yield.

Step 4 : In a 100 ml 1-neck round bottom flask, the intermediate ( 1.14 ) is placed in about 1.0 ml of water. To this solution, DACHPt (H ₂ O) ₂ is added and stirred for a further 12 hour period. The solid residue obtained is filtered, washed with water and lyophilized. The residue is dissolved in an excess of methanol, filtered and concentrated under reduced pressure to give cholesterol-oxaliplatin amphipathic compound 26 .

Synthesis of Compound 27

Step 1 : In a 50 mL 1-neck round bottom flask, BocHNCH ₂ COOH (about 370 mg, 2.08 mmol) is placed in CH ₂ Cl ₂ (about 10 mL) under a nitrogen atmosphere. Solid EDCl (about 400 mg, 2.08 mmol) and HOBT (about 285 mg, 2.08 mmol) are successively added to the reaction mixture. DIPEA is added to make the solution alkaline, and the reaction mixture is stirred for an additional 20 minutes. To this activated acid solution is added amine ( 1.06 ) (about 450 mg, 1.04 mmol) and the mixture is stirred at room temperature for about 12 hours and checked by TLC. After completion, the reaction mixture was quenched with water, and extracted with chloroform, dried over anhydrous Na ₂ SO _4, and concentrated in the future. The residue is purified by silica gel chromatography using methanol-chloroform as eluent to give intermediate ( 1.15 ).

Step 2 : In a 50 ml 1-neck round bottom flask, Boc protected amine ( 1.15 ) (about 600 mg, 0.99 mmol) is taken in CH ₂ Cl ₂ and the flask is cooled to about 0 ° C. To this solution, TFA is added and the mixture is stirred at the same temperature for about 3 hours. After completion, the reaction mixture is concentrated under a rotary evaporator and the crude product ( 1.16 ) is used in the next reaction without further purification.

Step 3 : In a 50 ml 1-neck round bottom flask, crude amine ( 1.16 ) (about 400 mg, 0.821 mmol) is placed in THF (about 10 ml) under a nitrogen atmosphere. The solution is cooled to about 0 < 0 > C under an ice bath and solid NaH (about 160 mg, 4.10 mmol) is added over night over a period of about 10 minutes. The resulting solution is stirred for an additional 20 minutes and ethyl bromoacetate is added. After completion, the reaction mixture was cooled to about 0 ℃, quenched with water, Ken, and extracted with ethyl acetate, dried over anhydrous Na ₂ SO _4, and concentrated in vacuo after. The residue is purified by silica gel chromatography using methanol-chloroform as eluent to give intermediate ( 1.17 ).

Step 4 : In a 50 ml 1-neck round bottom flask, the diester ( 1.17 ) (about 200 mg, 0.303 mmol) is placed in THF / water (about 3: 1) (about 4 ml) at about 0 ° C. Solid LiOH (about 15 mg, 0.606 mmol) is added to the reaction mixture and stirred at room temperature for about 6 hours. After completion, the reaction mixture is concentrated and diluted with water (about 4 mL). The aqueous layer was washed with succession of ethyl acetate and dichloromethane and lyophilized to give a solid powder of the acid salt ( 1.18 ) in quantitative yield.

Step 5 : In a 100 ml 1-neck round bottom flask, the intermediate ( 1.18 ) is placed in about 1.0 ml of water. To this solution, DACHPt (H ₂ O) ₂ is added and stirred for an additional 12 hours. The solid residue is filtered, washed with water, and then lyophilized. The residue is dissolved in an excess of methanol, filtered and concentrated under reduced pressure to give cholesterol-oxaliplatin amphipathic compound 27 .

Synthesis of Compound 28

Step 1 : To a solution of intermediate ( 1.02 ) (ca. 6 g, 0.011 mol) in dioxane (about 30 ml), diethylene glycol (about 20 ml) is added and allowed to reflux for about 4 hours. After completion, the reaction mixture is quenched with water (about 20 mL) and extracted with ethyl acetate. The organic layer washed with water (approximately 3 X 50 ㎖) and brine (about 20 ㎖) successively, and dried over anhydrous Na ₂ SO _4. The combined organic layers are concentrated under reduced pressure and the residue is purified by silica gel chromatography using methanol / chloroform as eluant to give intermediate ( 1.19 ).

Step 2 : To a solution of cholesteryl alcohol ( 1.19 ) (about 5 g, 10.54 mmol) and p-toluenesulfonyl chloride (about 4 g, 21.09 mmol) in DCM (about 25 mL) under nitrogen atmosphere was added pyridine About 13 ml) is added. The solution is stirred at about 0 < 0 > C for about 5 hours and checked by TLC. After completion, the solution is diluted with CHCl ₃ (about 20 ㎖) and wash with a 10% copper sulfate (II) solution (approximately 3 X 50 ㎖) and brine (about 20 ㎖) continuously. The organic layer was dried with anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The residue is purified by silica gel chromatography using ethyl acetate / hexane as eluent to give intermediate ( 1.20 ).

Step 3 : In a 50 ml round-bottomed flask, the tosyl compound ( 1.20 ) (about 3 g, 4.76 mmol) was placed in DMF (about 15 ml) under nitrogen atmosphere and stirred for about 30 min ≪ / RTI > To this solution, solid sodium azide (about 1.55 g, 23.84 mmol) is added, stirred at room temperature for about 18 hours, and checked by TLC. After completion, the reaction mixture is diluted with water (about 50 mL) and extracted with ethyl acetate (ca. 3 X 20 mL). The organic layer is washed with successive portions of water (about 2 X 20 mL) and brine (about 20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure and purified by flash chromatography to afford the intermediate (1.21).

Step 4 : Triphenylphosphine (TPP) (about 1.04 g, 4.02 mmol) is added to a solution of the azide ( 1.21 ) (about 1 g, 2.01 mmol) in dry DMF (about 10 mL) under a nitrogen atmosphere. The reaction mixture is stirred at room temperature for about 6 hours and water (about 1 ml) is added to it. The resulting solution is stirred at the same temperature for an additional 6 hours and checked by TLC. After completion, the organic solvent is removed in vacuo and the residue is purified by silica gel chromatography using methanol / chloroform as eluant to give the amine intermediate ( 1.22 ).

Step 5 : NaH (about 200 mg, 5.02 mmol) is added to the ice-cold solution of the amine ( 1.22 ) (about 800 mg, 1.68 mmol) in THF (about 10 mL) over a period of about 10 minutes under a nitrogen atmosphere. The resulting solution is stirred for about 20 minutes, ethyl bromoacetate (about 0.78 mL, 6.72 mmol) is added and stirred at room temperature for an additional 6 hours. After completion, the reaction mixture is cooled to about 0 C, quenched with water and extracted with ethyl acetate (ca. 2 X 20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated and purified by silica gel chromatography to give the diester intermediate (1.23).

Step 6 : In a 50 ml 1-neck round bottom flask, the diester ( 1.23 ) (about 220 mg, 0.340 mmol) is placed in THF / water (about 3: 1) (about 4 ml) at about 0 ° C. Solid LiOH (about 20 mg, 0.640 mmol) is added to the reaction mixture and stirred at room temperature for about 6 hours. After completion, the reaction mixture is concentrated and diluted with water (about 4 mL). The aqueous layer was washed with succession of ethyl acetate and dichloromethane and lyophilized to give a solid powder of the acid salt ( 1.24 ) in quantitative yield.

Step 7 : In a 50 ml 1-neck round bottom flask, the dilithium salt ( 1.24 ) is placed in water (about 1.0 ml). To this solution, DACHPt (H ₂ O) ₂ is added, stirred for a further 12 hours, and then filtered. The solution is lyophilized to yield cholesterol-oxaliplatin amphipathic compound 28 .

Synthesis of Compound 29

Step 1 : To a solution of the amine ( 1.06 ) (about 300 mg, 0.673 mmol) in THF (about 10 mL) is added NaH (about 108 mg, 2.692 mmol) over a period of about 10 minutes under a nitrogen atmosphere. The resulting solution is stirred for about 20 minutes and ethyl bromoacetate (about 0.1 mL, 0.874 mmol) is added. The resulting solution is stirred at room temperature for an additional 6 hours and checked by TLC. After completion, the reaction mixture is cooled to about 0 C, quenched with water and extracted with ethyl acetate (ca. 2 X 15 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated and purified by silica gel chromatography to give the diester intermediate (1.25).

Step 2 : In a 50 ml 1-neck round bottom flask, the diester ( 1.25 ) (about 200 mg, 0.388 mmol) is placed in THF / water (about 3: 1) (about 4 ml) at about 0 ° C. Solid LiOH (about 38 mg, 1.55 mmol) is added to the reaction mixture and stirred at room temperature for about 6 hours. After completion, the reaction mixture is concentrated and diluted with water (about 4 mL). The aqueous layer is acidified with NaHSO ₄ solution, extracted with dichloromethane (ca. 3 x 10 ml) and further concentrated to give a solid powder of the acid ( 1.26 ) in good yield.

Step 3 : In a 50 ml 1-neck round bottom flask, add acid ( 1.26 ) (about 70 mg, 0.143 mmol) in about 1.0 ml of DMF. To the solution, it was added to _{DACH-Pt (H 2 O)} 2 , and stirred for a further period of 12 hours. The reaction mixture is lyophilized to give cholesterol-oxaliplatin amphipathic compound 29 .

Synthesis of compounds 38, 39, 40, 41 and 42

The synthesis method for the compounds 38, 39, 40, 41 and 42 is similar to the synthesis method for the compound 25. Lipid moieties vary in the above compounds. The different lipid moieties (R) present in compounds 38 to 42 are as follows:

Compound 42:

 The synthetic routes of the above Compounds 38 to 42 are provided in Fig.

Modified Synthesis of Compound 25

Step 1 : To a solution of cholesterol ( 1.01 ) (about 10 g, 0.026 mol) in CH ₂ Cl ₂ (about 45 mL) was added pyridine (about 15 mL) and stirred for about 15 minutes. To the solution, p-toluenesulfonyl chloride (about 9.8 g, 0.052 mol) was added, stirred at 0 ° C for about 6 hours, and then examined by TLC. After completion, the reaction mixture was diluted with CHCl ₃ (about 20 ㎖), an about 1N HCl (3 X 50 ㎖) and brine (about 20 ㎖) and washed successively used. The organic layer was dried with anhydrous Na ₂ SO _4, and concentrated in vacuo to give the intermediate (1.02), the intermediate was used directly in the next reaction without further purification.

Step 2 : To a solution of tosylated cholesterol ( 1.02 ) (about 10 g, 0.018 mol) in dioxane (about 45 ml), ethylene glycol (about 15 ml) was added and refluxed for about 4 hours. TLC. After completion, the reaction mixture was extracted with ethyl acetate and washed successively with water (ca. 3 x 50 mL) and brine (ca. 20 mL). The organic layer was dried with anhydrous Na ₂ SO _4, concentrated in vacuo, the intermediate (1.03) was obtained by column purification.

Step 3 : To a solution of cholesteryl ethylene glycol ( 1.03 ) (about 6.95 g, 16.13 mmol) in dichloromethane (about 15 mL) was added pyridine (about 13 mL) under nitrogen atmosphere and stirred for about 15 min Respectively. To the solution was added p-toluenesulfonyl chloride (about 3.7 g, 19.35 mmol), stirred at about 0 ° C for about 5 hours, and checked by TLC. After completion, the reaction mixture was diluted with CHCl ₃ (about 20 ㎖), an about 1N HCl (3 X 50 ㎖) and brine (about 20 ㎖) and washed successively used. The organic layer was dried with anhydrous Na ₂ SO _4, the intermediate (1.04) was obtained by concentration in vacuo and purified by silica gel chromatography.

Step 4 : In a 50 mL round bottomed flask, 1.04 (about 6 g, 10.26 mmol) was added to DMF (about 20 mL) under nitrogen atmosphere and stirred for about 30 min (warmed if necessary) . To this solution, sodium azide (about 3.4 g, 51.33 mmol) was added, stirred at room temperature for about 18 hours, and checked by TLC. After completion, the reaction mixture was concentrated in vacuo to remove THF and purified by flash chromatography to give the intermediate ( 1.05 ).

Step 5 : TPP (about 1.5 g, 15.2 mmol) was added to a solution of azide ( 1.05 ) (about 3 g, 7.6 mmol) in dry DMF (about 15 mL) under a nitrogen atmosphere. The reaction was stirred at room temperature for about 6 hours and about 2 ml of water was added to the reaction mixture. The reaction mixture was stirred for an additional period of about 6 hours and checked by TLC. After completion, the reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography using methanol / chloroform as mobile phase to give the amine intermediate ( 1.06 ).

Step 6 : NaH (ca. 120 mg, 2.094 mmol) was added to the ice-cold solution of the amine ( 1.06 ) (about 300 mg, 0.698 mmol) in THF (about 5 mL) over about a 10 minute period. The resulting solution was stirred for about 20 minutes, ethyl bromoacetate was added and stirred at room temperature for a period of about 6 hours. After completion, the reaction mixture was cooled to about 0 C, quenched with water, and the compound extracted with ethyl acetate (ca. 2 X 20 mL). Dry the organic layer over anhydrous Na ₂ SO ₄ and concentrated and purified by silica gel chromatography, to obtain a 52% yield of the diester intermediate (1.07). ^{1 H NMR (500 MHz, CDCl} 3) δ: 5.34 (dd, J = 8.1, 5.5 Hz, 1H), 4.19 (q, J = 7.1 Hz, 4H), 3.73 - 3.61 (m, 6H), 3.14 (dt , J = 15.5, 5.5 Hz, 1H), 3.02 (t, J = 5.4 Hz, 2H), 2.28-0.64 (m, 49H, cholesterol skeleton).

Step 7 : In a 50 ml 1-neck round bottom flask, the diester compound ( 1.07 ) (about 218 mg, 0.363 mmol) is placed in THF / water (about 4 ml, at a ratio of about 3: 1) Lt; / RTI > To this cooled solution was added LiOH (ca. 34 mg, 1.45 mmol) and stirred at room temperature for a further 6 h period. After completion, the reaction mixture was concentrated under reduced pressure to remove THF and the aqueous layer was washed with ethyl acetate. The aqueous layer was lyophilized to give a solid dirithium salt of 1.08 in quantitative yield.

Step 8: DACH - Pt (H ₂ O) ₂ of  synthesis:

Dichloro (1,2-diamino-cyclohexane) platinum ( 1.09 ) (about 200 mg, 0.526 mmol) was placed in about 20.0 mL of H ₂ O in a 50 mL single round bottom flask. To this suspension, silver nitrate (about 178.7 mg, 1.052 mmol) was added and the reaction mixture was stirred at room temperature for about 24 hours. The milky solution was centrifuged and the solution was filtered through a 0.22 쨉 m syringe filter to yield DACH-Pt ( 1.10 ) hydrated to a quantitative yield (ca. 10 mg / ml).

Step 9 : In a 100 ml 1-neck round bottom flask, the intermediate ( 1.08 ) (about 202 mg, 0.363 mmol) was placed in about 1.0 ml of water. To this solution, DACHPt (H ₂ O) ₂ (about 13.8 mL) obtained in the previous step was added and stirred for an additional 12 hours. The solid residue was filtered and washed with water (about 20 mL). The white solid residue was lyophilized and dissolved in excess methanol, filtered and concentrated under reduced pressure to give cholesterol-oxaliplatin amphipathic compound 25 in about 85% yield. ¹ H NMR of compound _{25 (500 MHz, CDCl 3)} δ: 5.36 (s, 1H), 3.71 (s, 4H), 3.64 (m, 2H), 3.16 (m, 1H), 2.86 - 2.78 (m, 2H ), 2.36-0.62 (57 H, cholesterol skeleton). ¹³ of the IO -125_01 C NMR (125 MHz, CD 2 Cl 2 - CD3OD) δ: 183.13, 182.80, 171.64, 171.35, 140.13, 122.08, 79.93, 56.73, 56.17, 50.19, 42.22, 39.75, 39.41, 38.87, 38.66, 37.00, 36.71, 36.11, 35.75, 32.16, 31.84, 29.54, 28.24, 28.13, 28.08, 27.90, 24.34, 24.19, 24.13, 23.72, 22.31, 22.06, 20.97, 18.97, 18.94, 18.32, 11.44; IR ( KBr ) of Compound 25 : 3416.28, 3162.69, 2933.20, 1654.62, 1599.66, 1455.99, 1377.89, 1317.14, 1174.44, 1091.51, 1061.62; Compound 25 MALDI - TOF MS (m / z) of C39H67N3O5Pt = 853.644 (M) ^< ⁺ &^gt;; 195Pt ( 108 MHz , CD2Cl2 - MeOD ) -2316.5 and -2341.82 of Compound 25 ; Analytical Calcd. Identified for C ₃₉ H ₆₇ N ₃ O ₅ Pt C, 52.63 (54.91), H, 7.93 (7.92), N, 4.21 (4.93).

Modified Synthesis of Compound 26

Step 1 : To a solution of ethylenediamine (about 22.2 mL) in CH ₂ Cl ₂ (about 40 mL) was added a solution of compound 1.11 (about 5 g) in CH ₂ Cl ₂ (about 50 mL) Lt; / RTI > and the reaction mixture was stirred at the same temperature for about 1 hour and further stirred at room temperature for an additional period of about 20 hours. After completion (the test by TLC), quenched with water and the reaction mixture was extracted with dichloromethane (about 4 x 50 ㎖), dried combined organic layer over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography using methanol-chloroform as mobile phase to give intermediate ( 1.12 ).

^{1 H NMR (500 MHz, CDCl} 3) δ: 5.30 (s, 1H), 5.05 (s, 1H), 4.42 (s, 1H), 3.18 (s, 2H), 2.79 (s, 2H), 2.35-0.60 (m, 45H, cholesterol skeleton).

Step 2 : In a 50 ml one-neck round bottom flask, amine ( 1.12 ) (about 300 mg, 0.634 mmol) was placed in THF (about 5 ml) under a nitrogen atmosphere. The reaction mixture was cooled to about 0 < 0 > C under an ice bath and NaH (about 130 mg, 3.17 mmol) was added over night over a period of about 10 minutes. The resulting solution was stirred for about 20 minutes and ethyl bromoacetate was added. The reaction mixture was stirred at room temperature for about 2 hours and checked by TLC. After completion, the reaction mixture was cooled to about 0 ℃ and cold water quenched (about 5 ㎖), extracted with ethyl acetate (approximately 2 X 20 ㎖), dried over anhydrous Na ₂ SO _4, and concentrated in the future. The residue was purified by column chromatography using methanol-chloroform as mobile phase to give intermediate ( 1.13 ).

^{1 H NMR (500 MHz, CDCl} 3) δ: 5.85 (s, 1H), 5.39 (d, J = 4.9 Hz, 1H), 4.50 (m, 1H), 4.25 - 4.15 (m, 4H), 3.63 (m , 4H), 3.30 (bs, 2H), 2.98 (bs, 2H), 2.44-0.71 (m, 49H, cholesterol skeleton).

¹³ C NMR ( 500 MHz , CDCl ₃ ) ?: 171.32, 156.37, 140.00, 122.28, 74.14, 60.79, 56.66, 56.09, 55.16, 53.36, 49.97, 42.28, 39.71, 39.49, 38.57, 37.00, 36.54, 36.15, 35.77, 31.88, 31.85, 28.21, 28.14, 27.99, 24.26, 23.79, 22.80, 22.55, 21.01, 19.32, 18.68, 14.19, 11.83;

Step 3: In a 50 ml 1-neck round bottom flask, the diester ( 1.13 ) (about 1.7 g, 2.63 mmol) was placed in THF / water (about 3: 1) (about 16 ml). The reaction mixture was cooled to about 0 C under an ice bath and LiOH (ca. 130 mg, 5.27 mmol) was added to the reaction mixture. The resulting solution was stirred at room temperature for about 6 hours and checked by TLC. After completion, the reaction mixture was concentrated under reduced pressure to remove the THF and diluted with water (about 5 mL). The aqueous layer was washed with successive portions of ethyl acetate and CH ₂ Cl ₂ and lyophilized to yield intermediate ( 1.14 ) in quantitative yield.

Step 4 : In a 100 ml 1-neck round bottom flask, the intermediate ( 1.14 ) was placed in about 1.0 ml of water. To this solution, DACHPt (H ₂ O) ₂ was added and stirred for a further 12 hours. The resulting solid residue was filtered, washed with water and lyophilized. The residue was dissolved in excess methanol, filtered and concentrated under reduced pressure to give cholesterol-oxaliplatin amphipathic compound 26 . ¹ H NMR of compound _{26 (500 MHz, CDCl 3)} δ: 5.40 (s, 1H), 4.89 (bS, 1H), 4.52 (m, 1H), 3.61 (s, 4H), 3.40-3.28 (m, 2H ), 2.73-2.66 (m, 2H), 2.44-0.60 (57H, cholesterol skeleton). Of Compound ^{26 13 C NMR (125 MHz,} CD 2 Cl 2 - CD3OD) δ: 186.87, 186.49, 175.25, 174.91, 161.48, 161.24, 143.69, 126.49, 79.20, 60.62, 60.04, 53.92, 46.19, 43.62, 43.38, 42.4 , 42.32, 40.86, 40.46, 40.05, 39.68, 36.13, 35.80, 35.73, 33.97, 32.10, 31.96, 31.87, 28.21, 28.14, 27.70, 26.58, 26.32, 23.09, 22.51, 15.66; IR ( KBr ) of Compound 26 : 3403.74, 2931.27, 1665.23, 1632.45, 1444.42, 1382.71, 1131.05; Compound 26 MALDI - TOF MS (m / z) of C40H68N4O6Pt = 896.5292 (M) ^< ⁺ &^gt;; 195Pt ( 108 MHz , MeOD ) of compound 26 -2280.34 and -2305.06; Analytical Calcd. Identified for C ₄₀ H ₆₈ N ₄ O ₆ Pt C, 51.96 (53.62), H, 7.82 (7.65), N, 5.39 (6.25).

Modified Synthesis of Compound 27

Step 1 : BocHNCH ₂ COOH (about 370 mg, 2.08 mmol) was placed in CH ₂ Cl ₂ (about 10 mL) under a nitrogen atmosphere in a 50 mL 1-neck round bottom flask. Solid EDCl (about 400 mg, 2.08 mmol) and HOBT (about 285 mg, 2.08 mmol) are successively added to the reaction mixture. DIPEA was added to make the solution alkaline, and the reaction mixture was stirred for an additional 20 minutes. To this activated acid solution was added amine ( 1.06 ) (about 450 mg, 1.04 mmol) and the mixture was stirred at room temperature for about 12 hours and checked by TLC. After completion, the reaction mixture was quenched with water, and extracted with chloroform, dried over anhydrous Na ₂ SO _4, and concentrated in the future. The residue was purified by silica gel chromatography using methanol-chloroform as mobile phase to give intermediate ( 1.15 ).

Step 2 : Boc protected amine ( 1.15 ) (about 600 mg, 0.99 mmol) was placed in CH ₂ Cl ₂ in a 50 mL 1-neck round bottom flask and the flask was cooled to about 0 ° C. To this solution was added TFA and the mixture was stirred at the same temperature for about 3 hours. After completion, the reaction mixture was concentrated under a rotary evaporator and the crude product ( 1.16 ) was used in the next reaction without further purification.

Step 3 : In a 50 ml 1-neck round bottom flask, crude amine ( 1.16 ) (about 400 mg, 0.821 mmol) was placed in THF (about 10 mL) under a nitrogen atmosphere. The solution was cooled to about 0 < 0 > C under an ice bath and solid NaH (about 160 mg, 4.10 mmol) was added over night over a period of about 10 minutes. The resulting solution was stirred for an additional 20 minutes and ethyl bromoacetate was added. After completion, the reaction mixture was cooled to about 0 ℃, quenched with water, Ken, and extracted with ethyl acetate, dried over anhydrous Na ₂ SO _4, and concentrated in vacuo after. The residue was purified by silica gel chromatography using methanol-chloroform as mobile phase to give intermediate ( 1.17 ). ^{1 H NMR (500 MHz, CDCl} 3) δ: 5.33 - 5.29 (m, 1H), 4.19 - 4.12 (q, J = 7.25 Hz, 4H), 3.56 - 3.49 (m, 6H), 3.43 (dd, J = 11.6, 5.9 Hz, 2H), 3.39 (s, 2H), 3.14 (m, 1H), 2.44-0.71 (m, 50H, cholesterol skeleton). ¹³ C NMR ( 500 MHz , CDCl ₃ ) ?: 170.90, 170.66, 140.77, 121.54, 79.15, 66.33, 60.85, 58.82, 56.70, 56.09, 55.57, 50.12, 42.25, 39.71, 39.45, 39.35, 38.95, 37.14, 36.12, 35.71, 31.87, 31.83, 28.26, 28.16, 27.93, 24.22, 23.75, 22.74, 22.49, 21.00, 19.29, 18.65, 14.15, 11.79;

Step 4 : The diester ( 1.17 ) (about 200 mg, 0.303 mmol) was placed in THF / water (about 3: 1) (about 4 mL) at about 0 C in a 50 mL 1-neck round bottom flask. Solid LiOH (about 15 mg, 0.606 mmol) was added to the reaction mixture and stirred at room temperature for about 6 hours. After completion, the reaction mixture was concentrated and diluted with water (about 4 mL). The aqueous layer was washed with succession of ethyl acetate and dichloromethane and lyophilized to give a solid powder of the acid salt ( 1.18 ) in quantitative yield.

Step 5 : In a 100 ml 1-neck round bottom flask, the intermediate ( 1.18 ) was placed in 1 ml of water. To this solution, DACHPt (H ₂ O) ₂ was added and stirred for an additional 12 hours. The solid residue was filtered, washed with water, and then lyophilized. The residue was dissolved in an excess of methanol, filtered and concentrated under reduced pressure to give cholesterol-oxaliplatin amphipathic compound 27 . ¹ H NMR of compound _{27 (500 MHz, CDCl 3 -} CD3OD) δ: 5.28 (s, 1H), 4.11 (d, J = 14.1 Hz, 1H), 3.65-3.25 (m, 8H), 3.17-3.05 (m , 1H), 2.44-0.60 (57H, cholesterol skeleton). ¹³ C NMR of compound 27 (125 MHz, DMSOd6) δ : 180.1, 168.19, 166.47, 140.36, 121.06, 78.25, 65.47, 63.65, 61.23, 61.14, 60.31, 56.09, 55.48, 49.50, 41.76, 38.54, 36.57, 36.19, 35.56, 35.09, 31.32, 31.27, 28.88, 27.94, 27.68, 27.30, 23.77, 23.08, 22.58, 22.31, 20.51, 18.98, 18.46, 11.59; IR ( KBr ) of Compound 27 : 3447.72, 3245.64, 2935.69, 1617.40, 1392.53, 1096.25; Compound 27 MALDI- TOF MS of C41H70N4O6Pt (m / z) = 910.6240 (M) ^< ⁺ &^gt;; Of compound 27 195Pt (108 MHz, MeOD) -2260.12 -2271.67 and; The analysis calculated check for _{C 41 H 70 N 4 O 6} Pt C, 52.85 (54.11), H, 7.77 (7.75), N, 5.26 (6.16).

Example  4: Synthesis of compound of formula (III)

Synthesis of Compound 31

Step 1 : In a 50 ml one-neck round bottom flask, acetonide protected keto-acid (about 121.5 mg, 0.854 mmol) is added in about 2 ml of anhydrous THF and the mixture is cooled to about -78 < 0 > C. To this solution, LiHMDS (about 0.85 mL, 5 eq, 1 mmol solution in toluene) is added and the mixture is stirred at the same temperature for about 15 minutes. To this solution, a tosyl compound ( 1.04 ) (about 100 mg, 0.171 mmol) in THF (about 2 mL) is added and the mixture is stirred again at about -78 < 0 > C for about 2 hours. After completion, the reaction mixture is cooled to about 0 C, quenched with water and extracted with ethyl acetate (ca. 2 X 15 mL). The organic layer was dried with anhydrous Na ₂ SO _4, concentrated, purified by silica gel chromatography to give the diester intermediate (1.27).

Step 2 : Approximately 1 mL of acetonide protected compound ( 1.27 ) in THF is placed in a 50 mL round bottom flask and about 0 C HCl (about 1 M) is added. The reaction mixture is stirred at room temperature for about 3 hours and TLC is performed. After completion, the reaction mixture is diluted with water (about 5 mL) and extracted with ethyl acetate (about 20 mL). The organic layer was dried with anhydrous Na ₂ SO _4, concentrated, purified by silica gel chromatography to give the intermediate (1.28).

Step 3 : To a 50 ml 1-neck round bottom flask is added the hydroxylic acid (A) in DMF (about 1 ml) and the mixture is stirred at room temperature for about 30 minutes. The hydrated DACH is added to the reaction mixture at room temperature, the mixture is stirred for about 24 hours, and then lyophilized. The solid residue is washed with water (about 5 ml) and lyophilized to yield the final platinum adduct, compound 31 .

Synthesis of Compound 32

Step 1 : In a 50 ml 1-neck round bottom flask, the alcohol intermediate ( 1.03 ) is placed in about 5 ml of anhydrous CH ₂ Cl ₂ and cooled to about 0 ° C. To this solution, PCC (pyridinium chlorochromate) is added and the reaction mixture is stirred for about 3 hours at room temperature, after which the reaction is checked by TLC. After completion, the reaction mixture is concentrated and purified by silica gel chromatography to give the aldehyde intermediate.

Step 2 : To a 50 mL 1-necked round bottom flask is added the TPP (sodium tripotassium) salt in THF and the mixture is cooled to about 0 < 0 > C. To this solution, nBuLi is added and the reaction mixture is stirred for about 1 hour. To the resulting solution is slowly added the aldehyde prepared in the previous step in THF (about 5 ml). The resulting solution is stirred at about 0 < 0 > C for an additional 3 hours and the progress of the reaction is checked by TLC. After completion of the reaction, the reaction mixture is quenched with water and extracted with ethyl acetate. The combined organic layers obtained are concentrated and purified by silica gel chromatography.

Step 3 : To a 50 ml 1-neck round bottom flask, add liquid ammonia in THF at approximately -78 < 0 > C. To this solution, sodium metal is slowly added over a period of about 20 minutes. To the resulting blue solution, a benzyl protected compound in THF is added over a period of about 10 minutes. The resulting solution is stirred at the same temperature for about 3 hours and the progress of the reaction is checked by TLC. After completion of the reaction, the reaction mixture is left at room temperature for about 12 hours, then quenched with ammonium chloride solution, extracted with ethyl acetate, and finally concentrated under reduced pressure. The residue is purified by silica gel chromatography.

Step 4 : To a 50 ml 1-neck round bottom flask, the hydroxyl compound in CH ₂ Cl ₂ is added at about 0 ° C. To this solution is added a solid Dess-Martin Periodinane (DMP), the mixture is stirred for about 3 hours, and the reaction is monitored by TLC. After completion of the reaction, the reaction mixture is quenched with water and extracted with CH ₂ Cl ₂ . Thereafter, the organic layer is concentrated and purified by silica gel chromatography.

Step 5 : Lithium diisopropylamide (LDA) is added to a 50 ml 1-neck round bottom flask at about -78 < 0 > C. To this, tert-butyl acetate in THF is added and the mixture is stirred for about 0.5 h. To this solution is added slowly the aldehyde prepared in the previous step in THF (about 5 ml). The resulting solution is stirred at about -78 < 0 > C for an additional 2 h, and the reaction is monitored by TLC. After completion, the reaction mixture is quenched with water and extracted with ethyl acetate. The combined organic layers are concentrated and purified by silica gel chromatography.

Step 6 : To a 50 ml 1-neck round bottom flask, the hydroxyl compound in CH ₂ Cl ₂ is added at about 0 ° C. To this solution, solid des-Martin ferriodin (DMP) is added, the mixture is stirred for about 3 hours and the progress of the reaction is checked by TLC. After completion, the reaction mixture is quenched with water and extracted with CH ₂ Cl ₂ . The organic layer obtained is concentrated and purified by silica gel chromatography.

Step 7 : To a 50 mL 1-neck round bottom flask is added tert-butyl ester in THF and the solution is cooled to about 0 < 0 > C. To the cooled solution, about 1 (M) HCl is added and the reaction mixture is stirred at the same temperature for about 2 hours. After completion of the reaction, the compound is extracted with ethyl acetate and concentrated under reduced pressure. The residue is purified by silica gel chromatography.

Step 8 : To a 50 mL 1-neck round bottom flask is added hydroxyl acid in DMF (about 1 mL) and the mixture is stirred at room temperature for about 30 min. The hydrated DACH is added to the reaction mixture at room temperature, stirred for about 24 hours, and then lyophilized. The solid residue is washed with water (about 5 ml) and lyophilized to give the final platinum adduct, compound 32 .

Synthesis of Compound 33

Step 1 : To a 50 mL 1-necked round bottom flask, add about 5 mL of an alcoholic intermediate ( 1.03 ) in anhydrous CH ₂ Cl ₂ and cool to about 0 ° C. To this solution, PCC is added and the reaction mixture is stirred for about 3 hours at room temperature and the progress of the reaction is checked by TLC. After completion, the reaction mixture is concentrated, followed by purification by silica gel chromatography to obtain an aldehyde intermediate.

Step 2 : In a 50 ml 1-necked round-bottomed flask, LDA in THF is produced at about -78 < 0 > C. To this solution, 1,3-dioxinone in THF is added and the reaction mixture is stirred for about 0.5 hour. To this solution is slowly added the previously prepared aldehyde in THF (about 5 mL) and the resulting solution is stirred at about -78 < 0 > C for an additional 2 hours and the reaction is checked by TLC. After completion, the reaction mixture is quenched with water and extracted with ethyl acetate. The combined organic layers are concentrated and then purified by silica gel chromatography.

Step 3 : To a 50 mL 1-necked round bottom flask is added acetonide-protected compound in THF at about 0 < 0 > C. To this solution, 1 (M) HCl is added and the reaction mixture is stirred at the same temperature for about 2 hours. After completion of the reaction, the compound is extracted with ethyl acetate and concentrated under reduced pressure. The residue is purified by silica gel chromatography.

Step 4 : To a 50 mL 1-neck round bottom flask is added hydroxyl acid in DMF (about 1 mL) and the solution is stirred at room temperature for about 30 min. Hydrated DACH-Pt (H2O) is added to the reaction mixture at room temperature, and the reaction mixture is stirred for an additional 24 hours, and then lyophilized. The solid residue is washed with water (about 5 ml) and then lyophilized to give the final platinum adduct, compound 33 .

Synthesis of Compound 34 [wherein R = cholesterol or other lipids]

Step 1 : To a ice-cold solution of cholesterol ( 1.01 ) in CH ₂ Cl ₂ , pyridine is added and stirred for about 15 minutes. To this solution, p-toluenesulfonyl chloride is added and stirred at about 0 ° C for an additional 6 hours. After completion, the reaction mixture was diluted with CHCl _3, and washed with about 1N HCl and brine successively. The organic layer was dried with anhydrous Na ₂ SO _4, and concentrated in vacuo to give the intermediate (1.02), and used in the subsequent reaction of this intermediate without further purification.

Step 2 : To a solution of crude tosylcholesterol ( 1.02 ) in dioxane, 1,3-propanediol is added and the reaction mixture is refluxed for about 4 hours. After completion, the reaction mixture is extracted with ethyl acetate and washed successively with water and brine. Remove the organic layer with anhydrous Na ₂ SO _4, concentrated under vacuum and, finally, the residue was purified on a column of silica gel to give the alcohol intermediate.

Step 3 : To a ice-cold solution of the alcohol in CH ₂ Cl ₂ , pyridine is added and stirred for about 15 minutes. To this solution, p-toluenesulfonyl chloride is added and the reaction mixture is stirred at about 0 ° C for an additional 6 hours. After completion, the reaction mixture was diluted with CHCl _3, and washed with about 1N HCl and brine successively. The organic layer was dried with anhydrous Na ₂ SO _4, and concentrated in vacuo after. The residue is purified on a silica gel column to afford the tosyl intermediate.

Step 4 : In a 50 ml 1-neck round bottom flask, methyl-3-mercaptopropionate in DMF (about 10 ml) is added at about 0 < 0 > C under a nitrogen atmosphere. Potassium carbonate is added to the reaction mixture, followed by addition of the tosyl compound. The mixture is stirred at room temperature for an additional 24 h. After completion, the reaction mixture is quenched with water and then extracted with ethyl acetate. The organic layer was dried with anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The residue is finally purified by silica gel chromatography to give the sulfide intermediate.

Step 5 : In a 50 ml 1-neck round bottom flask, add the ester compound in THF / water and cool the mixture to about 0 < 0 > C. To this solution was added LiOH and stirred at room temperature for a further 3 hours. After completion, the reaction mixture is concentrated under reduced pressure to remove THF and further extracted with ethyl acetate. The organic layer was dried with anhydrous Na ₂ SO _4, and concentrated, to give the final silica gel chromatography to give the acid intermediate.

Step 6 : Into a 50 ml 1-neck round bottom flask is added the acid intermediate obtained in the previous step in CH ₂ Cl ₂ and the mixture is cooled to about 0 ° C. To this solution, m-chloroperoxybenzoic acid (mCPBA) (about 0.9 eq) is added and the reaction mixture is stirred for about 1 hour at the same temperature (i.e. 0 ° C) and the progress of the reaction is checked by TLC. After completion of the reaction, the reaction mixture is quenched with water and further extracted with CH ₂ Cl ₂ . The organic layer was dried with anhydrous Na ₂ SO _4, to obtain a concentrated, to give the oxidized portion by silica gel chromatography, Intermediate.

Step 7 : In a 50 ml 1-neck round bottom flask, the acid intermediate in DMF is added and the mixture is stirred at room temperature for about 15 minutes. To this solution, DACHPt (H ₂ O) ₂ is added and the reaction mixture is stirred for an additional 24 hours. The solution is lyophilized to give amphiphilic compound 34 in good yield.

Synthesis of Compound 35 [wherein R = cholesterol or other lipids]

Step 1 to Step 5 : The sulfide intermediate obtained during the synthesis of Compound 34 (Step 4 and Step 5) is used as the starting reaction material.

Step 6 : In a 50 mL 1-neck round bottom flask, the sulfide intermediate in CH ₂ Cl ₂ is added and the mixture is cooled to about 0 ° C. To this solution, mCPBA (about 1.8 eq) is added and the reaction mixture is stirred at the same temperature for about 1 hour and the progress of the reaction is checked by TLC. After completion, the reaction mixture is quenched with water and then extracted with CH ₂ Cl ₂ . The organic layer was dried with anhydrous Na ₂ SO _4, concentrated and purified by silica gel chromatography to obtain a completely oxidized intermediate.

Step 7 : In a 50 ml 1-neck round bottom flask, add the acid intermediate in DMF and stir at room temperature for about 15 min. To this solution, DACHPt (H ₂ O) ₂ is added and the reaction mixture is stirred for an additional 24 hours. The solution is lyophilized to give amphiphilic compound 35 in good yield.

Synthesis of Compound 36 [wherein R = cholesterol or other lipids]

Step 1 to Step 3 : The tosyl intermediate obtained during the synthesis of Compound 34 (Step 3) is used as the starting reaction material.

Step 4 : In a 50 mL round bottom flask, the tosyl intermediate in DMF (about 20 mL) is added under a nitrogen atmosphere and stirred for about 30 minutes (by warming if necessary) to give a clear solution. To this solution, sodium azide is added and the mixture is stirred at room temperature for about 18 hours and the progress of the reaction is monitored using TLC. After completion of the reaction, the reaction mixture is diluted with water, the compound is extracted with ethyl acetate, concentrated in vacuo and purified by flash chromatography to give the azide intermediate.

Step 5 : To a solution of the azide in dry DMF is added triphenylphosphine (TPP) under a nitrogen atmosphere. The reaction mixture is stirred at room temperature for about 6 hours, and water is added thereto. The reaction mixture is again stirred at the same temperature for an additional 6 hours and the progress of the reaction is monitored using TLC. After completion of the reaction, the organic solvent is removed in vacuo and the residue is purified by silica gel chromatography using methanol / chloroform as eluent to give the amine intermediate.

Step 6 : To the ice-cold solution of the amine in THF, NaH is added under a nitrogen atmosphere over a period of about 10 minutes. The resulting solution is stirred for about 20 minutes, after which ethyl bromoacetate is added. The reaction mixture is stirred at room temperature for an additional 6 hours and the progress of the reaction is monitored using TLC. After completion of the reaction, the reaction mixture is cooled to about 0 < 0 > C, quenched with water and extracted with ethyl acetate. The organic layer was dried with anhydrous Na ₂ SO _4, concentrated, purified by silica gel chromatography to give the ester intermediate.

Step 7 : To a 50 ml 1-necked round bottom flask, add the ester compound in THF / water and cool to about 0 < 0 > C. To this solution, LiOH is added and the reaction mixture is stirred at room temperature for a period of about 3 hours. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to remove THF and extracted with ethyl acetate. The organic layer was dried with anhydrous Na ₂ SO _4, and concentrated, to give the final silica gel chromatography to give the acid intermediate.

Step 8 : In a 50 mL 1-neck round bottom flask, add the acid in CH ₂ Cl ₂ and cool to about 0 ° C. To this solution, mCPBA (about 0.8 eq) is added and the mixture is stirred at the same temperature for about 1 hour and the progress of the reaction is monitored by TLC. After completion of the reaction, the reaction mixture is quenched with water and extracted with CH ₂ Cl ₂ . The organic layer was dried over anhydrous Na ₂ SO _4, concentrated, purified by silica gel chromatography to give the N- oxide intermediate.

Step 9 : In a 50 ml 1-neck round bottom flask, the N-oxide intermediate is placed in DMF and the mixture is stirred at room temperature for about 15 minutes. To this solution, DACHPt (H ₂ O) ₂ is added and the reaction mixture is stirred for a period of about 24 hours. The solution is lyophilized to give compound 36 in good yield.

Example  5: Synthesis of compound 30

Step 1 : Cholesterol ( 1.01 ) (about 1.0 g, 2.59 mmol) in 5 ml of anhydrous THF is placed in a 50 ml 1-neck round bottom flask under a nitrogen atmosphere and cooled to about 0 캜. To this solution is added NaH (about 414 mg, 10.344 mmol) and the mixture is stirred at the same temperature (i. E. 0 C) for about 30 minutes. To this solution, ethyl bromoacetate in THF (about 2 mL) (about 0.45 mL, 3.885 mmol) is added and the reaction mixture is again allowed to stir at room temperature for about 2 hours. After completion, the reaction mixture is cooled to about 0 < 0 > C, quenched with water and extracted with ethyl acetate (about 2 X 15 ml). After drying the obtained organic layer over anhydrous Na ₂ SO _4, concentrated and purified by silica gel chromatography to give the ester intermediate (1.29).

Step 2 : In a 50 ml 1-neck round bottom flask, add the ester ( 1.29 ) (about 220 mg, 0.465 mmol) in THF / water (about 3: 1) (about 4 ml) at about 0 ° C. Solid LiOH (about 33 mg, 1.39 mmol) is added to the reaction mixture and stirred at room temperature for about 6 hours. After completion of the reaction, the reaction mixture is acidified to a maximum pH of 3 using saturated NaHSO ₄ and then extracted with CHCl ₃ (ca. 3 x 10 mL). The organic layer was dried with anhydrous Na ₂ SO _4, concentrated in a rotary evaporator and purify by silica gel chromatography to give a pure acid intermediate (1.30).

Step 3: 50 ㎖ 1 gu in the round bottom flask, placed into the DACH (Cl) ₂ Pt (approximately 50 mg, 0.131 mmol) in DMF (about 5 ㎖), and stirred for about 10 minutes. AgNO ₃ (about 22 mg, 0.131 mmol) is added to the reaction mixture at room temperature and stirred for about 24 hours. After completion, the solid AgCl precipitate was removed by centrifugation and then filtered through a 0.2 micrometer syringe filter to yield a monochloro compound ( 1.31 ).

Step 4 : In a 50 ml 1-neck round bottom flask, add the acid ( 1.30 ) in DMF (about 1 ml) and stir at room temperature for about 30 min. Monochloro DACH platinum ( 1.31 ) is added to the reaction mixture at room temperature and stirred for about 24 hours. The solid residue is washed with water (about 5 ml) and lyophilized to give the final platinum adduct, compound 30 .

Example  6: Synthesis of Exemplary Compounds

Synthesis of Compound 63

Experimental procedure: Compound (A) (1.0 mmol) is placed in 10 ml of THF. To this is added sulfoacetic acid (3.0 mmol) and the resulting solution is stirred at room temperature for 24 hours. After completion of the TLC check, water is added to the reaction mixture and unreacted A is extracted using ethyl acetate. The water layer is used for the next step.

Experimental procedure : Add hydrated DACH platinum (0.1 mmol, 3 ml, 10 mg / ml solution) to a 50 ml 1-neck round bottom flask (RBF). Compound (B) (0.09 mmol) placed in 10 ml of water is added dropwise, and the resulting solution is stirred at room temperature for 24 hours. A white precipitate appeared. The precipitate is washed with water and dried in vacuo to give compound (C).

Synthesis of Compound 64

Experimental procedure : In a 25 ml one-neck round bottom flask, compound (B) (1.0 mmol) (synthesized according to the procedure described in compound 64a) is placed in 10 ml of THF. To this, selenium (1.0 mmol) is added and the resulting solution is stirred at room temperature for 24 hours. After completion of the TLC check, water is added to the reaction mixture and unreacted A is extracted using ethyl acetate. The water layer is used for the next step.

Experimental procedure : Add hydrated DACH platinum (0.1 mmol, 3 mL, 10 mg / mL solution) to a 50 mL 1-necked round bottom flask. Compound (B) (0.09 mmol) in 10 mL of THF was added dropwise, and the resulting solution was stirred at room temperature for 24 hours. TLC. Evaporation of the THF gives a pale yellow precipitate. The precipitate is washed with water and dried in vacuo to give compound (C).

Synthesis of Compound 65

Experimental procedure : In a 25 ml 1-neck round bottom flask, compound (B) (1.0 mmol) (synthesized according to the procedure described in compound 64a) is placed in 10 ml of CCl ₄ . To this is added dropwise chlorosulfonic acid (1.0 mmol) at 0 占 and the resulting solution is stirred at room temperature for 24 hours. After completion of the TLC check, the CCl ₄ is evaporated in vacuo. 50 ml of water are added and the crude product is extracted into chloroform to give B as a white powder.

Experimental procedure : In a round bottom flask, B (0.13 mmol) in 5 mL (1: 3 water: THF) is treated with 0.13 mmol sodium hydroxide at 0 < 0 > C and the resulting solution is stirred for 15 minutes. THF is evaporated and the aqueous layer is added dropwise to a solution of hydrated platinum diaminocyclohexane (0.13 mmol in 15 ml of water). A white precipitate formed during the reaction. The reaction mixture was centrifuged and the precipitate was washed with water to give C as a white powder.

Synthesis of Compound 37

Experimental Procedure: 25 ㎖ 1 ward in a round bottom flask, a (synthesized according to the procedure referred to compound 69) Compound (B) (1.0 mmol), until a clear solution is obtained, phosphoric acid (H ₃ PO ₃₎ ( 1.0 mmol), and stirred with pyridine (5 mmol) and triethylamine _{(Et 3 N) (2 mmol} ). Acetic anhydride (2 mmol) is added and the reaction mixture is stirred at 80 < 0 > C for 4 h. After all B has been consumed as indicated by TLC, 5 ml of water are added to the reaction mixture. Compound (C) is extracted by chloroform wash (25 mL x 3). The solvent is concentrated in vacuo to give C.

All subsequent steps up to reaching F are performed according to the procedure described for the manufacture of IO-180_01.

Synthesis of Compound 55

Experimental procedure : A (Compound (A) is synthesized according to the procedure mentioned in the synthesis of Compound 69). In a 25 ml one-neck round bottom flask, diphenylphosphinomethane (DPPM) (5.0 mmol) is added in 30 ml of THF. To this is added n-butyl-lithium (5.2 mmol) and the resulting solution is stirred at 0 < 0 > C for 15 min. To this solution, cholesteryl bromide (A) (4.0 mmol) is added and the reaction is stirred for 16 hours. After completion by TLC, water is added to the reaction mixture and the compound is extracted with ethyl acetate. The combined organic layers were concentrated in vacuo. Purification by column chromatography.

Experimental procedure : In a 25 ml 1-necked round-bottomed flask, compound (B) (1.0 mmol) is taken in 30 ml of THF. To this is added hydrogen peroxide (2.2 mmol, 35% solution) and the resulting solution is stirred at room temperature for 24 hours. TLC and after completion, water is added to the reaction mixture and the compound is extracted using ethyl acetate. The combined organic layers were concentrated in vacuo. Purification by column chromatography.

Experimental procedure : Add hydrated DACH platinum (0.1 mmol, 3 mL, 10 mg / mL solution) to a 50 mL 1-necked round bottom flask. Compound (C) (0.09 mmol) in 10 ml of THF was added dropwise and the resulting solution was stirred at room temperature for 24 hours. TLC. Evaporation of the THF gives a pale yellow precipitate. The precipitate is washed with water and dried in vacuo to give compound (E).

Synthesis of Compound 52

Experimental procedure : In a 50 ml 1-neck round bottom flask, A (synthesis of A is described in the preparation of the ligand of compound 25) (1 mmol) was placed in 10 ml of dry THF. Ph ₂ PCl (2 mmol) and triethylamine (2 mmol) are added. The reaction mixture is stirred at room temperature for 12 hours under nitrogen. The solvent is evaporated and column chromatography is performed to obtain F.

The synthesis of F to H is analogous to that described for the synthesis of compound 55.

Experimental procedure : In a 50 ml 1-neck round bottom flask, A (synthesis is described in the preparation of the ligand of compound 25) (1 mmol) is placed in 10 ml of dry THF. Ph ₂ PCl (2 mmol) and triethylamine (2 mmol) are added. The reaction mixture is stirred at room temperature for 12 hours under nitrogen. The solvent is evaporated and column chromatography is performed to obtain F.

Synthesis of compound (G, 43) is similar to the synthesis of compound 44.

Synthesis of compounds 46, 47 and 48

Experimental procedure : The synthesis of compound (C, 46) is similar to the synthesis of compound 49.

Experimental procedure : The synthesis of compound (C, 47) is similar to the synthesis of compound 50.

Experimental procedure : The synthesis of compound (C, 48) is similar to the synthesis of compound 50.

Synthesis of compounds 44 and 49

Experimental procedure : A (Compound (A) is synthesized according to the procedure mentioned in the synthesis of Compound 69). In a 25 ml one-neck round bottom flask, diphenylphosphinomethane (DPPM) (5.0 mmol) is added in 30 ml of THF. To this is added n-butyl-lithium (5.2 mmol) and the resulting solution is stirred at 0 < 0 > C for 15 min. To this solution, cholesteryl bromide (A) (4.0 mmol) is added and the reaction is stirred for 16 hours. After completion by TLC, water is added to the reaction mixture and the compound is extracted with ethyl acetate. The combined organic layers were concentrated in vacuo. Purification by column chromatography.

Synthesis of Compound 44: In a 25 ml one-neck round bottom flask, compound (B) (1.0 mmol) is added in 30 ml of THF. To this is added hydrated Pt (DACH) (1 mmol in 10 ml water) and the resulting solution is stirred at room temperature for 24 hours. Concentration of THF yields compound 44 as a precipitate.

Experimental procedure : In a 25 ml 1-neck round bottom flask, compound (B) (1.0 mmol) is taken in 30 ml of THF. To this is added hydrogen peroxide (1.2 mmol, 35% solution) and the resulting solution is stirred at room temperature for 24 hours. TLC and after completion, water is added to the reaction mixture and the compound is extracted using ethyl acetate. The combined organic layers were concentrated in vacuo. Purification by column chromatography.

Experimental procedure : Add hydrated DACH platinum (0.1 mmol, 3 mL, 10 mg / mL solution) to a 50 mL 1-necked round bottom flask. Compound (C) (0.09 mmol) in 10 ml of THF was added dropwise and the resulting solution was stirred at room temperature for 24 hours. TLC. Evaporation of the THF gives a pale yellow precipitate. The precipitate is washed with water and dried in vacuo to give compound (E).

Synthesis of Compound 50

Experimental procedure : In a 25 ml 1-neck round bottom flask, compound (B) (1.0 mmol) is taken in 30 ml of THF. To this is added sulfur (1.0 mmol) and the resulting solution is stirred at room temperature for 24 hours. After completion by TLC, water is added to the reaction mixture and the compound is extracted using ethyl acetate. The combined organic layers are concentrated in vacuo. Compound (D) was purified by column chromatography.

Experimental procedure : Add hydrated DACH platinum (0.1 mmol, 3 mL, 10 mg / mL solution) to a 50 mL 1-necked round bottom flask. Compound (C) (0.09 mmol) in 10 ml of THF was added dropwise and the resulting solution was stirred at room temperature for 24 hours. TLC. Evaporation of the THF gives a pale yellow precipitate. The precipitate is washed with water and dried in vacuo to give compound (D).

Synthesis of Compound 51

Experimental procedure : In a 25 ml 1-neck round bottom flask, compound (B) (1.0 mmol) is taken in 30 ml of THF. To this, selenium (1.0 mmol) is added and the resulting solution is stirred at room temperature for 24 hours. After completion by TLC, water is added to the reaction mixture and the compound is extracted using ethyl acetate. The combined organic layers are concentrated in vacuo. Compound (D) was purified by column chromatography.

Experimental procedure : Add hydrated DACH platinum (0.1 mmol, 3 mL, 10 mg / mL solution) to a 50 mL 1-necked round bottom flask. Compound (C) (0.09 mmol) in 10 ml of THF was added dropwise and the resulting solution was stirred at room temperature for 24 hours. TLC. Evaporation of the THF gives a pale yellow precipitate. The precipitate is washed with water and dried in vacuo to give compound (D).

Synthesis of Compound 54

Experimental procedure : Same as 50, two equivalents of sulfur are used.

Experimental procedure : Same as 51, two equivalents of selenium are used.

Synthesis of Compound 57

Experimental procedure : Same as 50, two equivalents of sulfur are used.

Experimental procedure : Same as 51, two equivalents of selenium are used.

Synthesis of compounds 58, 59 and 60

Experimental procedure : Add K ₂ PtCl ₄ (0.1 mmol, 3 ml, 10 mg / ml solution) to a 50 ml 1-neck round bottom flask. Compound (A) (0.1 mmol) placed in 10 ml of THF is added dropwise, and the resulting solution is stirred for 24 hours at room temperature. TLC. Evaporation of the THF gives a pale yellow precipitate. The precipitate is washed with water and dried in vacuo to give compound (D).

Synthesis of compounds 61 and 62

Experimental procedure : To a 50 ml 1-neck round bottom flask, add compound (B) (1 mmol; in 10 ml of DMF). Silver nitrate (2 mmol) is added and stirred for 24 hours. The white precipitate is separated by filtration. Compound (C) (1 mmol) placed in 10 ml of water is added dropwise to the filtrate, and the resulting solution is stirred for 24 hours at room temperature. TLC. The DMF is evaporated to give a pale yellow precipitate. The precipitate is washed with water and dried in vacuo to give compound 61/62.

Synthesis of Compound 78

Compound (A) (0.5 mmol) is added to 20 ml of water, and silver nitrate (1 mmol) is added. The reaction mixture is stirred for 24 hours, filtered and DMSO (0.5 mmol) is added. The reaction mixture is stirred for 2 hours at room temperature to give a yellow precipitate as 78. [

Synthesis to give compound 79 Reaction scheme

Synthesis to give compound 80 Reaction scheme

Synthesis for Compound 81 Reaction scheme

Synthesis for Compound 82 Reaction scheme

Synthesis for Compound 83 Reaction scheme

Synthesis for Compound 84 Reaction scheme

Synthesis for Compound 85 Reaction scheme

Synthesis of Compound 95

Compound (A) (1 mmol) is placed in a 50 mL round bottom flask containing 10 mL of THF. AgBF ₄ (1 mmol) is added and stirred at room temperature for 24 hours. The precipitate is filtered, and compound (B) (1 mmol in 10 ml of water) is added dropwise to the filtrate. After stirring at room temperature for 24 hours, the THF is evaporated and the resulting precipitate is filtered and washed with water to obtain compound 95.

Example  7: Synthesis of additional exemplary compounds

IO Synthesis of -131

Experimental procedure : To a solution of tosylated cholesterol ( A ) (7.4 mmol) in dioxane (50 mL), ethylene glycol (35 mL) was added and refluxed for 4 hours. TLC. After completion, the reaction mixture was concentrated in vacuo to remove dioxane, which was then extracted with ethyl acetate and washed successively with water (3 X 50 mL) and brine (20 mL). The organic layer was dried with anhydrous Na ₂ SO _4, and concentrated under vacuum to perform the column.

Experimental procedure : Triphenylphosphine (TPP) (9 mmol) and carbon tetrabromide (9 mmol) were added to a solution of cholesteryl ethylene glycol ( B ) (4.5 mmol) in 5 ml of DCM. The reaction mixture was stirred at room temperature for 6 hours and checked by TLC. After completion, the reaction mixture was diluted with CHCl ₃ (20 ㎖) and washed with water (3 X 50 ㎖) and brine (20 ㎖) continuously. The organic layer was dried with anhydrous Na ₂ SO _4, and concentrated under vacuum, through a flash column to give the pure compound (C).

Experimental procedure : Methyl-3-mercaptopropionate (C) (5.0 mmol) was placed in 30 mL of DMF in a 25 mL 1-necked round bottom flask. To this was added potassium carbonate (20.0 mmol) and the resulting solution was stirred at room temperature for 15 minutes. Cholesteryl bromide (B) (4.0 mmol) was added to the solution, and the reaction was stirred for 16 hours. After TLC was complete, water was added to the reaction mixture and the compound was extracted with ethyl acetate. The combined organic layers were concentrated in vacuo. Purification by column chromatography.

Experimental procedure : In a 50 ml 1-necked round-bottomed flask, compound (D) (1.87 mmol) was placed in 60 ml of DCM. To this was added mCPBA (1.31 mmol) and the resulting solution was stirred at 0 < 0 > C for 3 h. After completion by TLC, water was added to the reaction mixture and the compound was extracted with chloroform. The combined organic layers were concentrated in vacuo and subjected to column chromatography. _{1H NMR (CDCl 3): 0.66} (s), 0.84 to 0.47 (m), 1.82-1.97 (m ), 2.21 (m), 2.35 (m), 2.84 (m), 2.98 (m), 3.16 (t) , 3.21 (m), 3.89 (br, s), 5.33 (br, s). _{13C NMR (CDCl 3): 11.81} , 18.68, 19.32, 21.03, 22.52, 22.78, 23.78, 24.25, 26.96, 27.97, 28.18, 31.84, 35.74, 36.15, 36.79, 37.05, 38.78, 38.91, 39.47, 39.72, 42.27, 47.18 , 50.10, 52.14, 53.25, 53.29, 56.11, 56.71, 79.71, 121.90, 140.40, 171.74. Mass (mass) -ESI 571.4 (M + Na) IR (KBr) (?, Cm ^-1 ) 418 (w), 668 (m), 750 (m), 1020 (m), 1104 ), 1178 (w), 1259 (m), 1275 (m), 1455 (m), 1732 (m), 2933 (s), 3612 (m), 3723

Experimental Procedure: 50 ㎖ 1 ward in a round bottom flask, ester (E) (0.17 mmol) of 3 ㎖ of THF / H ₂ O: placed in a (3: 1) was cooled under an ice bath to 0 ℃. To this was added ice cold solution KOH (0.19 mmol in 2 mL), stirred at room temperature for 12 hours, and checked by TLC. After completion, the THF was evaporated and the residue was extracted with chloroform. The water layer was used for the next step.

Experimental procedure : Hydrated DACH platinum (3 mL, 10 mg / mL solution) was added to a 50 mL 1-necked round bottom flask. The salt (A) (0.09 mmol) in 10 ml of water was added dropwise and the resulting solution was stirred at room temperature for 24 hours. The white precipitate was isolated and washed with 30 mL of water to give the pure compound (G). IR (KBr) (?, Cm ^-1 ): 415 (w, br), 797 (w), 1024 (m), 1107 (m), 1259 , 1588 (m, br), 2933 (s), 3176 (w, br), 3440 (w, br). _{^{195 Pt NMR (CDCl 3):}} -2893

IO Synthesis of -148_01

IO -148_01 Synthesis of Intermediate Complexes

Experimental procedure : To a ice-cooled solution of cholesterol ( A ) (10 g, 25.883 mmol) in CH ₂ Cl ₂ (150 mL) was added dropwise pyridine (10.5 mL, 129.415 mmol) and stirred for 15 min. To this solution, p-toluenesulfonyl chloride ( B ) (14.75 g, 77.649 mmol) was added and stirred for 2 hours under dark conditions. After completion of the reaction by TLC, the organic phase was washed with 0.1 N HCl solution (5 X 50 mL) and water (2 X 50 mL); Dry the organic layer over anhydrous Na ₂ SO ₄ and concentrated in vacuo.

IO -148_01 Synthesis of Glycol Intermediates

Experimental procedure : To a solution of tosylated cholesterol ( A ) (10 g, 18.48 mmol) in dioxane (50 mL), ethylene glycol (35 mL) was added and refluxed for 4 hours. TLC. After completion, the reaction mixture was concentrated in vacuo to remove dioxane, which was then extracted with ethyl acetate and washed successively with water (3 X 50 mL) and brine (20 mL). The organic layer was dried with anhydrous Na ₂ SO _4, and concentrated under vacuum to perform the column.

IO -148_01 Synthesis of glycol tosyl intermediate

Experimental procedure : To a solution of cholesteryl ethylene glycol ( A ) (6 g, 13.93 mmol) in 30 ml of DCM under a nitrogen atmosphere was added p-toluenesulfonyl chloride ( B ) (3.25 g, 16.71 mmol) , And stirred for 15 minutes. To this solution was added pyridine (12 mL), stirred at 0 < 0 > C for 6 h and checked by TLC. After completion, the reaction mixture was diluted with CHCl ₃ (20 ㎖) and washed with saturated CuSO ₄ (3 X 50 ㎖) and brine (20 ㎖) continuously. The organic layer was dried with anhydrous Na ₂ SO _4, and concentrated under vacuum.

IO Synthesis of azide intermediate of -148_01

Experimental procedure : To compound ( A ) (7 g, 11.97 mmol) was added 20 ml of DMF under a nitrogen atmosphere, stirred for 30 minutes and, if necessary, warmed to give a clear solution. To this solution was added sodium azide ( B ) (1.5 g, 23.95 mmol) once, stirred at room temperature for 18 hours, and checked by TLC. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and the combined organic layers were concentrated in vacuo.

IO Of -148_01 Amine  Synthesis of intermediates

Experimental procedure : To azide ( A ) (5 g, 10.97 mmol) was added dry THF (20 mL) under nitrogen atmosphere and TPP (5.74 g, 21.94 mmol) was added. The reaction was stirred for 6 hours. Thereafter, 2 ml of water was added to the reaction mixture, and the reaction was maintained at the same temperature overnight. After completion of the reaction by TLC, the reaction mixture was concentrated in vacuo and loaded directly onto the column.

IO -148_01 N- Monoalkyl  Synthesis of intermediates

Experimental procedure : In a 50 ml 1-neck round bottom flask, amine ( A ) (200 mg, 0.465 mmol) was placed in anhydrous DCM (40 mL) at 0 <0> C under a nitrogen atmosphere. To this was added dropwise cooled DIEPA (0.06 mL, 0.372 mmol) and stirred at the same temperature for 20 minutes. To the mixture was added ethyl bromoacetate (0.03 mL, 0.279 mmol, in 10 mL of DCM) over a period of 1 hour. The reaction was monitored using TLC. After completion, the reaction mixture was directly concentrated in vacuo and subjected to column chromatography.

IO -148_01 N- Oxide  Synthesis of intermediates

Experimental procedure : In a 50 mL 1-neck round bottom flask, ester ( A ) (100 mg, 0.193 mmol) was placed in anhydrous CH ₂ Cl ₂ (10 mL) at 0 ° C under a nitrogen atmosphere. To this cooled solution, mCPBA (16.72 mg, 0.135 mmol) was added dropwise as a solution in DCM (2 mL) and stirred at the same temperature for 2 hours. The reaction was monitored using TLC. After completion, the reaction mixture was quenched with NaHCO ₃ , extracted with CHCl ₃ , dried over anhydrous sodium sulfate, concentrated and directly subjected to column chromatography.

IO Synthesis of the final ligand of -148_01

Experimental procedure : In a 50 ml 1-neck round bottom flask, the N-oxide intermediate ( A ) (100 mg, 0.188 mmol) was placed in anhydrous THF / H ₂ O (4 mL) at 0 ° C. To this cooled solution was added LiOH.H ₂ O (8 mg, 0.188 mmol) and the mixture was stirred at the same temperature for 1 hour. The reaction was monitored using TLC. After completion, the reaction mixture was concentrated in vacuo to remove the THF. The residue was diluted with water (10 mL), washed with DCM and ethyl acetate.

IO Synthesis of -148_01

Experimental procedure : Hydrated DACH platinum (70 mg, 0.188 mmol, 10 mg / ml solution) was added to a 50 ml 1-necked round bottom flask. To the solution, ligand (A) (100 mg, 0.188 mmol) in 10 ml of water was added dropwise. The resulting solution was stirred at room temperature for 3 hours. After completion, the reaction mixture was centrifuged to separate the precipitate. The precipitate was washed twice with water (10 mL) and lyophilized to obtain IO-148_01. ESIMS m / z = 827.4

IO Synthesis of -148_02

Steps 1 to 5 are similar to IO-148_01:

Step 6: Synthesis of N-methyl intermediate of IO-148_02

Experimental procedure : In a 50 ml 1-neck round bottom flask, ester ( A ) (1 g, 1.93 mmol) was placed in acetonitrile at 0 &lt; 0 &gt; C under a nitrogen atmosphere. To this mixture was added methyl iodide (273 mg, 1.93 mmol). The reaction was monitored using TLC. After completion, the reaction mixture was directly concentrated in vacuo and subjected to column chromatography.

Step 7: Synthesis of N-oxide intermediate of IO-148_02

Experimental procedure : In a 50 mL 1-neck round bottom flask, ester ( A ) (100 mg, 0.193 mmol) was placed in anhydrous CH ₂ Cl ₂ (10 mL) at 0 ° C under a nitrogen atmosphere. To this cooled solution, mCPBA (16.72 mg, 0.135 mmol) was added dropwise as a solution in DCM (2 mL) and stirred at the same temperature for 2 hours. The reaction was monitored using TLC. After completion, the reaction mixture was quenched with NaHCO ₃ , extracted with CHCl ₃ , dried over anhydrous sodium sulfate, concentrated and directly subjected to column chromatography.

Step 8: IO Synthesis of the final ligand of -148_02

Experimental procedure : In a 50 ml 1-neck round bottom flask, the N-oxide intermediate ( A ) (100 mg, 0.188 mmol) was placed in anhydrous THF / H ₂ O (4 mL) at 0 ° C. To this cooled solution was added LiOH.H ₂ O (8 mg, 0.188 mmol) and the mixture was stirred at the same temperature for 1 hour. The reaction was monitored using TLC. After completion, the reaction mixture was concentrated in vacuo to remove the THF. The residue was diluted with water (10 mL), washed with DCM and ethyl acetate.

Step 9: IO Synthesis of -148_02

Experimental procedure : Hydrated DACH platinum (70 mg, 0.188 mmol, 10 mg / ml solution) was added to a 50 ml 1-necked round bottom flask. To the solution, ligand (A) (100 mg, 0.188 mmol) in 10 ml of water was added dropwise. The resulting solution was stirred at room temperature for 3 hours. After completion, the reaction mixture was centrifuged to separate the precipitate. The precipitate was washed twice with water (10 mL) and lyophilized to obtain IO-148_01.

IO Synthesis of -183_01

Experimental procedure : To a ice-cold solution of cholesterol ( A ) (5 g, 12.93 mmol) in CH ₂ Cl ₂ (35 mL) was added pyridine (5.22 mL) and stirred for 15 min. To this solution was added p-toluenesulfonyl chloride ( B ) (6.15 g, 32.31 mmol), stirred at 0 ° C for 6 hours, and checked by TLC. After completion, the reaction mixture was diluted with CHCl ₃ (20 ㎖), and washed with a 1N HCl (3 X 50 ㎖) and brine (20 ㎖) continuously. The organic layer was dried with anhydrous Na ₂ SO _4, and concentrated under vacuum. Without purification, the entire compound is used in the next reaction.

Experimental procedure : Diethylene glycol (10 ml) was added to a solution of tosylated cholesterol ( A ) (10 g, 18.49 mmol) in dioxane (30 ml) and refluxed for 4 hours. TLC. After completion, the reaction mixture was extracted with ethyl acetate and washed successively with water (3 X 50 mL) and brine (20 mL). The organic layer was dried with anhydrous Na ₂ SO _4, and concentrated under vacuum to perform the column. (Yield: 38%)

Experimental procedure : In a 100 ml 1-neck round bottom flask, NaH (594 mg) was placed in THF (10 ml) under a nitrogen atmosphere. The reaction was cooled to 0 &lt; 0 &gt; C under an ice bath and to this was slowly added a solution of C (2.35 g, 4.95 mmol) in THF (15 mL). The resulting solution was stirred for 1 hour, ethyl bromoacetate was added slowly, stirred at room temperature for 6 hours and checked by TLC. After completion, the reaction mixture was cooled to 0 C, quenched with water and extracted with ethyl acetate. The organic layer was washed with water, dried over Na ₂ SO ₄ and was concentrated and purified by column chromatography to give the compound. (Yield ^{46%) 1 H NMR (CDCl} 3): 0.66 (s), 0.81-2.41 (m), 3.2 (br, s), 3.6-3.8 (m), 4.36 (s), 5.33 (s) 13 C _{NMR (CDCl 3): 11.83,} 18.68, 19.34, 21.03, 22.53, 22.39, 23.79, 24.26, 27.58, 28.21, 29.67, 31.84, 31.91, 35.35, 36.15, 36.82, 37.15, 38.89, 39.68, 39.75, 42.28, 50.12, 56.11, 56.73, 67.01, 68.76, 70.11, 70.95, 71.41, 79.64, 121.67, 140.74, 172.69

Experimental procedure : In a 100 ml 1-neck round bottom flask, the ester ( D ) (0.15 g, 0.28 mmol) was placed in 2 ml of THF / H ₂ O (3: 1) and cooled to 0 ° C in an ice bath. To this was added ice-cold solution LiOH (12 mg, 0.28 mmol), stirred at room temperature for 2 hours, and checked by TLC. After completion, the THF was removed from the reaction mixture by a rotavapor. Chloroform was added to the reaction mixture. The compound was extracted with water. The entire reaction mixture was then used in the next reaction after rotor viper treatment.

Experimental Procedure : DACH platinum (78 mg, 0.139 mmol) was placed in 5 mL of HPLC water (HPLC Water) in a 50 mL 1-neck round bottom flask. To the solution was added silver nitrate (47 mg, 0.278 mmol). The resulting solution was stirred at room temperature under protection from light. After 24 hours, the AgI precipitate was filtered off. The filtrate was used in the next step.

Experimental procedure: in 100 ㎖ 1-neck round bottom flask, the salt (E) (150 mg, 0.263 mmol) were dissolved in the number of 40 ㎖ HPLC, stirred for 5 min the resulting solution at room temperature and to this solution DACH (OH ₂ ) ₂ platinum (B) was added, which was stirred for 24 hours at room temperature under protection from light. The precipitate was filtered through a filter paper and washed simultaneously with HPLC water, HPLC methanol and HPLC acetone and dried. (Yield _{45%) C 72 H 124 N} 2 O 10 P ESIMS m / z = 1395.7 for ^{[M + Na] +1 H NMR} : (500 MHz, CDCl3): 5.96 (bs), 5.32 (s), 4.96 (bs), 3.92 (q), 3.61 (s), 3.15 (m), 2.57 (m), 2.37 (m), 2.21 (t), 1.91 (m), 1.48 (m), 1.11 (m), 0.98 (s), 0.90 (d), 0.85 (dd), 0.66 (s) ppm. ¹³ C NMR (500 MHz, CDCl 3): 177.22, 140.86, 121.56, 79.58, 70.70, 70.37, 70.31, 70.07, 67.26, 62.24, 56.75, 56.17, 50.15, 42.30, 39.77, 39.50, 39.08, 37.23, 36.85, 35.79, 32.04, 31.94, 31.88, 28.36, 28.22, 27.98, 24.62, 24.28, 23.85, 22.79, 22.54, 21.06, 19.38, 18.71, 11.85 ppm. IR: 418 (w), 668 (br s), 749 (m), 1110 (s), 1260 (s), 1640 (s), 2064

IO Synthesis of -183_02

Step 1:

Experimental procedure : A (the same procedure was obtained from reference [ PNAS ; 109, 2012 ; 11294]) (200 mg, 0.349 mmol) was dissolved in 2.5 mL of THF and 0.8 mL of water. To this was added 16 mg of LiOH and the mixture was stirred at room temperature for 24 hours. A white suspension appeared. THF was evaporated in vacuo and 40 mL of water was added to dissolve the white residue. The aqueous solution was washed with chloroform. The water layer is used for the next step.

Step 2

Experimental procedure : 0.17 mmol of cyclohexyldiamine platinum-dichloride, 0.34 g of silver nitrate and 7 ml of water are added to a 25 ml round bottom flask and stirred at room temperature for 48 hours. The solution was centrifuged (4,000 rpm; 10 min) and the white precipitate was filtered through a syringe filter (25 mm / 0.20 um). And washed with 2 ml of water. The filtrate was used in the next step.

Step 3

Experimental procedure : Compound (B) (0.26 mmol) in 20 ml of water was added dropwise to C (0.13 mmol) in water (10 ml). The reaction was continued at room temperature for 20 hours. The white precipitate was separated by filtration. The residue was washed with water (10 mL) to give D as a white powder. _{^{1 H NMR (CDCl 3 + CD}} 3 OD): 0.66 (s), 0.84- 2.5 (br, m), 3.32 (br, d), 4.45 (br, s), 5.34 (br, s) 13 C (CDCl _{3 + CD 3 OD) NMR:} 11.68, 18.53, 19.15, 20.89, 22.36, 22.62, 23.7, 24.12, 24.32, 27.84, 28.02, 29.53, 35.65, 36.03, 36.41, 38.36, 38.42, 39.27, 39.36, 39.58, 40.27, ESIMS: 1475.4 (M + Na) IR: 418 (m), 584 (m), 799 (s), 1027 m), 1260 (s), 1454 (m), 1535 (s), 1643 (s), 1700 (br, s), 2928

IO Synthesis of -147_02

IO Synthesis of -147_02:

Experimental Procedure: Compound B (composite are listed in the preparation of compound IO-183_01) (1 mmol) , phosphoric acid (1 mmol), pyridine (5 mmol) and triethylamine (2 mmol) to a round bottom flask (RBF) &Lt; / RTI &gt; and stirred until a clear solution appears. Acetic anhydride (2 mmol) is added dropwise and the reaction mixture is stirred at 80 &lt; 0 &gt; C for 3 hours. Cool to room temperature and add water. The compound is extracted with diethyl ether and concentrated under vacuum to give compound (C). The remainder of the reactions for obtaining F are similar to those described for the synthesis of IO-180_01.

IO Synthesis of -173_01

Experimental procedure : To a ice-cold solution of cholesterol ( A ) (5 g, 12.93 mmol) in CH ₂ Cl ₂ (35 mL) was added pyridine (5.22 mL) and stirred for 15 min. To this solution was added p-toluenesulfonyl chloride ( B ) (6.15 g, 32.31 mmol), stirred at 0 ° C for 6 hours, and checked by TLC. After completion, the reaction mixture was diluted with CHCl ₃ (20 ㎖), and washed with a 1N HCl (3 X 50 ㎖) and brine (20 ㎖) continuously. The organic layer was dried with anhydrous Na ₂ SO _4, and concentrated under vacuum. Without purification, the entire compound is used in the next reaction.

Experimental procedure : To a solution of tosylated cholesterol ( A ) (10 g, 0.018 mol) in dioxane (25 ml), ethylene glycol (15 ml) was added and refluxed for 4 hours. TLC. After completion, the reaction mixture was extracted with ethyl acetate and washed successively with water (3 X 50 mL) and brine (20 mL). The organic layer was dried with anhydrous Na ₂ SO _4, concentrated under vacuum and it was purified by silica gel chromatography. (Yield = 37%)

Experimental procedure : A mixture of compound (B) (1829 mg, 4.25 mmol) and Meldrum's acid (A) (612 mg, 4.25 mmol) in anhydrous 1,4-dioxane (40 mL) And heated at 110 ° C. After cooling to room temperature, the reaction mixture was partitioned using ethyl acetate and water. The organic extracts were dried with Na ₂ SO _4, and concentrated using a rotor vapor, it was purified by silica gel chromatography. (Yield ^{= 26%) 1 H NMR (} 500 MHz, CDCl3): 5.33 (s), 4.26 (s), 3.68 (s), 3.42 (s), 3.17 (s), 2.32 (d), 2.17 (s) , 1.99 m, 1.86 m, 1.48 m, 1.33 m, 1.24 m, 1.11 m, 0.98 m, 0.90 m, 0.85 m, ppm. ¹³ C NMR (500 MHz, CDCl3): 169.85, 167.25, 140.57, 121.84, 79.70, 65.43, 65.27, 56.73, 56.13, 50.13, 42.29, 40.48, 39.74, 39.49, 38.86, 37.13, 36.80, 36.16, 35.76, 31.91, 31.85, 29.67, 28.21, 27.98, 24.26, 23.80, 22.79, 22.54, 21.04, 19.33, 18.89, 11.84 ppm

Experimental procedure : DACH platinum (A) (100 mg, 0.263 mmol) was placed in 10 mL of HPLC water in a 50 mL 1-neck round bottom flask. To the solution was added silver nitrate (89 mg, 0.526 mmol). The resulting solution was stirred at room temperature under protection from light. After 24 hours, the AgCl precipitate was filtered off. The filtrate was used in the next step.

Experimental procedure : In a 50 ml one-neck round bottom flask, acid (B) (136 mg, 0.263 mmol) was placed in 15 ml of dry THF. To this solution, it was added dropwise DACH (OH _{2) 2} Pt (A) (95 mg, 0.263 mmol) under protection from light, and stirred for 24 hours. The total THF was then evaporated. The precipitate was filtered and the water portion was lyophilized. ESIMS (M 824)

IO Synthesis of -173_03

Experimental procedure : To a ice-cold solution of ethylenediamine ( B ) (22.2 mL) in 40 mL of DCM is added dropwise a solution of compound ( A ) (5 g) in DCM (50 mL) over a period of 45 min, Lt; / RTI &gt; for 1 hour and left at room temperature for an additional 20 hours. After the check by TLC completion of the reaction, quenched with water (4 x 100 ㎖), extract the organic layer with DCM (2 x 50 ㎖), dried over anhydrous Na ₂ SO _4, and concentrated under vacuum, silica gel Purification by column chromatography. Yield 90%.

Experimental procedure : A mixture of compound (A) (2.74 g, 5.8 mmol) and meldrum acid (A) (661 mg, 5.8 mmol) in anhydrous 1,4-dioxane (20 mL) Respectively. After cooling to room temperature, the reaction mixture was partitioned using ethyl acetate and water. The organic extracts were dried with Na ₂ SO _4, and concentrated using a rotor vapor. This was purified by silica gel column chromatography. Yield 50%.

Experimental procedure : Sodium hydride (620 mg, 15.516 mmol) was placed in THF (5 mL) under a nitrogen atmosphere in a 50 mL 1-necked round bottom flask. The reaction mixture was cooled to 0 C under an ice bath and cholesterol (A) (2.82 g, 5.172 mmol) in THF (10 mL) was added dropwise to the reaction mixture over a period of 10 min and left to stand for 30 min with stirring. Methyl iodide (2.42 g, 15.516 mmol) was slowly added to the solution, stirred at room temperature for 6 hours, and checked by TLC. After completion, the reaction mixture was cooled to 0 ℃, water Ken weighed, and extracted with ethyl acetate, dried over anhydrous Na ₂ SO _4, concentrated, and the ester (E) in 40% yield, was purified by silica gel chromatography .

Experimental procedure: in 50 ㎖ 1-neck round bottom flask, the ester (A) (0.154 g, 0.263 mmol) for 2 ㎖ of THF / H ₂ O: placed in a (3: 1) was cooled under an ice bath to 0 ℃. To this was added ice-cold solution LiOH ( B ) (11 mg, 0.263 mmol), stirred for 3 hours at room temperature, and checked by TLC. After completion, THF was removed from the reaction mixture by means of a rotor vortex. Chloroform was added to the reaction mixture. The compound was extracted with water. The entire reaction mixture was then used in the next reaction after rotor viper treatment.

Experimental procedure : DACH platinum (A) (100 mg, 0.263 mmol) was placed in 10 mL of HPLC water in a 50 mL 1-neck round bottom flask. To this solution was added silver nitrate (88 mg, 0.526 mmol). The resulting solution was stirred at room temperature under protection from light. After 24 hours, the AgCl precipitate was filtered off. The filtrate was used in the next step.

Experimental procedure : The acid (A) (154 mg, 0.263 mmol) was placed in 20 mL of HPLC water in a 100 mL 1-necked round bottom flask and the resulting solution was stirred at room temperature for 5 minutes and DACH (OH ₂ ) ₂ platinum (B) was added, which was stirred for 24 hours at room temperature under protection from light. The precipitate was filtered through a filter paper and washed simultaneously with HPLC water, HPLC methanol and HPLC acetone and dried. (Yield: 47%)

IO Synthesis of -176_01

Experimental procedure : DACH platinum (A) (100 mg, 0.263 mmol) was placed in a 20 mL HPLC water in a 50 mL 1-neck round bottom flask. To the solution was added silver nitrate (44 mg, 0.263 mmol). The resulting solution was stirred at room temperature under protection from light. After 24 hours, the AgCl precipitate was filtered off. The filtrate was used in the next step.

Experimental procedure : In a 100 ml 1-neck round bottom flask, acid (A) (the same ligand as LB 55c) (154 mg, 0.263 mmol) was added to 20 ml of HPLC water and the resulting solution was stirred at room temperature for 5 minutes , DACH (OH ₂ ) ₂ platinum (B) (0.263 mmol) was added to the solution, which was stirred for 24 hours at room temperature under the protection from light. The precipitate was filtered through a filter paper and washed simultaneously with HPLC water, HPLC methanol and HPLC acetone and dried. (Yield: 40%)

IO Synthesis of -179_01

Step-1

Experimental procedure : In a 50 ml 1-neck round bottom flask, aminomethylphosphonic acid (A) (0.77 mmol) is mixed with 2 ml of dry pyridine. Cholesterol (0.77 mmol) and DMAP (0.77 mmol) are added to the mixture and the resulting solution is stirred at room temperature for 16 hours. The resulting solution is acidified with dilute sulfuric acid and the compound (C) is extracted with chloroform wash.

Step-2

Experimental procedure : In a 25 ml 1-neck round bottom flask, add C (0.13 mmol) in 1 ml of THF. To this solution, KOH (0.26 mmol) in 1 ml of water is added at 0 占 폚. The precipitate appeared immediately. 2 ml of water are added to dissolve the precipitate, and the resulting solution is stirred at room temperature for 2 hours. The chloroform wash is applied to the reaction mixture and the aqueous layer is used in the next step.

Step 3

Experimental procedure : In a 50 mL 5-neck round bottom flask, add E (0.13 mmol) in 5 mL of water. D (0.13 mmol) in 15 mL of water is added at room temperature and the resulting solution is stirred at room temperature for 24 hours. A white precipitate formed during the reaction. The reaction mixture is centrifuged, the precipitate is washed with water and then lyophilized to give F as a white powder.

IO Synthesis of -179_02

Step-1

Experimental procedure : In a 50 ml 1-neck round bottom flask, phosphopropionic acid (A) (0.77 mmol, 119 mg) was placed in 5 ml of dry THF. Cholesterol (200 mg, 0.52 mmol) and DCC (160 mg, 0.77 mmol) were added at 0 &lt; 0 &gt; C and the resulting solution was stirred at room temperature for 16 hours. A white precipitate formed during the reaction. The white precipitate was isolated by filtration and washed with 5 mL of THF. The solvent was evaporated and washed with hexane to give the product as 150 mg of a white powder. ¹ H NMR (CDCl ₃ ): 0.67-2.66 (m), 4.22 (s), 5.36 (s), 8.18 (br, s). _{^{13 C NMR (CDCl 3):}} 11.83, 18.74, 19.23, 21.04, 22.55, 22.81, 23.97, 24.28, 24.71, 27.43, 28.00, 28.24, 29.84, 31.82, 31.94, 33.32, 35.85, 36.21, 36.39, 36.96, 39.49, (D) ESIMS (-ve mode): 521.3 (MH) &lt; RTI ID = 0.0 &gt;

Step-2

Experimental procedure : In a 25 ml one-neck round bottom flask, A (69 mg, 0.13 mmol) was added in 1 ml of THF. B (15 mg, 0.26 mmol) in 1 mL of water was added at 0 &lt; 0 &gt; C. The precipitate appeared immediately. 2 ml of water was added to dissolve the precipitate, and the resulting solution was stirred at room temperature for 2 hours. The chloroform wash was applied to the reaction mixture, and the aqueous layer was used in the next step.

Step 3

Experimental procedure : In a 100 ml one-necked round bottom flask, B (0.13 mmol) was placed in 5 ml of water. A (0.13 mmol) in 15 mL of water was added at room temperature and the resulting solution was stirred at room temperature for 2 hours. A white precipitate formed during the reaction. The reaction mixture was centrifuged, the precipitate was washed with water, and then lyophilized to give 50 mg of a white powder.

IO Synthesis of -179_03

Experimental procedure : Compound (A) is prepared according to the procedure described in the preparation of IO-183_01. All subsequent steps were performed according to the manufacture of IO-179_02.

IO Synthesis of -180_01

Experimental procedure : In a 50 ml 1-necked round-bottomed flask, A (the same compound as Step 1b product of Step 60b) (1 mmol) was placed in 25 ml of dry THF. Ethyl glycolate (1 mmol) and DCC (1 mmol) and DMAP (0.1 mmol) were added at 0 &lt; 0 &gt; C and the resulting solution was stirred at room temperature for 16 h. The compound was isolated as a pasty solid by silica gel column chromatography.

Experimental procedure : In a 25 ml 1-neck round bottom flask, B (0.13 mmol) was added in 3 ml of THF. LiOH (0.26 mmol) in 1 mL of water was added at 0 &lt; 0 &gt; C. The reaction mixture was stirred at room temperature for 4 hours. The chloroform wash was applied to the reaction mixture, and the aqueous layer was used in the next step.

Experimental procedure : In a 100 ml 1-necked round-bottomed flask, D (0.13 mmol) was placed in 5 ml of water. C (0.13 mmol) in 15 mL of water was added dropwise at room temperature, and the resulting solution was stirred at room temperature for 20 hours. A white precipitate formed during the reaction. The reaction mixture was centrifuged, the precipitate was washed with water and then lyophilized to give E as a white powder.

IO Synthesis of -180_02

Experimental procedure : In a 50 ml 1-neck round bottom flask, add A (the same compound as Step 1 product of Step 60a) (1 mmol) in 25 ml of dry THF. Ethyl glycolate (1 mmol) and DCC (1 mmol) and DMAP (0.1 mmol) are added at 0 &lt; 0 &gt; C and the resulting solution is stirred at room temperature for 16 hours. The compound is isolated as a pasty solid by silica gel column chromatography.

Experimental procedure : In a 25 ml 1-neck round bottom flask, add B (0.13 mmol) in 3 ml of THF. Add LiOH (0.26 mmol) in 1 mL of water at 0 &lt; 0 &gt; C. The reaction mixture is stirred at room temperature for 4 hours. The chloroform wash is applied to the reaction mixture and the aqueous layer is used in the next step.

Experimental procedure : In a 100 ml 1-neck round bottom flask, add D (0.13 mmol) in 5 ml of water. C (0.13 mmol) in 15 mL of water is added at room temperature and the resulting solution is stirred at room temperature for 20 hours. A white precipitate formed during the reaction. The reaction mixture is centrifuged, the precipitate is washed with water and then lyophilized to obtain E as a white powder.

IO Synthesis of -180_03

Experimental procedure : Compound (E) is prepared according to a procedure analogous to that described for the preparation of IO-180_01.

IO Synthesis of -184_01

Step 1:

Experimental procedure: 100 ㎖ 1-neck round bottomed flask, the ester (A) (1.272 g, 2.27 mmol) for 20 ㎖ of THF / H ₂ O: placed in a (3: 1) was cooled under an ice bath to 0 ℃. To this was added ice-cold solution LiOH (136 mg, 5.67 mmol), stirred overnight at room temperature and checked by TLC. After completion, the reaction mixture was extracted with ethyl acetate and washed sequentially with sodium bicarbonate (40 mL) and brine (20 mL). The organic layer was dried with anhydrous Na ₂ SO _4, concentrated under vacuum and, by doing the column, to obtain 1 g of pure B as a white powder.

Step 2:

Experimental procedure : A mixture of B (532 mg, 1 mmol) and H ₃ PO ₃ (2 mmol) is heated to 60 ° C. under N ₂ until a homogeneous mixture is obtained. PCl ₃ (1 mmol) was added dropwise, and the mixture was stirred at 60 ° C for 2 hours. The resulting mixture is cooled to room temperature and extracted with water. The aqueous solution is lyophilized to obtain the compound (C).

Experimental procedure : In a 25 ml 1-neck round bottom flask, add C (0.13 mmol) in 1 ml of THF. Sodium hydroxide (0.54 mmol) in 2 ml of water is added at 0 &lt; 0 &gt; C. The resulting solution is stirred at room temperature for 2 hours. The chloroform wash was applied to the reaction mixture, and the aqueous layer was used in the next step.

Experimental procedure : In a 100 ml 1-necked round bottom flask, add hydrated platinum diaminocyclohexane (0.13 mmol) in 15 ml of water. D (0.13 mmol) in 5 mL of water is added at room temperature and the resulting solution is stirred at room temperature for 2 hours. A white precipitate formed during the reaction. The reaction mixture was centrifuged and the precipitate was washed with water to give E as a white powder.

IO Synthesis of -190_01

8-Hydroxyquinoline (7.34 g, 0.05 mol) was dissolved in a continuous stirred solution of 66.7 ml of distilled water and 3 ml of concentrated sulfuric acid at 15 to 18 占 폚. Sodium nitrite (3.67 g) in distilled water (6.78 ml) was added dropwise to the reaction mixture over a period of 30 to 40 minutes at 15 to 18 캜, and the mixture was maintained at this temperature for 3 hours. The reaction mixture was neutralized with 40% sodium hydroxide solution. It was then acidified to pH 3.0 to 4.0 using glacial acetic acid. The resulting yellow precipitate was filtered, washed with distilled water and dried. Yield: 6.7 g (89.5%).

0.174 g (0.01 mol) of 5-nitroso-8-hydroxyquinoline in 25 mL of concentrated hydrochloric acid was allowed to warm. Tin (Sn) metal (0.236 g, 0.02 mol) was slowly added thereto in small portions. The reaction mixture was heated at reflux for 6 hours in a boiling water bath. The reaction mixture was allowed to cool to room temperature. To the reaction mixture was slowly added 20% sodium hydroxide solution to obtain a precipitate. 5-Amino-8-hydroxyquinoline was extracted with ether. Yield: 0.154 g (79.87%).

The cholesterol (1 g, 2.6 mmol) was dissolved in 40 mL of THF / DMF (1: 1) and 60% sodium hydride (w / w) in mineral oil (0.6 g, 15.5 mmol) Bromo-1,1-dimethoxyethane (1.21 mL, 7.8 mmol) was added dropwise, and the mixture was stirred at 90 DEG C under reflux for 18 hours. The mixture was cooled, and excess NaH was removed by the addition of CH ₂ Cl ₂ / MeOH (1: 1). After removal of the solvent was subjected to removal under vacuum, the residue was taken up in EtOAc, washed with water several times, dried over Na ₂ SO _4, filtered, and concentrated. The crude material was purified by flash column chromatography on silica gel using 2-10% PE in EtOAc to give the product as a white solid, 1.23 g, 94% yield.

To a solution of cholesterol acetal (0.5 g, 1 mmol) in 10 mL of CH ₂ Cl ₂ was added trifluoroacetic acid / water (1: 1) (2.5 mL, 16.2 mmol) and the mixture was stirred for 6 h at room temperature Respectively. The mixture was neutralized with 1N NaOH, extracted twice with CH ₂ Cl ₂ , dried over Na ₂ SO ₄ , filtered and concentrated to give the product as a white solid.

The product was obtained by refluxing stoichiometric amounts of aldehyde (0.429 g, 1 mmol) and amine (0.160 g, 1 mmol) in absolute ethanol (15 mL) in the presence of a catalytic amount of trifluoroacetic acid overnight. Upon cooling the reaction mixture the desired product precipitated, which was then filtered off and purified by washing with cold ethanol. Yield 0.4 g, 70%.

Sodium borohydride (0.875 g, 23.12 mmol) was added portionwise to cholesterol quinoline (0.617 g, 1.08 mmol) in a C ₂ H ₅ OH: THF mixture (1: 1) at room temperature under an inert atmosphere. After stirring at room temperature for 6 hours, the solvent was evaporated and the residue was washed with saturated brine solution and extracted with DCM to give a pale yellow crystalline solid. Yield: 384 mg (62%).

In a 100 ml 1-neck round bottom flask, cholesterol quinoline (0.151 g, 0.263 mmol) was added in 3 ml of THF and cooled to 0 占 폚 in an ice bath. To this was added ice-cold solution LiOH (11 mg, 0.263 mmol) in 1 mL of H ₂ O, stirred at room temperature for 2 hours, and checked by TLC. After completion, THF was removed from the reaction mixture by means of a rotor vortex. Chloroform was added to the reaction mixture. The compound was extracted with water. The entire reaction mixture was then used in the next reaction after rotor viper treatment.

In a 50 mL 1-neck round bottom flask, DACH platinum (100 mg, 0.263 mmol) was placed in 10 mL of HPLC water. To the solution was added silver nitrate (89 mg, 0.526 mmol). The resulting solution was stirred at room temperature under protection from light. After 24 hours, the AgCl precipitate was filtered off. The filtrate was used in the next step.

The resulting lithium salt (161 mg, 0.263 mmol) was added to 20 mL of HPLC water in a 100 mL 1-necked round bottom flask and the resulting solution was stirred at room temperature for 5 minutes. To this solution was added DACH (OH ₂ ) ₂ platinum was added and it was stirred under protection from light at room temperature for 24 hours. The precipitate was filtered through a filter paper and washed simultaneously with HPLC water, HPLC methanol and HPLC acetone and dried. (Yield: 60%).

compound IO -185_01, IO -186_01, IO -187_01, IO -188_01, IO -189_01, IO -183_03, IO -183_04, IO Synthesis of -180_04

Synthesis of Hydrated Cisplatin (B) : 0.17 mmol of diamine platinum-dichloride (A), 0.34 mmol of silver nitrate and 7 mL of water was added to a 25 mL round bottom flask and stirred at room temperature for 48 hours. The solution was centrifuged (4,000 rpm; 10 min) and the white precipitate was filtered through a syringe filter (25 mm / 0.20 um). And washed with 2 ml of water. The filtrate was used in the next step.

Synthesis of IO- 185: The procedure is analogous to that described for compound 25 .

Synthesis of IO- 186: The procedure is analogous to that described for compound 26 .

Synthesis of IO- 187 : The procedure is analogous to that described for compound 27 .

Synthesis of IO- 188: The procedure is analogous to that described for compound 28 .

Synthesis of IO- 189: The procedure is similar to that described for compound IO -131 .

Synthesis of IO- 183_03 : The procedure is similar to that described for compound IO- 183_01 .

Synthesis of IO- 183_04 : The procedure is similar to that described for compound IO- 183_02 .

Synthesis of IO- 180_04 : The procedure is similar to that described for compound IO- 180_01 .

Example  8: Preparation of lipid-based nanoparticles

Phosphatidylcholine (complete hydrogenation, HSPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine -N- [methoxy (polyethylene glycol) -2000] (ammonium salt) -PEG-OMe) and cholesterol are selected as co-lipids. (Examples 1 and 2 of the described obtained in) cholesterol of the present invention oxaliplatin lipid-based platinum compound and a co-lipid in (HSPC, DSPE-PEG-OMe and cholesterol) in dichloromethane and methanol in a glass vial In a molar ratio of 1: 2: 0.05: 0.5, respectively, to prepare liposome nanoparticles. The organic solvent is removed with a gentle flow of moisture-free nitrogen and the remaining dried lipid film is then held under high vacuum for about 8 hours. 300 mOsm buffers (sucrose and disodium hydrogenphosphate) are added to the vacuum-dried lipid film and the mixture allowed to hydrate at 60 ° C for 1 hour. The vial is vortexed at room temperature for about 2 to 3 minutes and occasionally shaken in a 45 &lt; 0 &gt; C water bath to produce multi-lamellar vesicles (mlV). Ml V is passed through an extruder sequentially through 400 占 퐉, 200 占 퐉 and 100 占 퐉 film to produce a compact uni-lamella vesicle (SUV). The particle size of the obtained nanoparticles is measured by a DLS instrument (Malvern).

Example  9: In vitro  Cell culture and assay of cell viability

Cell viability assays are performed using breast cancer cell lines (4T1), cervical cancer cell lines (HeLa) and Lewis lung cancer cell lines (LLC). 4T1 cells are cultured in RPMI 1640 medium supplemented with 10% FBS, 50 units ml- ¹ penicillin and 50 units ml- ¹ streptomycin-penicillin. HeLa and LLC cells are cultured in DMEM medium supplemented with 10% FBS, 50 units ml- ¹ penicillin and 50 units ml- ¹ streptomycin-penicillin. The trypsin treated cultured cancer cells are seeded into a 96 well flat bottom plate at a density of 3000 cells / well the day before drug treatment. The following day, platelet-cultured cells are treated with various concentrations of nanoparticle formulations (as prepared by Example 3) and treated with oxaliplatin as a control. The plate is then incubated at about 37 ° C in a 5% CO ₂ atmosphere for about 48 hours. About 10 [mu] l of MTT reagent (10 mg / ml) is added and incubated for 2 hours. The medium is removed and the precipitate is solubilized in about 100 [mu] l of 1: 1 DMSO-methanol. The absorbance of the solubilized precipitate sample is measured on a BioRad Elisa reader at 550 nm. Then, relative cell viability is calculated from the recorded absorbance data.

The nanoparticle composition of the present invention exhibits significant cancer cell killing efficacy ( FIG. 6 ). The nanoparticles were tested in different cancer cell lines as described above, and compounds with a six-membered coordination with platinum (Compound 2, Compound 5) were observed to have similar cell killing efficacy when compared to oxaliplatin (control). Other compounds having a 5 or 7-membered platinum coordination (Compound 1, Compound 6, Compound 3 and Compound 4) have better cell killing efficacy than oxaliplatin. Most importantly, among these four compounds, Compound 4 exhibits significantly better cancer cell killing activity than the oxaliplatin control.

In conclusion, the present invention is directed to reaching a variety of platinum-based amphipathic materials as disclosed above. The compounds have a general framework of platinum-linker-lipid. Additionally, the present invention is also directed to carbenes, and more particularly to platinum-containing carbenes, wherein said platinum-based carbenes are also used as platinum moieties in platinum-based amphipathic materials. The various platinum-group amphipathic materials of the present invention exhibit significantly improved efficacy in the treatment of cancer, and thus can be used as successful alternatives in the treatment of cancer.

Bio-assay

Cell culture: Mammalian cells were grown in a special culture medium supplemented with 10% fetal bovine serum (FBS) and antibiotics in a humidified environment containing 5% CO ₂ at 37 ° C.

Cell viability assays: The effect of supramolecular platinum conjugates on cancer cell viability was determined using MTT assays. 100 ㎕ Culture - cell cultures, and the plate was allowed to overnight at (3000 to 5000 cells / well), the humidified environment containing 5% CO ₂ at 37 ℃ attached in the 96-well plates in the medium. New media (100 L) containing different concentrations of compound were added to the cells and incubated for 72 hours. After incubation, MTT assays were used to determine cell viability. The MTT assay measures cell viability through the evaluation of active mitochondrial dehydrogenase, which converts MTT to water insoluble purple formazan crystals. Cell viability was plotted as a dose-response curve using curve fitting.

(MDA-MB-231), ovarian cancer (SKOV-3), cervical cancer (HeLa) and colorectal cancer (SW-620, HCT-116) cell line in comparison with oxaliplatin. The results showed significant inhibition of cell viability in the 0 to 25 [mu] M concentration range for all exemplary compounds tested, indicating a dose-response relationship ( Fig. 7a-f ). The IC ₅₀ values for individual exemplary compounds were lower than oxaliplatin, which reveals the better efficacy of these compounds on human cancer cells.

Cellular uptake of platinum compounds: MDA-MB-231 cells (1 × 10 ⁶ cells) were seeded in a 2 ml medium per well of a 6-well plate and grown for 24 hours. A volume of the compound required to achieve an approximate final concentration of 50 [mu] M platinum per well was added. Cells were incubated for 5 hours after compound addition, then washed twice with PBS, harvested by trypsin treatment, resuspended in PBS, and counted. The cells were centrifuged and the pellet was stored at -80 [deg.] C until further processing. The cell pellet was digested with 100 μl nitric acid at 70 ° C for 4 hours. After decomposition, the sample was diluted in 2% HCl and the amount of accumulated platinum was determined using atomic absorption spectrometry (AAS). The assay was validated using a linear standard curve generated from serial dilutions of certified stock platinum standards and the platinum cell uptake was expressed as ng of platinum per 1 x ¹⁰ cells.

The results show that the uptake of cisplatin and oxaliplatin is similar in MDA-MB-231 cells, while all of the exemplary compounds tested show a higher uptake (about 7 to 20 times) ( FIG. 8 ). These results demonstrate that the uptake of an exemplary compound when administered at a platinum equivalent concentration is significantly higher in cancer cells compared to cisplatin or oxaliplatin.

Measurement of Platinum in Mouse Tumor: 4T1 breast cancer cells were transplanted subcutaneously into Balb / c mice at day 0. Tumor-bearing mice were treated with oxaliplatin and compound 27 at a dose equivalent to 8 mg / kg platinum ( n = 3) at 9 days after tumor transplantation. The tumors were weighed approximately 40 mg and were homogenized by dissolving overnight in nitric acid at 110 ° C in an ACE high-pressure tube by grinding into fine powder in a mortar and pestle using liquid nitrogen. After acidification, each sample was diluted with 2% HCl and analyzed by atomic absorption spectrophotometry (AAS) to determine the absorbance associated with the platinum content. This assay was validated using linear standard curves generated from serial dilutions of certified stock platinum standards. The average platinum concentration is reported as ng of platinum per milligram of tissue.

As shown in Figure 9 , in mice treated with Compound 27 (as quantified per gram of tissue using atomic absorption spectrophotometry) for tumors compared to tumors harvested from mice dosed with equivalent amounts of oxaliplatin, There was a significantly higher accumulation of platinum. The findings of the present inventors suggest that the enhanced uptake of platinum in relation to the exemplary compounds may account for increased apoptosis in tumors.

All patents and other publications identified in the specification and the Examples are expressly incorporated herein by reference for all purposes. These publications are provided for their disclosure purposes only prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not preceeding such disclosure by a prior invention or for any other reason. All references to dates or the contents of these documents are based on information available to applicants and do not provide any acknowledgment of the accuracy of the dates or contents of these documents.

Although the preferred embodiments are described and illustrated in detail herein, various modifications, additions, substitutions, and so on can be made without departing from the spirit of the invention, and they are thus within the scope of the invention as defined in the following claims . It will also be appreciated by those skilled in the art that any of the various embodiments described and illustrated herein may be further modified to include the features shown in any of the other embodiments disclosed herein, .

Claims (44)

(a) a platinum moiety; And
(b) a lipid linked to said platinum moiety. The method according to claim 1,
Wherein said compound comprises a carbonyl moiety. 3. The method of claim 2,
Wherein the carbonyl moiety is a carboxylic acid selected from the group consisting of succinic acid, malonic acid, oxalic acid, keto acid, and any combination thereof. The method according to claim 1,
Wherein the platinum atom is conjugated to the lipid via a covalent bond, a coordination bond, or a combination thereof. The method according to claim 1,
Wherein the compound comprises at least one linker between the platinum moiety and the lipid. The method according to claim 1,
Said compound having the formula VIII:
(VIII)
Q-linker-lipid
In this formula,
Q is
(i)

(Wherein X is NH or N (CH ₂ COO ^- ) and Z is a platinum containing compound, wherein the platinum forms part of a ring;
(ii)

Wherein X ₃ is selected from the group comprising (CH ₂ ) _n , CH ₂ -NH and C ₄ H ₈ , X ₄ is CO or -CH-CH ₃ , Z is a platinum- And n is 0, 1, or 2;
(iii)

Wherein X is selected from the group comprising S ⁺ , C, S ⁺ = O, N ⁺ H and P = O; X ₁ is selected from the group comprising -CH, -CH ₂ and -CH ₂ O X ₂ is C = O and Z is a platinum-containing compound, wherein platinum forms part of a ring;
(iv)

Wherein X ₁ is (CH ₂ ) _n , X ₂ is C═O, Z is a platinum containing compound wherein platinum forms part of a ring, and n is 0, 1, or 2;
(v)

Wherein R ¹ , R ² and R ³ are independently selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, O-acyl, Or R ₁ and R ₂ together with the Pt atom or R ₂ and R ₃ together with the Pt atom form an optionally substituted cyclic or heterocyclyl or R ₁ and R _{2 together} with the Pt atom And R &lt; ₂ &gt; and R &lt; ₃ &gt; together with the Pt atom form an optionally substituted cyclic or heterocyclyl; or
(vi)

Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are independently selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, Lipid, or any combination thereof, or R ₁ and R ₂ together with the Pt atom form an optionally substituted cyclic or heterocyclyl, or R ₃ and R ₄ together with the Pt atom are optionally substituted Lt; RTI ID = 0.0 &gt; heterocyclyl &lt; / RTI &gt; The method according to claim 6,
Z is

, Where the R ₁ and R ₂ are independently selected from halogen, alkyl, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, thiol, thioalkyl, O- acyl, or is any combination of these, or R ₁ And R &lt; ₂ &gt; together with the Pt atom form an optionally substituted cyclic or heterocyclyl. 8. The method of claim 7,
Z is

, Wherein p is 0, 1, 2, or 3. 9. The method of claim 8,
and p is 2. The method according to claim 1,
The linker
_{(i) -X-CH 2 -X} 2 -X 1 - ( wherein, X is NH and; X ₁ is C (O) O, C ( O) NH, O (CH 2) -O, NH, or O X ₂ is (CH ₂ ) _n or C (O); and n is 0, 1, 2, 3, 4, or 5;
_{(ii) - (CH 2)} n O-, - (CH 2) n NHC (O) O-, - (CH 2) n OC (O) NH-, - (CH 2) n C (O) NH ( _{CH 2) m O-, - (} CH 2) n O (CH 2) m O-, - (CH 2) n O (O) -, - (CH 2) n NHC (O) (CH 2) m O -, or - (CH ₂ ) _n C (O) O-, wherein n and m are independently 0, 1, 2, 3, 4, or 5;
(iii) -X ₃ -X ₄ X ₅ -X ₆ -, wherein X ₃ is CH, CH ₂ or O, X ₄ , X ₅ and X ₆ are independently the same or different and -CH ₂ O- Or O; And
(iv) any combination of (i) to (iii)
&Lt; / RTI &gt; The method according to claim 1,
The linker is a bond, ethylene diamine, ethylene glycol, diethylene glycol, 1,3-propanediol, glycine, _{beta-alanine, -O-, -CH 2 O-NHCH} 2 CH 2 NHC (O) -, -NHCH 2 CH _{2 NHC (O) O-, -NHCH} 2 CH 2 -, -NHCH 2 CH 2 O-, -NHCH 2 C (O) -, -NHCH 2 C (O) O-, -NHCH 2 C (O) OCH ₂ CH ₂ CH ₂ -, -NHCH ₂ C (O) OCH ₂ CH ₂ CH ₂ O-, -NHCH ₂ C (O) NH-, -CH ₂ CH ₂ -, -CH ₂ CH ₂ O-, -CH _{2 CH 2 NHC (O) -} , -CH 2 CH 2 NHC (O) O-, -CH 2 CH 2 O-, -CH 2 C (O) NHCH 2 CH 2 -, -CH 2 C (O) NHCH ₂ CH ₂ O-, -CH ₂ CH ₂ OCH ₂ CH ₂ -, -CH ₂ CH ₂ OCH ₂ CH ₂ O-, -CH ₂ C (O) -, -CH ₂ C (O) _{2 CH 2 CH 2 -, -CH} 2 CH 2 CH 2 O-, = CHCH = CH 2 -, = CHCH = CHCH 2 O-, -CH = CHCH 2 -, -CH = CHCH 2 O- _{, -OCH 2 CH 2 O-, -CH} 2 -, -CH 2 O-, -NHC (O) CH 2 -, -NHC (O) CH 2 O-, -C (O) CH 2 -, -C (O) CH ₂ O-, -OC (O) CH ₂ -, -OC (O) CH ₂ O-, -C (O) CH ₂ CH ₂ C (O) NHCH ₂ CH ₂ - _{) CH 2 CH 2 C (O} ) NHCH 2 CH 2 -, -C (O) CH 2 CH 2 C (O) NHCH 2 CH 2 O-, -OC (O) CH 2 CH 2 C (O) NHCH 2 _{CH 2 O-, -C (O)} CH 2 CH 2 C (O) NHCH 2 CH 2 NHC (O) -, -OC (O) CH 2 CH 2 C (O) NHCH 2 CH 2 NHC (O) - , _{-C (O) CH 2 CH 2} C (O) NHCH 2 CH 2 NHC (O) O-, -OC (O) CH 2 CH 2 C (O) NHCH 2 CH 2 NHC (O) O-, and mixtures thereof &Lt; / RTI &gt; or any combination thereof. The method according to claim 1,
The lipid may be selected from the group consisting of fat, wax, sterol, steroid, bile acid, fat-soluble vitamin, monoglyceride, diglyceride, phospholipid, glycolipid, sulfolipid, aminolipid, chromolipid, glycerophospholipid, Which is a sterol selected from cholesterol, cholesterol, cholesterol chloroformate or derivatives thereof, and any combination thereof, selected from prenol lipid, saccharose lipid, polyketide, . 13. The method of claim 12,
Wherein said lipid is cholesterol or alpha-tocopherol. The method according to claim 1,
Wherein said compound is &lt; RTI ID = 0.0 &gt;
(i)
(I)

(Wherein,
X is NH;
X ₁ is selected from the group comprising COOH, CONH ₂ , O- (CH ₂ ) _n -OH, NH ₂ and OH;
X ₂ is (CH ₂ ) _n or CO;
X ₃ is selected from the group comprising (CH ₂ ) _n , CH ₂ -NH and C ₄ H ₈ ;
X ₄ is CH-CO or -CH _3, and;
Z is a platinum-containing compound, wherein platinum forms part of the ring of formula (I);
n is 0, 1 or 2;
(ii)
&Lt; RTI ID = 0.0 &

(Wherein,
X is NH or N-CH ₂ COO ^-, and;
X ₁ is _{- (CH 2) n OH,} - (CH 2) n NHCOOH, - (CH 2) n CONH (CH 2) n OH, (CH 2) n O (CH 2) n OH, (CH 2) _n C = O, - (CH ₂ ) _n NHCO (CH ₂ ) _n OH and (CH ₂ ) _n -COOH;
Z is a platinum-containing compound wherein platinum forms part of a ring of formula II;
n is 0, 1 or 2;
(iii)
(III)

(Wherein,
X is selected from the group comprising S ⁺ , C, S ⁺ = O, N ⁺ H and P = O;
X ₁ is selected from the group comprising -CH, -CH _2, and -CH ₂ O;
X ₂ is C = O;
X ₃ is selected from CH, CH ₂ or O;
X ₄ , X ₅ , X ₆ is selected from -CH ₂ O or O;
Z is a platinum-containing compound, wherein platinum forms part of a ring of formula (III);
(iv) a compound of formula IV:
(IV)

(Wherein,
X is CH ₂ OH;
X ₁ is (CH _{2) n} a;
X ₂ is C = O;
Z is a platinum containing compound wherein platinum forms part of a ring of formula (IV);
n is 0, 1 or 2;
(v)
(VI)

;

(vi)
(VII)

Compounds of formula V:
(V)

In this formula,
Wherein X ₁ , X ₂ , X ₃ and X ₄ are independently selected from O, P, S, Se, Cl, N, C, OA, OB, DACH, halide and chelated or non-chelated dicarboxylate bond Groups, and any combination thereof;
Wherein A and B are independently selected from the group consisting of C, P, S, N, and any combination thereof;
X ₄ is optional. Platinum moiety; And
The platinum-linked lipids
&Lt; RTI ID = 0.0 &gt;
Conjugating the lipid to the platinum moiety to obtain the compound. 17. The method of claim 16,
(a) reacting the lipid with a linker to obtain a first compound;
(b) optionally reacting said first compound of step (a) with a carbonyl moiety to obtain a second compound; And
(c) conjugating said first compound of step (a) or said second compound of step (b) with said platinum moiety to obtain said compound
&Lt; / RTI &gt; 17. The method of claim 16, wherein said compound is a compound of any one of claims 1 to 15. (a) a platinum moiety; And
(b) a lipid linked to said lipid
&Lt; / RTI &gt; 20. The nanoparticle of claim 19, wherein the compound is a compound of any one of claims 1 to 15. 20. The method of claim 19,
Wherein the nanoparticle further comprises a co-lipid and / or a stabilizer. 22. The method of claim 21,
Wherein the ratio of said compound to co-lipid and / or stabilizer ranges from 99: 1 to 1:99 (w / w), (mol / mol) or (vol / vol). 22. The method of claim 21,
The nanoparticles include soy-phosphatidyl choline and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy (polyethylene glycol) -2000] as co- Wherein the ratio of the compound to the co-lipids ranges from about 1: 1: 0.01 to about 1: 4: 3. 24. A pharmaceutical composition comprising nanoparticles of any one of claims 19 to 23. 15. A pharmaceutical composition comprising a compound of any one of claims 1 to 15. 26. The method according to claim 24 or 25,
The excipient may be a granulating agent, a binder, a lubricant, a disintegrant, a sweetener, a glidant, an anti-adherent, an antistatic agent, a surfactant, an antioxidant, a gum, a coating agent, a coloring agent, , Plasticizers, preservatives, suspending agents, emulsifiers, plant cellulosic materials, spheronization agents, and any combination thereof. 26. The method according to claim 24 or 25,
Wherein the composition is formulated into a dosage form selected from the group consisting of injectable, tablet, lyophilized powder, liposomal suspension, and any combination thereof. Comprising administering to a subject a therapeutically effective amount of a compound of any one of claims 1 to 15 or a nanoparticle of any one of claims 19 to 23 to a subject in need of treatment or management of cancer, A method of treating or managing cancer in a patient. 29. The method of claim 28,
The cancer is selected from the group consisting of breast cancer, head and neck cancer, ovarian cancer, testicular cancer, pancreatic cancer, oral-esophageal cancer, gastrointestinal cancer, hepatic cancer, gallbladder cancer, lung cancer, melanoma, skin cancer, sarcoma, blood cancer, brain cancer, glioblastoma, &Lt; RTI ID = 0.0 &gt; cancer, &lt; / RTI &gt; 29. The method of claim 28,
Wherein said administration is by intravenous administration, intraarticular administration, pancreaticoduodenal administration, intraperitoneal administration, portal vein administration, intramuscular administration, or any combination thereof. 24. The method according to any one of claims 19 to 23,
The nanoparticles have increased cell uptake of platinum relative to cisplatin or oxaliplatin in cancer cells. 24. The method according to any one of claims 19 to 23,
Wherein the nanoparticles have a higher accumulation of platinum in the tumor relative to cisplatin or oxaliplatin in an equivalent dose amount of cisplatin or oxaliplatin. 16. The method according to any one of claims 1 to 15,
Wherein said compound has increased cell uptake of platinum relative to cisplatin or oxaliplatin in cancer cells. 16. The method according to any one of claims 1 to 15,
Wherein said compound has a higher accumulation of platinum in the tumor relative to cisplatin or oxaliplatin in an equivalent dose amount of cisplatin or oxaliplatin. Method of preparing nanoparticles:
a. Providing a platinum compound, wherein the platinum compound comprises a platinum moiety and a lipid linked to the platinum moiety; And
b. Reacting the compound with a co-lipid in the presence of a solvent to obtain the nanoparticles. 35. The method of claim 34,
Wherein the platinum compound is produced according to the production method of any one of claims 16 to 18. 37. The method of claim 34 or 36,
Wherein the solvent is selected from the group comprising chloroform, methanol, dichloromethane, ethanol, and any combination thereof. 37. The method of claim 34 or 36,
The co-lipid may be selected from the group consisting of soybean-phosphatidyl choline (fully hydrogenated), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy (polyethylene glycol) (DOPC), DSPE-PEG-OMe, dioloylphosphatidylethanolamine (DOPE), and any combination thereof. 39. The method according to any one of claims 34 to 38,
Wherein step (b) further comprises a drying step, an incubation step and an optional stabilizer addition step. 40. The method of claim 39,
Wherein the stabilizer is selected from the group consisting of DSPE-PEG-OMe, DSPE-PEG-NH2, PEG, inorganic salts, carbohydrates, and any combination thereof. 41. The method of claim 40,
Wherein the inorganic salt is selected from the group consisting of ammonium chloride, potassium chloride, sodium chloride, disodium hydrogen phosphate, sodium dihydrogen phosphate, and any combination thereof. 41. The method of claim 40,
Wherein the carbohydrate is selected from the group consisting of glucose, dextrose, and any combination thereof. 43. The method according to any one of claims 35 to 42,
Wherein the co-lipid is soy-phosphatidyl choline and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy (polyethylene glycol) -2000]. 44. The method according to any one of claims 35 to 43,
Wherein the ratio of the platinum compound to the co-lipids is about 1: 1: 0.01 to about 1: 4: 3.

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