JP2006526567A - Composition for treating and / or preventing diseases characterized by the presence of metal ions - Google Patents

Abstract

The present invention relates generally to the treatment and / or prevention of Alzheimer's disease, other neurodegenerative diseases and / or diseases characterized by the presence of certain metal ions by using certain compositions comprising organosilicon compounds. The composition of the present invention can be administered to a mammal, such as a human. In some cases, the composition can include silanol, silane diol, silane triol, or cyclic organosilane and / or physiological conditions found in blood, stomach and / or gastrointestinal tract or brain or other organs. Silanol, silane diol or silane triol can be formed when exposed to. In some cases, the organosilicon compound may be bound to a moiety that can be transported across the brain-blood barrier into the brain, such as amino acids, peptides, proteins, viruses, and the like. The organosilicon compound may also be labeled (fluorescently or radioactively) in certain examples. In some embodiments, the composition or portion thereof can sequester aluminum or other ions, eg, by electrostatically binding to aluminum ions. The composition also includes other functionalities such as amines, certain alkyl and / or aryl moieties (including substituted alkyl and / or aryl) or hydrophobic moieties, such as through the blood-brain barrier of organosilicon compounds. Can be promoted.

Description

FIELD OF THE INVENTION The present invention is generally used to treat and / or prevent diseases characterized by the presence of metal ions, such as Alzheimer's disease, in particular with certain compositions comprising chelating agents and / or silicon compounds. It relates to treating and / or preventing such diseases.

2. Description of Related Art Many diseases can be characterized by an excess or imbalance of metal ions in the body, eg, organs or tissues. Excess metal ions may in some cases affect protein structure or function, or in certain diseases such as Alzheimer's disease, Parkinson's disease, various homeostatic diseases, cardiac arrhythmias, various central nervous systems ( CNS) disorders, plasma imbalances, dermatitis, Gerstmann-Staeussler-Scheinker disorders, familial insomnia, Menkes syndrome, lead poisoning and other heavy metal toxicity, or various prion diseases such as infection May cause or promote spongiform encephalopathy or Creutzfeldt-Jakob disease. In some cases, excess metal ions can also interfere with ion channel function, protein structure or folding, or enzyme function, which can lead to disease states. For example, many proteins and enzymes use metal ions to stabilize these conformations at or as a reactive site.

  Physiological removal or sequestration of metal ions can be useful in treating such diseases. However, it is known that there are very few biocompatible agents that can bind to ions that can be delivered to a target site. One example of a compound that can bind to ions in the body is ethylenediaminetetraacetic acid (“EDTA”). However, the half-life of EDTA in the body is relatively short. A typical dose of EDTA lasts only about 1 hour in the body, limiting the effectiveness of this form of treatment.

  One disease that can be characterized by excessive amounts of metal ions is Alzheimer's disease. Alzheimer's disease is a common form of senile dementia. Several studies have suggested that 25-50% of all people in their 80s can have Alzheimer's disease. Symptoms of Alzheimer's disease include memory loss, loss of language or cognitive ability, reduced reasoning ability and use of reduced language behavior. Behavioral disturbances can also exist. Changes in brain physiology can also occur, such as enlarged chambers, narrow cortical gyrus, or enlarged grooves. These changes were attributed to nerve loss. Deterioration of mental ability and brain function appears to be irreversible and can ultimately lead to death.

  Alzheimer's disease is actually a family of related neurodegenerative diseases. One feature of Alzheimer's disease and other such neurodegenerative diseases is the emergence and accumulation of fibrillar protein structures, commonly known as neurofibrillary tangles or senile plaques. Neurofilament (NF) protein is one component of neurofibrillary tangles. NF proteins can form filaments that can cause neurofibrillary tangles, for example, when NF proteins are hyperphosphorylated. Beta-amyloid, a protein containing about 42 amino acids, is one of the important components of some senile plaques.

Causes of Alzheimer's disease include genetic factors (eg, certain genes on chromosomes 1, 14, 19 and 21 are associated with increased susceptibility to Alzheimer's disease) or environmental factors that are particularly higher than normal aluminum levels It is. Several studies have shown that increased aluminum concentrations in the brain can be associated with neurofibrillary tangles or senile plaques. Aluminum can appear in complex with, for example, beta-amyloid or neurofilament proteins. One study suggested an association between aluminum found in water supplies and the occurrence of Alzheimer's disease. Aluminum can also originate from pharmaceuticals or other compounds such as antacid tablets. Aluminum can be found in the body in complex with other species, such as organic species, or dissolved in solution (eg, in blood or cerebrospinal fluid). For example, aluminum can be present as Al ³⁺ , Al (OH) ₃ , Al ₂ O _3, Al ₂ (SO ₄ ) _3, etc.

Summary of the Invention The present invention relates generally to the treatment and / or prevention of diseases characterized by the presence of metal ions, such as Alzheimer's disease. The subject matter of the present invention includes, in some cases, a plurality of different uses of interrelated products, alternative solutions and / or one or more systems and / or articles for a particular problem.

  In one aspect, the present invention includes a composition. In one group of embodiments, the composition, or at least a portion thereof, can enter an organ, such as the brain, by transport across the blood-brain barrier. In some cases, the composition also includes a pharmaceutically acceptable carrier.

  In certain embodiments, the composition comprises at least one of silanol, silane diol, silane triol and / or a compound capable of forming at least one of silanol, silane diol, or silane triol upon exposure to physiological conditions. Such compounds can include, for example, halogenated organosilicon compounds or cyclic organosilicon compounds. In some cases, the compound cannot polymerize significantly in solution. In other groups of embodiments, at least 50%, at least 75%, at least 90%, at least 95%, at least 97% or at least 99% of the compounds can maintain the monomer structure in vivo.

式中、Ｚ^１およびＺ^２の各々は、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含み、Ｊ^１およびＪ^２は、各々独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む、
を有する１つの化合物またはこの１つの塩を含む。Ｙ^１およびＹ^２の各々は、ＳｉおよびＮに相互に結合する部分（例えばアルキル部分、アリール部分、環状部分など）である。Ｊ^１０、Ｊ^１１、Ｊ^１２およびＪ^１３の各々は、独立して、Ｈであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む。１つの態様において、Ｊ^１０、Ｊ^１１、Ｊ^１２およびＪ^１３の各々は、独立して、水素、アルキルまたはアリールである。他の態様において、Ｊ^１０、Ｊ^１１、Ｊ^１２およびＪ^１３の少なくとも１つは、３個または４個より多くない炭素原子を有するアルキルである。 In one group of embodiments, the composition has one structure:

Wherein each of Z ¹ and Z ² is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² , wherein R comprises at least one carbon atom and X Is one halogen or one pseudohalogen, R ¹ contains at least one carbon atom and J ¹ and J ² are each independently H or one carbon atom, 1 Containing at least one of one nitrogen atom, one oxygen atom or one sulfur atom,
Or a salt thereof. Each of Y ¹ and Y ² is a moiety (for example, an alkyl moiety, an aryl moiety, or a cyclic moiety) that is bonded to Si and N. Each of J ¹⁰ , J ¹¹ , J ¹² and J ¹³ is independently H or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom. . In one embodiment, each of J ¹⁰ , J ¹¹ , J ¹² and J ¹³ is independently hydrogen, alkyl or aryl. In other embodiments, at least one of J ¹⁰ , J ¹¹ , J ¹² and J ¹³ is an alkyl having no more than 3 or 4 carbon atoms.

を有し、ここで、Ｙ^３は、水素または非水素原子を含むことができる。尚他の態様において、Ｙ^３は、疎水性部分を含む。本明細書中で種々の化学構造を参照して用いる、記号

は、通常の当業者により容易に理解されるように、化学構造が、基本的な化学構造に結合している場合を示す。例えば、前述の構造において、Ｙ^１およびＹ^２の少なくとも１つについて、２つの

の記号は、前述の構造が、それぞれ前述の構造の直前の基本的な化学構造中のＮおよびＳｉに結合する場合を示す。 In still other embodiments, at least one of Y ¹ and Y ² has the structure:

Where Y ³ can include hydrogen or a non-hydrogen atom. In still other embodiments, Y ³ includes a hydrophobic moiety. Symbols used herein with reference to various chemical structures

Indicates the case where the chemical structure is attached to the basic chemical structure, as will be readily understood by those of ordinary skill in the art. For example, in the structure described above, for at least one of ^{Y 1} and ^{Y 2,} the two

This symbol indicates the case where the aforementioned structure is bonded to N and Si in the basic chemical structure immediately before the aforementioned structure, respectively.

式中、Ｚ^１、Ｚ^２およびＺ^３の各々は、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含む、
またはこの塩を有する。Ｊの各々は、独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含み、Ｙは、ＳｉおよびＮに相互に結合する部分（例えばアルキル部分、アリール部分、環状部分など）である。 In another group of embodiments, the composition comprises a silicon compound that includes an aminoalkyl moiety. In one embodiment, the compound has one structure:

Wherein each of Z ¹ , Z ² and Z ³ is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² , wherein R represents at least one carbon atom. X is one halogen or one pseudohalogen and R ¹ contains at least one carbon atom,
Or have this salt. Each of J is independently H or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom, and Y is bonded to Si and N to each other (For example, an alkyl part, an aryl part, a cyclic part, etc.).

式中、Ｚ^１、Ｚ^２、Ｚ^３およびＺ^４の各々は、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含み、Ｊ^１およびＪ^２は、各々独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む、
を有する１つの化合物またはこの１つの塩を含む。化合物は、少なくとも１個の炭素原子を含むことができ、即ち、Ｚ^１、Ｚ^２、Ｚ^３およびＺ^４の少なくとも１つは、少なくとも１個の炭素原子を含む。ある態様において、Ｚ^１、Ｚ^２、Ｚ^３およびＺ^４は、すべて同時には、ＨまたはＲの１つではなく；Ｚ^１、Ｚ^２、Ｚ^３およびＺ^４は、すべて同時には、酢酸塩ではない。 In yet another group of embodiments, the composition of the present invention has the structure:

Wherein each of Z ¹ , Z ² , Z ³ and Z ⁴ is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² , wherein R is at least one Contains carbon atoms, X is one halogen or one pseudohalogen, R ¹ contains at least one carbon atom, and J ¹ and J ² are each independently H, or Contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom,
Or a salt thereof. The compound can contain at least one carbon atom, ie, at least one of Z ¹ , Z ² , Z ³ and Z ⁴ contains at least one carbon atom. In some embodiments, Z ¹ , Z ² , Z ³ and Z ⁴ are not simultaneously one of H or R; Z ¹ , Z ² , Z ³ and Z ⁴ are all simultaneously Absent.

式中、Ｚ^１およびＺ^２の各々は、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含み、Ｊ^１およびＪ^２は、各々独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む、
またはこの１つの塩を有することができる。この構造において、Ａは、炭素原子およびケイ素原子の少なくとも１つを含む部分である。Ｅ^１およびＥ^２の各々は（適用可能である場合には）、独立して、（ａ）ＯおよびＮＪ^３の１つ、または（ｂ）Ｓｉが部分Ａに共有結合するように不存在のいずれかである。Ｊ^３は、Ｈであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む。ある例において、Ｅ^１およびＥ^２は（適用可能である場合には）、共に不存在ではない。 In another group of embodiments, the compound has one structure, for example:

Wherein each of Z ¹ and Z ² is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² , wherein R comprises at least one carbon atom and X Is one halogen or one pseudohalogen, R ¹ contains at least one carbon atom and J ¹ and J ² are each independently H or one carbon atom, 1 Containing at least one of one nitrogen atom, one oxygen atom or one sulfur atom,
Or you can have this one salt. In this structure, A is a moiety containing at least one of a carbon atom and a silicon atom. Each of E ¹ and E ² (if applicable) is independently absent (a) one of O and NJ ³ or (b) Si is covalently bonded to moiety A Either. J ³ is H or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom. In certain instances, E ¹ and E ² (if applicable) are not both absent.

を有することができる。これらの構造において、各々のＡは、独立して、炭素原子およびケイ素原子の少なくとも１個を有する部分であり、各々のＺは、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含み、Ｊ^１およびＪ^２は、各々独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む。いくつかの場合において、組成物は、前述の構造のすべての塩を含むことができる。 In yet another group of embodiments, the composition of the present invention comprises a cyclic organosilicon compound, i.e., a cyclic organic compound containing at least one silicon atom. For example, a cyclic organosilicon compound has one structure:

Can have. In these structures, each A is independently a moiety having at least one of a carbon atom and a silicon atom, and each Z is independently H, X, R, OH, OR ¹ or NJ ¹ J ² , R contains at least one carbon atom, X is one halogen or one pseudohalogen, R ¹ contains at least one carbon atom, J ¹ and J ² are each independently H or contain at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom. In some cases, the composition can include all salts of the foregoing structure.

式中、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６の各々は、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含み、Ｊ^１およびＪ^２は、各々独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む、
またはこの１つの塩を有する。他の態様において、この組成物は、少なくとも１個のケイ素原子を含む繰り返し単位を有するポリマーを含む。 In yet another group of embodiments, the composition of the present invention comprises a compound having at least two silicon atoms. In one embodiment, the compound has one structure:

Wherein each of Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² , R Contains at least one carbon atom, X is one halogen or one pseudohalogen, R ¹ contains at least one carbon atom, and J ¹ and J ² are each independently H or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom,
Or have this one salt. In other embodiments, the composition comprises a polymer having a repeating unit comprising at least one silicon atom.

式中、Ｙ、Ｙ^１およびＹ^２の各々は、独立して、少なくとも１個の炭素原子を含む相互に結合する部分（例えばアルキル部分、アリール部分、環状部分など）であり、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６の各々は、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含み、Ｊ^１およびＪ^２は、各々独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む、
またはこの１つの塩を有することができる。Ｅ^１、Ｅ^２、Ｅ^３およびＥ^４の各々は、独立して、（ａ）ＯおよびＮＪ^３の１つ、または（ｂ）ＳｉがＹ部分に共有結合するように不存在のいずれかである。Ｊ^３は、Ｈであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含むことができる。典型的には、少なくとも１つのＥ部分が、構造内に存在する。 In still other embodiments, the compound has one structure, for example:

Wherein each of Y, Y ¹ and Y ² is independently a mutually linked moiety containing at least one carbon atom (eg, an alkyl moiety, an aryl moiety, a cyclic moiety, etc.), and Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ are each independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² , where R is at least one carbon Containing atoms, X is one halogen or one pseudohalogen, R ¹ contains at least one carbon atom, and J ¹ and J ² are each independently H or 1 Contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom,
Or you can have this one salt. Each of E ¹ , E ² , E ³ and E ⁴ is independently either (a) one of O and NJ ³ or (b) absent in the presence of Si covalently bonded to the Y moiety. is there. J ³ can be H or contain at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom. Typically, at least one E moiety is present in the structure.

式中、Ｘは、アルミニウムもしくは他の金属イオンに結合することができる１つのキレート剤であるか、またはアルミニウムもしくは他の金属イオンに結合することができる１つのキレート剤を形成することができる、
を有する。さらに、Ｙは、血液−脳障壁を横断しての化合物（またはこの一部）の輸送を促進することができる構造であり、構造

は、少なくとも１つの化学結合を含み、構造−は、生理学的条件下で、例えば脳内で、または血流内で、例えばＯＨに加水分解され得る部分である。いくつかの場合において、キレート剤は、イオンに結合するか、または他の方法では固定することができるすべての剤であってもよく、例えば、従って、これは、溶液中で遊離のままである代わりにキレート剤に複合するか、または他の方法で結合する。 In another group of embodiments, the compounds of the invention can bind to aluminum or other metal ions (or can form chelating agents that can bind to aluminum or other metal ions). Contains a chelating agent. In one embodiment, the compounds of the invention have one structure:

Wherein X is one chelator that can bind to aluminum or other metal ions, or can form one chelator that can bind to aluminum or other metal ions.
Have Furthermore, Y is a structure capable of facilitating the transport of the compound (or part thereof) across the blood-brain barrier,

Contains at least one chemical bond, and the structure is a moiety that can be hydrolyzed, for example to OH, under physiological conditions, for example in the brain or in the bloodstream. In some cases, the chelator may be any agent that can bind to ions or otherwise be immobilized, for example, it thus remains free in solution. Instead, it is conjugated to the chelator or otherwise bound.

  In another aspect, the present invention is a method. In one group of embodiments, the method provides the subject with a silanol compound, a silanediol compound, a silanetriol compound, a cyclic organosilicon compound and / or within the subject, a silanol compound, a silanediol compound or a silanetriol compound. Administering a therapeutically effective amount of a composition comprising at least one compound capable of being hydrolyzed to at least one of the following. In another group of embodiments, the method comprises administering to the subject one or more of the aforementioned compounds. In some cases, the subject is susceptible to or exhibits this sign of Alzheimer's disease. In other cases, the subject is susceptible to or displays signs of a disease characterized by excessive amounts of ions, such as metal ions. In some cases, the subject does not require treatment with the composition in other ways. For example, a subject may not need to have a disease that can be treated by inhibition of leukocyte elastase.

  In some embodiments, the compounds of the present invention can bind to (or otherwise interact with) aluminum and / or other metal ions, such as divalent or trivalent metal ions. And / or can be hydrolyzed within the subject to form a compound that can bind to aluminum and / or other metal ions. In some embodiments, the organosilicon compound or at least a portion thereof can enter an organ, such as the brain, by transport across the blood-brain barrier. However, in other embodiments, organosilicon compounds cannot enter an organ, such as the brain, and instead remain in the circulation in the bloodstream, for example before they enter the brain or other organ. In addition, the aluminum or other ions in the blood are removed or sequestered. The composition can also include a pharmaceutically acceptable carrier in some cases.

式中、Ｚ^１、Ｚ^２およびＺ^３の各々は、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含み、Ｊ^１およびＪ^２は、各々独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む、
を有する化合物またはこの１つの塩を含む治療的に有効な量の組成物を投与することを含む。明確化のために、本明細書中に記載した化学構造、例えば前述の化学構造のすべてにおいて、ケイ素に結合している原子のすべてを描写しているわけではない。いくつかの場合において、被検者は、アルツハイマー病または過剰量の金属イオンにより特徴づけられる他の疾患を罹患しやすいか、またはこの徴候を示す。構造

は、化合物が、被検者内に、例えば活性部位に位置する際には、正に帯電していることができる化合物の一部を示す。１つの態様において、被検者は、他の方法では、組成物での処置を必要としない。他の態様において、構造

は、化合物またはこの少なくとも一部が、器官中に進入するか、または血液−脳障壁を横断することを可能にする構造を有する化合物の一部である。 In another group of embodiments, the method provides the subject with one of the following structures:

Wherein each of Z ¹ , Z ² and Z ³ is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² , wherein R represents at least one carbon atom. X is one halogen or one pseudohalogen, R ¹ contains at least one carbon atom, and J ¹ and J ² are each independently H or one carbon Contains at least one of an atom, a nitrogen atom, an oxygen atom or a sulfur atom,
Administering a therapeutically effective amount of a composition comprising a compound having the formula: or a salt thereof. For clarity, not all of the atoms bonded to silicon are depicted in the chemical structures described herein, eg, all of the aforementioned chemical structures. In some cases, the subject is susceptible to or exhibits Alzheimer's disease or other diseases characterized by excessive amounts of metal ions. Construction

Indicates a portion of the compound that can be positively charged when the compound is located within the subject, eg, in the active site. In one embodiment, the subject does not require treatment with the composition otherwise. In other embodiments, the structure

Is a part of the compound or a compound having a structure that allows at least a part thereof to enter the organ or cross the blood-brain barrier.

  In one group of embodiments, the method provides the subject with a form capable of binding to aluminum and / or other metal ions, such as divalent or trivalent metal ions, within the subject. Administering a composition comprising a compound that can be converted, for example, by hydrolysis. In another group of embodiments, the method provides the subject with a therapeutically effective compound that includes a compound that can cross the blood-brain barrier and / or bind to aluminum and / or other metal ions. Administering an amount of the composition.

  In another group of embodiments, the method comprises administering to the subject a therapeutically effective amount of one composition comprising a compound containing at least two silicon atoms in the molecular structure of the compound. including. In one embodiment, the compound has at least about 100 g / mol, at least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at least about 500 g / mol, at least about 600 g / mol, at least about 700 g / mol. , At least about 800 g / mol, at least about 900 g / mol, at least about 1000 g / mol, or in some cases higher molecular weights. In other embodiments, the compound is a salt.

  In yet another group of embodiments, the method comprises administering to the subject a therapeutically effective amount of one composition comprising a compound having silicon and nitrogen atoms in the molecular structure of the compound. including.

  In yet another group of embodiments, the method is a method of chelating a metal in vivo. In one embodiment, the method comprises administering to the subject a therapeutically effective amount of a composition comprising a silicon polymer and in some cases a pharmaceutically acceptable carrier. In some examples, the silicon polymer may be hydroxylated and / or halogenated.

  In another group of embodiments, the method comprises the function of a protein having a non-functional or dysfunctional conformation (ie, functionalization below physiologically normal levels) into a functional conformation. It is a way to promote reversal. This method, in one embodiment, introduces a compound comprising silicon into a subject, wherein the subject has a protein, lipid or sugar attached to one or more metal atoms. Have or are suspected of having a disease or condition characterized by Proteins, lipids or sugars can have a non-functional or dysfunctional conformation when attached in this way to one or more metal atoms. The method can also include allowing at least some of the metal atoms to be transferred from the protein, lipid or sugar to the silicon compound. In some cases, the silicon polymer may be hydroxylated and / or halogenated.

式中、Ｚ^１、Ｚ^２、Ｚ^３およびＺ^４の各々は、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含み、Ｊ^１およびＪ^２は、各々独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む、
を有する１つの化合物またはこの１つの塩を含む。いくつかの場合において、Ｚ^１、Ｚ^２、Ｚ^３およびＺ^４の１つ、２つ、３つまたは４つは、各々ＯＨおよび／または酢酸塩であってもよい。他の態様において、この組成物は、ケイ酸塩、例えばケイ酸ナトリウムおよび／またはメタケイ酸塩、例えばメタケイ酸ナトリウムなどを含む。尚他の態様において、この組成物は、ケイ素塩を含む。 In yet another group of embodiments, the method comprises a therapeutically effective amount of 1 comprising a compound having a silicon atom in the nervous system of a subject susceptible to or exhibiting Alzheimer's disease. Administration of one composition. In one embodiment, the composition has one structure:

Wherein each of Z ¹ , Z ² , Z ³ and Z ⁴ is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² , wherein R is at least one Contains carbon atoms, X is one halogen or one pseudohalogen, R ¹ contains at least one carbon atom, and J ¹ and J ² are each independently H, or Contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom,
Or a salt thereof. In some cases, one, two, three or four of Z ¹ , Z ² , Z ³ and Z ⁴ may each be OH and / or acetate. In other embodiments, the composition comprises a silicate, such as sodium silicate and / or a metasilicate, such as sodium metasilicate. In yet other embodiments, the composition includes a silicon salt.

  In another aspect, the invention includes the use of the composition in the manufacture of a medicament for treating a disease characterized by the presence of metal ions, such as Alzheimer's disease. In one group of embodiments, the composition comprises one or more compounds as described above. Methods for treating a subject with a composition are described throughout the specification, and the invention also relates, in another aspect, to the composition in the manufacture of a medicament for treating a subject. It should be understood to include the use of

  In yet another aspect, the present invention relates to a method for making all of the embodiments described herein. In yet another aspect, the present invention relates to a method of using all of the embodiments described herein. In another aspect, the present invention relates to a method that facilitates all of the embodiments described herein.

  Other advantages, novel features and objects of the invention are non-limiting when considered in connection with the accompanying drawings, which are schematic and are not intended to be drawn to scale. It will be apparent from the following detailed description of embodiments. In the drawings, each identical or nearly identical component that is illustrated in various figures is represented by a single numeral. For purposes of clarity, not all components are labeled in all drawings, and not all components of each embodiment of the invention are shown, where the illustrations are It is not necessary to allow those skilled in the art to understand the present invention. In cases where the present specification and a document incorporated by reference include conflicting disclosure, the present specification shall control.

BRIEF DESCRIPTION OF THE DRAWINGS Non-limiting embodiments of the present invention will now be described by way of example with reference to the accompanying drawings, in which:
FIG. 1 illustrates a neurofilament sequence (SEQ ID NO: 1);
2A-2U illustrate various chemical structures useful in the present invention;

3A-3D illustrate the effect of sodium metasilicate hydrate on the neurofilament of FIG. 1 as shown by circular dichroism (CD) data plotted as ellipticity versus wavelength;
4A-4E illustrate the effect of sodium orthosilicate on the neurofilament of FIG. 1 as shown by CD data;
5A-5F illustrate the effect of 3-aminopropylsilanetriol on the neurofilament of FIG. 1 as shown by CD data;
6A-6D illustrate comparative CD data for sodium orthosilicate vs. 3-aminopropylsilanetriol;

7A-7D illustrate the effect of 3-cyanopropyltrichlorosilane on the neurofilament of FIG. 1 as shown by CD data;
8A-8D illustrate the effect of hexylmethyldichlorosilane on the neurofilament of FIG. 1 as shown by CD data;
9A-9D illustrate the effect of methylphenyldichlorosilane on the neurofilament of FIG. 1 as shown by CD data;
10A-10D illustrate the effect of dichlorodiethylsilane on the neurofilament of FIG. 1 as shown by CD data;
FIGS. 11A-11E illustrate the effect of dichlorodiisopropylsilane on the neurofilament of FIG. 1 as shown by CD data;
12A-12E illustrate the effect of (dichloro) methylsilylbutyronitrile on the neurofilament of FIG. 1 as shown by CD data;

FIG. 13 illustrates the effect of aluminum on human amyloid beta protein, exemplified by CD data;
FIG. 14 illustrates the effect of 3-cyanopropyltrichlorosilane on amyloid protein, exemplified by CD data;
FIG. 15 illustrates the effect of dichlorodiethylsilane on amyloid protein, exemplified by CD data;
FIG. 16 illustrates the effect of dichlorodiisopropylsilane on amyloid protein, exemplified by CD data;
FIG. 17 illustrates the effect of (dichloro) ethylmethylsilane on amyloid protein, exemplified by CD data;
FIG. 18 illustrates the effect of hexylmethyldichlorosilane on amyloid protein, exemplified by CD data;
FIG. 19 illustrates the effect of (dichloro) methylsilylbutyronitrile on amyloid protein, exemplified by CD data;
FIG. 20 illustrates the effect of dichlorosilacyclobutane on amyloid protein, exemplified by CD data;
FIG. 21 illustrates the effect of 1,7-dioxa-6-sila-spiro [5.5] undecane on amyloid protein, exemplified by CD data;
FIG. 22 illustrates the effect of sodium orthosilicate on amyloid protein, exemplified by CD data;
FIG. 23 illustrates the effect of triethoxysilylbutyronitrile on amyloid protein, exemplified by CD data;
FIG. 24 illustrates the effect of triethoxysilylpropionitrile on amyloid protein, exemplified by CD data;
FIG. 25 illustrates the effect of trihydroxysilylpropylmethyl phosphonate on amyloid protein, exemplified by CD data;
FIG. 26 illustrates the effect of triethylsilanol on amyloid protein, exemplified by CD data;
FIG. 27 illustrates the effect of tetrakis (dimethylamino) silane on amyloid protein, exemplified by CD data;
FIG. 28 illustrates the effect of tetraacetoxysilane on amyloid protein, exemplified by CD data;

Figures 29A-29B illustrate the transport of certain organosilicon compounds of the present invention across Caco-2 cells;
FIG. 30 illustrates the molecular transport of certain organosilicon compounds of the present invention across bMVEC cells.

DETAILED DESCRIPTION The present invention generally treats Alzheimer's disease, other neurodegenerative diseases and / or diseases characterized by the presence of certain metal ions by using certain compositions comprising organosilicon compounds and / or Relating to preventing. The compositions of the present invention can be administered to animals, such as humans. In some cases, the composition can include silanol, silanediol, silanetriol, or cyclic organosilane, and / or, for example, in the blood, stomach and / or gastrointestinal tract, or in the brain or other organs. Silanol, silane diol or silane triol can be formed by exposure to the physiological conditions found in. In some cases, organosilicon compounds can bind to moieties that can be transported across the blood-brain barrier into the brain, such as amino acids, peptides, proteins, viruses, and the like. The organosilicon compound can also be labeled (eg, fluorescently or radioactively) in certain instances. In some embodiments, the composition or portion thereof can be sequestered by electrostatically binding aluminum or other ions to, for example, aluminum ions. The composition also includes other functionalities such as amines, certain alkyl and / or aryl moieties (including substituted alkyl and / or aryl), or hydrophobic moieties, such as across the blood-brain barrier. Transport of all organosilicon compounds can be facilitated.

  The following application is incorporated herein by reference: US Pat. No. 5,523,295 by GD Fasman, published Jun. 4, 1996, entitled “Methods for Treating and Preventing Alzheimer's Disease”; O. Friedman, US Provisional Patent Application No. 60 / 427,203 by et al., filed Nov. 18, 2002, entitled “Composition for Treating and Preventing Alzheimer's Disease”; US Provisional Patent Application by O. Friedman, et al. 60 / 427,105, filed Nov. 18, 2002, entitled “Composition for treating and preventing Alzheimer's disease”; US Provisional Patent Application No. 60 / 427,104, November 2002 by O. Friedman, et al. Filed 18 days, entitled “Composition for Treating and Preventing Alzheimer's Disease”; US Provisional Patent Application No. 60 / 427,201, filed Nov. 18, 2002, entitled “Chelating Agent” by O. Friedman, et al. And O. Friedman, et al. According to U.S. Provisional Patent Application No. 60 / 456,345, March 20, 2003 filed, entitled "composition for treating and preventing diseases characterized by the presence of metal ions."

  The indefinite articles "a" and "an" as used herein and in the claims are understood to mean "at least one" unless clearly indicated otherwise. It should be.

  As used herein, “or” is understood to mean inclusive, ie including at least one of a list of many elements, but including more than one. In contrast, terms that are clearly indicated, such as “exclusive” or “exactly one”, mean that only one element of a list of many elements is included.

  The term “determining” as used herein generally means analyzing a species, eg, quantitatively or qualitatively, and / or detecting the presence or absence of a species. “Determine” also refers to analyzing an interaction between two or more species, eg, quantitatively or qualitatively and / or by detecting the presence or absence of an interaction. Can mean.

  As used herein, a substance uses an intrinsically useful transport process, such as diffusion or some endogenous transport system, from the blood to the brain or central nervous system, in vivo, under physiological conditions. "Is able to cross the blood-brain barrier". For example, a composition (or portion thereof) of the invention can comprise a sugar or peptide and / or as a substrate (ie, a mimic) in a sugar- and / or peptide transport system of the blood-brain barrier. Can be substituted (eg, endogenous transport protein), thus allowing transport of the composition across the blood-brain barrier to occur. “Blood-brain barrier” as used herein refers to this normal meaning used in the industry, ie, the cellular barrier that separates blood flow from the “nervous system” including the spinal cord, ie, the brain and central nervous system. Indicates.

  As used herein, “treatment of Alzheimer's disease” includes preventing, stopping, altering and / or reversing neurofibrillary tangles and / or senile plaque formation in the brain. `` Needs '' subjects, i.e. subjects with signs of Alzheimer's disease, subjects who are predisposed to Alzheimer's disease or otherwise at this increased risk, or are not showing signs of Alzheimer's disease However, it can be performed on a subject from whom it is desirable to reduce the risk of Alzheimer's disease (eg, vaccination or prophylactic treatment). As used herein, the term “patient” or “subject” refers to mammals such as humans and non-human mammals such as non-human primates, cows, horses, pigs, sheep, goats, dogs, cats, rabbits or animals. Includes a rodent such as a mouse or a rat.

  That any composition or method described herein with reference to Alzheimer's disease can also be used in some cases to treat other diseases characterized by excess metal ions. Should be understood. As used herein, diseases characterized by excessive amounts of ions include all diseases in which excessive amounts of ions (eg, metal ions) in a body organ or system can lead to health related problems. . Examples of such ions include, but are not limited to, iron, lead, aluminum, magnesium, calcium, mercury, strontium, beryllium, cobalt, zinc, nickel, arsenic, and the like. The ions can be divalent or trivalent (ie, have a net charge of ± 2 or ± 3, respectively) in certain examples. In some cases, the disease can result in abnormally folded proteins due to the presence of excess amounts of ions. In one example, Alzheimer's disease can be characterized by excessive amounts of aluminum ions in the brain.

  Other brain diseases that can be characterized by excessive amounts of ions include, for example, certain prion diseases such as infectious spongiform encephalopathy or Creutzfeldt-Jakob disease. Other diseases involving excessive amounts of ions such as metal ions include Parkinson's disease, various homeostatic diseases, cardiac arrhythmias, various central nervous system (CNS) disorders, plasma imbalance, dermatitis, Gerstmann-Stausler -Includes Schainker disorder, familial insomnia, Menkes syndrome or heavy metal toxicity or poisoning. In some cases, the disease can be caused by environmental factors such as excess ions from the environment, such as aluminum, lead or iron. In other cases, disease ions can be generated by meals, drinking water, and the like. The organ or system may be any organ or system in the body, such as in the bloodstream, brain, liver, kidney, skin, adipose tissue, and the like. Other diseases characterized by excessive amounts of ions can be readily identified by those of ordinary skill in the relevant arts.

を有する。この構造において、Ｒは、すべての好適な部分であってもよく；例えば、Ｒは、水素原子、メチルまたはイソプロピルであってもよい。１つのアミノ酸のＮＨ_２が次のアミノ酸のＣＯＯＨと反応して、ペプチド（−ＮＨ−Ｃ（Ｏ））結合を形成することにより、一連のアミノ酸を結合させて、ペプチドまたはタンパク質を形成することができる。アミノ酸は、天然のアミノ酸または天然でないアミノ酸であってもよい。本明細書中で用いる「天然のアミノ酸」は、本質的に一般的に見出される２０種のアミノ酸、即ちアラニン、アルギニン、アスパラギン、アスパラギン酸、システイン、グルタミン、グルタミン酸、グリシン、ヒスチジン、イソロイシン、ロイシン、リジン、メチオニン、フェニルアラニン、プロリン、セリン、スレオニン、トリプトファン、チロシンおよびバリンである。逆に、「天然でないアミノ酸」は、前述の構造に相当し、ここで、Ｒ部分が、２０種の天然のアミノ酸の１種に相当しないアミノ酸である。いくつかの場合において、アミノ酸はまた、ある様式で誘導体化されていてもよい。例えば、アミノ酸は、アミド化、エステル化されていてもよく、側方の部分は、アミノ酸などに結合していてもよい。他のアミノ酸誘導体化反応は、通常の当業者に知られている。 As used herein, “amino acid” has its ordinary meaning used in the field of biochemistry. Amino acids typically have the structure:

Have In this structure, R may be any suitable moiety; for example, R may be a hydrogen atom, methyl or isopropyl. NH _{2 of} one amino acid reacts with COOH of the next amino acid to form a peptide (—NH—C (O)) bond, thereby joining a series of amino acids to form a peptide or protein. it can. The amino acid may be a natural amino acid or a non-natural amino acid. As used herein, “natural amino acids” are essentially the 20 amino acids commonly found: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, Lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. Conversely, an “unnatural amino acid” corresponds to the structure described above, where the R moiety is an amino acid that does not correspond to one of the 20 natural amino acids. In some cases, the amino acids may also be derivatized in some manner. For example, the amino acid may be amidated or esterified, and the side portion may be bound to an amino acid or the like. Other amino acid derivatization reactions are known to those of ordinary skill in the art.

  As used herein, “alkyl” refers to its usual meaning as used in the field of organic chemistry. The alkyl or aliphatic moiety can contain many carbon atoms. This moiety can contain, for example, 1 to 15 carbon atoms, 1 to 10 carbon atoms, or 1 to 5 carbon atoms. In some embodiments, the alkyl moiety has fewer than 10 carbon atoms, fewer than 6 carbon atoms, fewer than 5 carbon atoms, fewer than 4 carbon atoms, or fewer than 3 carbon atoms. In some embodiments of the invention, alkyl chains having a certain size can be used to control the hydrophobicity of the composition. A carbon atom in the alkyl moiety in a suitable form, for example linear (ie n-alkyl, eg methyl (“Me”), ethyl (“Et”), propyl (“Pr”), butyl (“Bu” ), Pentyl (“Pe”) or hexyl (“Hx”), or branched (eg, a tert-butyl moiety, or an isoalkyl moiety, such as an isopropyl moiety).

  The alkyl moiety can include zero or one or more double or triple bonds within the structure, for example, as an alkene, alkyne, alkadiene, alkadiyne, alkynene, and the like. The alkyl moiety can also include substituents in some cases. For example, the alkyl moiety can be halogen, alkoxy (eg, methoxy, ethoxy or propoxy), amine (eg, primary, secondary, tertiary or quaternary amine), ether, carbonyl (eg, acetyl (“Ac”) moiety) or water. An oxide can be included as a substituent (ie, “substituted alkyl”). If more than one substituent is present, each substituent may be the same or different. In some cases, the alkyl moiety contains only carbon and hydrogen atoms; however, in other cases, the atoms within the alkyl moiety are also nitrogen, oxygen, sulfur, silicon, or any other suitable Atoms can be included.

  Similarly, a “cyclic” moiety as used herein includes this conventional definition used in the field of organic chemistry, ie, includes at least one ring of atoms and includes more than one ring of atoms. The part that can be done is shown. That is, the cyclic portion has at least one chain of atoms that does not have a terminal end. The chain can have, for example, three, four, five, six, seven, eight, nine, ten, or eleven or more atoms arranged in a ring. In some embodiments, the cyclic portion has a maximum size of at most 10 atoms, at most 8 atoms, or at most 7 atoms. In some cases, the cyclic moiety includes only carbon atoms in the ring of the cyclic moiety; however, in other cases, the atoms in the ring also include nitrogen, oxygen, sulfur, silicon, or at least It can include all other atoms that can be covalently bonded to two different atoms (ie, a “heterocyclic” moiety).

  Where the cyclic moiety includes more than one ring, the rings may be arranged in all orientations relative to each other, for example, the rings are fused (ie, at least two rings are common) It may be more than one atom (eg bicyclic moiety, tricyclic moiety, etc.), spiro (ie two rings have only one common atom), , May be substituted on other rings, two or more rings may be linked by an alkyl moiety, and the like. Cyclic moieties can include zero or one or more double or triple bonds within the structure, for example as cycloalkenes, cycloalkynes, cycloalkadienes, aromatic moieties, and the like. The term “aromatic” or “aryl” moiety indicates their usual meaning as used in the industry, for example, where at least two or more atoms of this moiety are delocalized pi. Involved in binding. An aryl moiety that includes one or more non-carbon atoms (eg, nitrogen) that participate in a delocalized pi bond is a “heteroaryl” moiety.

  As used herein, “silicon compound” includes all chemical compounds containing at least one silicon atom. The silicon compound may be water-soluble, fat-soluble, or exhibit amphiphilic properties, for example when placed in a subject. As used herein, an “organosilicon compound” refers to at least one silicon atom bonded to an organic moiety, such as an alkyl, aryl, alkoxy, cycloalkyl, amine (first, second, third, or fourth). It is a compound containing. An “organosilicon composition” includes at least one organosilicon compound and includes other compounds such as other physiologically active compounds and / or pharmaceutically acceptable carriers such as those further described below. It can be included as well. In some embodiments, the silicon atoms in the organosilicon compound may be hypercoordinate (ie, the silicon atoms may have a valence of 5 or 6).

  In one group of embodiments, the silicon compound comprises one or more “hydrolyzable” moieties (eg, under physiological conditions, simultaneously and / or by metabolic processes, eg, to the hydroxide moiety. Moieties that can be hydrolyzed), such as halogens, hydroxides, alkoxides, esters, ethers, and the like. Examples include, but are not limited to, halosilane, dihalosilane, trihalosilane, silanol, dihalosilanol, halosilanediol, silanetriol, halosilanol and the like. The terms “silanol”, “silanediol” and “halosilane” have their usual meanings used in the field of chemistry. For example, “silane diol” is a compound containing two hydroxide moieties covalently bonded to a silicon atom, and “silane triol” is a compound containing three hydroxide moieties covalently bonded to a silicon atom.

  Similarly, a “dihalosilane” (eg, dichlorosilane or bromochlorosilane) is a compound containing two halogen atoms (as defined further below) each bonded to a silicon atom (ie, where the halogen atom is , Which may be the same or different), are “halosilanols”, which are compounds that contain halogen and hydroxide moieties each bonded to a silicon atom within the compound. The terms such as “trihalosilane”, “dihalosilanol” and “halodisilanol” are defined similarly. The term “halogen” (or “halo-”) as used herein includes atoms of the halogen group commonly used in the chemical arts (eg, fluorine, chlorine, bromine or iodine). As used herein, a “pseudohalogen” is a moiety that is not a halogen atom but has properties similar to a halogen compound. Examples of pseudohalogens include CN, SCN, NCO, etc. and other hydrolyzable moieties that can form labile bonds with silicon (eg, imidazole, triazole, tetrazole, etc.). In many cases, the pseudohalogen moiety can be replaced with a halogen atom in all the structures described herein.

  The organosilicon compounds of the present invention, in one group of embodiments, comprise ions such as aluminum ions and physiological (or neurological) components of the brain or other organs such as beta-amyloid or other amyloid compounds, neurofilament proteins. Etc. can be inhibited and / or reversed. For example, one type of amyloid protein can be found in liver or muscle tissue. The compound can inhibit and / or reverse such interactions throughout the body, for example, in the brain or other organs, in the blood-brain barrier, in the bloodstream, and the like. The term “inhibits” includes inhibition that occurs before and / or after aluminum (or other metal ions) are complexed with a component. Inhibition may be partial or complete inhibition. One simple test illustrating the efficacy of the composition of the present invention is to add the composition to a solution containing ingredients, such as a suitable disease marker, when the added composition is exposed to aluminum. To determine whether changes in the structure and / or conformation of the component or marker can be prevented or reduced.

By way of example, for Alzheimer's disease, a suitable marker for the disease may be beta-amyloid or neurofilament protein (or cells capable of producing beta-amyloid or neurofilament protein) that are sensitive to aluminum, That is, here the structure and / or conformation of the marker changes upon exposure to aluminum. The composition can be added before or after the marker is exposed to aluminum or other ions. An example of this process is described in Example 1. Those of ordinary skill in the art will use “aluminum” as used herein in all forms of aluminum that can be found in the body, such as aluminum particles, aluminum oxide particles, aluminum ions (Al ³⁺ ), Al (OH) _3. , Al ₂ O ₃ , Al ₂ (SO ₄ ) _3, etc. Aluminum dissolves in all environmental sources such as drinking water; aluminum pots, pans, pipes, tools or tools; dust; medical device components; medications; jewelry; aerosols; deodorants and skin Other products applied; may come from aluminum cans etc.

  However, in some embodiments, the organosilicon compounds of the present invention are unable to enter the brain or other organs. In some embodiments, the organosilicon compounds can remain where they have been introduced into the body, or the organosilicon compounds can remain in circulation in the bloodstream. In one example, if the compound is injected directly into the brain (eg, as described further below), the compound cannot cross the blood-brain barrier and therefore remains in the brain. There are cases where it is possible. As another example, the compounds of the present invention are introduced into the systemic circulation to remove or sequester aluminum or other ions in the blood before they enter the brain or other organs. can do.

  The composition of the invention, in one group of embodiments, is administered to a subject to treat (eg, reverse), prevent and / or form and / or grow neurofibrillary tangles or senile plaques in the brain. Can be reduced. In humans with Alzheimer's disease or other neurodegenerative diseases, beta-amyloid and / or neurofilament proteins found in senile plaques and neurofibrillary tangles are in some cases phosphorylated and / or metal ions Deduced, eg complexed in the presence of aluminum, and / or dysfunctional or non-functional conformation (eg a structure lacking appropriate activity or a disease state), eg a beta-sheet obtain. Beta-sheets or other non-functional / dysfunctional conformations within these proteins can render beta-amyloid and / or neurofilament proteins insoluble and / or precipitate, thereby causing neurogens in the brain. Fibrous changes and / or senile plaque formation can result.

  In one group of embodiments, the compositions of the invention can bind to ions in the body, such as metal ions, or otherwise sequester. In one group of embodiments, the ions are divalent or trivalent. Ions can be present in excessive concentrations (eg, significantly higher than physiologically desirable concentrations) in the body or in an organ or system within the body. In some cases, the composition can sequester the ions by interaction of the ions with, for example, an oppositely charged portion of the composition.

  In some cases, the composition may allow molecules or structures affected by excess metal ions to return to this initial conformation, or the composition may, for example, contain excess metal ions. The presence of can prevent the formation of non-functional or deformed structures, such as in denatured or improperly folded or composed proteins. Thus, the compositions of the present invention can be determined, such as by their ability to allow a molecule or structure to return to this initial conformation. The composition can bind to and / or sequester excess amounts of ions, which can prevent, inhibit and / or reduce the interaction of ions with molecules or structures. For example, the presence of the composition of the invention in the brain allows certain neurofilament proteins to return to their original functional structure and / or beta-sheet conformation within the neurofilament protein. Or the formation of other functional or dysfunctional structures can be prevented.

  Organosilicon compounds can also bind to all aluminum (or other metal ions) present in the brain or other organs, thereby preventing at least some sequestering of aluminum or other metal ions. The interaction of aluminum with other components of the brain or other organs such as beta-amyloid or neurofilament proteins can be prevented and / or reduced. The interaction of the composition with aluminum or other metal ions can be, for example, ionic interactions, hydrogen bonding interactions, van der Waals interactions, metal ligand interactions, coordination interactions, hydrophobic interactions and / or Alternatively, a combination thereof may be used.

  The extent of such binding can be determined by one of ordinary skill in the art; for example, the organosilicon composition of the present invention is mixed with a solution containing a known concentration of aluminum ions or other metal ions to release free in solution. The resulting decrease in the concentration of aluminum or other metal ions (if present) can be determined using known techniques for detecting ions dissolved in solution, for example circular dichroism (CD ) Methods, atomic absorption spectroscopy, mass spectroscopy, radioactive tracer measurements, etc. can be used to determine or calculate.

  In some cases, sequestering ions, such as aluminum, in the body or brain or other organs with the organosilicon composition of the invention, for example, aluminum ions at the negatively charged portion of the organosilicon compound. Thus, the metal ion can be sequestered. For example, organosilicon compounds contain one or more hydroxide moieties that can be negatively charged (ie, deprotonated) under physiological conditions, and can contain electrostatic attraction or aluminum or other metal ions. It may be possible to bind to a compound. In one group of embodiments, the organosilicon compound may be silanol, silane diol, or silane triol. In another group of embodiments, the organosilicon compound comprises silanol, silane diol or silane triol, the compound, for example in the body under physiological conditions (eg at a temperature of 37 ° C. and / or in a generally aqueous environment). It may also be a silicon compound that can be formed by hydrolysis. In some embodiments, after the aluminum-organosilicon complex (or other ionic-organosilicon complex) is formed, the complex is also removed from the brain or other organs, such as physically removed, or It can be deactivated in other ways.

In one aspect, the composition includes a silicon-containing compound. Silicon compounds include, for example, acids, salts, bases, oxides and the like, for example, silicic acid (H ₄ SiO ₄ ), silicon tetraacetate, sodium silicate, sodium metasilicate, and the like. Additional examples are described below. Silicon compounds may bind to or otherwise interact with aluminum or other metal ions, for example, in the central nervous system or other organs, or in the bloodstream, as described further below. It can be done.

In one group of embodiments, the present invention comprises a composition comprising one or more compounds shown below (numbered 1-35), optionally with a pharmaceutically acceptable carrier. I will provide a:

式中、Ｚ^１、Ｚ^２、Ｚ^３およびＺ^４の各々は、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲン（例えばニトリル）であり、Ｒ^１は、少なくとも１個の炭素原子を含み、Ｊ^１およびＪ^２は、各々独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む、
またはこの１つの塩を有することができる。化合物は、この例においては、少なくとも１個の炭素原子を含み、即ち、Ｚ^１、Ｚ^２、Ｚ^３およびＺ^４の少なくとも１つは、少なくとも１個の炭素原子を含む。ある態様において、Ｚ^１、Ｚ^２、Ｚ^３およびＺ^４は、すべて同時には、ＨまたはＲの１つではなく；Ｚ^１、Ｚ^２、Ｚ^３およびＺ^４は、すべて同時には、酢酸塩ではない。 In another group of embodiments, the composition comprises a silicon compound or an organosilicon compound, i.e. a compound comprising at least one silicon atom bonded to an organic moiety. In one group of embodiments, the compound has one structure, for example:

Wherein each of Z ¹ , Z ² , Z ³ and Z ⁴ is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² , wherein R is at least one Contains carbon atoms, X is one halogen or one pseudohalogen (eg nitrile), R ¹ contains at least one carbon atom, and J ¹ and J ² are each independently H Or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom,
Or you can have this one salt. The compound in this example contains at least one carbon atom, ie at least one of Z ¹ , Z ² , Z ³ and Z ⁴ contains at least one carbon atom. In some embodiments, Z ¹ , Z ² , Z ³ and Z ⁴ are not simultaneously one of H or R; Z ¹ , Z ² , Z ³ and Z ⁴ are all simultaneously Absent.

式中、Ｚ^１、Ｚ^２、Ｚ^３およびＺ^４の各々は、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含み、Ｊ^１およびＪ^２は、各々独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む、
を有する１つの化合物またはこの１つの塩を含む。いくつかの場合において、Ｚ^１、Ｚ^２、Ｚ^３およびＺ^４の１つ、２つ、３つまたは４つは、各々ＯＨおよび／または酢酸塩であってもよい。他の態様において、この組成物は、ケイ酸塩、例えばケイ酸ナトリウムおよび／またはメタケイ酸塩、例えばメタケイ酸ナトリウムなどを含む。 In another group of embodiments, the composition has one structure:

Wherein each of Z ¹ , Z ² , Z ³ and Z ⁴ is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² , wherein R is at least one Contains carbon atoms, X is one halogen or one pseudohalogen, R ¹ contains at least one carbon atom, and J ¹ and J ² are each independently H, or Contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom,
Or a salt thereof. In some cases, one, two, three or four of Z ¹ , Z ² , Z ³ and Z ⁴ may each be OH and / or acetate. In other embodiments, the composition comprises a silicate, such as sodium silicate and / or a metasilicate, such as sodium metasilicate.

式中、Ｚ^１およびＺ^２の各々は、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含み、Ｊ^１およびＪ^２は、各々独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む、
またはこの１つの塩を有することができる。この構造において、Ａは、炭素原子およびケイ素原子の少なくとも１つを有する部分である。Ｅ^１およびＥ^２の各々は（適用可能である場合には）、独立して、（ａ）ＯおよびＮＪ^３の１つ、または（ｂ）Ｓｉが部分Ａに共有結合するように不存在のいずれかである。Ｊ^３は、Ｈであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む。ある例において、Ｅ^１およびＥ^２は（適用可能である場合には）、共に不存在ではなく、Ｓｉは、不存在ではないＡおよびＥ^１またはＥ^２に結合していることができる。 In another group of embodiments, the compound has a structure, for example:

Wherein each of Z ¹ and Z ² is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² , wherein R comprises at least one carbon atom and X Is one halogen or one pseudohalogen, R ¹ contains at least one carbon atom and J ¹ and J ² are each independently H or one carbon atom, 1 Containing at least one of one nitrogen atom, one oxygen atom or one sulfur atom,
Or you can have this one salt. In this structure, A is a moiety having at least one of a carbon atom and a silicon atom. Each of E ¹ and E ² (if applicable) is independently absent (a) one of O and NJ ³ or (b) Si is covalently bonded to moiety A Either. J ³ is H or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom. In certain examples, E ¹ and E ² (if applicable) are not both absent, and Si can be bound to A and E ¹ or E ² that are not absent.

を有する。 In yet another group of embodiments, the compound may be a cyclic organosilicon compound. In some cases, more than one ring may be present in a compound, for example as a bicyclic or spiro ring system (ie where the rings are one, two, three or Share 4 or more atoms). In some cases, the two rings of the bicyclic or spiro structure can each contain an alkyl moiety. By way of example, a compound in one embodiment has a structure, for example:

Have

In these structures, each of A ¹ , A ² and A ³ is independently a moiety having at least one of one carbon atom and one silicon atom, and each of E ¹ and E ² is Independently, (where applicable) either (a) one of O and NJ ³ or (b) absent in such a way that Si is covalently bonded to moiety A ¹ . Z is one of H, X, R, OH, OR ¹ or NJ ¹ J ² , R contains at least one carbon atom, and X is one halogen or one pseudohalogen , R ¹ contains at least one carbon atom. In some cases, E ¹ and E ² are not both absent. E ³ and E ⁴ (if applicable) are independently either (a) one of O and NJ ⁴ or (b) absent in such a way that Si is covalently bonded to the moiety A ² It may be. Each J is independently H or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom. In some cases, the compositions of the present invention can include all salts of the aforementioned chemical structures.

  In some cases, the cyclic organosilicon compound can include one or more hydrolyzable structures, for example by hydrolysis of the compounds of the invention, for example by exposure to physiological conditions. Thus, silanol, silane diol or silane triol can be formed. For example, a cyclic organosilicon compound can include an ester or amine moiety that is hydrolyzed to form a hydroxide, thus opening one or more rings of the cyclic organosilicon compound. Can do.

式中、Ｙ、Ｙ^１およびＹ^２の各々は、独立して、少なくとも１個の炭素原子を含む相互に結合する部分（例えばアルキル部分、アリール部分、環状部分など）であり、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６の各々は、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含み、Ｊ^１およびＪ^２は、各々独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む、
またはこの１つの塩を有する。Ｅ^１、Ｅ^２、Ｅ^３およびＥ^４の各々は（適用可能である場合には）、独立して、（ａ）ＯおよびＮＪ^３の１つ、または（ｂ）ＳｉがＹ部分に共有結合するように不存在のいずれかである。Ｊ^３は、Ｈであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含むことができる。典型的には、少なくとも１つのＥ部分が、構造内に存在する。 In yet another group of embodiments, the compound may have a structure having at least two silicon atoms. In some cases, the compound may be a polymer, such as a polymer having a repeating unit having at least one silicon atom, as described further below. In some cases, the compound has one structure, for example:

Wherein each of Y, Y ¹ and Y ² is independently a mutually linked moiety containing at least one carbon atom (eg, an alkyl moiety, an aryl moiety, a cyclic moiety, etc.), and Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ are each independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² , where R is at least one carbon Containing atoms, X is one halogen or one pseudohalogen, R ¹ contains at least one carbon atom, and J ¹ and J ² are each independently H or 1 Contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom,
Or have this one salt. Each of E ¹ , E ² , E ³ and E ⁴ (when applicable) is independently (a) one of O and NJ ³ or (b) Si covalently bonded to the Y moiety. To be either absent. J ³ can be H or contain at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom. Typically, at least one E moiety is present in the structure.

In all of the above embodiments, any one, two, three, four, five or six of Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ are applicable In some cases) each independently may be halogen (X), such as F, Cl, Br, I etc. or pseudohalogen. In some cases, the halogen or pseudohalogen may be hydrolyzable to OH under physiological conditions.

In another group of embodiments, any one, two, three, four, five or six of Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ are (applicable In each case) may independently be a hydroxide (OH) or alkoxy (OR ¹ , where R ¹ comprises at least one carbon atom). In some examples, the hydroxide can be deprotonated under physiological conditions (ie, to O ⁻ ). In some cases, the alkoxy can be hydrolyzed (eg, within a subject) to form a hydroxide. Non-limiting examples of alkoxy moieties include methoxy (OMe), ethoxy (OEt), propoxy (OPr), isopropoxy, butoxy (OBu), tert-butoxy, sec-butoxy, acetoxy (OAc) and the like. The alkoxy moiety may in some cases be a substituted alkoxy moiety, such as a chloromethoxy or bromochloromethoxy moiety.

Any one, two, three, four, five or six of Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ (if applicable) are each independently Thus, it may be a moiety containing at least one carbon atom in all the above embodiments. For example, R is alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, etc.), cycloalkyl, aromatic A group moiety (eg phenyl, benzyl, substituted phenyl or benzyl, etc.), aminoalkyl, hydroxyalkyl (eg hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl etc.), cyanoalkyl (ie at least one CN Including alkyl such as cyanoethyl, cyanopropyl, cyanobutyl, and the like. Nitrile containing moieties (eg ethyl nitrile, propionitrile, butyronitrile, etc.) may be particularly useful in some cases. The nitrile moiety may allow the compound to bind to metal ions such as aluminum.

  In some cases, the nitrile moiety may facilitate transport or penetration of the compound across the blood-brain barrier, for example, as described further below. In some embodiments, the alkyl moiety can further include one or more side moieties. The side moiety may be any non-hydrogen atom or moiety, such as an alkyl moiety, such as a methyl moiety or a cycloalkyl moiety. A side part (or parts) can be used to change the metabolic function of a compound so that the compound can have some degree of hydrophobicity or other physical properties, eg, to allow detection of the compound. As is possible, the compound can be selected such that it is possible to have certain immunological properties. In one group of embodiments, the hydrophobic side chain is attached to a compound, such as an alkyl moiety, a cyclic moiety or an aryl moiety. In some cases, the cyclic moiety may be an unsaturated structure, such as a cyclohexyl structure.

を有する部分を含むことができる。いくつかの場合において、例えば、ある生理学的条件下で、ホスホノ部分内の一方または両方のＯＨ部分を、Ｏ⁻に加水分解することができる。いくつかの例において、ホスホノ部分により、化合物が、金属イオン、例えばアルミニウムに結合することが可能になり得る。 In all of the above embodiments, the compound has a phosphono moiety, ie, the structure:

A portion having In some cases, for example, in certain physiological conditions, one or both of the OH portion of the phosphono moiety, O ^- may be hydrolyzed to. In some examples, the phosphono moiety may allow the compound to bind to a metal ion, such as aluminum.

In all of the above embodiments, any one, two, three, four, five or six of Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ are applicable In some cases) each independently can contain a nitrogen-containing moiety, such as an amine, hydroxylamine, oxime, nitro moiety, and the like. As one example, the nitrogen-containing moiety can include a sulfur atom that can be attached to the nitrogen atom, eg, in a sulfonamide, ie, as the structure N—SO ₂ —Ar, where Ar is aryl (heteroaryl (The bond has been removed for clarity). In other examples, the nitrogen-containing moiety is attached to the nitrogen atom, for example in hydroxylamine (N—OH), oxime (N—OR, R contains at least one carbon atom) or nitro moiety (NO ₂ ). Can contain oxygen atoms. In still other examples, the nitrogen-containing moiety is, for example, hydrazide (N—NH ₂ ), substituted hydrazide (N—NHJ or N—NHJ ¹ J ² , where each J is a carbon atom, nitrogen atom, oxygen atom or sulfur atom. For example, acyl, sulfonyl, etc.) and can contain two nitrogen atoms that can be bonded to each other.

In all of the above embodiments, any one, two, three, four, five or six of Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ are applicable Each independently) having the formula NJ ¹ J ² , wherein J ¹ and J ² are each independently H or one carbon atom, one nitrogen atom, one It contains at least one of an oxygen atom or one sulfur atom. J ¹ and J ² can each contain atoms other than carbon and hydrogen atoms, such as sulfur, nitrogen or oxygen. As one example, NJ ¹ J ² may be an amine. In some cases, the amine N may be covalently bonded to Si. However, in other cases, the amine N may not be covalently bonded to Si, and one or more carbon atoms may bond the amine N to Si (ie, amino A cycloalkyl moiety, such as an aminoaryl moiety, or an aminoalkyl moiety, such as aminopropyl, aminobutyl, aminopentyl, and the like. The amine may be a primary amine, secondary amine, tertiary amine or quaternary amine.

式中、Ａは、窒素原子と水酸化物との間の実質的な相互作用が生じる（

により示す）ことを可能にするすべてのアルキルおよび／またはアリール部分であり、Ｊ^１、Ｊ^２およびＪ^３の各々は、独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む、
を有することができるか、または体内で加水分解もしくはプロトン化されて、この構造を形成することができる。 In one group of embodiments, at least one aminoalkyl and / or aminoaryl moiety can interact with one or more hydroxide moieties wherein the amine moiety is covalently bonded to the silicon atom of the compound. To choose. Hydroxides portion of the aminoalkyl and / or amino aryl moiety (which, for example, OH or O ^- may be present as) by interaction with, in some instances, compounds, for example, decomposition or polymerization in solution (E.g., spontaneous polymerization in water). Significant or detectable degradation or polymerization in solution can be prevented, for example, by self-interactions within the compound, thereby allowing substantial and / or stable polymerization of the compound to adjacent molecules. It can be prevented or inhibited. For example, the compound has a structure, for example:

Where A is a substantial interaction between the nitrogen atom and the hydroxide (

By indicating) that are all alkyl and / or aryl moiety allowing each of J ^1, J ² and J ³ are either independently H, or one carbon atom, one nitrogen atom, Containing at least one of one oxygen atom or one sulfur atom,
Or can be hydrolyzed or protonated in the body to form this structure.

Examples of suitable alkyl include those previously described. In the foregoing structure, for clarity reasons, not all atoms bonded to silicon are depicted. By way of example, in an aminoalkyl moiety, the aminoalkyl moiety can include 2, 3, 4, 5, or 6 carbon atoms between the nitrogen and silicon atoms. In some cases, the aminoalkyl moiety may be aminopropyl, aminobutyl or aminoisobutyl. Non-limiting examples of compounds having an aminoalkyl moiety include:

これらの構造において、明瞭の理由により、ケイ素に結合した元素のすべてを示しているわけではない。これらのおよび他のアミノアルキル部分の組み合わせ、例えばビス（ジメチルアミノエチル）（トリメチルアミノエチル）エチル部分はまた、想像される。 In some embodiments, the aminoalkyl moiety can include more than one amino moiety, such as in a bis (aminoalkyl) alkyl moiety or a tris (aminoalkyl) alkyl moiety. Examples of compounds having such a structure include, but are not limited to:

In these structures, for reasons of clarity, not all elements bonded to silicon are shown. Combinations of these and other aminoalkyl moieties such as bis (dimethylaminoethyl) (trimethylaminoethyl) ethyl moieties are also envisioned.

これらの構造において、Ｚ^１およびＺ^２の各々は、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含み、Ｊ^１およびＪ^２は、各々独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む。Ｊ^１０、Ｊ^１１、Ｊ^１２およびＪ^１３の各々は、独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む。いくつかの場合において、Ｚ^１およびＺ^２は、各々独立して、１つのハロゲンもしくは１つのプソイドハロゲン、例えば塩素もしくはＣＮであるか、またはアルコキシ、例えばメトキシであってもよい。ある態様において、Ｊ^１０、Ｊ^１１、Ｊ^１２およびＪ^１３の各々は、独立してアルキル、例えばメチル、エチル、プロピル、ブチル、ペンチルなどであってもよい。 Another example is provided by the following structure:

In these structures, each of Z ¹ and Z ² is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² , wherein R contains at least one carbon atom. , X is one halogen or one pseudohalogen, R ¹ contains at least one carbon atom, and J ¹ and J ² are each independently H or one carbon atom It contains at least one of one nitrogen atom, one oxygen atom or one sulfur atom. Each of J ¹⁰ , J ¹¹ , J ¹² and J ¹³ is independently H or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom. In some cases, Z ¹ and Z ² are each independently one halogen or one pseudohalogen, such as chlorine or CN, or may be alkoxy, such as methoxy. In certain embodiments, each of J ¹⁰ , J ¹¹ , J ¹² and J ¹³ may independently be alkyl, such as methyl, ethyl, propyl, butyl, pentyl, and the like.

前述の構造において、各々のＡｋは、独立してアルキルを含み、各々のＡｒは、独立してアリール（例えばアミノアリール）を含み、Ｊは、独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む。いくつかの場合において、ケイ素組成物は、前に記載したアミンを含む、アミノアルキルおよびアミノシクロアルキルの両方を含むことができる。 In other examples, the aminoalkyl moiety of the compound can include a cyclic structure (ie, an aminocycloalkyl moiety), such as an aryl moiety, a saturated or unsaturated cyclic moiety, a heteroaryl moiety, and the like. The aminocycloalkyl moiety can optionally include one or more alkyl moieties, eg, between the aryl or cycloalkyl moiety and the silicon atom. Non-limiting examples of aminocycloalkyl compounds include the following:

In the foregoing structure, each Ak independently includes alkyl, each Ar independently includes aryl (eg, aminoaryl), J is independently H, or one carbon atom. It contains at least one of one nitrogen atom, one oxygen atom or one sulfur atom. In some cases, the silicon composition can include both aminoalkyl and aminocycloalkyl, including the amines described above.

これらの構造において、Ａは、炭素原子およびケイ素原子の少なくとも１つを有する部分（例えばアルキル、シクロアルキル、アリールなど）であり、各々のＪは、独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む。前述の構造において、明瞭の理由により、ケイ素に結合した原子のすべてを描写しているわけではない。 In one group of embodiments, the compound is an aminosilicon compound or a salt thereof, ie, a compound in which the nitrogen atom is covalently bonded to the silicon atom. The compound may be, for example, silanol, silane diol or silane triol or a compound capable of forming silanol, silane diol or silane triol, for example by hydrolysis under physiological conditions. The aminosilicon compound is cyclic in some cases. Non-limiting examples of cyclic amino silicon compounds include:

In these structures, A is a moiety having at least one of a carbon atom and a silicon atom (eg, alkyl, cycloalkyl, aryl, etc.) and each J is independently H or one carbon It contains at least one of an atom, a nitrogen atom, an oxygen atom or a sulfur atom. In the foregoing structure, for clarity reasons, not all atoms bonded to silicon are depicted.

これらの構造において、各々のＺは、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含む。各々のＪは、独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む。各々のＹ部分は、独立して、少なくとも１個の原子（例えば水素、ハロゲン、プソイドハロゲン、アルキル部分、アリール部分、環状部分など）を含む。 Specific non-limiting examples of cyclic amino silicon compounds include the following:

In these structures, each Z is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² , R contains at least one carbon atom, and X is One halogen or one pseudohalogen and R ¹ contains at least one carbon atom. Each J is independently H or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom. Each Y moiety independently contains at least one atom (eg, hydrogen, halogen, pseudohalogen, alkyl moiety, aryl moiety, cyclic moiety, etc.).

であり、式中、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６の各々は、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含み、Ｊ^１およびＪ^２は、各々独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む。 In all of the above embodiments, any one, two, three, four, five or six of Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ are (applicable In some cases) each independently contains a silicon atom. Thus, the compound may have at least 2, at least 3, at least 4, at least 5, etc. silicon atoms in this structure. In one embodiment, the compound is a polymer. Examples of compounds having two silicon atoms in this structure are:

Wherein each of Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² . Yes, R contains at least one carbon atom, X is one halogen or one pseudohalogen, R ¹ contains at least one carbon atom, and J ¹ and J ² are each It is independently H or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom.

により示す：

In some cases, the compound can have a structure that allows multiple silicon hydroxide moieties to interact with aluminum or other metal ions simultaneously, or is hydrolyzed under physiological conditions. It has a structure that makes it possible to form the structure. A schematic, non-limiting example is illustrated below, where M indicates the position of the metal ion, and each R moiety in the illustrated structure is independently bonded to a silicon atom. Contains at least one atom (eg, alkyl moiety, aryl moiety, cyclic moiety, amine, etc.). Z ¹ and Z ² are each independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² , R contains at least one carbon atom, and X is one Halogen or one pseudohalogen, R ¹ contains at least one carbon atom, and J ¹ and J ² are each independently H, or one carbon atom, one nitrogen atom, It contains at least one of one oxygen atom or one sulfur atom. In these non-limiting examples, the (non-covalent) interaction of SiO ⁻ with metal ions is

Shown by:

これらの構造において、Ｙは、少なくとも１個の原子（例えば水素、ハロゲン、プソイドハロゲン、アルキル部分、アリール部分、環状部分など）を含む。 Non-limiting examples of such structures include the following:

In these structures, Y contains at least one atom (eg, hydrogen, halogen, pseudohalogen, alkyl moiety, aryl moiety, cyclic moiety, etc.).

In certain cases, the compound is a polymer having a repeating unit comprising at least one silicon atom. In some cases, the silicon may be functionalized as previously described (eg, the silicon atom of the repeat unit is one of H, X, R, OH, OR ¹ or NJ ¹ J ² Or may be covalently bonded to two or more, R contains at least one carbon atom, X is one halogen or one pseudohalogen, and R ¹ is at least one carbon atom. And J ¹ and J ² are each independently H or contain at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom). For example, in one embodiment, the compound is a polymer that includes repeating units having silanol, silane diol, or silane triol functionality, or the polymer is hydrolyzed to form silanol, silane diol, or silane triol functionality. Containing repeating units.

これらの構造において、Ｙは、少なくとも１個の原子（例えば水素、ハロゲン、プソイドハロゲン、アルキル部分、アリール部分、環状部分など）を含み、Ｒは、少なくとも１個の炭素原子を含み、ｎおよびｍは、正の整数である。ポリマーが、コポリマーである（例えば前に示したように）場合には、コポリマーは、例えば、ブロックコポリマー、ランダムコポリマー、交互コポリマー、グラフトコポリマーなどであってもよい。 Non-limiting examples include the following:

In these structures, Y contains at least one atom (eg, hydrogen, halogen, pseudohalogen, alkyl moiety, aryl moiety, cyclic moiety, etc.), R contains at least one carbon atom, and n and m is a positive integer. Where the polymer is a copolymer (eg, as indicated above), the copolymer may be, for example, a block copolymer, a random copolymer, an alternating copolymer, a graft copolymer, and the like.

これらの構造において、各々のＡは、独立して、炭素原子およびケイ素原子の少なくとも１個を有する部分であり、各々のＺは、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含み、Ｊ^１およびＪ^２は、各々独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む。いくつかの場合において、各々のＡは、化合物を一層疎水性に、もしくは一層疎水性ではなくするように、および／または血液−脳障壁を横断しての化合物の通過を促進するように選択することができる。 In one group of embodiments, the compounds of the invention are cyclic organosilicon compounds or salts thereof having at least one ester moiety. Non-limiting examples of such compounds include the following:

In these structures, each A is independently a moiety having at least one of a carbon atom and a silicon atom, and each Z is independently H, X, R, OH, OR ¹ or NJ ¹ J ² , R contains at least one carbon atom, X is one halogen or one pseudohalogen, R ¹ contains at least one carbon atom, J ¹ and J ² are each independently H or contain at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom. In some cases, each A is selected to make the compound more hydrophobic or less hydrophobic and / or to facilitate passage of the compound across the blood-brain barrier. be able to.

前述の構造において、Ｚ^１およびＺ^２は、各々独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含み、Ｊ^１およびＪ^２は、各々独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む。前述の構造において、明瞭の理由により、ケイ素に結合した原子のすべてを描写しているわけではない。 Non-limiting examples of cyclic organosilicon esters of the present invention include:

In the foregoing structure, Z ¹ and Z ² are each independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² , wherein R comprises at least one carbon atom, X is one halogen or one pseudohalogen, R ¹ contains at least one carbon atom, and J ¹ and J ² are each independently H or one carbon atom, It contains at least one of one nitrogen atom, one oxygen atom or one sulfur atom. In the foregoing structure, for clarity reasons, not all atoms bonded to silicon are depicted.

式中、Ａ^１、Ａ^２、Ａ^３、Ａ^４、Ａ^５、Ａ^６、Ａ^７、Ａ^８、Ａ^９、Ａ^１０、Ａ^１１およびＡ^１２の各々は、独立して、Ｈであるかまたは少なくとも１個の炭素原子を含む、
を有する。明瞭の理由により、ケイ素に結合した原子のすべてを描写しているわけではない。いくつかの場合において、Ａの各々を、オキサシリナン環の共通の炭素原子により接合された２つのＡ部分が同一であるように、選択することができる。ある場合において、Ａの各々を、化合物が対照的もしくは非キラルであるように、または化合物が、非対照もしくはキラルであるように選択することができる。１つの態様において、各々のＡは、Ｈまたはアルキル部分、例えばメチル、エチル、プロピルなどのいずれかである。 In other examples, the compound has the structure:

Wherein each of A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ , A ⁷ , A ⁸ , A ⁹ , A ¹⁰ , A ¹¹ and A ¹² is independently H Or containing at least one carbon atom,
Have For clarity reasons, not all atoms bonded to silicon are depicted. In some cases, each of A can be selected such that the two A moieties joined by a common carbon atom of the oxacillinane ring are identical. In certain cases, each of A can be selected such that the compound is symmetric or non-chiral, or the compound is non-control or chiral. In one embodiment, each A is either H or an alkyl moiety, such as methyl, ethyl, propyl, and the like.

これらの構造において、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６の各々は、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含み、Ｊ^１およびＪ^２は、各々独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む。 As previously described, the compound can have more than one silicon atom in some embodiments. Additional non-limiting examples include the following:

In these structures, each of Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² . , R contains at least one carbon atom, X is one halogen or one pseudohalogen, R ¹ contains at least one carbon atom, and J ¹ and J ² are each independently H or at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom.

により図式的に表す）、これにより、分子を、いくつかの場合において一層小さい程度に帯電させるか、または双性イオン性とする（即ち、分子が、正に帯電した部分と負に帯電した部分とを有するか、または分子が、正味の双極子モーメントを有する）部分を有することができる。一層小さい程度に帯電した化合物により、いくつかの場合において、例えば血液−脳障壁を横断して、または細胞膜を横断して、化合物の脳中への輸送が促進され得る。例えば、化合物は：

式中、Ｚ^１およびＺ^２の各々は、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含み、Ｊ^１およびＪ^２は、各々独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む、
により表され得る。いくつかの場合において、化合物は、塩として存在することができる。 In yet another aspect, the compounds of the present invention are positively charged under physiological conditions in the body (herein the symbols

Which makes the molecule charged to a lesser extent in some cases or zwitterionic (i.e., the portion where the molecule is positively charged and negatively charged). Or the molecule has a moiety that has a net dipole moment. Smaller charged compounds may facilitate transport of the compound into the brain in some cases, eg, across the blood-brain barrier or across cell membranes. For example, the compound is:

Wherein each of Z ¹ and Z ² is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² , wherein R comprises at least one carbon atom and X Is one halogen or one pseudohalogen, R ¹ contains at least one carbon atom and J ¹ and J ² are each independently H or one carbon atom, 1 Containing at least one of one nitrogen atom, one oxygen atom or one sulfur atom,
Can be represented by: In some cases, the compound can exist as a salt.

は、アミン部分である。例えば、アミン部分の窒素原子は、化合物の１つの部分上に位置することができ、これにより、ある生理学的溶液または条件に曝露した際に、化合物の当該部分に正の電荷が付与され得る。好適なアミンの例には、上記したものが含まれる。アミンは、第一アミン、第二アミン、第三アミンまたは第四アミンであってもよい。例えば、アミンが第三アミンである場合には、アミンは、ジメチルアミン、エチルメチルアミン、プロピルメチルアミン、ジエチルアミンなどであってもよい。特定の非限定的な例には、ビス（ジアルキルアミノアルキル）シランジオール、ビス（トリアルキルアミノアルキル）シランジオールまたはトリス（トリアルキルアミノアルキル）シラントリオールが含まれる。１つよりも多いアミン部分が、化合物内に存在する場合には、アミンは、各々同一であっても異なっていてもよい。（例えば生理学的条件下で）正の電荷を付与することができる他の部分には、例えば、アミジン、グアニジン、アリールアミン、ヘテロアリールアミン、ピリジン、イミダゾールなどが含まれる。 In one group of embodiments,

Is an amine moiety. For example, the nitrogen atom of the amine moiety can be located on one part of the compound, which can impart a positive charge to that part of the compound when exposed to certain physiological solutions or conditions. Examples of suitable amines include those described above. The amine may be a primary amine, secondary amine, tertiary amine or quaternary amine. For example, when the amine is a tertiary amine, the amine may be dimethylamine, ethylmethylamine, propylmethylamine, diethylamine, and the like. Particular non-limiting examples include bis (dialkylaminoalkyl) silanediol, bis (trialkylaminoalkyl) silanediol or tris (trialkylaminoalkyl) silanetriol. If more than one amine moiety is present in the compound, the amines may each be the same or different. Other moieties that can impart a positive charge (eg, under physiological conditions) include, for example, amidine, guanidine, arylamine, heteroarylamine, pyridine, imidazole, and the like.

Also contemplated are combinations of one or more moieties that can be positively charged under physiological conditions within the compounds of the present invention, such as compounds having an amine moiety and a guanidine moiety, a guanidine moiety and pyridine. Of course, when the molecule is charged, if the compound is positively charged, one or more counterions such as organic or inorganic anions such as chloride, fluoride, bromide, Sulfates, carbonates, acetates and the like may also be present or associated with this compound. Specific non-limiting examples of such compounds include the following:

  In other aspects, the compound can have a structure that facilitates transport of the compound into the organ or across the blood-brain barrier. In one group of embodiments, the compound is transported into the organ of the compound or across the blood-brain barrier (eg, by diffusion or using transport systems such as transport proteins or ion channels). It can be designed to optimize the hydrophobicity of the promoting composition. In some cases, the ability of a compound to move into an organ or across the blood-brain barrier is determined when the compound binds to a metal ion, such as aluminum, or to the brain or other organ. It may be lost when it enters or is in transit (ie, within a cell that forms a blood-brain barrier, etc.). In other cases, the compound can maintain or improve this ability to migrate into the organ or across the blood-brain barrier when bound to metal ions.

  In one group of embodiments, attaching positive, negative and / or hydrophobic moieties to the compound to achieve a selected hydrophobic and / or selected electrical dipole moment of the compound. it can. The hydrophobicity of a compound can be determined by one of ordinary skill in the art using all suitable tests, e.g., compound, two-phase liquid system, e.g., water-octanol system, or other suitable known to those of ordinary skill in the art. It can be determined by splitting in the system. For example, the hydrophobicity of a compound can be determined by dividing the compound in a water-octanol system and determining the percentage of the compound in the octanol phase relative to the aqueous phase (eg, per mass basis or other quantitative In measurement). The water-octanol partition factor can be selected to optimize blood-brain barrier penetration in certain instances and may depend on actual physiological conditions. See, for example, Lohmann, et al., “Predicting Blood-Brain Barrier Permeability of Drugs: Evaluation of Different In Vitro Assays,” J. Drug Targeting, 10 (4): 263-276, 2002.

  In some cases, the octanol / water partition ratio for the hydrophobic compound is at least about 1.25: 1 (octanol: water), at least about 1.5: 1, at least about 1.75: 1, at least about 2 1, at least about 5: 1, at least about 10: 1, at least about 20: 1, at least about 50: 1, at least about 100: 1, at least about 300: 1, or at least about 1000: 1 or more. In some cases, hydrophobic compounds can more easily enter the brain or other organs across the blood-brain barrier or other similar barriers or membranes. Accordingly, in one embodiment, the compound comprises one or more hydrophobic or lipophilic moieties, such as alkyl moieties, cycloalkyl moieties, aryl moieties, and the like.

式中、Ｘは、アルミニウムもしくは他の金属イオンに結合することができる１つのキレート剤であるか、またはアルミニウムもしくは他の金属イオンに結合することができる１つのキレート剤を形成することができる、
を有する。さらに、Ｙは、血液−脳障壁を横断しての化合物（またはこの一部）の輸送を促進することができる構造であり、構造

は、少なくとも１つの化学結合を含み、構造−は、生理学的条件下で、例えば脳、血液−脳障壁内で、または血流内で加水分解され得る部分である。いくつかの場合において、構造

は、構造Ｘおよび構造Ｙを結合する少なくとも１個の原子を含む（例えば、構造

は、ＸとＹとの間を架橋する２個の原子、ＸとＹとの間を架橋する３個の原子、ＸとＹとの間を架橋する４個の原子、ＸとＹとの間を架橋する５個の原子などを含むことができる）。 In another group of embodiments, the compounds of the invention can bind to aluminum or other metal ions (or can form chelating agents that can bind to aluminum or other metal ions). Contains a chelating agent. In one embodiment, the compounds of the invention have one structure:

Wherein X is one chelator that can bind to aluminum or other metal ions, or can form one chelator that can bind to aluminum or other metal ions.
Have Furthermore, Y is a structure capable of facilitating the transport of the compound (or part thereof) across the blood-brain barrier,

Includes at least one chemical bond, and the structure is a moiety that can be hydrolyzed under physiological conditions, for example, in the brain, blood-brain barrier, or in the bloodstream. In some cases, the structure

Includes at least one atom connecting structure X and structure Y (eg, structure

Are two atoms that bridge between X and Y, three atoms that bridge between X and Y, four atoms that bridge between X and Y, and between X and Y Can contain 5 atoms to crosslink).

  Suitable hydrolyzable structures that link X and Y together include, for example, an alkoxide moiety, an ester moiety, or an ether moiety, as described above, for example. Other suitable hydrolyzable structures are known to those of ordinary skill in the art. In some cases, the hydrolyzable structure can be selected to control the rate of degradation of the compound in the brain (eg, in the structure described above, when X is activated by the release of Y). . For example, compounds having Si-F bonds can be hydrolyzed at a relatively slow rate, while compounds having Si-Cl or Si-Br bonds can be hydrolyzed at a relatively fast rate. A slow rate of degradation may be desirable in some cases, for example when a slow or controlled release of the compound is desired. Different compounds with different halogens can also be administered together to provide short and long term activity in some cases.

などの構造を有することができる。 By way of example, in one embodiment, Y targets a component of the blood-brain barrier, eg, transport by an endogenous transport pathway, a protein or other substance naturally transported by a targeted endogenous transport protein. A target portion that can be promoted by simulating. For example, the composition may be hexose transporter, monocarboxylate transporter, amino acid transporter, glucose transporter, peptide transporter (eg transporter for enkephalin, vasopressin, apamin etc.), protein transporter (eg transferrin) Can be selected to simulate a substrate for such as. For example, compounds of the present invention intended for transport across the blood-brain barrier using carbohydrate transporters include:

It is possible to have a structure such as

In these structures, each of Z ¹ , Z ² and Z ³ is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² , where R is at least one carbon Contains atoms, X is one halogen or one pseudohalogen, and R ¹ contains at least one carbon atom. Each J is independently H or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom, and Y is a moiety bonded to each other (eg, Alkyl moiety, aryl moiety, cyclic moiety, etc.) and Cb comprises a carbohydrate moiety (or part thereof). In some cases, Cb is an entity substantially derived from a carbohydrate or portion thereof. For example, a reaction of a carbohydrate with an amino silicon composition or an amidated silicon compound can be used to obtain a composition of the compound. In some cases, the carbohydrate is derived from an aldehyde sugar (“aldocarbose”) (eg, aldohexose or aldopentose) or a ketone sugar (“ketocarbose”) (eg, ketohexose or ketopentose), or an aldocarbose or ketocarbose It may be a part to do. For example, the carbohydrate may be amidated, aminated, esterified or the like. Other carbohydrate derivatization reactions are known to those of ordinary skill in the art. In some cases, at least a portion of the carbohydrate may be an aldehyde sugar or a ketone sugar.

などの構造を有することができる。これらの構造において、Ｚ^１、Ｚ^２およびＺ^３の各々は、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含む。また、各々のＪは、独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含み、Ｙは、相互に結合する部分（例えばアルキル部分、アリール部分、環状部分など）であり、Ａａは、１種もしくは２種以上のアミノ酸（即ち、ｎは、１、２、３、ペプチド、タンパク質などであってもよい）および／または１種もしくは２種以上のアミノ酸誘導体を含む。いくつかの場合において、ｎは、約５０より小さい、約２０より小さい、約１０より小さい正の整数であってもよい。 As another example, the compound is:

It is possible to have a structure such as In these structures, each of Z ¹ , Z ² and Z ³ is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² , where R is at least one carbon Contains atoms, X is one halogen or one pseudohalogen, and R ¹ contains at least one carbon atom. Each J is independently H, or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom, and Y is a moiety bonded to each other (Eg, an alkyl moiety, an aryl moiety, a cyclic moiety, etc.) and Aa is one or more amino acids (ie, n may be 1, 2, 3, peptide, protein, etc.) and / or Or one or more amino acid derivatives. In some cases, n may be a positive integer less than about 50, less than about 20, or less than about 10.

  By reacting such compounds with, for example, suitable aminosilicon compounds with carbohydrates, amino acids, peptides, proteins, hormones, neurotransmitters, etc. using coupling reactions known to those of ordinary skill in the art, Can be prepared.

  In another group of embodiments, the compounds of the invention can be packaged or introduced into a virus, such as a virus that targets the brain or other organs. For example, the virus can be loaded with a compound that can form and / or release silanol, silanediol, or silanetriol by hydrolysis, and / or release from the virus. In some cases, the virus is assembled into a viral envelope of the virus in the presence of one or more compounds of the invention, thereby facilitating internal loading of the virus with the compounds of the invention. Can be prepared.

を有する化合物を、蛍光部分上の、またはこれに結合したアシル、イソシアネートまたはイソチオシアネート部分と反応させ、これにより検出可能な化合物を得ることができる。 In yet another aspect, the compound can have a detectable moiety, ie, a moiety that facilitates external detection, eg, in vivo or in vitro. For example, a portion of the compound can be radioactively and / or fluorescently labeled. Such compounds can be prepared using coupling reactions known to those of ordinary skill in the art. As an example, the structure:

Can be reacted with an acyl, isocyanate or isothiocyanate moiety on or attached to the fluorescent moiety, thereby yielding a detectable compound.

を有する化合物を、蛍光部分上の、またはこれに結合したＮＨ_２、ＳＨまたはＯＨ部分と反応させて、検出可能な化合物を得ることができる。前述の構造において、各々のＺは、独立して、Ｈ、Ｘ、Ｒ、ＯＨ、ＯＲ^１またはＮＪ^１Ｊ^２の１つであり、Ｒは、少なくとも１個の炭素原子を含み、Ｘは、１つのハロゲンまたは１つのプソイドハロゲンであり、Ｒ^１は、少なくとも１個の炭素原子を含み、Ｊ^１およびＪ^２は、各々独立してＨであるか、または１つの炭素原子、１つの窒素原子、１つの酸素原子もしくは１つの硫黄原子の少なくとも１つを含む。Ｙは、ＳｉおよびＮに相互に結合する部分（例えばアルキル部分、アリール部分、環状部分など）である。通常の当業者は、前述の構造において用いるのに適する蛍光標識を知っている。１つの特定の例として、蛍光標識は、ＦＩＴＣまたはＦＩＴＣ誘導体、フルオレセイン、ＧＦＰなどであってもよい。 In another example, the structure:

Can be reacted with NH ₂ , SH or OH moieties on or bound to the fluorescent moiety to obtain a detectable compound. In the foregoing structure, each Z is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² , R comprises at least one carbon atom, and X is One halogen or one pseudohalogen, R ¹ contains at least one carbon atom, and J ¹ and J ² are each independently H or one carbon atom, one nitrogen It contains at least one of an atom, an oxygen atom or a sulfur atom. Y is a moiety bonded to Si and N (for example, an alkyl moiety, an aryl moiety, a cyclic moiety, etc.). Those of ordinary skill in the art are aware of fluorescent labels suitable for use in the above-described structures. As one particular example, the fluorescent label may be FITC or a FITC derivative, fluorescein, GFP, and the like.

The detectable moiety comprises in another group of embodiments a radioactive atom such as ³ H, ¹⁴ C, ³³ P, ³² P, ¹²⁵ I, ¹³¹ I, ³⁵ S, and the like. One of ordinary skill in the art knows suitable methods for introducing radioactive labels into the compounds of the present invention. As one particular example, if the detectable moiety is tritium ( ³ H or T), tritium can be introduced into the compound using a reduction reaction. For example, tritiated lithium aluminum hydride (eg, LiAlT ₄ , LiAlHT ₃ , LiAlH ₂ T ₂ and / or LiAlH ₃ T) is reacted with a functional moiety to reduce the functional moiety and into a tritium-labeled compound. Can lead to the introduction.

前述の構造において、各々のＲ（またはＲ^１およびＲ^２を有する構造について、Ｒ^１およびＲ^２の少なくとも１つ）は、少なくとも１個のケイ素原子を含む。前述の構造におけるすべてのＴについて、実際の反応生成物は、標識された（トリチウム化された）、および標識されていない水素原子の混合物を含むことを理解するべきである。 Non-limiting examples of useful reduction reactions include the following:

In the foregoing structure, each R (or at least one of R ¹ and R ² for structures having R ¹ and R ² ) includes at least one silicon atom. It should be understood that for all Ts in the above structure, the actual reaction product contains a mixture of labeled (tritiated) and unlabeled hydrogen atoms.

  In one aspect of the invention, the compositions of the invention can be assayed for transport across a subject's cells. In one group of embodiments, the cells are cells that can be used to model blood-brain barriers, such as Caco-2 cells or bMVEC cells (“bovine microvascular epithelial cells”). For example, transport of a composition of the invention across a cell monolayer is used to determine or predict the rate of transport or uptake of the composition (or a portion thereof) across the blood-brain barrier. be able to. The transport of the composition can be determined using, for example, CD or similar techniques such as atomic absorption, spectroscopy, mass spectroscopy, radioactive tracer measurements, and the like.

  In some cases, the composition of the present invention can be determined by this transport behavior across a cell monolayer, i.e., the composition of the present invention is Can be transported at a reasonable speed. Thus, compositions that can “cross” the blood-brain barrier (or other membranes) are in some cases due to the ability of the compound to cross a monolayer of cells, eg, Caco-2 cells or bMVEC cells. Can be determined. Other examples of suitable cell models can be found in Lohmann, et al., “Predicting Blood-Brain Barrier Permeability of Drugs: Evaluation of Different In Vitro Assays,” J. Drug Targeting, 10 (4): 263-276, 2002. Are listed.

  In another group of embodiments, the toxicity of the test compound to cells, eg, human cells, is determined. Selecting a test compound that is substantially non-toxic to subject cells is provided. As used herein, “substantially non-toxic” means that a test compound is administered to a subject with an acceptable amount of damage to the subject cells (preferably without detectable damage). Means that it can be administered. Damage to cells can be indicated by altered cell metabolism, cell morphology, cell mitosis, necrosis, apoptosis, and the like. An acceptable amount of damage can be determined by one skilled in the art in a routine experiment. The amount of damage that can be tolerated can depend on the route of administration, the risk of side effects versus the benefit of administration, and the like.

  In other aspects, the compositions and methods of the invention can be used in diagnostic or assay procedures. For example, the compositions of the invention can be used in assays such as aluminum detection assays or metal ion detection assays. A sample having a known or unknown concentration of aluminum or other metal ions can be added to a solution containing the composition of the present invention, and the composition (or part thereof) to aluminum or other metal ions can be added. The amount or degree of binding can be determined using techniques known to those of ordinary skill in the art, for example using circular dichroism or mass spectroscopy. As another example, the invention is used in a cell culture system, for example in a cell culture comprising nerves and / or other types of cells, such as cells capable of producing beta-amyloid and / or neurofilament proteins. Can do.

  In one group of embodiments, the composition of the invention is added to cell culture, optionally with known or unknown concentrations of aluminum or other metal ions, and the organosilicon composition of the invention with aluminum or other metal ions. The net effect of the combination with the object on the cell function is determined using techniques known to those of ordinary skill in the art. In another group of embodiments, cell culture is used to detect and / or determine the concentration of aluminum (or other metal ions) in a sample using the methods and compositions of the invention, In such cases, it may be a sample of biological origin. In one embodiment, appropriate dosages are achieved to achieve certain results (eg, a certain concentration of free aluminum ions) when the composition is applied to a subject using cell culture, diagnostics or assays. Can be determined.

  Another aspect of the present invention provides a method for administering a composition of the present invention to a subject. When administered, the compositions of the invention are applied in a pharmaceutically acceptable amount that is therapeutically effective as a pharmaceutically acceptable formulation. The term “pharmaceutically acceptable” as used herein indicates this ordinary meaning as used in the industry. Pharmaceutically acceptable compounds are generally compatible with the other substances in the formulation and are generally not harmful to the subject. The compositions of the invention (or prodrug forms of the compositions) can be administered to a subject at any therapeutically effective dose or treatment. A “therapeutically effective” dose or amount at least partially prevents or reverses the adverse effects of previously described metal ions, such as symptoms associated with neurofibrillary tangles or the formation of senile plaques in the brain. be able to. A therapeutically effective amount can be determined by one of ordinary skill in the art using, for example, no more than routine experimentation using the factors further described below. In one embodiment, a subject treated in this manner does not need to have a disease or condition that can be treated by inhibition of leukocyte elastase.

  In administering a composition of the invention to a subject, dosages, dosing schedules, routes of administration, etc. can be selected to provide a known activity of the composition of the invention. The dosage can be estimated based on the results of the experimental model, optionally in combination with the results of the assay of the composition of the invention. Dosage can be adjusted appropriately to achieve a desired local or systemic drug level, depending on the mode of administration. The dose can be given once or several times per day. In some cases, parenteral administration of the composition may be 1 to several times lower per day compared to oral administration. If the response of a particular subject is inadequate at such doses, higher doses (or effectively higher doses via different, more localized delivery routes) should be allowed for the subject. Can be used to some extent. Multiple doses per day may also be considered in some cases to achieve an appropriate level of composition within the subject or within the subject's active site, eg, within the brain.

  The dose of the composition to the subject may be such that a therapeutically effective amount of the composition (or a portion thereof, eg, an organosilicon compound) reaches or enters the brain or other active site. it can. The dosage may be given in some cases as a maximum while avoiding or minimizing all potentially detrimental side effects to the subject. For example, the dose of the organosilicon composition may be from about 0.1 mcmol / kg (“micromol” / kg) to about 50 mcmol / kg, or from about 0.5 mcmol / kg to about 5.0 mcmol / kg. The amount of composition actually administered depends on the desired final concentration at the active site, the method of administration to the subject, the efficacy of the composition, the lifetime of the composition within the subject (ie half-life), concentration It depends on factors such as the timing of administration with respect to body and / or plaque formation, the frequency of treatment, and the effects of treatment that can be performed simultaneously.

  The delivered dose may also depend on the symptoms associated with the subject and in some cases may vary from subject to subject. For example, the subject's age, sex, weight, size, environment, physical condition or current state of health also affects the concentration of the required dose and / or composition (or part thereof) at the active site Can do. Medication changes can occur on different days between different individuals or even within the same individual. It may be preferable to use the highest dose, ie the highest safe dose according to reasonable medical judgment. Preferably, the dosage form is such that it does not substantially adversely affect the subject. Accordingly, the particular dose or doses given to a subject can be determined by the ordinary skilled artisan using no more than routine experimentation.

  Administration of the composition of the present invention can be accomplished by any medically acceptable method that allows the composition (or part thereof) to reach this target. The particular mode chosen will, of course, depend on factors such as the particular composition, the severity of the condition of the subject being treated or the dosage required for therapeutic efficacy. As used herein, a “medically acceptable” mode of treatment provides an effective level of composition (or a portion thereof) within a subject without causing clinically unacceptable adverse effects. It is a mode that can be produced. A “target” or “active site” is a component of the body in which a composition of the present invention (or a portion thereof) binds to and / or is adversely affected by the presence of metal ions and metal ions, For example, a position where the interaction between beta-amyloid or neurofilament proteins can be inhibited. Inhibition of metal ions can occur before or after the metal ions have complexed or otherwise inactivated such components that have been adversely affected. Non-limiting examples of such targets include blood flow or brain.

  Any medically acceptable method can be used to administer the composition to the subject. Administration may be localized (ie, a particular region, physiological system, tissue, organ or cell type) or systemic depending on the condition to be treated. For example, the composition is orally, vaginally, rectally, buccal, pulmonary, topically, intranasally, transdermally by parenteral injection or implantation, by surgical administration, or Administration can be by any other method of administration in which access to the target by the composition of the present invention is achieved. As another example, all the compositions described herein can be injected directly into the brain, spinal cord or other organs, or the composition can be injected into a region, for example, cerebrospinal fluid Can be injected into and transported into the brain, spinal cord or other organs. Examples of parenteral modes that can be used in the present invention include intravenous, intradermal, subcutaneous, intracavity, intramuscular, intraperitoneal, epidural or intrathecal.

  Examples of implantation modalities include all implantable or injectable drug delivery systems. In one embodiment, the implantable delivery system is a subdural article that includes an organosilicon composition that is placed in direct contact with the brain, for example, by surgery. The article can have all suitable forms for implantation in the brain, such as sponges, films, blankets, pads, wafers, disks, and the like. In some cases, the article can be removed (and optionally replaced with a new article) after a suitable period of time has elapsed, eg, after a predetermined time, such as a day, a week, or a month. In certain instances, the article is treated when certain conditions are achieved, for example after an amount or percentage of the composition has diffused out of the article and / or when an amount of aluminum has bound to the article. Can be removed. In other cases, the article can remain permanently in the subject. For example, a sponge can include one or more compositions of the present invention that can be released from the sponge by implantation or can remain fixed within the sponge.

  Oral administration may be preferred in some embodiments for convenience to the subject and for reasons of dosing schedule. Compositions suitable for oral administration can be presented as discrete units, such as hard or soft capsules, pills, cachets, tablets, troches or medicinal candy, each containing a predetermined amount of active compound of the composition . Other oral compositions suitable for use in the present invention include solutions or suspensions in aqueous or non-aqueous liquids such as syrups, elixirs or emulsions. In another group of embodiments, the composition can be used to enhance the nutritional value of a food or beverage.

  In certain embodiments of the invention, administration of the composition of the invention can be designed to provide continuous exposure to the composition over a period of time, such as hours, days, weeks, months or years. This can be achieved by repeated administration of the composition according to one of the methods described above, or by a sustained or controlled release delivery system that delivers the composition without repeated administration over an extended period of time. Can be achieved. Administration of the composition using such a delivery system can be, for example, by oral dosage form, bolus injection, transdermal patch or subcutaneous implantation. In some cases, maintaining a substantially constant concentration of the composition may, for example, remove metal ions, such as aluminum, from the body and promote excretion of metal ions through the kidneys and intestines. It may be preferred to allow or react with body components that have been adversely affected by metal ions, such as neurofibrillary tangles or senile plaques. However, avoiding elevated levels of the composition in the body for a short period of time minimizes the precipitation of silicate kidney stones in some cases, for example in the presence of non-physiological levels of silicon and silicon-containing compounds May be desirable to do.

  Other delivery systems suitable for use in the present invention (eg, where release kinetics change and / or control is desired) include time-released delayed release, sustained release or controlled release delivery systems. Including. Such systems can in many cases avoid repeated administration of the composition and increase the convenience to the subject. Many types of release delivery systems are available and are known to those of ordinary skill in the art. These include, for example, systems based on polymers such as polylactic acid and / or polyglycolic acid, polyanhydrides, polycaprolactone and / or combinations thereof; sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as Non-polymeric systems based on lipids, including mono-, di- and triglycerides; hydrogel release systems; systems based on liposomes; systems based on phospholipids; silastic systems; systems based on peptides; wax coatings; Compressed tablets used; or partially fused implants.

  Specific examples include erosion systems in which the composition is contained in a matrix form (eg, as described in US Pat. Nos. 4,452,775, 4,675,189 and 5,736,152), or the active ingredient controls the release rate Examples include, but are not limited to, diffusion systems (eg, as described in US Pat. Nos. 3,854,480, 5,133,974, and 5,407,686). The formulation may be, for example, as a microparticle, hydrogel, polymer reservoir, cholesterol matrix or polymer system. In some embodiments, the system may allow sustained or controlled release of the composition to occur, for example, by controlling the diffusion or erosion / degradation rate of the formulation containing the composition. Further, a pump-based hardware delivery system can be used to deliver one or more aspects of the invention.

  The use of long-term release implants may be particularly suitable in some embodiments of the present invention. As used herein, “long term release” means that the implant comprising the composition produces a therapeutically effective level of the composition at least 30 days or 45 days, preferably at least 60 days or 90 days or some Means that it is configured and tuned for delivery over a longer period of time. Long-term release implants are well known to those of ordinary skill in the art and include some of the release systems described above.

  In certain embodiments of the invention, a composition of the invention is administered to a subject having a family history of Alzheimer's disease or other diseases characterized by excessive amounts of metal ions, or a subject having a genetic predisposition to the disease. To be administered. In other embodiments, the composition is administered to a subject who has reached a particular age or is more likely to have the disease. In still other embodiments, the composition can be administered to a subject who exhibits signs of disease (eg, early or advanced). In yet other embodiments, the composition can be administered to a subject as a preventative measure. In some embodiments, the composition resides in a subject based on demographic or epidemiological studies, such as an area where a high concentration of metal ions, such as aluminum, is present in groundwater. Administration to humans; or persons in specific fields, such as workers in the aluminum or lead industry, or workers using aluminum compounds or materials.

  Alzheimer's disease can be characterized in a subject by one of ordinary skill in the art prior to treatment with the composition of the present invention. For example, a biological sample for a subject, such as a blood test, urine test, biopsy, spinal tap, etc., can be analyzed using an appropriate analytical technique, such as for ions (eg, metal ions, eg, aluminum). The concentration can be determined and compared to normal values. For example, the ion concentration can be determined by NMR, mass spectrometry, ICP, emission spectroscopy, fluorescence spectroscopy, ELISA, chemical staining or indicator. As another example, a subject is tested directly using, for example, MRI, CAT scanning, x-ray, etc., and the disease is present or may be present (ie, the subject is susceptible to the disease) Or not. In another group of embodiments, the subject can be diagnosed by a medical professional using conventional practices for having or at risk for Alzheimer's disease.

Alzheimer's disease, for example, a medical history that includes information such as general human health, past medical problems and / or difficulties the subject has in performing daily activities; medical tests such as blood, Urine or cerebrospinal fluid testing; neuropsychological tests such as memory, problem solving, attention, counting and language testing; and / or brain scanning using eg EEG, MRI, CAT or PET scanning; and behavioral indicators such as Diagnosis can be made by considering memory loss, personality change, dementia, language behavior problems, cognitive or reasoning problems, eating problems, ataxia, motor control problems, and the like. Research studies have also shown a general decrease in cerebrospinal fluid (CSF) beta-amyloid levels, with an increase in tau protein indicating a subject who has or is at risk for this disease ¹ . Improvement or cessation of at least some of the aforementioned symptoms can be associated with the effectiveness of the composition of the present invention. Of course, efficacy can be measured by any of the techniques known to those skilled in the art, including but not limited to those listed above.
¹ Harrison's Principles of Internal Medicine, 15th edition, CD-ROM, McGraw-Hill, 2001

  Administration of the compositions of the invention (or prodrug forms of the compositions) alone or other therapeutic agents and / or compositions (eg, Alzheimer's disease or other diseases characterized by excessive amounts of metal ions) Other agents or compositions that can be used to treat In certain embodiments, the compositions of the invention are introduced with a suitable pharmaceutically acceptable carrier, eg, in a liposome, introduced into a polymer release system, or liquid, eg, in a dissolved or colloidal form. Suspend in and mix. The carrier can be either soluble or insoluble, depending on the application. Compositions of the present invention that may be pharmaceutically acceptable include not only active compounds but also formulation components that can be used with the active compounds, such as salts, carriers, buffers, emulsifiers, diluents, additives, chelates. Agents, desiccants, antioxidants, antibacterial agents, preservatives, binders, extenders, solubilizers or stabilizers are also included. For example, if the formulation is a liquid, the carrier may be a solvent, partial solvent or non-solvent, and may be aqueous or organic based.

  Examples of suitable formulation ingredients include diluents such as calcium carbonate, sodium carbonate, lactose, kaolin, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or acacia Lubricants such as magnesium stearate, stearic acid or talc; time delay materials such as glycerol monostearate or glycerol distearate; suspensions such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone; dispersion Or wetting agents such as lecithin or other naturally occurring phosphatides; thickeners such as cetyl alcohol or beeswax Buffers such as acetate and salts thereof, citric acid and salts thereof, boric acid and salts thereof or phosphoric acid and salts thereof; or preservatives, such as benzalkonium chloride, chlorobutanol, include parabens or thimerosal. Suitable carrier concentrations can be determined by one of ordinary skill in the art using no more than routine experimentation. A composition of the invention can be formulated into a formulation in solid, semi-solid, liquid or gaseous form, such as tablets, capsules, elixirs, powders, granules, ointments, solutions, depositories, inhalants or injectables. Can be prescribed. One of ordinary skill in the art will be aware of other suitable formulations or can confirm this using only routine experimentation.

  In general, pharmaceutically acceptable carriers suitable for use in the present invention are well known to those of ordinary skill in the art. As used herein, a “pharmaceutically acceptable carrier” does not significantly interfere with the effectiveness of the biological activity of one or more active compounds to be administered, eg, composition prior to use. It means a non-toxic substance used as a formulation ingredient to stabilize or protect one or more active compounds in a product. The term “carrier” refers to an organic or inorganic component that may be natural or synthetic and that combines one or more active compounds of the present invention to facilitate application of the composition. The carrier is co-mingle or otherwise with one or more active compounds of the present invention and with each other such that there is substantially no interaction that impairs the desired pharmaceutical efficacy. Can be mixed. Pharmaceutically acceptable carriers include, for example, diluents, emulsifiers, fillers, salts, buffers, additives, desiccants, antioxidants, preservatives, binders, extenders, chelating agents, stabilizers, Solubilizers, silica and other materials well known in the industry are included.

  Formulations include sterile aqueous or non-aqueous solutions, suspensions, and emulsifiers that may be isotonic with the blood of the subject in certain embodiments. Examples of non-aqueous solvents are polypropylene glycol, polyethylene glycol, vegetable oils such as olive oil, sesame oil, coconut oil, peanut oil, injectable organic esters such as ethyl oleate or fixed oils containing synthetic mono- or diglycerides. Aqueous carriers include alcoholic / aqueous solutions, emulsions or suspensions, including water, saline and buffered media. Parenteral vehicles include sodium chloride solution, 1,3-butanediol, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oil. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (eg, those based on Ringer's dextrose), and the like. Preservatives and / or other additives such as antimicrobial agents, antioxidants, chelating agents and inert gases may also be present. One skilled in the art can readily determine various parameters for preparing and formulating the compositions of the present invention without resorting to undue experimentation.

  In some embodiments, the invention includes the step of bringing into association or contacting the composition or compound of the invention with a suitable carrier capable of constituting one or more supplemental ingredients. The final composition may be applied in any suitable manner, for example, uniformly and intimately with the liquid carrier, finely divided solid carrier or both, optionally with one or more formulation ingredients as previously described. It can be prepared by associating and then shaping the product as required.

  In some embodiments, the compounds of the invention can exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salts” includes salts of compounds prepared, for example, in combination with an acid or base, depending on the desired composition and the particular compound found within the mode of treatment. Pharmaceutically acceptable salts can be prepared as alkali metal salts such as lithium, sodium or potassium salts; or as alkaline earth metal salts such as beryllium, magnesium or calcium salts. Examples of suitable bases that can be used to form salts include ammonium or mineral bases such as sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and the like.

  Examples of suitable acids that can be used to form salts include inorganic or mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, nitric acid, carbonic acid, monohydrogen carbonate, phosphorus Acids, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, phosphorous acid and the like are included. Other suitable acids include organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p- Examples include tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, glucuronic acid, galacturonic acid, salicylic acid, formic acid, naphthalene-2-sulfonic acid, and the like. Still other suitable acids include amino acids such as alginic acid, aspartic acid, glutamic acid and the like.

  In one aspect of the invention, the composition includes homologues, analogs, derivatives, enantiomers and / or these functionally equivalent compositions of the compounds of the invention, eg, all of the aforementioned compounds. Detecting or treating such homologues, analogs, derivatives, enantiomers and their functionally equivalent compositions of this compound for Alzheimer's disease or other diseases characterized by the presence of metal ions Can be used in all assays, methods or compositions described above. “Sensually equivalent” generally refers to a subject who exhibits signs of Alzheimer's disease or other diseases characterized by the presence of metal ions, is susceptible to such diseases, or is otherwise Treatment of subjects at increased risk, or subjects who do not show signs of such disease, but for whom it is desirable to reduce the risk of such disease (eg, vaccination or prophylactic treatment) ) Means a composition that is possible.

  It is understood that those of ordinary skill in the art can manipulate the conditions in a manner that prepares such homologues, analogs, derivatives, enantiomers and functionally equivalent compositions. Accordingly, homologues, analogs, derivatives, enantiomers and / or functionally equivalent compositions that are approximately as effective or more effective than the base compound should also be used in the methods of the invention. Is intended. The synthesis of such compositions can be accomplished by typical chemical modification methods such as those routinely practiced in the industry.

  Another aspect of the present invention provides all of the compositions (or portions thereof) of the present invention and performs combinatorial synthesis on the compositions, preferably of homologues, analogs, derivatives, enantiomers and compositions. Including a method comprising obtaining these functionally equivalent compositions. Assays are performed on homologues, analogs, derivatives, enantiomers or functionally equivalent compositions to demonstrate this efficacy in the treatment, prevention or inhibition of Alzheimer's disease or other diseases characterized by the presence of metal ions. Can be determined. Combinatorial synthesis can include subjecting a plurality of compositions described herein to combinatorial synthesis using techniques known to those of ordinary skill in the art.

  The present invention is also useful in the treatment of Alzheimer's disease or other diseases characterized by the presence of metal ions, optionally in a kit, including instructions for using the composition for the treatment of such diseases. Provide all of the aforementioned packaged compositions. That is, the kit may be used for the use of the composition for involvement in all biological or chemical mechanisms disclosed herein associated with Alzheimer's disease or other diseases characterized by the presence of metal ions. Description can be included. The kit can include a description of the use of the compositions described herein. The kit can also include instructions for using a combination of two or more of the compositions of the invention. The instructions can also be given to administer the drug by any suitable technique described previously.

  The present invention also includes, in some embodiments, facilitating treatment of Alzheimer's disease or other diseases characterized by the presence of metal ions with all the techniques and compositions described herein. “Promoted” as used herein refers to, for example, sales, advertisements, assignments, licenses, contracts, instructions, education, research, which may be associated with the methods and compositions of the invention described herein. Includes all methods of doing business including, but not limited to, imports, exports, agreements, subsidies, loans, trade, commerce, resale, distribution, exchange, etc. Promotion can also include, in some cases, seeking approval from government agencies to sell the compositions of the invention for pharmaceutical purposes. Methods of promotion include, but are not limited to, business (public or private), contract or subcontracting contractors, educational facilities such as vocational schools and universities, research facilities, hospitals or other clinical facilities, government agencies, etc. It can be done by all groups.

  Promotional activities are all forms of instructions or communications specifically related to the present invention (eg based on documents, verbal and / or electronic communications, eg based on email, telephone, facsimile, internet, web, etc.) But is not limited to these). As used herein, “instructions” can define components such as instruction roles (eg, instructions, guidance, warnings, signs, cautions, FAQs (“Frequently Asked Questions”)), and typically The use of the composition in the treatment or prevention of documents, for example related to or related to and / or related to the packaging of the composition, such as Alzheimer's disease or other diseases characterized by the presence of metal ions, or The instructions also include all the instructions provided in all ways so that the user clearly recognizes that the instructions should be associated with the composition, eg, as described herein. Instructional communication in form (eg, verbal, electronic, digital, optical, visual, etc.) can be included.

  As used herein, a “kit” includes any one or combination of the compositions of the invention and / or homologues, analogs, derivatives, enantiomers and their functionally equivalent compositions and instructions. But also in connection with the composition of the present invention so that the clinical expert clearly recognizes that the instructions should be associated with the particular composition, eg, as described above. Define a package that can include instructions in all forms specified. The kits described herein can also include one or more containers, which in some cases can include a composition, such as those described above. The kit can also include instructions for mixing, diluting and / or administering the composition. The kit also includes other containers and compositions having one or more solvents, surfactants, preservatives and / or diluents (eg, saline (0.9% NaCl) or 5% dextrose). A container for mixing, dilution or administration to a subject can be included.

  The composition of the kit can be provided in all suitable forms, for example as a liquid solution or as a dry powder. When the provided composition is a dry powder, the composition can be reconstituted by adding a suitable solvent that can also be provided. In embodiments that use a liquid form of the composition, the liquid form can be concentrated or used. The solvent will depend on the formulation of the composition and the mode of use or administration. Suitable solvents for the pharmaceutical composition are well known and available in the literature.

The kit may comprise, in one group of embodiments, a carrier that is sectioned and received strictly limited to one or more container means, such as vials, tubes, etc., each section in the method Contains one of the distinct elements to be used. For example, one of the categories can contain a positive control for the assay. In addition, the kit can include containers for other components of the composition, eg, buffers that are useful in the assay.
The functionality and advantages of these and other aspects of the invention will be more fully understood from the following examples. The following examples are intended to illustrate the benefits of the present invention, but do not exemplify the full scope of the invention.

Example 1
In this example, circular dichroism (CD) is used to model NF-M17 (glu-glu-lys-gly-lys-), a model peptide from human neurofilaments when exposed to certain compounds of the invention. The conformational change of ser-pro-val-pro-lys-ser-pro-val-glu-glu-lys-gly) (SEQ ID NO: 1) (Figure 1) was monitored. These compounds included certain hydroxy derivatives of organosilanes and certain organosilicon compounds monools, diols and triols. These compounds were tested for their ability to restore the NF-M17 CD spectrum to this initial shape.

The experiment was performed as follows. NF-M17, a peptide containing the 17 amino acid region of a medium-sized subunit protein of human neurofilament, was synthesized with a purity higher than 95%. For CD titration, the peptide was dissolved in 2,2,2-trifluoroethanol (TFE) at a concentration of 0.4 mg / ml (0.2 mM). An aluminum solution (20 mM) was also prepared in TFE. Sodium metasilicate and sodium orthosilicate were dissolved in water. The sodium metasilicate solution was acidified to pH 6.0. The first CD spectra collected contained mainly information about the peptides only. Increasing addition of aluminum ions was made until 8 equivalents (8 microliter addition) of metal ions were added to the solution containing the peptide. Next, the maximum conformational change in 8 equivalents of aluminum was titrated with SiO ₄ ^4- . The addition to the solution was done as an increase in peptide molar equivalents and did not exceed 32 equivalents. CD spectra were collected and analyzed after each addition.

  The following silanetriols or their precursors were tested: 3-aminopropylsilanetriol (APST), 3- (trihydroxysilyl) propylmethylphosphonic acid sodium salt (TSPMP), n- after hydrolysis in water Octyltrichlorosilane (OTCS) and 3-cyanopropyltrichlorosilane (CPTCS) after hydrolysis in water. The following silanediols or their precursors were also tested in this example: diphenylsilanediol (DPSD), hexylmethyldichlorosilane (HMDS), methylphenyldichlorosilane (MPDS), dichlorodiethylsilane (DCDES), dichlorodiisopropyl. Silane (DCDIPS) and (dichloro) methylsilylbutyronitrile (DCMSBN). The following silanols or their precursors were also tested: potassium trimethylsilanolate (PTMS), tert-butyldimethylsilanol (TBDMS), triethylsilanol (TES) and benzyldiethylsilanol (BDS). APST, DPSD and APTES were obtained from Gelest, Inc. (Tullytown, PA). TFE, TSPMP, PTMS, TBDMS, TES, TPS, DCDIPS, DCDES, DCMSBN and BDS were obtained from Sigma-Aldrich (St. Louis, MO). OCS and CPTCS were obtained from Lancaster Synthesis (Windham, NH). These structures are shown in FIG.

  APST (FIG. 2A), TSPMP (FIG. 2B), PTMS (FIG. 2K), TBDMS (FIG. 2L), TES (FIG. 2M) and BDS (FIG. 2N) were each dissolved in TFE at a final concentration of 20 mM. Addition of 2 microliters to 100 microliters of peptide solution represented 2 equivalents.

  OTCS (Figure 2C), CPTCS (Figure 2D), HMDS (Figure 2F), DCDES (Figure 2H), DCDIPS (Figure 2I) and DCMSBN (Figure 2J) were each hydrolyzed in water to a final concentration of 20 mM. Diluted. MPDS was first dissolved in 50% TFE in water and then brought to a final concentration of 20 mM. MPDS (FIG. 2G) was first dissolved in 50% TFE in water and diluted to a final concentration of 20 mM. DPSD (FIG. 2E) was first dissolved in dimethyl sulfoxide (DMSO) and then brought to a final concentration of 20 mM in TFE. DMSO blanks (without peptide) were collected for each dilution (0.04% -1%).

  The results of these experiments are summarized in Table 1, FIGS. 3 and 4, show control experiments using sodium metasilicate nonahydrate and sodium orthosilicate, respectively, as the source of silicate ions. For sodium metasilicate, the CD curve showed some return to this initial shape at about 32 equivalents (FIG. 3D). However, sodium orthosilicate showed a return to the initial shape starting at 4 equivalents (FIG. 4C). Around 16 equivalents, the CD spectrum for sodium orthosilicate is similar in shape to the spectrum of the first NF-M17 (FIG. 4D).

Table 1

The APST solution used was a 22-25 wt% solution in water. The APST solution was able to recover the NF-M17 / aluminum CD spectrum to this initial shape and had better recovery at higher equivalents (FIG. 5). The APST solution also showed improved chelation of aluminum compared to sodium orthosilicate (Figure 6).
The TSPMP solution used was a 42 wt% solution in water. This triol did not successfully recover the first spectrum of NF-M17. The peptide precipitated from solution with increasing addition of TSPMP solution (data not shown).

The OTCS solution used was a 100% solution. With the addition of water, the organochlorosilane solution was gelled and did not recover the initial spectrum of the NF-M17 peptide (data not shown).
The CPTCS solution used was as a 100% solution. The CPTCS solution did not gel when water was added, and the solution recovered the CD spectrum of NF-M17 / aluminum to this initial shape around 32 equivalents (FIG. 7).

  DPSD did not recover the initial spectrum of NF-M17. The peptide precipitated from solution with increasing addition of DPSD solution (data not shown). In contrast, solutions of HMDS (FIG. 8), MPDS (FIG. 9), DCDES (FIG. 10), DCDIPS (FIG. 11), and DCMSBN (FIG. 12) each show the first CD spectrum of NF-M17 / aluminum. , Recovered to this initial shape around 32 equivalents.

PTMS, TBDMS, TES, and BDS solutions (data not shown) each did not recover the initial spectrum of the NF-M17 peptide.
In conclusion, organosilanes, diols, and triols recovered the initial CD spectrum of NF-M17 and thus showed the recovery of the initial conformation of NF-M17. Diols and triols can form a multivalent cross-linked entity that can preferably bind to aluminum and remove it from NF-M.

Example 2
This prophetic example illustrates a method for treating Alzheimer's disease in a human subject with a composition of the invention comprising an organosilicon compound that inhibits the interaction between aluminum and beta-amyloid. .
The subject is given the composition orally once a day in the form of a pill. The daily dose concentration is 4.0 mcmol / kg. Administration is carried out over a period of about 6 months. This treatment interferes with neurofibrillary tangles and further development of senile plaques.

Example 3
The amyloid peptide in TFE is believed to have a large degree of alpha-helical structure that has changed to a beta-sheet structure due to the presence of aluminum ions. This conversion is seen as signal flattening in the CD spectrum. Thus, a reagent that partially or completely restores the initial beta-amyloid signal can be interpreted as the binding of aluminum to the reagent, allowing the peptide to regain this natural alpha-helical property. To do.

  Amyloid peptide (human amyloid beta-protein 1-42, SynPep) is dissolved in a solution of 80% trifluoroethanol (“TFE”) / 20% water at 10 mg / ml to make a stock solution at 4 ° C. Stored in The stock solution was diluted from 0.45 nm / ml to 0.50 nm / ml in TFE for use in these experiments. The molecular weight of the peptide was 4315 Da; thus 0.45 mg / ml is equivalent to 100 micromolar. Aluminum perchlorate was dissolved in TFE at a concentration of 10 mg / ml. Silicate test reagents were dissolved and hydrolyzed in water, typically at 60 mM.

  CD spectra were determined for each sample as follows. The sample was placed in a JASCO J-810 spectropolarimeter in a cuvette with a volume of 100 ml and a passage length of 500 mm. The sensitivity of the instrument was about 100 millimeters. Each spectrum was scanned in a wavelength range of about 180 nm to about 260 nm, or about 180 nm to about 280 nm. The data interval was about 0.2 nm. The scan setting was made with a 1 second response at about 50 nm / min under continuous scanning. The presented data is data from two stores.

  Initially, TFE alone was scanned as a control to confirm a standard spectrum. Next, only the beta-amyloid peptide was scanned at the beginning of each reagent test. A 2-4 microliter aliquot of 10 mM aluminum perchlorate was then added with a 2-20 microliter micropipettor and a new scan was recorded. Mixing in the cuvette was done with a 100 microliter pipettor. Other experiments (not shown) revealed a significant flattening of the peptide spectrum with the addition of 8-12 microliters of aluminum (equal to about 8-12 molar equivalents). Aliquots of test compounds were added to the peptide and aluminum in the cuvette at 2-4 microliters at a time, mixed well, and the spectrum between each addition was assayed. This procedure was repeated for each compound. The cuvette was washed thoroughly with approximately 100 microliters of TFE 3-5 times during the assay.

  The compounds tested in this example were: 3-cyanopropyltrichlorosilane (CPTCS) (Figure 2D), dichlorodiethylsilane (DCDES) (Figure 2H), dichlorodiisopropylsilane (DCDIPS) (Figure 2I). (Dichloro) ethylmethylsilane (DCEMS) (FIG. 2O), hexylmethyldichlorosilane (HMDS) (FIG. 2F), (dichloro) methylsilylbutyronitrile (DCMSBN) (FIG. 2J), dichlorosilacyclobutane (DCSCB) ( 2P), 1,7-dioxa-6-silaspiro [5.5] undecane (SDSU) (FIG. 2Q), sodium orthosilicate, triethoxysilylbutyronitrile (TESB) (FIG. 2R), triethoxysilylpropio Nitrile (TESP) (FIG. 2S), phosphonate Hydroxysilyl propyl methyl (TSPM) (FIG. 2B), triethyl silanol (TES) (Fig. 2M), tetrakis (dimethylamino) silane ( "tetrakis") (Figure 2T) and tetra acetic silane (TAS) (Figure 2U). These compounds were obtained from Gelest (Morrisville, PA), Sigma-Aldrich (St. Louis, MO), Lancaster Synthesis (Windham, NH), Fluka (St. Louis, MO) and Alpha Aesar (Ward Hill, MA). It was.

  FIG. 13 illustrates the effect of aluminum on amyloid peptide. In FIG. 13, the CD spectrum of amyloid peptide decreases with higher concentrations of aluminum.

  FIG. 14 illustrates the effect of CPTCS on the aluminum-amyloid peptide system. In FIG. 14, adding 12 equivalents of aluminum to a solution containing amyloid peptide results in a major decrease in the CD spectrum. However, further addition of CPTCS can restore the CD spectrum of the peptide. A moderate reversal was seen at 6 and 12 equivalents, while an almost complete reversal of the effect of aluminum on the peptide was seen with the addition of 24 equivalents of CTPCS.

  Similar results were seen with DCDES. In FIG. 15, the addition of 8 equivalents of aluminum resulted in a major decrease in the CD spectrum of amyloid peptide, while the addition of DCDES to the system at least partially restored the CD spectrum, with higher equivalents of DCDES provided a greater amount of recovery. Similarly, DCDIPS (FIG. 16), DCEMS (FIG. 17), HMDS (FIG. 18), DCMSBN (FIG. 19), DCSCB (FIG. 20), SDSU (FIG. 21), sodium orthosilicate (FIG. 22), TESB (FIG. 23), TESP (FIG. 24), TSPMP (FIG. 25), TES (FIG. 26), Tetrakis (FIG. 27) and TAS (FIG. 28), respectively, after the peptide was exposed to aluminum, the first CD spectrum of the peptide At least partially recovered.

Example 4
In this example, the transport of various organosilicon compounds of the present invention across a cell monolayer that mimics the blood-brain barrier is illustrated. Two different cell lines were used as model blood-brain barrier systems: Caco-2 cells and bMVEC cells. The organosilicon compound was detected by EPA method 200.7 using inductively coupled plasma spectroscopy (ICP) using an ultrasonic nebulizer.

Caco-2 is a cell line derived from the human intestinal epithelium that is commonly used to study molecular transport across the epithelium with tight junctions. The Caco-2 cells used in these experiments were from Dr. Neil Simister's laboratory at Brandeis University, generated from ATCC (American Type Culture Collection). Cells were grown in Dulbecco's Modified Eagle Medium (DMEM) with 5% fetal calf serum, 50 microgram / ml gentamicin at 37 ° C. with 5% CO ₂ . Cells grown in Isgrove's medium and RPMI-1640 instead of DMEM showed a similar number of times and similar morphology to reach assembly (data not shown). Caco-2 cells were assayed by measuring electrical resistance with World Precision Instruments EVOM-G to form an electrically tight junction.

Cells were grown in tissue culture flasks and split (passed) when the assembly reached approximately 4: 1. Cells were seeded for experiments on Corning Costar Transwell inserts, polyester or polycarbonate with 0.4 micrometer pores. Cells on the transparent polyester film could be directly observed using phase contrast microscopy. Cells were fed with fresh media every 2-4 days. Cells were used for the assay when the electrical resistance of the cell monolayer was at least 400 ohm / cm ² .

  Bovine microvascular epithelial cells are primary cells from bovine brain purchased frozen from Cambrex Bio Science. These cells were grown on collagen-coated membrane inserts that were overcoated with fibronectin. The medium used was endothelial basic medium 2 (Clonetics), which captured bECGF, ascorbic acid, platelet-deficient horse serum, penicillin, streptomycin and fungizone (provided as a kit by Cambrex). One aliquot of cells was diluted, split, and seeded with 48 6.5 mm membranes (Corning Coster polyester, 0.4 micrometer pores). Cells were fed with fresh media every 2-3 days and used when visually assembled.

  Six compounds were tested for transport across two cell lines in this example: SDSU, DCSCB, TSPM, TESB, DCMSBN, and DCEMS. Data from these experiments are evident in FIGS. 29A and 29B (Caco-2 cells) and FIG. 30 (bMVEC). In FIGS. 29A and 29B, the transport of these organosilicon compounds is plotted as a function of frequency and time. The starting concentration on the apical side for each compound is in the range of 1 mM to 10 mM. In all cases, a significant amount of transport across Caco-2 cells is observed, with higher amounts observed for TESB, DCMSBN and DCEMS (FIG. 29B) than TSPM, DCSCB and SDSU (FIG. 29A). It was done.

FIG. 30 illustrates the transport of these compounds across bMVEC cells. In FIG. 30, the data is plotted for transport after 4 and 24 hours for two different donor concentrations. In all cases, a significant amount of transport was observed, with higher amounts occurring at the higher concentration peaks.
This example thus illustrates that various compounds of the present invention can be successfully transported across the blood-brain barrier.

Example 5
This example illustrates a method of making 1,7-dioxa-6-sila-spiro [5.5] undecane (FIG. 2Q) in one embodiment of the invention.

A 2 liter, 4-necked flask equipped with a dry ice condenser, upper stirrer, pot thermometer and funnel was charged with 54.29 g of SiCl ₄ . 4-Chloro-1-butanol was added through a funnel at a pot temperature below 40 ° C. over a period of about 30 minutes. The mixture was stirred at room temperature for about 4 hours. Next, 250 ml of ether was added, followed by 4.86 g of magnesium powder (turning). After stirring at room temperature for 14 hours, 125 ml of tetrahydrofuran (“THF”) was added in 5 parts over a period of 1 hour. After all the magnesium powder was consumed, another 4.86 g of magnesium was added, followed by another 125 ml of tetrahydrofuran. The mixture was stirred at room temperature for 6 hours and then allowed to settle overnight. The superliquid was transferred to another flask and the salt was washed with 125 ml ether. The solutions were combined and then distilled using a short column. 5.32 g (12.4% yield) of the desired product was obtained by heating at 8 mm Hg and a head temperature of 55 ° C.

Schematically, this reaction can be expressed as follows:

The physical data for this reaction is as follows:

  While some aspects of the invention have been described and illustrated herein, a person of ordinary skill in the art will perform the function and / or the results and / or one or two described herein. To obtain the above advantages, various other means and / or structures are readily envisioned and each such alteration and modification is considered to be within the scope of the present invention. More generally, those skilled in the art will mean that all parameters, dimensions, materials and forms described herein are exemplary, and that actual parameters, dimensions, materials and forms are It will be readily understood that it depends on the particular application or applications that use the teachings. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Accordingly, the foregoing aspects are presented by way of example only, and methods other than those specifically described and / or claimed are within the scope of the appended claims and their equivalents. It should be understood that can be implemented in The present invention is directed to each individual feature, system, material and / or method described herein. Further, all combinations of two or more of such features, systems, articles, materials and / or methods are inconsistent with each other in such features, systems, articles, materials and / or methods. If not, it is included within the scope of the present invention.

It is to be understood that the definitions used herein dominate beyond the normal meaning of dictionary definitions, references in literature introduced by reference, and / or defined terms.
Also, in the contrary, in all methods claimed in this application that involve more than one action, the order of the actions of the method is not necessarily limited to the order in which the actions of the method are cited, unless explicitly indicated otherwise. You should understand that.

  In the claims and in the foregoing specification, all transitional phrases such as `` comprising '', `` including '', `` carrying '', `` having '', `` containing '' ) "," Involving "," holding "and the like are to be understood as meaning unrestricted, i.e. including but not limited. Only the transitional phrases “consisting of” and “consisting essentially of” are transitions that are restricted or in accordance with the restrictions, respectively, as described in the US Patent Office Patent Examination Manual, Section 2111.03. It shall be a phrase.

It is a figure which shows a neurofilament arrangement | sequence (sequence number 1). One example of a chemical structure useful in the present invention is shown. Other examples of chemical structures useful in the present invention are shown. Other examples of chemical structures useful in the present invention are shown. Other examples of chemical structures useful in the present invention are shown. Other examples of chemical structures useful in the present invention are shown. Other examples of chemical structures useful in the present invention are shown. Other examples of chemical structures useful in the present invention are shown. Other examples of chemical structures useful in the present invention are shown. Other examples of chemical structures useful in the present invention are shown. Other examples of chemical structures useful in the present invention are shown. Other examples of chemical structures useful in the present invention are shown. Other examples of chemical structures useful in the present invention are shown. Other examples of chemical structures useful in the present invention are shown. Other examples of chemical structures useful in the present invention are shown. Other examples of chemical structures useful in the present invention are shown. Other examples of chemical structures useful in the present invention are shown. Other examples of chemical structures useful in the present invention are shown. Other examples of chemical structures useful in the present invention are shown. Other examples of chemical structures useful in the present invention are shown. Other examples of chemical structures useful in the present invention are shown. Other examples of chemical structures useful in the present invention are shown. FIG. 2 shows the effect of sodium metasilicate hydrate on the neurofilament of FIG. 1 as shown by circular dichroism (CD) data plotted as ellipticity versus wavelength. FIG. 2 shows the effect of sodium metasilicate hydrate on the neurofilament of FIG. 1 as shown by circular dichroism (CD) data plotted as ellipticity versus wavelength. FIG. 2 shows the effect of sodium metasilicate hydrate on the neurofilament of FIG. 1 as shown by circular dichroism (CD) data plotted as ellipticity versus wavelength. FIG. 2 shows the effect of sodium metasilicate hydrate on the neurofilament of FIG. 1 as shown by circular dichroism (CD) data plotted as ellipticity versus wavelength. It is a figure which shows the effect of sodium orthosilicate with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of sodium orthosilicate with respect to the neurofilament of FIG. 1 shown with CD data. It is a figure which shows the effect of sodium orthosilicate with respect to the neurofilament of FIG. 1 shown with CD data. It is a figure which shows the effect of sodium orthosilicate with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of sodium orthosilicate with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of 3-aminopropyl silane triol with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of 3-aminopropyl silane triol with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of 3-aminopropyl silane triol with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of 3-aminopropyl silane triol with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of 3-aminopropyl silane triol with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of 3-aminopropyl silane triol with respect to the neurofilament of FIG. 1 shown by CD data. FIG. 5 shows comparative CD data for sodium orthosilicate versus 3-aminopropylsilanetriol. FIG. 5 shows comparative CD data for sodium orthosilicate versus 3-aminopropylsilanetriol. FIG. 5 shows comparative CD data for sodium orthosilicate versus 3-aminopropylsilanetriol. FIG. 5 shows comparative CD data for sodium orthosilicate versus 3-aminopropylsilanetriol. It is a figure which shows the effect of 3-cyanopropyl trichlorosilane with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of 3-cyanopropyl trichlorosilane with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of 3-cyanopropyl trichlorosilane with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of 3-cyanopropyl trichlorosilane with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of hexyl methyl dichlorosilane with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of hexyl methyl dichlorosilane with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of hexyl methyl dichlorosilane with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of hexyl methyl dichlorosilane with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of the methylphenyl dichlorosilane with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of the methylphenyl dichlorosilane with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of the methylphenyl dichlorosilane with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of the methylphenyl dichlorosilane with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of the dichlorodiethylsilane with respect to the neurofilament of FIG. 1 shown with CD data. It is a figure which shows the effect of the dichlorodiethylsilane with respect to the neurofilament of FIG. 1 shown with CD data. It is a figure which shows the effect of the dichlorodiethylsilane with respect to the neurofilament of FIG. 1 shown with CD data. It is a figure which shows the effect of the dichlorodiethylsilane with respect to the neurofilament of FIG. 1 shown with CD data. It is a figure which shows the effect of the dichlorodiisopropylsilane with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of the dichlorodiisopropylsilane with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of the dichlorodiisopropylsilane with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of the dichlorodiisopropylsilane with respect to the neurofilament of FIG. 1 shown by CD data. It is a figure which shows the effect of the dichlorodiisopropylsilane with respect to the neurofilament of FIG. 1 shown by CD data. FIG. 2 shows the effect of (dichloro) methylsilylbutyronitrile on the neurofilament of FIG. 1 as shown by CD data. FIG. 2 shows the effect of (dichloro) methylsilylbutyronitrile on the neurofilament of FIG. 1 as shown by CD data. FIG. 2 shows the effect of (dichloro) methylsilylbutyronitrile on the neurofilament of FIG. 1 as shown by CD data. FIG. 2 shows the effect of (dichloro) methylsilylbutyronitrile on the neurofilament of FIG. 1 as shown by CD data. FIG. 2 shows the effect of (dichloro) methylsilylbutyronitrile on the neurofilament of FIG. 1 as shown by CD data. It is a figure which shows the effect of aluminum with respect to human amyloid beta protein illustrated by CD data. It is a figure which shows the effect of 3-cyanopropyl trichlorosilane with respect to the amyloid protein illustrated by CD data. It is a figure which shows the effect of the dichlorodiethylsilane with respect to the amyloid protein illustrated by CD data. It is a figure which shows the effect of the dichloro diisopropylsilane with respect to amyloid protein illustrated by CD data. It is a figure which shows the effect of (dichloro) ethylmethylsilane with respect to amyloid protein illustrated by CD data. It is a figure which shows the effect of hexylmethyldichlorosilane with respect to the amyloid protein illustrated by CD data. It is a figure which shows the effect of the (dichloro) methylsilyl butyronitrile with respect to the amyloid protein illustrated by CD data. It is a figure which shows the effect of the dichlorosilacyclobutane with respect to the amyloid protein illustrated by CD data. It is a figure which shows the effect of 1,7- dioxa-6-sila-spiro [5.5] undecane with respect to amyloid protein illustrated by CD data. It is a figure which shows the effect of sodium orthosilicate with respect to amyloid protein illustrated by CD data. It is a figure which shows the effect of the triethoxysilyl butyronitrile with respect to the amyloid protein illustrated by CD data. It is a figure which shows the effect of the triethoxy silyl propionitrile with respect to the amyloid protein illustrated by CD data. It is a figure which shows the effect of the phosphonate trihydroxysilylpropyl methyl with respect to the amyloid protein illustrated by CD data. It is a figure which shows the effect of the triethylsilanol with respect to the amyloid protein illustrated by CD data. It is a figure which shows the effect of the tetrakis (dimethylamino) silane with respect to the amyloid protein illustrated by CD data. It is a figure which shows the effect of tetraacetoxysilane with respect to amyloid protein illustrated by CD data. FIG. 2 shows transport of certain organosilicon compounds of the present invention across Caco-2 cells. FIG. 3 shows transport of other organosilicon compounds of the present invention across Caco-2 cells. FIG. 2 shows molecular transport of certain organosilicon compounds of the present invention across bMVEC cells.

Claims (180)

One subject who is susceptible to or presents with Alzheimer's disease has the following structure:

In the formula:
Each of Z ¹ , Z ² , Z ³ and Z ⁴ is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² ;
R contains at least one carbon atom;
X is one halogen,
R ¹ contains at least one carbon atom;
J ¹ and J ² are each independently H or contain at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom;
In the formula:
At least one of Z ¹ , Z ² , Z ³ and Z ⁴ comprises at least one carbon atom;
Z ¹ , Z ² , Z ³ and Z ⁴ are all not simultaneously one of H or R;
Z ¹ , Z ² , Z ³ and Z ⁴ are not all acetates at the same time;
One compound having the following or one salt thereof;
Administering a therapeutically effective amount of a composition comprising in combination with one pharmaceutically acceptable carrier.   2. The method of claim 1, wherein the subject does not require treatment with the composition otherwise.   2. The method of claim 1, wherein the composition is unable to cross the subject's blood-brain barrier.   2. The method of claim 1, wherein the composition is capable of crossing the subject's blood-brain barrier. The method of claim 1, wherein at least one of Z ¹ , Z ² , Z ³ and Z ⁴ is independently X. The method of claim 5, wherein at least two of Z ¹ , Z ² , Z ³ and Z ⁴ are independently X. The method of claim 6, wherein ^{three of} Z ¹ , Z ² , Z ³ and Z ⁴ are independently X. Z ^1, at least one ^Z 2, ^{Z 3} and ^{Z 4} is a Cl, A method according to claim 5. Z ^1, at least two ^Z 2, ^{Z 3} and ^{Z 4} is a Cl, A method according to claim 8. The method of claim 9, wherein at least three of Z ¹ , Z ² , Z ³ and Z ⁴ are Cl. The method of claim 1, wherein at least one of Z ¹ , Z ² , Z ³ and Z ⁴ is OH. The method of claim 11, wherein at least two of Z ¹ , Z ² , Z ³ and Z ⁴ are OH. Z ^1, three ^Z 2, ^{Z 3} and ^{Z 4} is a OH, The method of claim 12. The method of claim ¹ , wherein at least one of Z ¹ , Z ² , Z ³ and Z ⁴ is independently OR ¹ . Z ^1, at least two ^Z 2, ^{Z 3} and ^{Z 4} is a OR ¹ is independently method according to claim 14. The method of claim 15, wherein at least three of Z ¹ , Z ² , Z ³ and Z ⁴ are independently OR ¹ . The method of claim 16, wherein each of Z ¹ , Z ² , Z ³ and Z ⁴ is independently OR ¹ . The method of claim 14, wherein at least one of Z ¹ , Z ² , Z ³ and Z ⁴ is OEt. The method of claim 18, wherein at least two of Z ¹ , Z ² , Z ³ and Z ⁴ are OEt. ^{Z 1,} Z 2, at least 3 of the ^{Z 3} and ^{Z 4} is a OEt, The method of claim 19. Z ^1, at least one ^Z 2, ^{Z 3} and ^{Z 4} is a OAc, The method of claim 14. The method of claim 21, wherein at least two of Z ¹ , Z ² , Z ³ and Z ⁴ are OAc. ^{Z 1,} Z 2, at least 3 of the ^{Z 3} and ^{Z 4} is a OAc, The method of claim 22. Z ^1, at least one ^Z 2, ^{Z 3} or ^{Z 4} is a tert- butoxy, method of claim 14. Z ^1, at least two ^Z 2, ^{Z 3} and ^{Z 4} is a tert- butoxy The method of claim 24. Z ^1, at least three ^Z 2, ^{Z 3} and ^{Z 4} is a tert- butoxy The method of claim 25. The method of claim 1, wherein at least one of Z ¹ , Z ² , Z ³ and Z ⁴ is independently NJ ¹ J ² . Z ^1, at least two ^Z 2, ^{Z 3} and ^{Z 4} is a ^NJ 1 ^{J 2} are independently method of claim 27. The method according to Z ^{1, Z} 2, ^{Z 3} and at least three ^{Z 4} is a ^NJ 1 ^{J 2} are independently claim 28. Z ^{1, Z} 2, ^{Z 3} and ^{Z 4} are independently a ^NJ 1 ^{J 2,} The method of claim 29. At least one ^NJ 1 ^{J 2} is NH _2, A method according to claim 27. At least one ^NJ 1 ^{J 2} is ^{NHR 10, R 10} comprises at least one carbon atom, the method of claim 27. At least one ^NJ 1 ^{J 2} is ^NR 10 ^{R 11,} each of ^{R 10} and ^{R 11} are independently at least one carbon atom, the method of claim 27. The method of claim 1, wherein at least one of Z ¹ , Z ² , Z ³ and Z ⁴ comprises a carbon atom covalently bonded to Si. Z ^1, at least one of ^Z 2, ^{Z 3} and ^{Z 4} is a R independently method of claim 34. Z ^{1, Z} 2, ^{Z 3} and at least two ^{Z 4} is a R independently method of claim 35. Z ^1, three ^Z 2, ^{Z 3} and ^{Z 4} is a R independently method of claim 36.   36. The method of claim 35, wherein at least one R is alkyl.   40. The method of claim 38, wherein at least one alkyl is methyl.   40. The method of claim 38, wherein at least one alkyl is ethyl.   40. The method of claim 38, wherein at least one alkyl is isopropyl.   40. The method of claim 38, wherein at least one alkyl is tert-butyl.   40. The method of claim 38, wherein at least one alkyl is hexyl.   40. The method of claim 38, wherein at least one alkyl is octyl. The method of claim 1, wherein at least one of Z ¹ , Z ² , Z ³ and Z ⁴ independently comprises one aminoalkyl. At least one aminoalkyl has one structure:

46. The method of claim 45, comprising: The method of claim 1, wherein at least one of Z ¹ , Z ² , Z ³ and Z ⁴ independently comprises one cyanoalkyl. At least one cyanoalkyl has one structure:

48. The method of claim 47, comprising: The method of claim 1, wherein at least one of Z ¹ , Z ² , Z ³ and Z ⁴ independently comprises one aromatic moiety.   50. The method of claim 49, wherein the at least one aromatic moiety is benzyl.   50. The method of claim 49, wherein the at least one aromatic moiety is phenyl. The method of claim 1, wherein at least one of Z ¹ , Z ² , Z ³ and Z ⁴ comprises one phosphono moiety. The method of claim 1, wherein at least one of Z ¹ , Z ² , Z ³ and Z ⁴ comprises one silicon atom. The method of claim 1, wherein each of Z ¹ and Z ² is independently X, and each of Z ³ and Z ⁴ is independently R. The method of claim 1, wherein each of Z ¹ , Z ² and Z ³ is independently X and Z ⁴ is R. The method of claim ¹ , wherein each of Z ¹ , Z ² and Z ³ is independently OR ¹ and Z ⁴ is R. The method of claim ¹ , wherein each of Z ¹ , Z ² and Z ³ is independently OR ¹ and Z ⁴ is OH. The method of claim 1, wherein each of Z ¹ , Z ² and Z ³ is OH and Z ⁴ is R. The method of claim 1, wherein each of Z ¹ and Z ² is OH, and each of Z ³ and Z ⁴ is independently R. The method of claim 1, wherein Z ¹ is OH and each of Z ² , Z ³ and Z ⁴ is independently R. The method of claim 1, wherein each of Z ¹ , Z ² and Z ³ is OH and Z ⁴ comprises one amine. The method of claim ¹ , wherein each of Z ¹ , Z ² and Z ³ is independently OR ¹ and Z ⁴ comprises one amine. The method of claim 1, wherein each of Z ¹ , Z ^2, and Z ³ is OH and Z ⁴ comprises one aminoalkyl. The method of claim ¹ , wherein each of Z ¹ , Z ² and Z ³ is independently OR ¹ and Z ⁴ comprises one aminoalkyl. A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising: A compound has one structure:

The method of claim 1, comprising:   2. The method of claim 1, wherein administering comprises administering the composition into the subject's brain. One subject who is susceptible to or presents with Alzheimer's disease has the following structure:

In the formula:
Each of Z ¹ and Z ² is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² ;
R contains at least one carbon atom;
X is one halogen,
R ¹ contains at least one carbon atom;
J ¹ and J ² are each independently H or contain at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom;
In the formula:
A is a moiety having at least one of a carbon atom and a silicon atom;
Each of E ¹ and E ² is independently either (a) one of O and NJ ³ or (b) absent such that Si is covalently bonded to moiety A;
Thus E ¹ and E ² are not both absent,
J ³ is H or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom;
One compound having the following or one salt thereof;
Administering a therapeutically effective amount of a composition comprising in combination with one pharmaceutically acceptable carrier.   94. The method of claim 92, wherein the subject does not require treatment with the composition otherwise.   94. The method of claim 92, wherein the composition is unable to cross the subject's blood-brain barrier.   94. The method of claim 92, wherein the composition is capable of crossing the subject's blood-brain barrier. At least one of Z ¹ and ^{Z 2} is a X independently method of claim 92. Each of Z ¹ and ^{Z 2} are independently a X, A method according to claim 96. At least one of Z ¹ and ^{Z 2} is a Cl, A method according to claim 96. Each of Z ¹ and ^{Z 2} are Cl, A method according to claim 98. At least one of E ¹ and ^{E 2} but is absent The method of claim 92. Each of E ¹ and ^{E 2} is absent The method of claim 100. At least one of E ¹ and ^{E 2} but O, and The method of claim 92. Each of E ¹ and ^{E 2} are O, and The method of claim 102. At least one of E ¹ and ^{E 2} is a NJ ³ independently method of claim 92. E ¹ and each independently NJ ³ of ^{E 2,} The method of claim 104. A is one structure:

94. The method of claim 92, comprising:   94. The method of claim 92, wherein the compound is chiral.   94. The method of claim 92, wherein the compound is achiral. A compound has one structure:

94. The method of claim 92, comprising: One subject who is susceptible to or presents with Alzheimer's disease has the following structure:

In the formula:
Each of A ¹ and A ² is independently a moiety having at least one of a carbon atom and a silicon atom;
Each of E ¹ and E ² is independently either (a) one of O and NJ ³ or (b) absent such that Si is covalently bonded to moiety A ¹ ;
Thus E ¹ and E ² are not both absent,
J ³ is H or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom;
And in the formula:
Each of E ³ and E ⁴ is independently either (a) one of O and NJ ⁴ or (b) absent such that Si is covalently bonded to moiety A ² ;
J ⁴ is H or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom;
One compound having the following or one salt thereof;
Administering a therapeutically effective amount of a composition comprising in combination with one pharmaceutically acceptable carrier.   111. The method of claim 110, wherein the subject does not require treatment with the composition otherwise.   111. The method of claim 110, wherein the composition is unable to cross the subject's blood-brain barrier.   111. The method of claim 110, wherein the composition can cross the subject's blood-brain barrier. At least one of E ¹ and ^{E 3} but is O, The method of claim 110. Each of E ¹ and ^{E 3} are O, and The method of claim 114. A structure in which at least one of A ¹ and A ² is one:

111. The method of claim 110, comprising: Each of A ¹ and A ² has one structure:

117. The method of claim 116, comprising: E ^1, at least one of ^E 2, ^{E 3} and ^{E 4} but is absent The method of claim 110. E ^1, at least two ^E 2, ^{E 3} and ^{E 4} but is absent The method of claim 110. A compound has one structure:

111. The method of claim 110, comprising:   111. The method of claim 110, wherein the compound is chiral.   111. The method of claim 110, wherein the compound is achiral. A compound has one structure:

111. The method of claim 110, comprising: One subject who is susceptible to or presents with Alzheimer's disease has the following structure:

In the formula:
Y contains at least one carbon atom;
Each of Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² ;
R contains at least one carbon atom;
X is one halogen,
R ¹ contains at least one carbon atom;
J ¹ and J ² are each independently H or contain at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom;
In the formula:
Each of E ¹ and E ² is independently one of O and NJ ³ ;
J ³ is H or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom;
One compound having the following or one salt thereof;
Administering a therapeutically effective amount of a composition comprising in combination with one pharmaceutically acceptable carrier.   125. The method of claim 124, wherein the subject does not require treatment with the composition otherwise.   125. The method of claim 124, wherein the composition is unable to cross the subject's blood-brain barrier.   129. The method of claim 124, wherein the composition is capable of crossing the subject's blood-brain barrier. One subject who is susceptible to or presents with Alzheimer's disease has the following structure:

In the formula:
Each of Y ¹ and Y ² independently comprises at least one carbon atom;
Each of Z ¹ , Z ² , Z ³ and Z ⁴ is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² ;
R contains at least one carbon atom;
X is one halogen,
R ¹ contains at least one carbon atom;
J ¹ and J ² are each independently H or contain at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom;
In the formula:
Each of E ¹ , E ² , E ³ and E ⁴ is independently one of O and NJ ³ ;
J ³ is H or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom;
One compound having the following or one salt thereof;
Administering a therapeutically effective amount of a composition comprising in combination with one pharmaceutically acceptable carrier.   129. The method of claim 128, wherein the subject does not require treatment with the composition otherwise.   Administering to a subject susceptible to or exhibiting Alzheimer's disease a therapeutically effective amount of a composition comprising at least one of a silanol compound, a silanediol compound and a silanetriol compound ,Method.   134. The method of claim 130, wherein the subject does not require treatment with the composition otherwise.   A composition comprising a compound susceptible to Alzheimer's disease or exhibiting this sign comprising a compound that can be hydrolyzed to at least one of a silanol compound, a silanediol compound, and a silanetriol compound within the subject. Administering a therapeutically effective amount.   135. The method of claim 132, wherein the subject does not require treatment with the composition otherwise.   One subject susceptible to or exhibiting Alzheimer's disease includes a compound that can be hydrolyzed within the subject to form a compound that can bind to a trivalent metal ion Administering a therapeutically effective amount of the composition.   135. The method of claim 134, wherein the subject does not require treatment with the composition otherwise.   135. The method of claim 134, wherein the compound that can be hydrolyzed comprises silicon.   135. The method of claim 134, wherein the compound capable of binding to a trivalent metal ion comprises silicon.   135. The method of claim 134, wherein the trivalent metal ion is an aluminum ion.   Administering a therapeutically effective amount of a composition comprising a cyclic organosilicon compound to a subject susceptible to or exhibiting Alzheimer's disease.   140. The method of claim 139, wherein the subject does not require treatment with the composition otherwise.   140. The method of claim 139, wherein the cyclic organosilicon compound is at least bicyclic.   140. The method of claim 139, wherein the cyclic organosilicon compound comprises a spiro moiety.   Administering to a subject susceptible to or exhibiting Alzheimer's disease a therapeutically effective amount of a composition comprising a compound having silicon and nitrogen atoms within the molecular structure of the compound ,Method.   145. The method of claim 143, wherein the subject does not require treatment with the composition otherwise.   145. The method of claim 143, wherein the nitrogen atom is covalently bonded to the silicon atom.   145. The method of claim 143, wherein the nitrogen atom is not covalently bonded to the silicon atom.   145. The method of claim 143, wherein the compound contains more than one nitrogen atom.   145. The method of claim 143, wherein the compound contains more than one silicon atom.   Administering to a subject susceptible to or exhibiting Alzheimer's disease a therapeutically effective amount of a composition comprising a compound comprising at least two silicon atoms in the molecular structure of the compound. Including.   149. The method of claim 149, wherein the subject does not require treatment with the composition otherwise.   150. The method of claim 149, wherein the compound is a polymer.   Administering to a subject susceptible to or exhibiting Alzheimer's disease a therapeutically effective amount of a composition comprising a polymer having a repeating unit comprising at least one silicon atom, Method.   153. The method of claim 152, wherein the subject does not require treatment with the composition otherwise.   153. The method of claim 152, wherein at least one of the at least one silicon atom of the repeat unit is bonded to a halogen.   153. The method of claim 152, wherein at least one of the at least one silicon atom of the repeat unit is bonded to OH.   153. The method of claim 152, wherein at least one of the at least one silicon atom of the repeat unit is bonded to OR and R comprises at least one carbon atom. At least one silicon atom of the repeating unit is bonded to NJ ¹ J ² and J ¹ and J ² are each independently H, or one carbon atom, one nitrogen atom 153. The method of claim 152, comprising at least one of one oxygen atom or one sulfur atom. One structure:

In the formula:
Each of Z ¹ , Z ² , Z ³ and Z ⁴ is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² ;
R contains at least one carbon atom;
X is one halogen,
R ¹ contains at least one carbon atom;
J ¹ and J ² are each independently H or contain at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom;
In the formula:
At least one of Z ¹ , Z ² , Z ³ and Z ⁴ comprises at least one carbon atom;
Z ¹ , Z ² , Z ³ and Z ⁴ are all not simultaneously one of H or R;
Z ¹ , Z ² , Z ³ and Z ⁴ are not all acetates at the same time;
One compound having the following or one salt thereof;
A composition comprising in combination with one pharmaceutically acceptable carrier. One structure:

In the formula:
Each of Z ¹ and Z ² is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² ;
R contains at least one carbon atom;
X is one halogen,
R ¹ contains at least one carbon atom;
J ¹ and J ² are each independently H or contain at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom;
In the formula:
A is a moiety having at least one of one carbon atom and one silicon atom;
Each of E ¹ and E ² is independently either (a) one of O and NJ ³ or (b) absent such that Si is covalently bonded to moiety A;
Thus E ¹ and E ² are not both absent,
J ³ is H or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom;
One compound having the following or one salt thereof;
A composition comprising in combination with one pharmaceutically acceptable carrier. One structure:

In the formula:
Each of A ¹ and A ² is independently a moiety having at least one of one carbon atom and one silicon atom;
Each of E ¹ and E ² is independently either (a) one of O and NJ ³ or (b) absent such that Si is covalently bonded to moiety A;
Thus E ¹ and E ² are not both absent,
J ³ is H or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom;
In the formula:
Each of E ³ and E ⁴ is independently either (a) one of O and NJ ⁴ or (b) absent such that Si is covalently bonded to moiety A ² ;
J ⁴ is H or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom;
One compound having the following or one salt thereof;
A composition comprising in combination with one pharmaceutically acceptable carrier. One structure:

In the formula:
Y contains at least one carbon atom;
Each of Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² ;
R contains at least one carbon atom;
X is one halogen,
R ¹ contains at least one carbon atom;
J ¹ and J ² are each independently H or contain at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom;
In the formula:
Each of E ¹ and E ² is independently one of O and NJ ³ ;
J ³ is H or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom;
One compound having the following or one salt thereof;
A composition comprising in combination with one pharmaceutically acceptable carrier. One structure:

In the formula:
Each of Y ¹ and Y ² independently comprises at least one carbon atom;
Each of Z ¹ , Z ² , Z ³ and Z ⁴ is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² ;
R contains at least one carbon atom;
X is one halogen,
R ¹ contains at least one carbon atom;
J ¹ and J ² are each independently H or contain at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom;
In the formula:
Each of E ¹ , E ² , E ³ and E ⁴ is independently one of O and NJ ³ ;
J ³ is H or contains at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom;
One compound having the following or one salt thereof;
A composition comprising in combination with one pharmaceutically acceptable carrier.   Administering a therapeutically effective amount of one composition comprising one compound having one silicon atom to one nervous system of one subject susceptible to or exhibiting Alzheimer's disease Including a method.   166. The method of claim 163, wherein administering comprises administering the composition to the brain. The compound has one structure:

In the formula:
Each of Z ¹ , Z ² , Z ³ and Z ⁴ is independently one of H, X, R, OH, OR ¹ or NJ ¹ J ² ;
R contains at least one carbon atom;
X is one halogen,
R ¹ contains at least one carbon atom;
J ¹ and J ² are each independently H or contain at least one of one carbon atom, one nitrogen atom, one oxygen atom or one sulfur atom;
164. The method of claim 163, having the one salt.   166. The method of claim 165, wherein the composition comprises a pharmaceutically acceptable carrier. Z ^1, at least one ^Z 2, ^{Z 3} and ^{Z 4} is a OH, The method of claim 165. Z ^1, at least two ^Z 2, ^{Z 3} and ^{Z 4} is a OH, The method of claim 167. ^{Z 1,} Z 2, at least 3 of the ^{Z 3} and ^{Z 4} is a OH, The method of claim 168. Each Z ^{1, Z} 2, ^{Z 3} and ^{Z 4} are OH, The method of claim 169. Z ^1, at least one ^Z 2, ^{Z 3} and ^{Z 4} is a acetate The method of claim 165. Z ^1, at least two ^Z 2, ^{Z 3} and ^{Z 4} is a acetate The method of claim 171. Z ^1, at least three ^Z 2, ^{Z 3} and ^{Z 4} is a acetate The method of claim 172. Each Z ^{1, Z} 2, ^{Z 3} and ^{Z 4} are acetate The method of claim 173.   164. The method of claim 163, wherein the composition comprises silicate.   175. The method of claim 175, wherein the composition comprises sodium silicate.   164. The method of claim 163, wherein the composition comprises metasilicate.   178. The method of claim 177, wherein the composition comprises sodium metasilicate.   166. The method of claim 163, wherein the silicon compound is selected from the group consisting of salts, acids, oxides, and combinations thereof.   166. The method of claim 163, wherein the composition is unable to cross the subject's blood-brain barrier.

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