JP2013014602A - High-purity texaphyrin metal complex - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a high-purity texaphyrin metal complex, a method for making the complex, and a method for using the complex to treat a disease or the like including cancer and atherosclerosis.SOLUTION: The texaphyrin metal complex has anticancer activity and is represented by formula 1 (wherein: M is a trivalent metal cation such as Gd; each X is OHor the like; Rto Rare independently H, OH or the like; Rand Rare independently H or 1 to 6C alkyl; and each x is independently selected from 2 to 6).

Description

(Field of Invention)
High purity texaphyrin metal complexes, methods of making such complexes, and diseases, disorders,
And the use of such high purity texaphyrin metal complexes for treating cancer and conditions (including cancer and atherosclerosis) are disclosed herein.

(Background of the Invention)
Cancer is a serious threat in modern society. Globally, more than 10 million people are diagnosed with cancer annually, and this number is estimated to increase to 15 million people every year by 2020. Cancer causes 6 million deaths annually, that is, 12% of the world die from cancer. Current treatment options are often limited, but there are a wide range of options. Of the 1.2 million newly diagnosed cancers annually in the United States, approximately 50% are treated using radiation therapy as part of early disease management. Approximately 150,000 additional recurrent cancer patients in the United States can receive radiation therapy each year. Approximately 350,000 cancer patients receive chemotherapy every year in the United States.

High levels of circulating cholesterol are associated with atherosclerosis, which can cause life-threatening blockages of blood vessels to the heart and brain. Unstable angina, myocardial infarction (heart attack), and sudden ischemic death remain the leading cause of morbidity and mortality in developed countries. Current estimates are that 1.1 million people in the United States will develop new or recurrent coronary attacks each year, and over 45% of these patients may die from coronary attacks.

Texaphyrin is a small molecule with a cyclic chemical structure that contains one of several metal atoms. The physical and chemical characteristics of a texaphyrin molecule are determined by the nature of the ring and the type of metal atom inserted into the ring. Texaphyrin is designed to selectively concentrate in diseased tissues such as tumor cells and atherosclerotic plaques in blood vessels. Within diseased cells, texaphyrin blocks a critical step in cellular metabolism and disrupts bioenergy processes. Texaphyrin is designed to provide a beneficial therapeutic approach for a wide range of diseases. They can be used for the treatment of a variety of diseases, including cancer, atherosclerosis and cardiovascular disease, including neurodegenerative diseases, inflammatory diseases, and HIV / AIDS.

(Summary of Invention)
Disclosed herein are compositions comprising high purity texaphyrin metal complexes wherein the identity of the substituents on the texaphyrin complex is at least about 98% identical to the substituents on all texaphyrin complexes in the sample. Also disclosed herein are compositions comprising high purity synthetic precursors of high purity texaphyrin complexes. Also disclosed herein are methods for synthesizing such high purity texaphyrin metal complexes and such high purity precursors. The identity of the poly (ethylene glycol) substituent on the aromatic moiety is at least about 98 with the substituent on the wholly aromatic moiety in the sample.
A method for pegylation of aromatic moieties that are% identical is also disclosed herein. Also disclosed herein are pharmaceutical compositions comprising such high purity texaphyrin metal complexes. Also disclosed herein are methods of treating a disorder, disease or condition in a human patient comprising administering to the patient an effective amount of such a high purity texaphyrin metal complex.

  A first aspect disclosed herein is represented by formula 1:

（式中、
Ｍは、Ｇｄ^＋３およびＬｕ^＋３からなる群から選択される３価の金属陽イオンであり、各
Ｘは、ＯＨ⁻、ＡｃＯ⁻、Ｃｌ⁻、Ｂｒ⁻、Ｉ⁻、Ｆ⁻、Ｈ_２ＰＯ_４ ⁻、ＣｌＯ⁻、Ｃｌ
Ｏ_２ ⁻、ＣｌＯ_３ ⁻、ＣｌＯ_４ ⁻、ＨＣＯ_３ ⁻、ＨＳＯ_４ ⁻、ＮＯ_３ ⁻、Ｎ_３ ⁻、ＣＮ⁻
、ＳＣＮ⁻、およびＯＣＮ⁻からなる群から独立して選択され、Ｒ_３、Ｒ_４、Ｒ_５、Ｒ_６
、Ｒ_７、およびＲ_８は、独立して、Ｈ、ＯＨ、Ｃ_ｎＨ_{（２ｎ＋１）}Ｏ_ｙ、またはＯＣ_ｎＨ
_{（２ｎ＋１）}Ｏ_ｙであり、Ｒ_１、Ｒ_２は、独立して、ＨまたはＣ_１〜Ｃ_６アルキルであり
、ここで、Ｒ_３、Ｒ_４、Ｒ_５、Ｒ_６、Ｒ_７、およびＲ_８のうちの少なくとも１つは、少な
くとも１つのヒドロキシル置換基を有するＣ_ｎＨ_{（２ｎ＋１）}Ｏ_ｙまたはＯＣ_ｎＨ_{（２ｎ
＋１）}Ｏ_ｙであり、ｎは、１〜１１の正の整数であり、ｙは０またはｎ以下の正の整数で
あり、各ｘは、２、３、４、５、および６からなる群から独立して選択される）の化合物
を含む高純度の組成物であって、ここで、前記組成物中の式１の化合物の少なくとも約９
８．４％が同一の構造を有する、高純度の化合物である。１つの実施形態では、ＭはＧｄ
^＋３である。１つの実施形態では、Ｒ_４およびＲ_７はＣ_３Ｈ_６ＯＨであり、Ｒ_５およびＲ
_６はＣ_２Ｈ_５であり、Ｒ_３およびＲ_８はＣＨ_３であり、Ｒ_１およびＲ_２はＨである。１つ
の実施形態では、各ｘは３である。１つの実施形態では、各ＸはＡｃＯ⁻である。別の実
施形態では、ＭはＬｕ^＋３である。１つの実施形態では、Ｒ_４およびＲ_７はＣ_３Ｈ_６ＯＨ
であり、Ｒ_５およびＲ_６はＣ_２Ｈ_５であり、Ｒ_３およびＲ_８はＣＨ_３であり、Ｒ_１および
Ｒ_２はＨである。１つの実施形態では、各ｘは３である。１つの実施形態では、各ＸはＡ
ｃＯ⁻である。さらなる実施形態または別の実施形態では、各Ｘは、糖誘導体、コレステ
ロール誘導体、ＰＥＧ酸、有機酸、有機硫酸塩、有機リン酸塩、リン酸塩、または無機リ
ガンドからなる群から選択される。さらなる実施形態または別の実施形態では、Ｘは、グ
ルコン酸、グルクロン酸、コール酸、デオキシコール酸、メチルホスホン酸、フェニルホ
スホン酸、リン酸、ギ酸、プロピオン酸、酪酸、ペンタン酸、３，６，９−トリオキソデ
カン酸、３，６−ジオキソヘプタン酸、２，５−ジオキソヘプタン酸、メチル吉草酸、グ
リコール酸、ピルビン酸、シュウ酸、リンゴ酸、マロン酸、コハク酸、マレイン酸、フマ
ル酸、酒石酸、クエン酸、メタンスルホン酸、エタンスルホン酸、安息香酸、サリチル酸
、３−フルオロ安息香酸、４−アミノ安息香酸、桂皮酸、マンデル酸、およびｐ−トルエ
ン−スルホン酸からなる群から選択される酸に由来する。

(Where
M is a trivalent metal cation selected from the group consisting of Gd ⁺³ and Lu ⁺³ , and each X is OH ⁻ , AcO ⁻ , Cl ⁻ , Br ⁻ , I ⁻ , F ⁻ , H ₂ PO _4. ⁻ , ClO ⁻ , Cl
O ₂ ⁻ , ClO ₃ ⁻ , ClO ₄ ⁻ , HCO ₃ ⁻ , HSO ₄ ⁻ , NO ₃ ⁻ , N ₃ ⁻ , CN ⁻
, SCN ⁻ , and OCN ^−, independently selected from R ₃ , R ₄ , R ₅ , R ₆
, R ₇ , and R ₈ are independently H, OH, C _n H _{(2n + 1)} O _y , or OC _n H
_{(2n + 1)} O _y , R ₁ , R ₂ are independently H or C ₁ -C ₆ alkyl, where R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R _At least one of ₈ is C _n H _{(2n + 1)} O _y or OC _n H _(2n with at least one hydroxyl substituent
₊₁₎ O _y , n is a positive integer of 1 to 11, y is a positive integer of 0 or less than n, and each x is a group consisting of 2, 3, 4, 5, and 6 And a compound of formula (I) selected from the group consisting of at least about 9 of the compounds of formula 1 in said composition
8.4% are highly pure compounds having the same structure. In one embodiment, M is Gd
⁺³ . In one embodiment, R ₄ and R ₇ are C ₃ H ₆ OH, and R ₅ and R
₆ is C ₂ H ₅ , R ₃ and R ₈ are CH ₃ , and R ₁ and R ₂ are H. In one embodiment, each x is 3. In one embodiment, each X is AcO ^- a. In another embodiment, M is Lu ⁺³ . In one embodiment, R ₄ and R ₇ are C ₃ H ₆ OH
R ₅ and R ₆ are C ₂ H ₅ , R ₃ and R ₈ are CH ₃ , and R ₁ and R ₂ are H. In one embodiment, each x is 3. In one embodiment, each X is A
cO ⁻ . In further or alternative embodiments, each X is selected from the group consisting of sugar derivatives, cholesterol derivatives, PEG acids, organic acids, organic sulfates, organic phosphates, phosphates, or inorganic ligands. In a further or alternative embodiment, X is gluconic acid, glucuronic acid, cholic acid, deoxycholic acid, methylphosphonic acid, phenylphosphonic acid, phosphoric acid, formic acid, propionic acid, butyric acid, pentanoic acid, 3, 6, 9-trioxodecanoic acid, 3,6-dioxoheptanoic acid, 2,5-dioxoheptanoic acid, methylvaleric acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, From the group consisting of fumaric acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzoic acid, salicylic acid, 3-fluorobenzoic acid, 4-aminobenzoic acid, cinnamic acid, mandelic acid, and p-toluene-sulfonic acid Derived from the selected acid.

In one embodiment, at least about 98.4% of the compounds of Formula 1 in the composition have the same molecular weight, and the same molecular weight is defined by isotopic variations.
Is eliminated. In one embodiment, at least about 98.7% of the compound of formula 1 in the composition
Have the same molecular weight, and the same molecular weight eliminates isotopic variations. In one embodiment, at least about 99% of the compounds of Formula 1 in the composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.3% of the compounds of Formula 1 in the composition have the same molecular weight, and the same molecular weight excludes isotopic variations.
In one embodiment, at least about 99.5% of the compounds of Formula 1 in the composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of the compounds of Formula 1 in the composition have the same structure. In one embodiment, at least about 99% of the compounds of Formula 1 in the composition have the same structure. In one embodiment, at least about 99.3% of the compounds of Formula 1 in the composition have the same structure. In one embodiment, at least about 99.5% of the compounds of Formula 1 in the composition have the same structure.

  A second embodiment disclosed herein is represented by formula 2:

（式中、Ｒ_３、Ｒ_４、Ｒ_５、Ｒ_６、Ｒ_７、およびＲ_８は、独立して、Ｈ、ＯＨ、Ｃ_ｎＨ_{（
２ｎ＋１）}Ｏ_ｙ、またはＯＣ_ｎＨ_{（２ｎ＋１）}Ｏ_ｙであり、Ｒ_１、Ｒ_２は、独立して、Ｈ
またはＣ_１〜Ｃ_６アルキルであり、ここで、Ｒ_３、Ｒ_４、Ｒ_５、Ｒ_６、Ｒ_７、およびＲ_８
のうちの少なくとも１つは、少なくとも１つのヒドロキシル置換基を有するＣ_ｎＨ_{（２ｎ
＋１）}Ｏ_ｙまたはＯＣ_ｎＨ_{（２ｎ＋１）}Ｏ_ｙであり、ｎは、１〜１１の正の整数であり、
ｙは０またはｎ以下の正の整数であり、各ｘは、２、３、４、５、および６からなる群か
ら独立して選択される）の化合物および許容可能なその酸付加塩を含む高純度の組成物で
あって、組成物中の式２の化合物の少なくとも約９８．４％が同一の構造を有する、高純
度の組成物である。１つの実施形態では、Ｒ_４およびＲ_７はＣ_３Ｈ_６ＯＨであり、Ｒ_５お
よびＲ_６はＣ_２Ｈ_５であり、Ｒ_３およびＲ_８はＣＨ_３であり、Ｒ_１およびＲ_２はＨである
。１つの実施形態では、各ｘは３である。１つの実施形態では、許容可能な酸付加塩は、
塩酸、臭化水素酸、硫酸、硝酸、リン酸、メタンスルホン酸、エタンスルホン酸、ｐ−ト
ルエンスルホン酸、およびサリチル酸からなる群から選択される。１つの実施形態では、
許容可能な酸付加塩は、塩酸塩である。

(Wherein R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ are independently H, OH, C _n H _{(
2n + 1)} O _y , or OC _n H _{(2n + 1)} O _y , and R ₁ and R ₂ are independently H
Or C ₁ -C ₆ alkyl, where R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R _8.
At least one of the C _n H _(2n having at least one hydroxyl substituent
₊₁₎ O _y or OC _n H _{(2n + 1)} O _y , n is a positive integer from 1 to 11,
y is a positive integer less than or equal to 0 or n, each x being independently selected from the group consisting of 2, 3, 4, 5, and 6) and acceptable acid addition salts thereof A high purity composition, wherein at least about 98.4% of the compounds of Formula 2 in the composition have the same structure. In one embodiment, R ₄ and R ₇ are C ₃ H ₆ OH, R ₅ and R ₆ are C ₂ H ₅ , R ₃ and R ₈ are CH ₃ , and R ₁ and R ₂ are H. In one embodiment, each x is 3. In one embodiment, the acceptable acid addition salt is
It is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. In one embodiment,
An acceptable acid addition salt is the hydrochloride salt.

In one embodiment, at least about 98.4% of the compounds of Formula 2 in the composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of the compounds of Formula 2 in the composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 9 of the compounds of formula 2 in the composition
9% have the same molecular weight, and the same molecular weight eliminates isotope variants. In one embodiment, at least about 99.3% of the compounds of Formula 2 in the composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.5% of the compounds of Formula 2 in the composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of the compounds of Formula 2 in the composition have the same structure. In one embodiment, at least about 99% of the compounds of Formula 2 in the composition have the same structure. In one embodiment, at least about 99 of the compounds of formula 2 in the composition
. 3% have the same structure. In one embodiment, at least about 99.5% of the compounds of Formula 2 in the composition have the same structure.

  A third aspect disclosed herein is represented by formula 4:

（式中、
Ｒ_１およびＲ_２は、独立して、ＨまたはＣ_１〜Ｃ_６アルキルであり、各ｘは、２、３、４
、５、および６からなる群から独立して選択される）の化合物を含む高純度の組成物であ
って、組成物中の式４の化合物の少なくとも約９８．４％が同一の構造を有する、高純度
の組成物である。１つの実施形態では、Ｒ_１およびＲ_２はＨである。１つの実施形態では
、各ｘは３である。

(Where
R ₁ and R ₂ are independently H or C ₁ -C ₆ alkyl, each x being 2, 3, 4
And a compound of formula (4) selected from the group consisting of 5, and 6), wherein at least about 98.4% of the compounds of formula 4 in the composition have the same structure A highly pure composition. In one embodiment, R ₁ and R ₂ are H. In one embodiment, each x is 3.

In one embodiment, at least about 98.4% of the compounds of formula 4 in the composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of the compounds of formula 4 in the composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 9 of the compound of formula 4 in the composition
9% have the same molecular weight, and the same molecular weight eliminates isotope variants. In one embodiment, at least about 99.3% of the compounds of formula 4 in the composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.5% of the compounds of formula 4 in the composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of the compounds of formula 4 in the composition have the same structure. In one embodiment, at least about 99% of the compounds of formula 4 in the composition have the same structure. In one embodiment, at least about 99 of the compounds of formula 4 in the composition
. 3% have the same structure. In one embodiment, at least about 99.5% of the compounds of Formula 4 in the composition have the same structure.

  A fourth aspect disclosed herein is represented by formula 5:

（式中、
Ｒ_１およびＲ_２は、独立して、ＨまたはＣ_１〜Ｃ_６アルキルであり、各ｘは、２、３、４
、５、および６からなる群から独立して選択される）の化合物を含む高純度の組成物であ
って、組成物中の式５の化合物の少なくとも約９８．４％が同一の構造を有する、高純度
の組成物である。１つの実施形態では、Ｒ_１およびＲ_２はＨである。１つの実施形態では
、各ｘは３である。

(Where
R ₁ and R ₂ are independently H or C ₁ -C ₆ alkyl, each x being 2, 3, 4
And a compound of formula 5), wherein at least about 98.4% of the compounds of formula 5 in the composition have the same structure A highly pure composition. In one embodiment, R ₁ and R ₂ are H. In one embodiment, each x is 3.

In one embodiment, at least about 98.4% of the compounds of formula 5 in the composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of the compounds of formula 5 in the composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 9 of the compound of formula 5 in the composition
9% have the same molecular weight, and the same molecular weight eliminates isotope variants. In one embodiment, at least about 99.3% of the compounds of formula 5 in the composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.5% of the compounds of Formula 5 in the composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of the compounds of formula 5 in the composition have the same structure. In one embodiment, at least about 99% of the compounds of formula 5 in the composition have the same structure. In one embodiment, at least about 99 of the compounds of formula 5 in the composition
. 3% have the same structure. In one embodiment, at least about 99.5% of the compounds of formula 5 in the composition have the same structure.

  A fifth aspect disclosed herein is represented by formula 4:

（式中、
Ｒ_１およびＲ_２は、独立して、ＨまたはＣ_１〜Ｃ_６アルキルであり、各ｘは、２、３、４
、５、および６からなる群から独立して選択される）の化合物の精製サンプルを合成する
方法であって、精製サンプル中の式４の化合物の少なくとも約９８．４％が同一の構造を
有し、以下の工程：
式５：

(Where
R ₁ and R ₂ are independently H or C ₁ -C ₆ alkyl, each x being 2, 3, 4
5) and a compound selected from the group consisting of 6 and 6), wherein at least about 98.4% of the compound of formula 4 in the purified sample has the same structure. And the following steps:
Formula 5:

の化合物を約９０％のＨＮＯ_３を含むＡｃＯＨと約０〜５℃で少なくとも３０分間反応さ
せる工程と、精製サンプル中に形成された式４の化合物の少なくとも約９８．４％が同一
の構造を有することを含む、方法である。１つの実施形態では、Ｒ_１およびＲ_２はＨであ
る。１つの実施形態では、各ｘは３である。

Of the step of reacting at least 30 minutes the compound in AcOH and about 0 to 5 ° C. containing HNO ₃ to about 90%, at least about 98.4% identical structure of the compound of Formula 4 formed in the purified sample It is a method including having. In one embodiment, R ₁ and R ₂ are H. In one embodiment, each x is 3.

In one embodiment, at least about 98.4% of the compound of Formula 4 in the purified sample has the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of the compound of Formula 4 in the purified sample has the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 99% of the compounds of formula 4 in the purified sample have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.3% of the compounds of formula 4 in the purified sample have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.5% of the compounds of Formula 4 in the purified sample have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of the compounds of formula 4 in the purified sample have the same structure. In one embodiment, at least about 99% of the compounds of formula 4 in the purified sample have the same structure. In one embodiment, at least about 99.3% of the compounds of formula 4 in the purified sample have the same structure. In one embodiment, at least about 99.5% of the compounds of formula 4 in the purified sample have the same structure.

  A sixth aspect disclosed herein is represented by formula 5:

（式中、
Ｒ_１およびＲ_２は、独立して、ＨまたはＣ_１〜Ｃ_６アルキルであり、各ｘは、２、３、４
、５、および６からなる群から独立して選択される）の化合物の精製サンプルを合成する
方法であって、精製サンプル中の式５の化合物の少なくとも約９８．４％が同一の構造を
有し、以下の工程：
式７：

(Where
R ₁ and R ₂ are independently H or C ₁ -C ₆ alkyl, each x being 2, 3, 4
Wherein the compound of formula 5 in the purified sample has the same structure. And the following steps:
Formula 7:

のトシル化化合物を、式６：

Tosylated compounds of formula 6:

のｏ−ジヒドロキシベンゼンとＫｅＣＯ_３および非プロトン性溶媒の存在下で反応させる
工程と、混合物を約６５℃で約２４時間加熱する工程を含み、精製サンプル中に形成され
た式５の化合物の少なくとも約９８．４％が同一の構造を有する、方法である。さらなる
実施形態または別の実施形態では、混合物を、非プロトン性溶媒の還流温度で加熱する。

Reacting o-dihydroxybenzene in the presence of KeCO ₃ and an aprotic solvent and heating the mixture at about 65 ° C. for about 24 hours, comprising at least the compound of formula 5 formed in the purified sample About 98.4% of the methods have the same structure. In further or alternative embodiments, the mixture is heated at the reflux temperature of the aprotic solvent.

In one embodiment, the aprotic solvent is an aldehyde, ketone, dimethyl sulfoxide, dimethylformamide, pyridine, diethyl ether, ethyl acetate, propyl acetate,
Selected from the group consisting of isopropyl acetate, butyl acetate, acetonitrile, benzonitrile, sulfur dioxide, tetrahydrofuran, and hexamethylphosphoramide. In one embodiment, the aprotic solvent is tetrahydrofuran. In a further embodiment or another embodiment, R ₁ and R ₂ are H. In one embodiment, each x is 3 and the aprotic solvent is tetrahydrofuran.

In one embodiment, at least about 98.4% of the compound of Formula 5 in the purified sample has the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of the compound of Formula 5 in the purified sample has the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 99% of the compounds of Formula 5 in the purified sample have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.3% of the compounds of formula 5 in the purified sample have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.5% of the compound of Formula 5 in the purified sample has the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of compounds of Formula 5 in the purified sample have the same structure. In one embodiment, at least about 99% of the compounds of formula 5 in the purified sample have the same structure. In one embodiment, at least about 99.3% of the compounds of formula 5 in the purified sample have the same structure. In one embodiment, at least about 99.5% of the compounds of formula 5 in the purified sample have the same structure.

A seventh aspect disclosed herein is a pharmaceutical composition comprising a compound of formula 1 and a pharmaceutically acceptable carrier, wherein at least about 98. of the compound of formula 1 in the pharmaceutical composition. 4%
Are pharmaceutical compositions having the same structure. In one embodiment, M is Gd ⁺³ . In one embodiment, R ₄ and R ₇ are C ₃ H ₆ OH and R ₅ and R ₆ are C ₂ H
₅ , R ₃ and R ₈ are CH ₃ , and R ₁ and R ₂ are H. In one embodiment, each x is 3. In one embodiment, each X is AcO ^- a. In another embodiment, M is Lu ⁺³ . In a further embodiment, R ₄ and R ₇ are C ₃ H ₆ OH,
R ₅ and R ₆ are C ₂ H ₅ , R ₃ and R ₈ are CH ₃ , and R ₁ and R ₂ are H
It is. In a further embodiment, each x is 3. In a further embodiment, each X is AcO.
^- . In further or alternative embodiments, each X is selected from the group consisting of sugar derivatives, cholesterol derivatives, PEG acids, organic acids, organic sulfates, organic phosphates, phosphates, or inorganic ligands. In a further or alternative embodiment, X is gluconic acid, glucuronic acid, cholic acid, deoxycholic acid, methylphosphonic acid, phenylphosphonic acid, phosphoric acid, formic acid, propionic acid, butyric acid, pentanoic acid, 3, 6, 9-trioxodecanoic acid, 3,6-dioxoheptanoic acid, 2,5-dioxoheptanoic acid, methylvaleric acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, Fumaric acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzoic acid, salicylic acid, 3
-Fluorobenzoic acid, 4-aminobenzoic acid, cinnamic acid, mandelic acid, and p-toluene-
Derived from an acid selected from the group consisting of sulfonic acids.

In one embodiment, at least about 98.4% of the compound of Formula 1 in the pharmaceutical composition has the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of the compounds of Formula 1 in the pharmaceutical composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 99% of the compounds of Formula 1 in the pharmaceutical composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.3% of the compounds of Formula 1 in the pharmaceutical composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.5% of the compounds of Formula 1 in the pharmaceutical composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of the compounds of Formula 1 in the pharmaceutical composition have the same structure. In one embodiment, at least about 99% of the compounds of Formula 1 in the pharmaceutical composition have the same structure. In one embodiment, at least about 99.3% of the compounds of Formula 1 in the pharmaceutical composition have the same structure. In one embodiment, at least about 99.5% of the compounds of Formula 1 in the pharmaceutical composition have the same structure. In one embodiment, the pharmaceutically acceptable carrier is suitable for parenteral administration.

An eighth aspect disclosed herein includes an effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt, solvate, isomer, tautomer, metabolite, analog, or pro thereof. Administering to a subject in need of a purified composition comprising a drug, and a method of treating cancer comprising comprising at least about 98.4% of a compound of formula 1 in said purified composition having the same molecular weight. is there.
In one embodiment, the method further comprises surgery, radiation therapy, chemotherapy, gene therapy, immunotherapy, or a combination thereof. In one embodiment, the cancer is glioblastoma, lymphoma, leukemia, renal cell cancer, head and neck cancer, breast cancer, prostate cancer.
er), ovarian cancer, and lung cancer.

A ninth aspect disclosed herein includes an effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt, solvate, isomer, tautomer, metabolite, analog, or pro thereof. A method of treating cardiovascular disease comprising administering to a subject in need a purified composition comprising a drug and wherein at least about 98.4% of the compound of formula 1 in the purified composition has the same molecular weight. It is. In one embodiment, the cardiovascular disease is selected from the group consisting of coronary artery disease, saphenous vein graft disease, and peripheral arterial disease. In a further embodiment, M is Lu ⁺³ ,
The subject further receives photodynamic therapy. In one embodiment, the subject receives photodynamic therapy after receiving the compound of Formula 1. In another embodiment, the target area is illuminated with light having a wavelength between about 725 nm and 760 nm. In further or alternative embodiments, each X is selected from the group consisting of sugar derivatives, cholesterol derivatives, PEG acids, organic acids, organic sulfates, organic phosphates, phosphates, or inorganic ligands. In a further or alternative embodiment, X is gluconic acid, glucuronic acid, cholic acid, deoxycholic acid, methylphosphonic acid, phenylphosphonic acid, phosphoric acid, formic acid, propionic acid, butyric acid, pentanoic acid,
3,6,9-trioxodecanoic acid, 3,6-dioxoheptanoic acid, 2,5-dioxoheptanoic acid, methylvaleric acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid , Maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzoic acid, salicylic acid, 3-fluorobenzoic acid, 4-aminobenzoic acid, cinnamic acid, mandelic acid, and p-toluene-sulfonic acid Derived from an acid selected from the group consisting of

In one embodiment of the eighth and ninth aspects above, M is Gd ⁺³ . In one embodiment, R ₄ and R ₇ are C ₃ H ₆ OH, R ₅ and R ₆ are C ₂ H ₅ , and R ₃
And R ₈ is CH ₃ and R ₁ and R ₂ are H. In one embodiment, each x is 3
It is. In one embodiment, each X is AcO ^- a. In another embodiment, M is Lu ⁺³
It is. In a further embodiment, R ₄ and R ₇ are C ₃ H ₆ OH, and R ₅ and R ₆
Is C ₂ H ₅ , R ₃ and R ₈ are CH ₃ , and R ₁ and R ₂ are H. In a further embodiment, each x is 3. In a further embodiment, each X is AcO ^- a. In further or alternative embodiments, each X is a sugar derivative, a cholesterol derivative, PE
It is selected from the group consisting of G acids, organic acids, organic sulfates, organic phosphates, phosphates, or inorganic ligands. In a further or alternative embodiment, X is gluconic acid, glucuronic acid, cholic acid, deoxycholic acid, methylphosphonic acid, phenylphosphonic acid, phosphoric acid,
Formic acid, propionic acid, butyric acid, pentanoic acid, 3,6,9-trioxodecanoic acid, 3,6-dioxoheptanoic acid, 2,5-dioxoheptanoic acid, methylvaleric acid, glycolic acid, pyruvic acid, shu Acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzoic acid, salicylic acid, 3-fluorobenzoic acid, 4-aminobenzoic acid, cinnamic acid, It is derived from an acid selected from the group consisting of mandelic acid and p-toluene-sulfonic acid.

In one embodiment of the eighth and ninth aspects above, at least about 98.4% of the compounds of Formula 1 in the composition have the same molecular weight, and the same molecular weight excludes isotopic variations. The 1
In one embodiment, at least about 98.7% of the compounds of Formula 1 in the composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 99% of the compounds of Formula 1 in the composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.3% of the compound of formula 1 in the composition
Have the same molecular weight, and the same molecular weight eliminates isotopic variations. In one embodiment, at least about 99.5% of the compounds of Formula 1 in the composition have the same molecular weight, and the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of the compounds of Formula 1 in the composition have the same structure. In one embodiment, at least about 99% of the compounds of Formula 1 in the composition have the same structure. In one embodiment, the formula 1 in the composition
At least about 99.3% of the compounds have the same structure. In one embodiment, at least about 99.5% of the compounds of Formula 1 in the composition have the same structure.

As described herein, the term “chemotherapy” refers to various methods (intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, inhalation, or suppository form). Administration of one or more anticancer drugs and / or other drugs to a cancer patient.

As described herein, the term “old process” refers to Sessler et al., US Pat. No. 5,994,535, which is hereby incorporated by reference in its entirety. Refers to the described process.

The term “purified sample” or “purified composition” refers to a composition having a high degree of uniformity in the chemical structure (or molecular weight (excluding isotopic variations)) of a compound having a specific general chemical formula. That is, a plurality of compounds in a composition can be a species of a particular general chemical formula, but in purified samples or purified compositions, such compounds have a high proportion of the same chemical formula (or molecular weight (isotope variant). Except))). The term “altitude” or “high ratio” value is defined herein as a specific value, such as, for example, at least about 98.4% and at least about 98.7%. Purified samples or compositions contain other chemicals (solvates, salts, reagents, pharmaceutical excipients,
And further therapeutic agents and the like). A critical aspect is that the composition has a specific general chemical formula (or molecular weight (excluding isotopic variations)), in particular Formula 1, Formula 2
The chemical structure (or molecular weight (excluding isotope variants)) of the compounds having the structures of Formula 3, Formula 4, and Formula 5 is highly uniform. The homogeneity of a particular purified composition or purified sample can be determined by various analytical methods, including by way of example only chromatography and spectroscopic methods and spectroscopic methods.

As described herein, the term “parenteral administration” refers to the administration of at least one agent by means other than the gastrointestinal tract. Parenteral routes of administration include infusion into various compartments of the body, including but not limited to intravenous, subcutaneous, intramuscular, and intraperitoneal.

As described herein, the term “pharmaceutically effective amount” or “effective amount” is non-toxic but sufficient to obtain the desired biological, therapeutic, and / or prophylactic result. Say quantity. Desired results include alleviation and / or alleviation of disease signs, symptoms, or causes, or any other desired change in the biological system. One skilled in the art can determine the effective amount in any individual case using routine experimentation.

As described herein, the term “pharmaceutically acceptable” or “pharmacologically acceptable” may mean a material that is not biologically or undesirable (ie,
The material can be administered to a solid without affecting any components of the included composition or interacting in any detrimental manner).

As described herein, the term “photodynamic therapy” refers to a treatment that combines a light source with a photosensitizer (a drug activated by light).

As described herein, the term “radiotherapy” refers to exposing a patient to high-energy radiation, including but not limited to x-rays, gamma rays, and neutrons. Treatment types include, but are not limited to, teleradiation therapy, internal radiation therapy, implant radiation, brachytherapy, total body radiation therapy, and radiation therapy.

As used herein, the term “same molecular weight” refers to compounds having the same molecular weight (excluding isotopic variants and counterion identity). That is, the molecular weight of the compound is determined by adding the atomic weights of all atoms in the formula (but excluding the counterion (ie, the X group in Formula 1)). In particular, for the purposes of this definition, a compound may be substituted for ¹ H in the structure
Since it has ² H, it does not differ in molecular weight from another compound (ie, isotope variants do not constitute a different molecular weight). By way of example only, a compound having the same molecular weight as Formula 1 has the same M, R ₃ , R ₄ , R ₅ , R ₅ , R ₇ , R ₈ , R ₁ , and R ₂ groups, and n, Although y and x are the same value, the identity of the X group can be different.

As used herein, the term “identical structure” refers to compounds having the same chemical structure (excluding isotope variants and counterions). By way of example only, compounds having the same structure as Formula 1 are identical M, R ₃ , R ₄ , R ₅ , R ₅ , R ₇ , R ₈ , R ₁ , and R
_It has _two groups and n, y, and x have the same value, but the identity of the X group can be different.

As described herein, the term “surgery” refers to systematic activity by hand using a hand or device on the body of a human or other mammal to obtain a curative, corrective, or diagnostic effect. Refers to any therapeutic or diagnostic procedure involving.

As described herein, the term “treatment” and its grammatical equivalents refers to attempting to achieve or achieve a therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of at least a portion of the underlying disorder being treated. For example, in cancer patients, therapeutic benefits include eradication or amelioration of at least a portion of the underlying cancer. The therapeutic benefit also includes one or more of the physiological symptoms associated with the underlying disorder for which the patient is ameliorated, even though the patient may still suffer from the underlying disorder. Includes at least some eradication or improvement. Disclosed herein for prophylactic benefits to patients at risk of developing cancer or patients who have reported one or more physiological symptoms of such conditions, even if the condition is not diagnosed Or the compositions disclosed herein can be administered.

(Incorporation as a reference)
Unless stated otherwise, all publications and patent applications mentioned in this specification are to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Incorporated herein by reference.

FIG. 1 schematically summarizes an exemplary synthesis of the texaphyrin metal complexes described herein. FIG. 2 shows an exemplary chromatogram comparing the purity of the compound of Formula 4 synthesized by the previous process with that according to the improved process disclosed herein. FIG. 3 shows an exemplary chromatogram comparing the purity of the compound of Formula 1 synthesized by the previous process with that according to the improved process disclosed herein.

(Detailed description of the invention)
Texaphyrin Sessler et al., In US Pat. No. 5,994,535 (incorporated herein by reference in its entirety), reported the synthesis of “texaphyrin” that absorbs strongly in the tissue penetration range of 730 nm to 770 nm. ing. This compound, both present in free base form, has various metal cations (Cd ²⁺ , Hg ²⁺ , In ³⁺ , Y ³⁺ , Nd ³⁺ , Eu ³⁺ , Sm
³⁺ , La ³⁺ , Lu ³⁺ , Gd ³⁺ etc.) and the formation of complexes with other cations of the lanthanoid series. Texaphyrin has been used in the treatment of cancer and atherosclerosis.
The composition of texaphyrin synthesized by the previous process is polydisperse with a polyethylene glycol chain length (i.e., the composition of texaphyrin synthesized by the previous process is different in structure but has a common general chemical structure. Included multiple species to share).
This structural diversity is due, at least in part, to the heterogeneity of polyethylene glycol substituent identity. As a result, high purity samples (ie, the polydispersity of polyethylene glycol chains is less than about 1.6%) were not available for treatment. The synthetic process disclosed herein provides a breakthrough in this area by obtaining a method for the synthesis of high purity texaphyrin (ie, the polydispersity of the polyethylene glycol chain is less than about 1.6%). To do.

There are a number of disadvantages associated with low purity in the sample (for example, the difficulty in optimizing solubility in pharmaceutical formulations where the effective concentration of the drug can vary from preparation to preparation, Difficult to optimize, and difficult to stabilize the formulation). By improving the purity of the compounds disclosed herein, such solubility, optimization of volume,
The disadvantage of drug stabilization is overcome. Improved purity can further reduce side effects associated with low purity pharmaceutical formulations, improve the measured formulation half-life, and improve drug targeting.
A representative synthesis of a texaphyrin metal complex, although not limited to the scope of the compositions and methods described herein, is shown in FIG. Compounds of formula 8 (each x being 3) are tosylated to compounds of formula 7. Treatment of the tosylated compound of formula 7 with the o-dihydroxybenzene derivative of formula 6 in the presence of K ₂ CO ₃ and an aprotic solvent provides the compound of formula 5. Examples of aprotic solvents are aldehydes, ketones, dimethyl sulfoxide, dimethylformamide, pyridine, diethyl ether, ethyl acetate, propyl acetate, isopropyl acetate,
It can be selected from the group consisting of butyl acetate, acetonitrile, benzonitrile, sulfur dioxide, tetrahydrofuran, hexamethylphosphoramide and the like. In one embodiment disclosed herein, the solvent is tetrahydrofuran.

Nitration of the compound of formula 5 in the presence of nitric acid and acetic acid provides the compound of formula 4. In this way, a high purity sample having the structure of Formula 4 is obtained, wherein at least about 98.4% of the compound of Formula 4 in the high purity sample has the same structure (and the same molecular weight (isotopic variation). (That is, both polyethylene glycol chain lengths of the aromatic moiety have the same chain length).

In some embodiments disclosed herein, at least about 98.7%, 99%, 99.3%, or 99.5% of the compound of Formula 4 in the high purity sample has the same structure (And the same molecular weight (isotope variants are excluded)) (ie, both polyethylene glycol chain lengths of the aromatic moiety have the same chain length (including the same “x” value per general formula)) )
. FIG. 2 is a chromatogram comparison of the purity of a composition comprising a compound of formula 4 synthesized by a previous process and that according to the process disclosed herein.

Table 1 compares the purity of compositions comprising a compound of formula 4 made by the previous process and the process disclosed herein.

  (Table 1-Purity of compositions containing compounds of formula 4)

より高い純度の化合物は、式５の化合物の形成で使用した溶媒に起因し得る。式４の化
合物の構築中に、１つの特定の不純物が、以下に示す構造：

The higher purity compound may be attributed to the solvent used in forming the compound of formula 5. During the construction of the compound of formula 4, one particular impurity is the structure shown below:

を有することがわかった。この不純物は、式８の化合物中に含まれるエチレングリコール
モノメチルエーテル量に基づいて予想される量よりも多い量で見出された。本明細書中に
記載の組成物および方法の範囲に制限されないが、この不純物が、以下：

It was found to have This impurity was found in an amount greater than would be expected based on the amount of ethylene glycol monomethyl ether contained in the compound of Formula 8. Without being limited to the scope of the compositions and methods described herein, this impurity may include the following:

に示す中間体Ａを介した式７の化合物からの式５の化合物の合成の反応工程に由来すると
予想される。１，４−ジオキサン型分子Ａは、トシレートに置換するためのエーテル酸素
の分子内攻撃によって形成される。式６のｏ−ジヒドロキシベンゼン誘導体は、Ａと反応
して、式５の化合物または以下：

It is expected to be derived from the reaction step of the synthesis of the compound of formula 5 from the compound of formula 7 via intermediate A shown in The 1,4-dioxane-type molecule A is formed by intramolecular attack of ether oxygen to replace with tosylate. An o-dihydroxybenzene derivative of formula 6 reacts with A to give a compound of formula 5 or

に示すモノエチレングリコール／トリエチレングリコール不純物（モノ／トリ）のいずれ
かを形成することができる。

Any of the following monoethylene glycol / triethylene glycol impurities (mono / tri) can be formed.

Without being limited to the scope of the compositions and methods described herein, it is expected that 1,4-dioxane cation A can be stabilized in the ethanol solvent used in the previous process. In the methods disclosed herein, THF minimizes the formation of mono / tri impurities. Table 2 shows the percentage of mono / tri impurities obtained in different solvents. Ethanol gives 0.43% mono / tri impurities, whereas THF gives 0.08%.
% Mono / tri impurities are obtained.

  (Table 2-Comparison of mono / tri impurities in different solvents)

反応後の式４の化合物から式３ａのフェニレンジアミンが得られ、これと式３ｂの化合
物との縮合によって高純度のサンプルが得られ、高純度のサンプル中の式２の構造を有す
る化合物の少なくとも約９８．４％が同一の構造（および同一の分子量（同位体変形物が
排除される））を有する（すなわち、芳香族部分の両ポリエチレングリコール鎖長は、同
一鎖長を有する）。本明細書中に開示のいくつかの実施形態では、高純度のサンプル中の
式２の化合物の少なくとも約９８．７％、９９％、９９．３％、または９９．５％は、同
一の構造（および同一の分子量（同位体変形物が排除される））を有する（すなわち、芳
香族部分の両ポリエチレングリコール鎖長は、同一鎖長を有する（一般式当たり同一の「
ｘ」値を含む））。

A phenylenediamine of the formula 3a is obtained from the compound of the formula 4 after the reaction, and a high-purity sample is obtained by condensation of this with the compound of the formula 3b. About 98.4% have the same structure (and the same molecular weight (isotope variants are excluded)) (ie, both polyethylene glycol chain lengths of the aromatic moiety have the same chain length). In some embodiments disclosed herein, at least about 98.7%, 99%, 99.3%, or 99.5% of the compound of Formula 2 in the high purity sample has the same structure (And the same molecular weight (isotope variants are excluded)) (ie, both polyethylene glycol chain lengths of the aromatic moiety have the same chain length (the same “
x ”value))).

The compound of formula 2 is oxidatively complexed with a trivalent metal cation (M) to obtain a high purity sample, wherein at least about 98. of the compound having the structure of formula 1 in the high purity sample. 4%
Have the same structure (and the same molecular weight (isotope variants are excluded)) (ie, both polyethylene glycol chain lengths of the aromatic moiety have the same chain length). In some embodiments disclosed herein, at least about 98. of the compound of Formula 1 in the high purity sample.
7%, 99%, 99.3%, or 99.5% have the same structure (and the same molecular weight (excluded isotope variants)) (ie both polyethylene glycol chains of the aromatic moiety) The lengths have the same chain length (including the same “x” value per general formula) Suitable M includes, by way of example only, Mn ⁺³ , Co ⁺³ , Ni ⁺³ , Y ⁺³ , In ⁺³ , Pr ⁺³ , Pr ⁺³ , Nd ^+
3 , Sm ⁺³ , Eu ⁺³ , Gd ⁺³ , Tb ⁺³ , Dy ⁺³ , Er ⁺³ , Fe ⁺³ , Ho ^{+
3, Ce +3, Tm +3,} Yb +3, Lu +3, contains ^{La +3,} and ^{U +3,} Further examples of ^M, Mn ^+2, 2 divalent metal cations such as Co ^{+2, Ni} +2, and ^{Fe +2} Ions are included. In some embodiments disclosed herein, the trivalent metal cation is
Gd ⁺³ or Lu ⁺³ . Table 3 compares the purity of the compound samples of Formula 1 made by the previous process and the process disclosed herein. The process disclosed herein improves purity to at least 98.4%, compared to 96.6% purity by the previous process. FIG. 3 is a chromatogram comparison of the purity of a composition comprising a compound of Formula 1 made by the previous process and the process disclosed herein.

  (Table 3—Purity of the composition containing the compound of Formula 1)

式３ａと３ｂとの縮合工程では、分子のトリピロール部分の種々の置換基の導入を、置
換フェニレンジアミンとの縮合前の合成工程でのピロール環の３位および／または４位で
の適切な置換によって行うことができる。ベンゼン環の置換基を、ピロール環との縮合前
のベンゼン環における適切な置換によって得ることができる。
サンプルまたは組成物の純度を決定するための例示的方法
本明細書中に開示の組成物および方法の範囲に制限されないが、化合物の純度を決定す
るためのいくつかの方法を記載する。

In the condensation step of formulas 3a and 3b, the introduction of various substituents on the tripyrrole part of the molecule, the appropriate substitution at the 3- and / or 4-positions of the pyrrole ring in the synthesis step prior to the condensation with the substituted phenylenediamine Can be done by. Substituents on the benzene ring can be obtained by appropriate substitution on the benzene ring prior to condensation with the pyrrole ring.
Exemplary Methods for Determining Sample or Composition Purity Without being limited to the scope of the compositions and methods disclosed herein, several methods are described for determining compound purity.

Chromatographic methods intended to be used for purity determination are, by way of example only, molecular size exclusion chromatography, native gel electrophoresis, high performance liquid chromatography (
HPLC), liquid chromatography (LC), liquid chromatography combined with mass spectrometry (LC / MS), gas chromatography (GC), gas chromatography combined with mass spectrometry (GC / MS), supercritical analysis chromatography, gel permeation chromatography, Ion exchange chromatography and reverse phase high performance liquid chromatography.

Other methods intended to be used for purity determination are, by way of example only, end group analysis, vapor pressure osmometry, freezing point depression / ebuliometry
(Freezing point / boiling point rise), viscosity analysis, small angle X-ray scattering, laser beam scattering, light absorption and scattering, ultracentrifugation, field flow fractionation, matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) Mass spectrometry, nuclear magnetic resonance analysis, and crystallization.
Cancer Targeting Methods Although not limited to the scope of the compositions and methods disclosed herein, the methods are used to treat some specific cancers or tumors. Cancer types (some of which may overlap in scope) are just a few examples: adrenal cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer,
Bone cancer, bone metastasis, adult CNS brain tumor, childhood CNS brain metastasis, brain metastasis, breast cancer, Castleman disease, cervical cancer, childhood non-Hodgkin lymphoma, colon cancer and rectal cancer, endometrial cancer, esophageal cancer,
Ewing sarcoma family tumor, eyeball cancer, gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gastrointestinal choriocarcinoma, hematological malignancy, Hodgkin's disease, Kaposi's sarcoma, kidney cancer, pharyngeal cancer and hypopharyngeal cancer, acute Lymphocytic leukemia, acute myeloid leukemia, childhood leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, liver cancer, lung cancer, lung carcinoid tumor, non-Hodgkin lymphoma,
Male breast cancer, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral and oral pharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, Penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (adult soft tissue cancer), melanoma skin cancer, non-melanoma skin cancer, stomach cancer, testicular cancer, thymic cancer, Includes thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Waldenstrom's macroglobulinemia. In one embodiment, the cancer is selected from the group consisting of metastatic brain tumor, lung cancer, glioblastoma, lymphoma, leukemia, renal cell carcinoma (kidney cancer), head and neck cancer, breast cancer, prostate cancer, and ovarian cancer. The

Disclosed herein are methods and compositions for treating lung cancer comprising administration of a high purity composition of Formula 1. Treatment options for lung cancer (which can be given to a patient in combination with administration of a high purity composition of Formula 1) include, by way of example only, surgery, immunotherapy, radiation therapy, chemotherapy, photodynamic therapy, or These combinations are included. Some possible surgical options for treating lung cancer are segmental or wedge resection, lobectomy, or pulmonary resection. Radiation therapy can be teleradiation therapy or brachytherapy.

Disclosed herein are methods and compositions for treating CNS neoplasms comprising administration of a high purity composition of Formula 1. Treatment options for CNS neoplasms (which can be given to a patient in combination with administration of a high purity composition of Formula 1) include, by way of example, surgery, radiation therapy,
Includes immunotherapy, fever therapy, gene therapy, chemotherapy, and a combination of radiation therapy and chemotherapy. Physicians can also prescribe steroids to reduce swelling inside the CNS.

Disclosed herein is a method for treating kidney cancer comprising administration of a high purity composition of Formula 1. Kidney cancer (also called renal cell carcinoma or adenocarcinoma) is a disease in which malignant cells are found in the lining of tubules in the kidney. Treatment options for kidney cancer (which can be given to a patient in combination with administration of a high purity composition of Formula 1) include surgery, radiation therapy, chemotherapy, and immunotherapy, by way of example only. Some possible surgical options for the treatment of kidney cancer are
Only one example includes partial nephrectomy, simple nephrectomy, and radical nephrectomy. Radiation therapy can be teleradiation therapy or brachytherapy. Stem cell transplantation can be used to treat kidney cancer.

In one embodiment, disclosed herein is a method for treating lymphoma comprising administration of a high purity composition of Formula 1. Treatment options for lymphoma (which can be given to patients in combination with administration of a high purity composition of Formula 1) include, by way of example, high in combination with chemotherapy, immunotherapy, radiation therapy, and stem cell transplantation. Dose chemotherapy is included. Radiation therapy can be teleradiation therapy or brachytherapy.

Disclosed herein is a method for treating breast cancer comprising administration of a high purity composition of Formula 1. Treatment options for breast cancer (which can be given to a patient in combination with administration of a high purity composition of Formula 1) include, by way of example only, surgery, immunotherapy, radiation therapy, chemotherapy, endocrine therapy, or these Is included. Breast massectomy and mastectomy are two possible surgical procedures available to breast cancer patients.

Disclosed herein is a method for treating ovarian cancer comprising administration of a high purity composition of Formula 1. Treatment options for ovarian cancer (which can be given to a patient in combination with administration of a high purity composition of Formula 1) are, by way of example only, surgery, immunotherapy, chemotherapy, hormone therapy, radiation therapy, or These combinations are included. Some possible surgical procedures include weight loss, unilateral or bilateral oophorectomy and / or unilateral or bilateral tubectomy.

Disclosed herein is a method for treating cervical cancer comprising administration of a high purity composition of Formula 1. Treatment options for cervical cancer (which can be given to a patient in combination with administration of a high purity composition of Formula 1) include, by way of example, surgery, immunotherapy, radiation therapy, and chemotherapy . Some possible surgical procedures are cryosurgery, hysterectomy, and radical hysterectomy. Radiation therapy for cervical cancer patients includes teletherapy or brachytherapy.

Disclosed herein is a method for treating prostate cancer comprising administration of a high purity composition of Formula 1. Treatment options for prostate cancer (which can be given to patients in combination with administration of the high purity composition of Formula 1) include, by way of example only, surgery, immunotherapy, radiation therapy, cryosurgery,
Hormone therapy and chemotherapy are included. Possible surgical procedures for treating prostate cancer include, by way of example, diffuse retropubic prostatectomy, diffuse perineal prostatectomy, and laparoscopic radical prostatectomy. Some radiotherapy options include teleradiation therapy (including three-dimensional conformal radiation therapy), intensity-modulated radiation therapy, and conformational proton beam radiation therapy.
y). Brachytherapy (seed transplantation or intra-tissue radiation therapy) is also an available method of treating prostate cancer. Cryosurgery is another possible method used to treat localized prostate cancer cells. Hormone therapy, also called androgen deprivation therapy or androgen suppression therapy, can be used to treat prostate cancer. Several methods are available for this therapy, including orchiectomy to remove the testicles where 90% of the androgen is produced.
Another method is to luteinizing hormone-releasing hormone (L
HRH) Analog administration. Available LHRH analogs include leuprolide, nafarelin, goserelin, triptorelin, and histrelin. An LHRH antagonist such as Abarelix can also be administered. Antiandrogens that block the body's androgenic activity are another available therapy. Such agents include flutamide, bicalutamide, and nilutamide. This therapy is typically combined with LHRH analog administration or orchiectomy, which is called combined androgen blockade (CAB). Chemotherapy may be appropriate if the prostate tumor has spread outside the prostate and hormone therapy is not effective. Anticancer drugs can be administered to slow prostate cancer growth, reduce symptoms, and improve quality of life.

Disclosed herein is a method for treating leukemia comprising administration of a high purity composition of Formula 1. Treatment options for leukemia (which can be given to a patient in combination with administration of a high purity composition of Formula 1) include, by way of example only, immunotherapy, radiation therapy, chemotherapy, bone marrow transplantation,
Or peripheral blood stem cell transplantation is included. Radiation therapy includes teleradiation therapy, which can be accompanied by side effects. Anticancer drugs can be used in chemotherapy to treat leukemia. Monoclonal antibody therapy can be used to treat AML patients. Prior to administration, small molecules or radioactive chemicals can be provided to the patient to provide a means of killing leukemia cells in the body. Gemtuzumab ozogamicin, a monoclonal antibody that binds to CD33 on AML cells, can be used to treat AML patients who cannot tolerate prior chemotherapy regimens. Bone marrow transplantation or peripheral blood stem cell transplantation can be used to treat AML patients. Some possible transplant procedures are allogeneic transplants or autologous transplants.

Disclosed herein is a method for treating head and neck cancer comprising administration of a high purity composition of Formula 1. Treatment options for head and neck cancer (which can be given to a patient in combination with administration of the high purity composition of Formula 1) are, by way of example only, surgery, irradiation, chemotherapy, multimodality therapy, gene therapy , Alone or in combination thereof.
Methods for Treating Cardiovascular Diseases Methods for treating cardiovascular diseases are disclosed herein. Cardiovascular disease has two main components: heart (heart) disease and blood vessel (blood vessel) disease.
Coronary artery diseases These are diseases of the arteries that supply blood to the heart muscle. Coronary artery disease, often known as CAD, is the most common form of heart disease in industrialized countries and is the leading cause of heart attacks far from others. Coronary artery disease generally means that blood flow through the artery does not function properly. The most common way in which obstruction occurs is by a condition called atherosclerosis (generally a preventable vascular disease type). These arteries (usually the inner surface is smooth) can become clogged slowly with fat mass, cholesterol, and other substances (called atherosclerotic plaques). As a result, the supply of blood (including oxygen and nutrients) towards the myocardium is impeded (myocardial ischemia). When the myocardial oxygen demand exceeds the oxygen supply, the coronary arteries become narrower, resulting in chest pain (angina). If the oxygen supply imbalance persists for more than a few minutes, the myocardium begins to die and can cause a heart attack (myocardial infarction). This can occur asymptomatically (asymptomatic heart attack), especially in diabetic patients. Furthermore, the lack of blood can cause a severe impairment of the heart rhythm known as arrhythmia or dysrhythmia, even for short periods of time. Coronary artery disease can cause sudden death by arrhythmia without any prior warning. A heart attack can, for example, cause congestive heart failure, both of which are cardiovascular disease types. Other cardiovascular diseases are, by way of example only, cardiomyopathy, valvular heart disease, pericardial disease, congenital heart disease, and congestive heart failure.

Vascular diseases include, by way of example only, hypertension, aneurysms, occlusive arterial diseases, vasculitis, venous thrombosis.
Peripheral artery disease (PAD)
In PAD, fatty deposits accumulate on the inner surface of the arterial wall. These blockers limit the blood circulation of the arteries leading primarily to the kidneys, stomach, arms, legs, and feet. In its early stages, common symptoms are convulsions and fatigue of the active leg and buttocks. Such convulsions subside when the patient is at rest. This is called “intermittent claudication”. PAD patients often accumulate fat in the heart and brain arteries. Because of this association, PAD patients have a higher risk of death from heart attacks and strokes. Treatment includes, by way of example only, drugs that help improve walking distance, antiplatelet drugs, and cholesterol-lowering drugs (statins).
Angioplasty or surgery may be necessary.
Great Saphenous Vein Graft Disease This term refers to a stenosis (either localized or diffuse) of the saphenous vein used as a bypass graft. A follow-up study of patients undergoing bypass surgery showed that up to 10% of vein grafts were occluded by discharge and increased to 20% by the end of the first year after surgery. Over time, the onset and progression of the disease continues so that only one third of the vein grafts that do not occlude in one year by 10 years are not significantly affected. By 10 years, approximately 20% of patients will need reoperation. Treatment includes, by way of example only, drug therapy, surgery, and angioplasty.

The methods disclosed herein include administration of a compound of Formula 1 or a compound of Formula 1 and at least one treatment identified in the paragraph above (by way of example only, surgery, radiation therapy, chemotherapy, transplantation therapy, etc.). ) Can have a beneficial effect on patients suffering from the above diseases. The choice of therapy that can be co-administered with the compositions disclosed herein will depend, in part, on the condition being treated. For example, for the treatment of cancer, the compound of Formula 1 can be used in combination with radiation therapy, monoclonal antibody therapy, chemotherapy, bone marrow transplantation, gene therapy, immunotherapy, or combinations thereof. As another example, CAD or PAD
For the treatment of the compounds of formula 1 can be used in combination with surgery, radiation therapy, chemotherapy or transplantation therapy.
Formulations, Routes of Administration, and Effective Dose Another aspect disclosed herein relates to pharmaceutical compositions comprising a compound of Formula 1 and a pharmaceutically acceptable excipient. Such pharmaceutical compositions can be used to treat cancer or cardiovascular disease in the methods described herein.

The compound of formula 1 can be provided as a prodrug and / or interconverted to the compound of formula 1 in vivo after administration. Compounds of formula 1 and / or prodrugs or pharmaceutically acceptable salts thereof can be used in the development of formulations for use in the methods disclosed herein. Further, in some embodiments, the compounds can be used in combination with one or more other compounds or one or more other forms.
The compound of Formula 1 can be formulated in the same dosage form (eg, one cream, intravenously suitable formulation, solution, suppository, tablet, or capsule).

The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds disclosed herein and which are not biologically or otherwise undesirable. For example, pharmaceutically acceptable salts do not interfere with the beneficial beneficial effects of the compounds disclosed herein in cancer treatment.

Typical salts include, by way of example only, salts formed by mixing a compound of formula 1 in a suitable buffer such as a phosphate buffer or passing the compound of formula 1 through a suitable ion exchange column. included. In addition, if a compound disclosed herein contains a carboxyl group or other acidic group, the compound can be converted to a pharmaceutically acceptable addition salt with an inorganic or organic base. Examples of suitable bases include, by way of example only, sodium hydroxide, potassium hydroxide, ammonia, tromethamine, meglumine, cyclohexylamine, dicyclohexyl-amine, ethanolamine, diethanolamine, and triethanolamine.

The high purity composition of Formula 1 can be used in any acceptable mode of administration of drugs with similar utility as described in patients and patient applications incorporated by reference above (rectal, buccal, intranasal, and Percutaneous routes, intraarterial injections, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, inhalation, impregnated or coated devices (eg, stents (ie, arterial insertion cylindrical polymers), etc.) Can be administered in either a single dose or multiple doses.

One mode of administration is parenteral (eg, including injection). Forms in which the high purity composition of Formula 1 can be incorporated for administration by injection include sesame oil, corn oil,
Aqueous or oily suspensions or emulsions with cottonseed oil or peanut oil and elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical excipients are included. Saline is also used for injection as usual. Ethanol, glycerol, propylene glycol, and liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Various antibacterial and antifungal agents (
For example, parabens, chlorobutanol, phenol, sorbic acid, tiromesal, etc.) can prevent microbial action.

Sterile injectable solutions are prepared by incorporating the various other ingredients listed above into the required amount of the high purity composition of Formula 1 in an appropriate solvent, as required, followed by sterile filtration. Generally, the dispersion is a sterile vehicle (veh) containing a basic dispersion medium and the other ingredients listed above as required.
icle) by incorporating various sterilized high purity compositions of Formula 1.
In the case of sterile powders for the preparation of sterile injectable solutions, the method of preparation involves vacuum drying techniques and lyophilization from which the pre-filter sterilized solution yields a highly pure composition of Formula 1 and powders of any further desired ingredients Technology.

A highly pure composition of Formula 1 can be prepared using procedures known to those skilled in the art in view of the present disclosure, for example:
It can be impregnated by diffusion or coated on the stent, for example in gel form.

Oral administration is another route of administration of the high purity composition of Formula 1. Embodiments include oral administration, such as through capsules or enteric tablets that prevent degradation of the high purity composition of Formula 1 in the stomach. In making a pharmaceutical composition comprising at least a high purity composition of Formula 1, the active ingredient is usually diluted with an excipient and / or may be in the form of a capsule, sachet, paper, or other container. It encloses in such a carrier. Where the excipient serves as a diluent, the excipient is a solid, semi-solid, or liquid material (described above) that acts as a vehicle, carrier, or medium for the high purity composition of Formula 1. obtain. Thus, the composition can be a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or liquid medium), ointment (eg, high purity of Formula 1) Soft gelatin capsules and hard gelatin capsules, sterile injection solutions,
As well as in the form of sterile packaging powders.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose , Sterile water, syrup, and methylcellulose. The formulation may further include: a lubricant (such as talc, magnesium stearate, and mineral oil).
, Wetting agents, emulsifying and suspending agents, preservatives (such as methyl- and propylhydroxy-benzoates), sweeteners, and flavoring substances.

Formulation of the high purity composition of Formula 1 such that the high purity composition of Formula 1 is released rapidly, sustained, or delayed after administration to a patient using procedures known in the art. can do. Controlled release drug delivery systems for oral administration include osmotic pump systems and elution systems that include polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are described in U.S. Pat. Nos. 3,845,770, 4,326,525, 4th.
902, 514, and 5,616,345. Another formulation for use in the methods described herein uses transdermal delivery devices (“patches”). Such transdermal patches can be used to inject controlled amounts of the high purity composition of Formula 1 continuously or discontinuously (see, eg, US Pat. No. 5,023,252, ibid.). 4,9
92,445, and 5,001,139). Such a patch can be constructed for continuous, pulsatile, or on-demand delivery of a pharmaceutical agent.

The composition is optionally formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as single dosages for human subjects and other mammals, each unit comprising a suitable pharmaceutical excipient (eg, tablet, capsule, A predetermined amount of active material calculated to achieve the desired therapeutic effect in combination with
including. High purity compositions of Formula 1 are effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. For oral administration, each dosage unit contains 10 mg to 2 g of the high purity composition of Formula 1, and for parenteral administration, 10 to 700 mg (including about 350 mg) of the high purity composition of Formula 1. Including things. The amount of compound actually administered depends on the relevant circumstances (condition being treated, route of administration chosen, the compound actually administered and its relative activity, the patient's age, weight and reactivity, and the severity of the patient's symptoms) The doctor decides in consideration of the degree).

For the preparation of solid compositions such as tablets, the high purity composition of Formula 1 is mixed with pharmaceutical excipients to form a solid formulation comprising a uniform mixture of the high purity composition of Formula 1. To do. When these pre-formulated compositions are homogeneous, the active ingredient is uniformly dispersed throughout the composition, resulting in:
It means that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

The tablets or pills described herein can be coated or otherwise formulated to provide a dosage form that provides the benefit of prolonged action or to protect against acidic conditions of the stomach . For example, a tablet or pill may comprise an inner dispensing component and an outer dispensing component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that can withstand disintegration in the stomach and allow the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings. Such materials include a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

Compositions for inhalation or insufflation include solutions and suspensions including pharmaceutically acceptable aqueous or organic solvents or mixtures thereof and powders. Liquid or solid compositions may include suitable pharmaceutically acceptable excipients described herein. In order to obtain a local or systemic effect, such compositions are administered by the oral or nasal respiratory route. Through the use of an inert gas, a pharmaceutically acceptable solvent containing the composition can be nebulized. The nebulized solution can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a face mask tent or intermittent positive pressure respiratory. Solution, suspension, or powder compositions can be administered orally or intranasally from devices that deliver the formulation in an appropriate manner.

The specific dose will vary depending on the particularly pure composition of Formula 1 selected, the dosage regimen to be followed, and the specific therapeutic energy, or drug being administered, and will be about 0.01 mg / kg. A dosage in the range of / treatment to about 100 mg / kg / treatment, preferably about 0.1 mg / kg / treatment to about 50 mg / kg / treatment is used. Due to the wide range of available properties such as solubility, lipophilicity, low toxicity, and improved stability, the most effective dose depends specifically on the selected apical ligand.
As an example of photodynamic therapy, a high purity composition of Formula 1 having lutetium as a metal in texaphyrin can be administered in solution (optionally 5% mannitol USP). About 1.0
A dosage of ˜2.0 mg / kg to about 4.0-7.0 mg / kg (including 3.0 mg / kg) is used, but in some cases the maximum tolerated dose is higher, eg about 5 mg / Kg. Texaphyrin is administered by intravenous injection followed by a minimum of a few minutes or about 3
Wait up to about 72 or 96 hours (depending on the treatment being performed) from time to promote intracellular uptake and clearance from plasma and extracellular matrix prior to light irradiation.

The dosage level for a given application is a single dose or multiple doses (eg before each light exposure)
In the range of about 0.05 mg / kg to about 20 mg / kg. For example, lower dosage ranges could be applicable to intra-arterial injection or impregnated stents.

The optimal length of time between the high purity composition of Formula 1 and phototherapy can vary depending on the mode of administration, dosage form, and type of target tissue. Typically, the high purity composition of Formula 1 will last from a few minutes to several hours, depending on the high purity composition of Formula 1, formulation, dosage, infusion rate, tissue type, and tissue size.

When using photodynamic therapy, the target area is treated with light (eg, about 740 ± 16.5 nm). After administration of the photosensitized high purity composition of Formula 1, the treated tissue is treated at wavelengths similar to the absorbance of the high purity composition of Formula 1 (usually about 440 nm to 540 nm, about 700 to 800 nm, about 45
0-520 nm, about 720-780 nm, about 460 nm-500 nm, or about 725-
760 nm). The light source can be a laser, a light emitting diode, or filtered light, eg, derived from a xenon lamp. Light can be administered locally, endoscopically, stroma (eg, with a fiber optic probe), or intraarterial. In one embodiment, light is administered using a slit lamp delivery system. The fluence and irradiance during light treatment can vary depending on the type of tissue, the depth of the target tissue, and the amount of overlapping fluid or blood. For example, a total light energy of about 100 J / cm ² , depending on the target tissue, 20
Delivery can be from 0 mW to 250 mW.
Administration of Chemotherapeutic Agents A high purity composition of Formula 1 can be administered before, simultaneously with, or after administration of one or more chemotherapeutic agents. The high purity composition of Formula 1 can be administered as a single dose or can be administered in multiple doses over time intervals. The highly pure composition of Formula 1 is administered at the same time as the chemotherapeutic agent, about 1 minute to about 12 hours, preferably about 5 minutes to about 5 hours, more preferably about 4 to 5 hours. Can be administered. The administration protocol can be repeated, for example, 1 to 3 times. A successful time frame in vivo is the administration of the high purity composition of Formula 1 from about 5 minutes to about 5 hours after administration of the chemotherapeutic agent, and this protocol is administered once a week for 3 weeks. Do over. Administration can be by intraarterial injection, intravenous, intraperitoneal, intramuscular, subcutaneous, oral, topical, or via a device such as a stent.

The high purity composition of Formula 1 and the chemotherapeutic agent can be administered to a subject before, at the same time, or after the vascular intervention. The method can begin approximately simultaneously with a vascular intervention (eg, an angioplasty procedure, etc.). Multiple or single treatments can be used before, simultaneously with, or after this procedure. “Almost simultaneously with vascular intervention” refers to a period within the effectiveness of the vascular intervention. Typically, an initial administration of a high purity composition of Formula 1 and a chemotherapeutic agent is required for vascular intervention 6
Within -12 hours, preferably within 6 hours after intervention. Follow-up administration can be performed every week, every two weeks, or every month. The specific protocol design will depend on each subject, the condition of the subject, the dosage level design, and the judgment of the attending physician.
Administration for radiation sensitization A highly pure composition of formula 1 wherein the metal is gadolinium is mixed with a solution containing about 2 mM of the compound of formula 1 (optionally 5% mannitol USP / water (sterile nonpyrogenic solution In a further composition or another composition, the solution comprises about 2.2 mM of the compound of formula 1 (in addition to the other compounds described herein). 0.1 mg / kg to about 29
. A dosage of 0 mg / kg can be delivered, preferably about 3.0 to about 15.0 mg / kg (volume of about 90-450 mL) can be used. Optionally, about 6.0 mg / kg
Can be used with premedication using antiemetics. The compound is administered via intravenous infusion over about 5-10 minutes, followed by about 2-5 hours to facilitate intracellular uptake and clearance from plasma and extracellular matrix prior to irradiation.

When using whole brain radiation therapy, a series of 10 30 Gy irradiations can be performed over the course of the day, excluding the end and holidays. Treatment of brain metastases uses ⁶⁰ Co teletherapy or isocenter technology, contralateral electric field and no lenses (exclusi
on of the eyes) ≧ 4 MV with an isocenter distance of at least 80 cm
Whole brain megavolt radiation therapy is performed using a linear accelerator. The minimum dose rate at the central plane in the brain on the central axis is about 0.5 Gy / min.

The high purity composition of Formula 1 used as an irradiation sensitizer can be administered before, simultaneously with, or after irradiation with ionizing radiation. The high purity composition of Formula 1 can be administered as a single dose as an infusion or can be administered in two or more doses separated by a time interval. When administering a high purity composition of Formula 1 in two or more doses, the interval between administrations of the high purity composition of Formula 1 is from 1 minute to several days, from about 5 minutes to about 1 day, or About 10 minutes to about 1
It can be 0 hours. The administration protocol can be repeated, for example, 1 to 10 times or more. The dose level for radiation sensitization is about 0.05 mg / kg to about 20 mg.
A lower dosage range is preferred for intra-arterial injections or impregnated stents that are administered in single or multiple doses (eg, before each radiation).

Administration can be by intraarterial injection, intravenous, intraperitoneal, intramuscular, subcutaneous, oral, topical, or stent (
For example, it may be an impregnated or coated device such as an arterial insertion cylindrical polymer). In one aspect of the treatment methods described herein, a constant dose of the high purity composition of Formula 1 can be administered to each patient with restenosis or at risk for restenosis.

The subject can be administered a high purity composition of Formula 1 before, simultaneously with, or after vascular intervention, followed by light irradiation. The method can be initiated, for example, prior to vascular intervention (such as about 24-48 hours prior) or approximately simultaneously. Multiple or single treatments can be used before, simultaneously with, or after this procedure. “Almost simultaneously with vascular intervention” refers to a period within the effectiveness of the vascular intervention. Typically, the initial administration of the high purity composition of Formula 1 is within 1 to 24 hours of vascular intervention, preferably within about 5 to 24 hours after intervention. Every week, every two weeks,
Follow-up administration can be performed monthly or at longer intervals. The specific protocol design will depend on each subject, the condition of the subject, the dosage level design, and the judgment of the attending physician.
Sonodynamic Therapy The use of texaphyrin in sonodynamic therapy is described in US patent application Ser. No. 09 / 111,148, which is converted to US Provisional Application No. 60 / 155,256, 2
Filed on Jan. 5, 2001 (US patent application Ser. No. 09 / 755,824),
Currently abandoned (incorporated herein by reference). Texaphyrin is administered prior to ultrasonic administration. Texaphyrin can be administered in a single dose or in two or more doses separated by a time interval. Parenteral administration (including intravenous and intraarterial injection) is typical. Other common routes of administration can also be used.

Focused array transducer driven by power amplifier
nsducer) generates ultrasonic waves. The transducer can change the diameter and spherical curvature to vary the focus of the ultrasound output. A commercially available therapeutic ultrasound device,
It can be used in the implementation of such a method. The duration and wave frequency (including the wave type used) can be varied, and the preferred treatment duration will vary from case to case within the judgment of the attending physician. Both the traveling wave mode pattern and the standing wave pattern cavitate the affected tissue successfully. When traveling waves are used, the second harmonic can be advantageously overlapped on the fundamental. The type of ultrasound used in this way is
Low-intensity ultrasound, non-thermal ultrasound (ie, generated at wavelengths of about 0.1 MHz and 5.0 MHz and an intensity range between about 3.0 W / cm ² and 5.0 W / cm ² Ultrasonic)
It is.

In further applications, a compound of Formula 1 where M is Gd ⁺³ can be administered with NAD (P) H, ascorbate, and other reducing agents under near physiological conditions where reactive oxygen species are generated. . The depletion of these reducing agents inhibits the biochemical pathways in which reducing agents are used to repair damage inflicted by reactive oxygen species in vivo. Such methods can be used to treat cancer and cardiovascular disease. US Pat. No. 6,825,1
See 86 (incorporated herein by reference in its entirety). The ability of a composition comprising a compound of Formula 1 to catalyze the oxidation of these reducing agents is expected to improve as the purity of the composition is improved. Thus, the high purity compositions described herein are expected to have improved catalytic and therapeutic effectiveness.

While embodiments are shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided for illustrative purposes only. Those skilled in the art will readily implement numerous variations, modifications, and substitutions without departing from the invention. It should be understood that various alternatives to the embodiments described herein can be used in the practice of the present invention. It is intended that the following claims define the scope of the invention and that methods and structures be covered within the scope of these claims and their equivalents.

All solvents and reagents were reagent grade quality, are commercially available and were used at the time of arrival.

Example 1
Synthesis of Compound of Formula 7 (x = 3) While maintaining at 0 to 10 ° C., the compound of formula 8 (x = 3; 74 g) in tetrahydrofuran (
39 g) The solution was added to aqueous sodium hydroxide (25%, 235 g) (see FIG. 1). It is important to keep the temperature within this range. At 0-10 ° C., a solution of p-toluenesulfonyl chloride (TsCl, 78 g) in tetrahydrofuran (126 g) was added to the compound of formula 8 over 4 hours. The reaction mixture is stirred for up to 90 minutes and 0-10
Neutralized by addition of dilute hydrochloric acid at 33 ° C. (33%, 115 g). The lower aqueous layer was discarded and the organic layer was washed twice with brine (24%, 55 ml). The resulting tetrahydrofuran solution of the compound of formula 7 is used directly in the next step.

(Example 2)
Synthesis of compound of formula 5 (x = 3; R ₁ = R ₂ = H) A solution of o-dihydroxybenzene (25 g), potassium carbonate (61 g), and compound of formula 7 (x = 3) is mixed and 7 until the residual ratio of the compound No. 7 is 0.5% or less (24 to 4
(Refer to FIG. 1). The reaction mixture was filtered and the filter cake was washed twice with tetrahydrofuran (92 g). The combined filtrate was concentrated under reduced pressure to 110 ° C. The residue was cooled and treated with a 20-30 ° C. aqueous sodium hydroxide solution (6.5%, 315 g). Dichloromethane (106 ml) was added and the mixture was stirred and separated. The organic phase was washed with water (150 ml) and distilled to dryness at atmospheric pressure up to 100 ° C. The residue was dissolved in acetic acid (ca. 60 g) and used as the acetic acid solution in the next step.

(Example 3)
Compounds of formula _{4 (x = 3; R 1} = R 2 = H) Compound 5 Synthesis formula 5 _{(x = 3; R 1 =} R 2 = H) in acetic acid solution, 90% nitric acid 0 to 5 ° C. (5
80 g). The reaction is stirred at this temperature for 30-60 minutes, then 0-10 ° C.
The reaction was stopped by the addition of water (620 ml). The reaction mixture is diluted with dichloromethane (
265 ml, followed by 130 ml) and the combined organic phases are washed with a pH of 5.5-8.
5 aqueous sodium hydroxide solution (5%, about 360 kg), then water (350 ml
). Dichloromethane was distilled under reduced pressure to replace IPA (50 g), which was also distilled to release the crude compound of formula 4 as an oil at 50-60 ° C. The crude compound of formula 4 is
Slowly added to IPA (600 g) at 2-6 ° C. (critical parameter) and the mixture was held at this temperature for at least 1 hour. The precipitated compound of formula 4 was filtered and washed with cold IPA.
The wet cake was melted at 50-60 ° C. and the crystallization procedure was repeated. The wet cake was dried at 25 ° C. under reduced pressure.

Claims (32)

Formula 1:

(Where
M is a trivalent metal cation selected from the group consisting of Gd ⁺³ and Lu ⁺³ , and each X is OH ⁻ , AcO ⁻ , Cl ⁻ , Br ⁻ , I ⁻ , F ⁻ , H ₂ PO _4. ⁻ , ClO ⁻ , Cl
O ₂ ⁻ , ClO ₃ ⁻ , ClO ₄ ⁻ , HCO ₃ ⁻ , HSO ₄ ⁻ , NO ₃ ⁻ , N ₃ ⁻ , CN ⁻
, SCN ⁻ , and OCN ^−, independently selected from R ₃ , R ₄ , R ₅ , R ₆
, R ₇ , and R ₈ are independently H, OH, C _n H _{(2n + 1)} O _y , or OC _n H
_{(2n + 1)} O _y , R ₁ , R ₂ are independently H or C ₁ -C ₆ alkyl, where R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R _At least one of ₈ is C _n H _{(2n + 1)} O _y or OC _n H _(2n with at least one hydroxyl substituent
₊₁₎ O _y
n is a positive integer of 1 to 11, y is a positive integer of 0 or n, and each x is 2,
A high-purity composition comprising a compound selected independently from the group consisting of 3, 4, 5, and 6),
Wherein at least about 98.4% of the compound of Formula 1 in the composition has the same structure;
High purity composition. The composition of claim 1, wherein M is Gd ⁺³ . R ₄ and R ₇ are C ₃ H ₆ OH, R ₅ and R ₆ are C ₂ H ₅ , R ₃ and R ₈ are CH ₃ , and R ₁ and R ₂ are H The composition according to claim 2. 4. The composition of claim 3, wherein each x is 3. The composition according to claim 4, wherein each X is AcO 2 ^— . The composition of claim 1, wherein at least about 99.3% of the compounds of Formula 1 in the purified composition have the same molecular weight. The composition of claim 1, wherein at least about 99.3% of the compounds of Formula 1 in the purified composition have the same structure. Formula 4:

(Where
R ₁ and R ₂ are independently H or C ₁ -C ₆ alkyl, each x being 2, 3, 4
Wherein the compound of formula 4 in the purified sample has the same structure, wherein the compound of formula 4 is independently selected from the group consisting of 5 and 6) The following steps:
Formula 5:

Reacting with AcOH containing about 90% HNO ₃ at about 0-5 ° C. for at least 30 minutes, wherein at least about 99% of the compound of formula 4 formed in the purified sample is the same Having a molecular weight of 9. The method of claim 8, wherein each x is 3. 9. The method of claim 8, wherein at least about 99.3% of the compounds of formula 4 in the purified sample have the same structure. The compound of formula 5 is represented by formula 7:

Tosylated compounds of formula 6:

Obtained as a purified sample synthesized by a method comprising the steps of: reacting o-dihydroxybenzene in the presence of KeCO ₃ and an aprotic solvent; 9. The method of claim 8, wherein at least about 98.4% of the compound of formula 5 formed in the sample has the same structure. The aprotic solvent is an aldehyde, ketone, dimethyl sulfoxide, dimethylformamide, pyridine, diethyl ether, ethyl acetate, propyl acetate, isopropyl acetate,
12. The method of claim 11, selected from the group consisting of butyl acetate, acetonitrile, benzonitrile, sulfur dioxide, tetrahydrofuran, and hexamethylphosphoramide. The method of claim 12, wherein the aprotic solvent is tetrahydrofuran. The method of claim 11, wherein each x is 3. 12. The method of claim 11, wherein at least about 99.3% of compounds of formula 5 in the purified sample have the same structure. Formula 1:

(Where
M is a trivalent metal cation selected from the group consisting of Gd ⁺³ and Lu ⁺³ , and each X is OH ⁻ , AcO ⁻ , Cl ⁻ , Br ⁻ , I ⁻ , F ⁻ , H ₂ PO _4. ⁻ , ClO ⁻ , Cl
O ₂ ⁻ , ClO ₃ ⁻ , ClO ₄ ⁻ , HCO ₃ ⁻ , HSO ₄ ⁻ , NO ₃ ⁻ , N ₃ ⁻ , CN ⁻
, SCN ⁻ , and OCN ^−, independently selected from R ₃ , R ₄ , R ₅ , R ₆
, R ₇ , and R ₈ are independently H, OH, C _n H _{(2n + 1)} O _y , or OC _n H
_{(2n + 1)} O _y , R ₁ , R ₂ are independently H or C ₁ -C ₆ alkyl, where R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R _At least one of ₈ is C _n H _{(2n + 1)} O _y or OC _n H _(2n with at least one hydroxyl substituent
₊₁₎ O _y
n is a positive integer of 1 to 11, y is a positive integer of 0 or n, and each x is 2,
A compound of formula 1 in said pharmaceutical composition, wherein said compound is selected from the group consisting of 3, 4, 5, and 6) and a pharmaceutically acceptable carrier A pharmaceutical composition wherein at least about 98.4% of said have the same structure. 17. A pharmaceutical composition according to claim 16, wherein M is Gd ^{+ 3} . R ₄ and R ₇ are C ₃ H ₆ OH, R ₅ and R ₆ are C ₂ H ₅ , R ₃ and R ₈ are CH ₃ , and R ₁ and R ₂ are H 18. A pharmaceutical composition according to claim 17, wherein 19. A pharmaceutical composition according to claim 18, wherein each x is 3. Wherein each X is AcO ^- a pharmaceutical composition according to claim 19. At least about 99.3% of the compounds of Formula 1 in the pharmaceutical composition have the same molecular weight;
The pharmaceutical composition according to claim 16. 17. The pharmaceutical composition of claim 16, wherein at least about 99.3% of the compounds of formula 1 in the pharmaceutical composition have the same structure. 17. A pharmaceutical composition according to claim 16, wherein the pharmaceutically acceptable carrier is suitable for parenteral administration. Effective amount formula 1:

(Where
M is a trivalent metal cation selected from the group consisting of Gd ⁺³ and Lu ⁺³ , and X
Are OH ⁻ , AcO ⁻ , Cl ⁻ , Br ⁻ , I ⁻ , F ⁻ , H ₂ PO ₄ ⁻ , ClO ⁻ , ClO.
_{^{2 -, ClO 3 -, ClO}} 4 -, HCO 3 -, HSO 4 -, NO 3 -, N 3 -, CN -,
Independently selected from the group consisting of SCN ⁻ , and OCN ⁻ , R ₃ , R ₄ , R ₅ , R ₆ ,
R ₇ and R ₈ are independently H, OH, C _n H _{(2n + 1)} O _y , or OC _n H _{(
2n + 1)} O _y and R ₁ , R ₂ are independently H or C ₁ -C ₆ alkyl;
Here, at least one of R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ is C _n H _{(2n + 1)} O _y or OC _n H ₍ with at least one hydroxyl substituent _{). 2n +
1)} O _y
n is a positive integer of 1 to 11, y is a positive integer of 0 or n, and each x is 2,
A compound selected from the group consisting of 3, 4, 5, and 6), or a pharmaceutically acceptable salt, solvate, isomer, tautomer, metabolite, analog, or Treatment of a cancer comprising administering to a human patient in need a purified composition comprising a prodrug, wherein at least about 98.4% of the compound of Formula 1 in the purified composition have the same molecular weight Method. 25. The method of claim 24, wherein M is Gd ^{+ 3} . R ₄ and R ₇ are C ₃ H ₆ OH, R ₅ and R ₆ are C ₂ H ₅ , R ₃ and R ₈ are CH ₃ , and R ₁ and R ₂ are H 26. The method of claim 25, wherein: 27. The method of claim 26, wherein each x is 3. Wherein each X is AcO ^- a A method according to claim 27. At least about 99.3% of the compound of Formula 1 in the purified sample have the same molecular weight;
25. A method according to claim 24. 25. The method of claim 24, wherein at least about 99.3% of compounds of Formula 1 in the purified sample have the same structure. 25. The method of claim 24, further comprising administering to the human patient a further therapy selected from the group consisting of surgery, radiation therapy, chemotherapy, gene therapy, immunotherapy, or combinations thereof. 25. The method of claim 24, wherein the cancer is a metastatic brain tumor.

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