CN101578098B - Medicine, medicine guider, magnetic detection device and drug design method - Google Patents
Medicine, medicine guider, magnetic detection device and drug design method Download PDFInfo
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- CN101578098B CN101578098B CN200780032275.1A CN200780032275A CN101578098B CN 101578098 B CN101578098 B CN 101578098B CN 200780032275 A CN200780032275 A CN 200780032275A CN 101578098 B CN101578098 B CN 101578098B
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Abstract
The present invention can solve technical problem in the past, realizes the drug delivery system being easy to practical application.By be made up of organic compound or inorganic compound, by crosslinked between the modification of side chain and/or side chain the magnetic medicine of tool, use magnetic force to guide to target tissue or affected part.
Description
Technical field
The present invention relates to medicine, medicine guider, magnetic detection device and drug design method.
Background technology
Usually, arriving affected part after drug administration to organism, producing therapeutic effect by playing pharmacological action on the local location of this affected part, if but medicine arrives tissue (that is, normal structure) beyond affected part, then can not become a kind for the treatment of.Therefore, how effectively guide drugs arrival affected part is very important on therapeutic strategy.The technology that this guide drugs arrives affected part is called as drug delivery, and its research and development in recent years are actively carried out.This drug delivery has at least two advantages.An advantage is in affected tissue, obtain fully high drug level.If this is because the drug level in affected part does not reach more than certain value, do not find pharmacological effect, the therapeutic effect of expecting when concentration is low, can not be obtained.Second advantage is that only medicine, to affected tissue, and is not guided to unnecessary normal structure by guide drugs.Thus, side effect can be suppressed.
Described drug delivery plays optimum efficiency in the treatment of cancer using anticarcinogen to carry out.Because most of anticarcinogen suppresses the cell proliferation of mitotically active cancerous cell, the therefore cell proliferation of the also mitotically active tissue of T suppression cell, such as bone marrow or root of hair, gastrointestinal mucosal etc. in the normal tissue.Therefore, in the cancer patient accepting administration with anticancer agents, there is the side effect such as anemia, alopecia, vomiting.Because these side effect become white elephant for patient, therefore must limit dosage, thus there is the problem that fully can not obtain the pharmacological effect of anticarcinogen.In addition, the worst situation, may cause death due to side effect.Therefore, expect to guide anticarcinogen to arrive cancerous cell by drug delivery, and concentrate on cancerous cell, make it play pharmacological effect, while suppressing side effect thus, effectively can carry out treatment of cancer.
Apart from anticancer agents, it is also conceivable to the application in such as male erectile dysfunction curative.Male erectile dysfunction curative and nitro preparations used time, exist and cause the systemic hypotension of severe and cause dead example, especially for existing problems the middle-aging male had a heart disease.This is because treatment of erectile dysfunction medicine might not concentrate on affected part, but acts on system vascular, improves the vasorelaxation action that nitro preparations has.Therefore, can think, guide male erectile dysfunction curative to arrive affected part by drug delivery, and concentrate on affected part, make it play pharmacological effect, suppress the side effect caused owing to also using with nitro preparations to produce thus.
As the concrete grammar of drug delivery, such as, studying the guiding of working load body (carrier) to affected part, the method is easily concentrating on the carrier of affected part by drug loading, makes carrier that medicine is transported to affected part.Studying and using various antibody, microsphere or magnetic as carrier.Wherein, magnetic is considered to potential especially carrier, is studying and will to be attached to as the carrier of magnetic on medicine and to be gathered in the method (for example, referring to following patent documentation 1) of affected part by magnetic field.This bootstrap technique is simple and easy to do, makes the treatment of targeting affected part become possibility, therefore thinks for the anticarcinogen with high cell toxicity it is special effective method.
Patent documentation 1: Japanese Unexamined Patent Publication 2001-10978 publication
Summary of the invention
But, as mentioned above when using the load of magnetic as carrier, point out: the size of oral administration difficulty, usually carrier molecule is large or there is technical problem with the bond strength of drug molecule and affinity aspect, thus practical application has difficulties.
The present invention carries out in view of the above problems, its object is to solve the drug delivery system that existing technical problem also realizes being easy to practical application.
To achieve these goals, in the present invention, as the 1st kind of solution relating to medicine, it is characterized in that, be made up of organic compound or inorganic compound, by crosslinked between the modification of side chain and/or side chain, there is magnetic.
In addition, in the present invention, as the 2nd kind of solution relating to medicine, it is characterized in that, described organic compound is Forskolin (forskolin).
In addition, in the present invention, as the 3rd kind of solution relating to medicine, it is characterized in that, in above-mentioned 1st kind of solution, described organic compound is effective compositions in male erectile dysfunction treatment.
In addition, in the present invention, as the 4th kind of solution relating to medicine, it is characterized in that, in above-mentioned 1st kind of solution, described inorganic compound is metal complex.
In addition, in the present invention, as the 5th kind of solution relating to medicine, it is characterized in that, in above-mentioned 4th kind of solution, described metal complex is the cis geometric isomer with anti-cancer properties.
In addition, in the present invention, as the 6th kind of solution relating to medicine, it is characterized in that, in above-mentioned 5th kind of solution, described cis geometric isomer is cisplatin.
In addition, in the present invention, as the 1st kind of solution relating to medicine guider, it is characterized in that, will the medicine with any one solution in above-mentioned 1st ~ 6 in body be administered to, utilize the magnetic guiding of this medicine to the affected part of regulation.
In addition, in the present invention, as the 1st kind of solution relating to magnetic detection device, it is characterized in that, by detecting the magnetic with the medicine of any one solution in above-mentioned 1st ~ 6 be administered in body, detecting the In vivo kinetics process of this medicine.
In addition, in the present invention, as the 1st kind of solution relating to drug design method, it is characterized in that, for the crosslinked molecular model carried out as the organic compound of drug use or inorganic compound setting between the modification of side chain and/or side chain, distributed by the spin-charge densities of trying to achieve by carrying out numerical computations to this molecular model and judge whether described molecular model has magnetic, based on being judged to be that the magnetic molecular model of tool designs medicine.
In addition, in the present invention, as the 2nd kind of solution relating to drug design method, it is characterized in that, in above-mentioned 1st kind of solution, judge that described molecular model is ferromagnetism or ferrimagnetism based on described spin-charge densities distribution.
In addition, in the present invention, as the 3rd kind of solution relating to drug design method, it is characterized in that, in the above-mentioned 1st or 2 kinds of solutions, judge the magnetic intensity of described molecular model based on described spin-charge densities distribution.
According to the present invention, because medicine self has magnetic, therefore can not use the existing carrier be made up of magnetic, and medicine is guided to the affected part in body by the magnetic utilizing medicine self to have.Its result can solve oral administration difficulty, carrier molecule usually comparatively large or with the bond strength of drug molecule, affinity in the technical problem etc. that exists, the drug delivery system being easy to practical application can be realized.
Accompanying drawing explanation
Fig. 1 is the basic molecular structural model figure of Forskolin in an embodiment of the invention.
Fig. 2 is the molecular structure model figure of the forskolin derivative A in an embodiment of the invention with ferrimagnetism.
Fig. 3 represents the three-dimensional molecular structure model of forskolin derivative A in an embodiment of the invention and the figure of spin-charge densities distribution.
Fig. 4 is the molecular structure model figure in an embodiment of the invention with ferromagnetic forskolin derivative B.
Fig. 5 represents the three-dimensional molecular structure model of forskolin derivative B in an embodiment of the invention and the figure of spin-charge densities distribution.
Fig. 6 is the flow chart of the drug design method in one embodiment of the present invention.
Fig. 7 is the basic molecular structural model figure of PDE5 inhibitor of an embodiment of the invention Plays composition, and three-dimensional molecular structure model and spin-charge densities distribution.
Fig. 8 is the basic molecular structural model figure of PDE5 inhibitor derivates in an embodiment of the invention, and three-dimensional molecular structure model and spin-charge densities distribution.
Fig. 9 is the basic molecular structural model figure of cisplatin in an embodiment of the invention.
Figure 10 is the basic molecular structural model figure of cis-platinum derivative in an embodiment of the invention (cis-Pt-a3), and three-dimensional molecular structure model and spin-charge densities distribution.
Figure 11 is the analysis result of the spin-charge densities of the derivant that in an embodiment of the invention, cis-platinum derivative and the platinum by cis-platinum derivative are replaced into other metallic elements and obtain.
Figure 12 is the basic molecular structural model figure representing cis-platinum derivative NK121 in an embodiment of the invention, and three-dimensional molecular structure model and spin-charge densities distribution.
Figure 13 is the figure representing cisplatin hydrolytic process in vivo in an embodiment of the invention.
Figure 14 is cisplatin hydrolysis product [Pt (OH in an embodiment of the invention
2)
2(dien)]
2+three-dimensional molecular structure model and spin-charge densities distribution.
Figure 15 is the 1st example of the output picture of the computer shown in the process of the spin-charge densities by computer simulator operand compound.
Figure 16 is the 2nd example of the output picture of the computer shown in the process of the spin-charge densities by computer simulator operand compound.
Figure 17 is the schematic diagram of MRI.
Figure 18 is the perspective view of MRI device entirety.
Figure 19 be by magnetic and medicated to the MRI image output in the example of rat administration.
Figure 20 is the MRI image output representing the concentration dependent in MRI image with object medicine.
Figure 21 is the sketch of the summary of the experimental system representing checking Chinese medicine position, magnetic field.
Figure 22 is the performance plot of the result of the fluctuation measurement cell number represented based on magnetic field drug concentration.
Figure 23 is the perspective view of other embodiments of the guiding device represented in the present invention.
Figure 24 is the MRI measurement result of the kidney represented for mice.
Symbol description
A, B ... forskolin derivative
Detailed description of the invention
With reference to the accompanying drawings an embodiment of the invention are described.
[the 1st embodiment]
First, as the 1st embodiment, use organic compound, be more specifically used as the Forskolin of drug candidate agent to be described.
Fig. 1 is the basic molecular structural model figure of Forskolin.In the figure, R
6, R
7and R
13represent the atom of side chain or the position of molecular linkage for modifying Forskolin, according to the atom of bonding or the type of molecule over these locations, the physical property of Forskolin changes.In the figure, at R
6locate bonding H, at R
7place bonding CH
3, at R
13place bonding CH=CH
2compound be the Forskolin that occurring in nature exists, will by change artificially side chain structure, namely change and modify R
6, R
7and R
13atom or molecule and the Forskolin generated is called forskolin derivative.In addition, in FIG, C
1~ C
13represent carbon atom (C).
Fig. 2 is the basic molecular structural model figure of the forskolin derivative A with magnetic (ferrimagnetism).As shown in the drawing, forskolin derivative A is the R of the Forskolin existed by above-mentioned occurring in nature
6become COCH
2cH
2nCH
3, R
7become CH
2, will C be bonded in simultaneously
9on oxygen atom (O) be bonded in C
13on carbon atom crosslinked to form.
Fig. 3 represents three-dimensional molecular structure and the spin-charge densities distribution of the above-mentioned forskolin derivative A tried to achieve by the computer simulation based on first-principle molecular dynamics method.First-principle molecular dynamics method at Delley, B.J.Chem.Phys., 1990,92,508-517, Delley, B.J.Chem.Phys., 2000,113,7756-7764, Haselgrove, C.B.MathComp., 1961,15,323-337, Ellis, D.E.Int.J.QuantumChem., 1968,2S, 35-42, Ellis, D.E.; Painter, G.S.Phys.Rev.B, open in 1970,2,2887-2898.
In figure 3, region 1 represents downward spin-charge densities, and region 2 ~ 5 represents spin-charge densities upwards.This region is selected to be that spin-charge densities is high owing to calculating the equal pitch contour of spin-charge densities.The character of the magnetic that compound has is decided by the balance of spin upwards and downward spin.Forskolin derivative A is due to mixing existence downward spin states 1 ' as shown in Figure 2 and spin states 2 ' ~ 5 ' upwards, and therefore known its is ferrimagnetic body.
On the other hand, Fig. 4 is the basic molecular structural model figure of the forskolin derivative B with magnetic (ferromagnetism).As shown in the drawing, forskolin derivative B is the R of the Forskolin existed by above-mentioned occurring in nature
6become COCH
2cH
2nCH
3, R
7become CH
2, R
13become CH-CH
3, will C be bonded in simultaneously
9on oxygen atom be bonded in C
13on carbon atom crosslinked to form.
As described above, Fig. 5 represents three-dimensional molecular structure and the spin-charge densities distribution of the forskolin derivative B tried to achieve by the computer simulation based on first-principle molecular dynamics method.In Figure 5, region 10 ~ 12 represents spin-charge densities upwards.Thus, only there is spin states 10 ' ~ 12 ' upwards as shown in Figure 4 in forskolin derivative B, therefore known its is ferromagnetic body.
Thus, by with regulation atom or molecular modification Forskolin side chain and be cross-linked between the side chain existed on assigned position, the magnetic forskolin derivative of tool and medicine can be generated.In fig. 2, be cross-linked in the part be illustrated by the broken lines.Like this, by with regulation atom or molecular modification medicine side chain and/or be cross-linked between the side chain existed on assigned position, the magnetic size of medicine can be controlled.Introduce which kind of functional group or be cross-linked in which way, can pass through computer simulation, user is suitable for selecting.
The system realizing this computer simulation is the system possessing known hardware resource as computer, namely possesses: memorizer, CPU etc. have the arithmetic unit of computing circuit, export the display device of operation result.Memorizer possesses the data base of the three dimensional structure of the known organic compound of regulation and inorganic compound and realizes the software program of computer simulation.This software can add/change/eliminate the side chain of each compound, and be cross-linked between the side chain of regulation, the region that the spin-charge densities described in calculating is high, thus determine the spin-charge densities as structure entirety.As this program, such as commercially available product (Dmol3, ア Network セ Le リ ス company) can be utilized.
User adds the position of side chain for the input of chemical combination portion, or changes side chain, or the side chain that selection eliminates, and in addition, sharp memory-aided support program is specified and be formed crosslinked position to arithmetic unit.Arithmetic unit accepts this input value, computing spin-charge densities, and its result is outputted on display screen.In addition, user, by adding the structured data of existing compound in computer systems, which, can know the spin-charge densities of existing compound.
Below, the magnetic drug design method of described tool is described.Fig. 6 is the flow chart of the processing sequence representing this drug design method.Process illustrated is below carried out in the computer simulator based on first-principle molecular dynamics method.
First, owing to having more than 200 kinds as the forskolin derivative of drug use, therefore therefrom select the forskolin derivative as evaluation object, and its chemical formula is input to (step S1) in computer simulator.At this, suppose that the biological A of selected above-mentioned Forskolin carries out following explanation as the situation of forskolin derivative.The compound library made in advance is utilized to identify the kind of the derivant of each compound.User by the atomic number of each atom of each compound and its Position input in arithmetic unit.
Figure 15 is the picture be presented at when the operation of step 1 in output device.As shown in Figure 15 (1), the element ordinal of input 1 atom and atomic coordinates.As shown in figure (2), specify with the bond styles between mouse-click atom, such as singly-bound, double bond, triple bond etc.
Accept the arithmetic unit of this input, according to said procedure, based on the chemical formula of forskolin derivative A, the initial value (step S2) of setting spin (certainly spinning up) wave function Φ ↑ (r) upwards, downward spin (spin is downwards) wave function Φ ↓ (r), spin-up effective potential V ↑ (r), spin downward effective electromotive force V ↓ (r), spin-up charge densities ρ ↑ (r) and downward charge density ρ ↓ (r) of spin.In addition, r is the variable of the coordinate represented in three dimensions.
Deposit in case as isolated atom in three dimensions at each atom forming forskolin derivative A, for each corresponding atom, try to achieve its spin-up wave function Φ ↑ (r), the initial value of spin-up wave function Φ ↑ (r) is the summation of all spin-up wave function Φ ↑ (r) tried to achieve thus.
Similarly, deposit in case in three dimensions at each atom as isolated atom, for each corresponding atom, try to achieve its downward wave function Φ ↓ (r) that spin, the initial value of downward wave function Φ ↓ (r) that spin is their summation.In addition, spin-up wave function Φ ↑ (r) is in case deposited as isolated atom in three dimensions based at each atom forming forskolin derivative A, for each corresponding atom, try to achieve its spin-up effective potential V ↑ (r), the initial value of spin-up effective potential V ↑ (r) is the summation of all spin-up effective potential V ↑ (r) tried to achieve for each corresponding atom.Similarly, downward wave function Φ ↓ (r) of spin is in case deposited as isolated atom in three dimensions based at each atom, for each corresponding atom, the initial value of trying to achieve spin downward effective electromotive force V ↓ (r), effective electromotive force V ↓ (r) is the summation of downward effective electromotive force V ↓ (r) of spin tried to achieve for each corresponding atom.
In addition, by spin-up wave function Φ ↑ (r) tried to achieve for each corresponding atom described above is substituted into following arithmetic expression (1), the initial value of spin-up charge densities ρ ↑ (r) is tried to achieve.In addition, by downward wave function Φ ↓ (r) of spin tried to achieve for each corresponding atom described above is substituted into following arithmetic expression (2), the initial value of downward charge density ρ ↓ (r) that spin is tried to achieve.In addition, in following arithmetic expression (1), Φ ↑
*r () is the conjugate complex number of spin-up wave function Φ ↑ (r).In following arithmetic expression (2), Φ ↓
*r () is the conjugate complex number of downward wave function Φ ↓ (r) of spinning.
ρ
↑(r)＝∑Φ
↑ *(r)Φ
↑(r)…(1)
ρ
↓(r)＝∑Φ
↓ *(r)Φ
↓(r)…(2)
Below, based on the initial value of above-mentioned spin-up effective potential V ↑ (r) and downward effective electromotive force V ↓ (r) of spin and the initial value of spin-up charge densities ρ ↑ (r) and downward charge density ρ ↓ (r) of spin, solve following KohnSham equation (3) and (4), calculate spin-up wave function Φ ↑ (r), downward wave function Φ ↓ (r) that spin of forskolin derivative A thus, certainly spin up energy eigenvalues ε ↑ and spin downward energy eigenvalues ε ↓ (step S3).
Then, based on the forskolin derivative A tried to achieve in step s3 spin-up wave function Φ ↑ (r) and spin downward wave function Φ ↓, calculate spin-up charge densities ρ ↑ (r) of forskolin derivative A, spin downward charge density ρ ↓ (r), spin-up effective potential V ↑ (r) and downward effective electromotive force V ↓ (r) (step S4) of spin, judge this spin-up charge densities ρ ↑ (r) and downward charge density ρ ↓ (r) of spin whether with the preceding value of this spin-up charge densities ρ ↑ (r) and downward charge density ρ ↓ (r) that spin, i.e. initial value equal (step S5).In this step S5, be defined as "No", namely when spin-up charge densities ρ ↑ (r) is not identical with the currency of trying to achieve in step S4 with the preceding value (initial value) of downward charge density ρ ↓ (r) of spin, by spin-up effective potential V ↑ (r) tried to achieve in step s 4 which, spin downward effective electromotive force V ↓ (r), spin-up charge densities ρ ↑ (r) and downward charge density ρ ↓ (r) of spin is set as new initial value (S6), carry out step S3, by again solving KohnSham equation (3) and (4), calculate new spin-up wave function Φ ↑ (r), spin downward wave function Φ ↓, from spin up energy eigenvalues ε ↑ and spin downward energy eigenvalues ε ↓.Namely, in step s 5, repeat the process of step S3 to S6, until spin-up charge densities ρ ↑ (r) and spin downward charge density ρ ↓ (r) preceding value equal with currency, try to achieve thus spin-up wave function Φ ↑ (r) meeting KohnSham equation (3) and (4), downward wave function Φ ↓ (r) that spin, certainly spin up energy eigenvalues ε ↑ with spin downward energy eigenvalues ε ↓.
On the other hand, in step s 5, be defined as "Yes", namely when the preceding value of spin-up charge densities ρ ↑ (r) and downward charge density ρ ↓ (r) of spin is equal with currency, as mentioned above, based on spin-up wave function Φ ↑ (r) meeting KohnSham equation (3) and (4), spin downward wave function Φ ↓ (r), from spin up energy eigenvalues ε ↑ and spin downward energy eigenvalues ε ↓, calculate the interatomic force acting on each atom, optimization (step S7) is carried out to the structure of forskolin derivative A simultaneously.Namely, spin-up wave function Φ ↑ (r) tried to achieve by repeating step S3 ~ S6 and downward wave function Φ ↓ (r) of spin etc., be optimum in model in two dimensional surface as shown in Figure 2, need the structure considering forskolin derivative A in three dimensions in practice.
Particularly, in the step s 7, make each atom of formation forskolin derivative A on the optimal direction inferred by spin-up wave function Φ ↑ (r) and downward wave function Φ ↓ (r) of spin, only move the distance of regulation in three dimensions, calculate the interatomic force now acting on each atom.Interatomic force is at this moment 0, each atom not movement when, can judge that the structure of forskolin derivative A obtains optimization.Thus, calculate the interatomic force acting on each atom after moving, judge whether this interatomic force is 0 (step S8).In this step S8, in "No", namely interatomic force is not 0, under structure does not obtain optimized situation, try to achieve spin-up wave function Φ ↑ (r) and downward wave function Φ ↓ (r) of spin in the structure after each atom moves, spin-up effective potential V ↑ (r) that simultaneously will be tried to achieve by this spin-up wave function Φ ↑ (r) and downward wave function Φ ↓ (r) of spin, spin downward effective electromotive force V ↓ (r), spin-up charge densities ρ ↑ (r) and downward charge density ρ ↓ (r) of spin is set as new initial value (step S9), repeat the process of step S3 to step S8.At this, the reason being back to step S3 is, the structure change after moving according to each atom, and spin-up wave function Φ ↑ (r) and downward wave function Φ ↓ (r) of spin changes.In addition, storing the structure after each atom moves, when again carrying out step S7, making each atom only move the distance of regulation again from previous designs.
When carrying out optimization to the structure of described forskolin derivative A, as shown in Figure 2, three dimensional structure is made to force change, to make to be bonded in C
9on oxygen atom and be bonded in C
13on carbon atom be cross-linked.In addition, the atom selected for carrying out described being cross-linked can at random be changed.
On the other hand, in this step S8, "Yes", the interatomic force that namely acts on each atom be 0, obtain optimized situation by the structure of the forskolin derivative A such as Jahn-Teller effect under, based on spin-up wave function Φ ↑ (r) in this optimization structure and downward wave function Φ ↓ (r) of spin, try to achieve spin-charge densities distribution (step S10) as shown in Figure 3.
At this, according to the selected forskolin derivative as evaluation object, the spin-charge densities distribution in the region 1 ~ 5 shown in Fig. 3 can not be produced, or produce spin-charge densities distribution, but the region that the size (i.e. magnetic intensity) that there is this spin-charge densities is very little.Described forskolin derivative can not be judged to be to have magnetic.Therefore, based on spin-charge densities distribution, first judge whether the forskolin derivative selected as evaluation object has magnetic (step S11).
In step s 11, under "No", namely selected as evaluation object the forskolin derivative not magnetic situation of tool, carry out step S1, the forskolin derivative again selecting other carries out magnetic evaluation again.On the other hand, in step s 11, in "Yes", namely selected as the evaluation object magnetic situation of forskolin derivative tool, be ferromagnetism or ferrimagnetism (step S12) based on spin-charge densities distribution judgement.
As mentioned above, spin-charge densities distribution represents the distribution of spin-up charge densities and the downward charge density of spin, therefore when these spin-up charge densities and the downward charge density mixing of spin exist, can judge that there is ferrimagnetism, only exist spin-up charge densities and spin downward charge density in any one time, can judge that there is ferromagnetism.
Forskolin derivative A, spin-up charge densities (region 2 ~ 5) and the downward charge density of spin (region 1) mixing exist as shown in Figure 3, are therefore judged to be the forskolin derivative (step S13) of ferrimagnetism.On the other hand, such as, if selected forskolin derivative is forskolin derivative B, then only there is spin-up charge densities (region 10 ~ 12) as shown in Figure 5, be therefore judged to be ferromagnetic forskolin derivative (step S14).Also magnetic intensity can be tried to achieve based on spin-charge densities distribution.In addition, in already described example, the side chain of compound is R in FIG
6, R
7, R
13part, main chain is the part removing these side chains from the structural formula of Fig. 1.
As mentioned above, according to this drug design method/design system, can judge with various atom or molecular modification side chain and the magnetic of forskolin derivative crosslinked arbitrarily between side chain, to judge to generate forskolin derivative based on the magnetic molecular model of tool, the magnetic medicine of tool can be manufactured thus.Can not use the existing load (carrier) be made up of magnetic, and medicine is guided to the affected part in body by the magnetic utilizing medicine self to have.Its result can solve current oral administration difficulty, carrier molecule usually comparatively large or with the bond strength of drug molecule, affinity in the technical problem etc. that exists, the drug delivery system being easy to practical application can be realized.
In above-mentioned 1st embodiment, in forskolin derivative A and B, three dimensional structure is made to force change, to make to be bonded in C
9on oxygen atom and be bonded in C
13on carbon atom be cross-linked, but be not limited to this, other atoms can be selected to be cross-linked.In addition, do not carry out crosslinked and only by changing the atom or molecule of modifying side chain, can determine whether that there is magnetic yet.
In addition, in above-mentioned 1st embodiment, Forskolin is used to be described as organic compound.But, be not limited to this, also can use other organic compound.The following organic compound as other, to be effective to male erectile dysfunction treatment compositions, more specifically to suppressing the compositions (hereinafter referred to as PDE5 inhibitor) of activity of PDE5 (PDE5) to be described.In addition, be used as the therapeutic agent of the male erectile dysfunctions such as viagra as the medicine of effective ingredient using this PDE5 inhibitor.
Fig. 7 (a) is the basic molecular structural model figure of the PDE5 inhibitor of standard composition, and Fig. 7 (b) represents three-dimensional molecular structure and the spin-charge densities distribution of the PDE5 inhibitor of the standard composition of being tried to achieve by the computer simulation in said medicine method for designing.On the other hand, Fig. 8 (a) is the basic molecular structural model figure of the PDE5 inhibitor derivates carrying out side chain modification to the PDE5 inhibitor of standard composition and obtain.Fig. 8 (b) is shown and is simulated by above computer and the three-dimensional molecular structure of PDE5 inhibitor derivates of trying to achieve and spin-charge densities distribution.In Fig. 8 (b), region 20 ~ 23 represents spin-charge densities upwards, and region 24 ~ 26 represents downward spin-charge densities.Thus, PDE5 inhibitor derivates is the ferrimagnetic body that the spin states 20 ' ~ 23 ' upwards as shown in Fig. 8 (a) exists with the mixing of downward spin states 24 ' ~ 26 '.
That is, as shown in these Fig. 7 and 8, the PDE5 inhibitor of standard composition does not have magnetic, but the PDE5 inhibitor derivates modified by side chain and generate is identified and has magnetic.Thus, use using the male erectile dysfunction therapeutic agent of PDE5 inhibitor derivates as effective ingredient with described magnetic, result is known, and medicine concentrates on affected part and makes it play pharmacological action, and can suppress due to nitro preparations and with and the side effect that produces.
[the 2nd embodiment]
, as the 2nd embodiment, utilize inorganic compound below, more specifically, utilize the cisplatin as anticarcinogen to be described.Cisplatin is metal complex (platinum complex), in anticarcinogen, be also classified as platinum preparation.
Fig. 9 is the basic molecular structural model figure of the cisplatin of standard composition.Utilize the computer simulation in the drug design method illustrated in the 1st embodiment, confirm that the cisplatin that this standard forms does not have magnetic.On the other hand, Figure 10 (a) is that the basic molecular structural model figure of cis-platinum derivative (cis-Pt-a3) carrying out side chain modification to the cisplatin of standard composition and obtain, Figure 10 (b) are represented and simulated by above computer and the three-dimensional molecular structure of cis-platinum derivative (cis-Pt-a3) of trying to achieve and spin-charge densities distribution.
In Figure 10 (b), region 30 ~ 32 represents spin-charge densities upwards.It can thus be appreciated that cis-platinum derivative (cis-Pt-a3) is the ferromagnetic body of the spin states 30 ' ~ 32 ' upwards existed as shown in Figure 10 (a).That is, by the computer simulation in this drug design method, confirm that cis-platinum derivative (cis-Pt-a3) has magnetic.Therefore, by using using the anticarcinogen of cis-platinum derivative (cis-Pt-a3) as effective ingredient with such magnetic, it can be made to concentrate on cancerous tissue and to play pharmacological action, and the generation of side effect can be suppressed.
The magnetic of medicine is stronger, more effectively medicine can be guided to affected part, can expect stronger pharmacological action and the suppression to side effect.Therefore, the present inventor, by the computer simulation in this drug design method, has carried out the parsing of magnetic intensity to various cis-platinum derivative.Below, this analysis result is described.Because magnetic intensity and spin-charge densities exist proportionate relationship, therefore carry out the parsing of the spin-charge densities in various cis-platinum derivative in the present embodiment.
First, as reference, will from magnetic iron ore (Fe
3o
4) crystal on the total atom number that cuts be 101, while be about 8
microgranule be set as molecular model, simulated by above computer, after optimization is carried out to electronic state and structure, carry out spin-charge densities parsing.Then, with the spin-charge densities of above-mentioned magnetic iron ore for standard, identical spin-charge densities is carried out for various cis-platinum derivative and resolves.Operation interface when Figure 16 is the process of the step 12 being equivalent to above-mentioned computer simulation, (1) spin-charge densities of magnetite microparticles for comparing.● represent that spin-charge densities is just, zero represents that spin charge density is negative.(2) spin-charge densities for calculating.Magnetic kind is ferrimagnetism (spin-charge densities is just), is 10% relative to magnetic iron ore magnetic intensity.
In addition, except cis-platinum derivative, for parsing platinum (Pt) being replaced into palladium (Pd), rhodium (Rh), iridium (Ir), gold (Au), nickel (Ni), silver (Ag), copper (Cu), cobalt (Co) and the various derivants that obtain carry out spin-charge densities too.It can thus be appreciated that, the platinum of cis-platinum derivative is replaced into above-mentioned metallic element and the derivant that generates, same with cisplatin or cis-platinum derivative, there is the effect hindering the DNA relevant with cancer cell multiplication.
Figure 11 represents when the spin-charge densities of magnetic iron ore is standardized into " 1 ", by various cis-platinum derivative and the platinum of cis-platinum derivative to be replaced into palladium (Pd), rhodium (Rh), iridium (Ir), gold (Au), nickel (Ni), silver (Ag), copper (Cu), cobalt (Co) and the analysis result of the spin-charge densities of various derivants that obtains.
Known as shown in figure 11, among cis-platinum derivative, NK121 has the spin-charge densities of about 60% compared with magnetic iron ore, compared with other cis-platinum derivative as magnetic and medicated be effective.This cis-platinum derivative NK121 once entered clinical development by safety testing, but due to its antitumaous effect and cisplatin suitable, therefore think that it is not better than the advantage of cisplatin and have ceased exploitation.Therefore, rely on magnetic field that medicine is guided to affected part if take this cis-platinum derivative NK121, then drug effect increases, and also can suppress side effect significantly.In addition, Figure 12 represents the basic molecular structural model figure of cis-platinum derivative NK121.As shown in the drawing, cis-platinum derivative NK121 is the ferromagnetic body of the spin states 40 ' ~ 42 ' existed upwards.
In addition, the platinum (Pt) of cis-platinum derivative is replaced into palladium (Pd) and the derivant obtained also has spin-charge densities to a certain degree, confirms as magnetic.In addition, among the derivant obtained the platinum (Pt) of cis-platinum derivative is replaced into rhodium (Rh), find that cis-Rh-a3 has the spin-charge densities of about 50% compared with magnetic iron ore, it is as effectively magnetic and medicated.In addition, the platinum (Pt) of cis-platinum derivative is replaced into iridium (Ir) and the derivant obtained, spin-charge densities is very little, thinks that it does not have large effect as magnetic and medicated.In addition, the platinum (Pt) of cis-platinum derivative is replaced into gold (Au) and the derivant obtained also has spin-charge densities to a certain degree, thinks that it is magnetic.
In addition, find the platinum of cis-platinum derivative (Pt) to be replaced into nickel (Ni) and the derivant obtained, generally have the spin-charge densities of about 50% compared with magnetic iron ore, it is as effectively magnetic and medicated.In addition, the platinum (Pt) of cis-platinum derivative is replaced into silver (Ag) and the derivant obtained also has spin-charge densities to a certain degree, confirms as magnetic.In addition, the platinum (Pt) of cis-platinum derivative is replaced into copper (Cu) and the derivant obtained also has spin-charge densities to a certain degree, confirms as magnetic.In addition, find the platinum of cis-platinum derivative (Pt) to be replaced into cobalt (Co) and the derivant obtained compared with magnetic iron ore, generally have the spin-charge densities of very high about 95%, it is as magnetic and medicated very effective.
As mentioned above, drug design method according to the present embodiment, not only for the medicine be made up of organic compound but also for the medicine be made up of inorganic compound, can resolve whether there is magnetic by its molecular model, by studying the medicine with high magnetic intensity (i.e. good drug efficacy) in advance, active drug can be designed very efficiently.
In addition, the derivant that above-mentioned cis-platinum derivative and the platinum by cis-platinum derivative are replaced into other metallic elements and obtain is cis geometric isomer.The inhibitory action of such cis geometric isomer couple DNA relevant with cancer cell multiplication is stronger than trans geometric isomer, so used as anticarcinogen.But, drug design method according to the present embodiment, medicine as object is not limited to the cis geometric isomer such as anticarcinogen, even the metal complex be made up of trans geometric isomer or other inorganic compound, also whether can have magnetic to it and resolve.Therefore, the metal complex be made up of trans geometric isomer or other inorganic compound are formed, the magnetic medicine of tool can also be designed.
Then, the guiding device that magnetic for above-mentioned tool medicine is guided to affected part is described.As long as this guiding device produces magnetic field, can be the device of various form.Such as, as an example, the application of NMR imaging equipment (MRI:MagneticResonanceImaging) can be considered, as long as its structure can control this introduction by magnetic field medicine to affected part to human body radia magnetic field.In addition, such as, also can attach at the skin surface of affected part the material that Magnet etc. produces magnetic force.Thus the medicine near arrival affected part, while being directed to affected part, resting on affected part owing to concentrating, therefore can not have side effects to other normal cells.If utilize above-mentioned guiding device, then can optionally and intensively magnetic for tool medicine is guided to affected part.
In addition, utilize the magnetic being administered to medicine in body, the In vivo kinetics process of this medicine can also be detected, such as, detect its aggregate amount for the diseased tissue of cancerous tissue etc.More specifically, using magnetic for tool medicine as tracer, the magnetic produced by magnetic detection device tracking medicine carrys out the In vivo kinetics of detection of drugs.By such magnetic detection device, just detection of drugs can arrive the In vivo kinetics processes such as the time of affected part to it from vivo medicine-feeding, the research of medicine, exploitation can not only be contributed to, the dosage that anticarcinogen is suitable can also be determined.As described below, owing to using between the magnetic and medicated accumulation (concentration) of MRI and MRI image, there is dependency relation, so by analyzing MRI image, the accumulated state of medicine in diseased tissue can be specified, determines suitable dosage.
In addition, utilize magnetic and the pharmacological action thereof of the medicine be administered in body, can functional imaging diagnosis be carried out.More specifically, for the protein (being such as called as the protein of " P glycoprotein ") occurred a large amount of in the cancerous tissue that grade malignancy is high, there is the medicine (such as Forskolin) high to its affinity.By making Forskolin have magnetic, giving cancer patient Forskolin, its aggregate amount to cancerous tissue can be detected.Aggregate amount to cancerous tissue is more, and the grade malignancy of this cancer can be diagnosed higher, if aggregate amount is few, then the cancer of this patient may be optimum and BR > F break.That is, the grade malignancy diagnosis of cancer only can not be undertaken by MRI image by the biopsy that adopts or operation all the time.
Diseased tissue is not cancer, for the neurotransmitteies such as the acetylcholine in brain, 5-hydroxy tryptamine, dopamine receptor related disease too.Such as, the order of severity of dementia of the Alzheimer type disease can be judged by the magnetic and medicated trend of the MRI image check of head and receptor protein specific binding.
But the cisplatin of the standard composition shown in known Fig. 9, if be administered in body, is then hydrolyzed by the hydrolytic process to the reaction 1 ~ 3 shown in Figure 13, the final hydrolyzate [Pt (OH generating cisplatin
2)
2(dien)]
2+.As mentioned above, the cisplatin of the standard composition shown in Fig. 9 does not have magnetic, but the present inventor finds, according to this drug design method, and the hydrolyzate [Pt (OH of this cisplatin
2)
2(dien)]
2+it is magnetic.Figure 14 represents the hydrolyzate [Pt (OH of cisplatin
2)
2(dien)]
2+three-dimensional molecular structure and spin-charge densities distribution.As shown in the drawing, the hydrolyzate [Pt (OH of cisplatin
2)
2(dien)]
2+there is the region 50 and 51 of spin-charge densities upwards, therefore find that it is ferromagnetic body.
Thus, even the cisplatin of standard composition, owing to there is magnetic after being administered in body, therefore affected part can be guided to by above-mentioned guiding device, in addition, carry out detection bodies internal dynamics process by magnetic detection device, its aggregate amount to cancerous tissue can be specified.
Figure 17 is the block diagram representing MRI principle.By magnetic for described tool pharmaceutical preparation by the Human body package after the method administration such as oral, injection, transfusion in magnetic field.From sending the electric wave of coil 170 to human-body emitting characteristic frequency.Resonated by the atomic nucleus of the drug molecule of administration, spontaneous generation electric wave.Receive this electric wave by receiving coil and synthesize MR image.Its result can visually detect in the position of people's drug disposition and trend.
Because the nuclear state of the atomic nucleus from medicine that form tissue in the tissue absorbed the drug is different, so MRI control unit 174 can by the MR signal suitably selecting the frequency of emitting radio waves, analysis specific atoms nuclei sends, distinguish the signal of medicine and the signal of tissue, detect which tissue medicine is present in.
Figure 18 is the perspective view of MRI entirety.180 is examining table, experimenter is placed in herein, makes in its magnetic gate (magnetgantry) 182 moving into formation tea caddy shape.Magnetic gate has magnetic field generation device and detects the coil of MR signal.The magnetic field intensity of magnetic gate is redefined for 0.2,0.5,1.0 or 1.5Tesla (unit).By making experimenter move in magnetic field, the medicine given is made to coordinate the movement in this magnetic field, trend in the body that can control medicine.
Thus by using MRI, trend in the body that can detect magnetic compound, also can guide to the target site in body simultaneously by magnetic compound.Also magnetic compound can be used as MRI contrast agent.
Except utilizing MRI, also can adopt other modes.Breast carcinoma is specifically described.Breast carcinoma is present in breast.If dimensionally determine transverse direction, longitudinal direction and the degree of depth, then can determine the cancerous tissue position in breast carcinoma.Prior employing MR or CT etc. determines the position of breast carcinoma.
Permanent magnet is loaded in the underwear (medicated bra) having cancer side.After administration with anticancer agents, put on the underwear of Magnet.Directly anticarcinogen is injected to cancerous tissue.Such as, to the intra-arterial injection of breast, or inject in cancerous tissue.Subsequently, in order to make anticarcinogen can not be diffused into whole body from cancerous tissue, the medicated bra that Magnet is housed is put on.
In addition, also following mode can be adopted.Vein gives anticarcinogen.The anticarcinogen of intravenously administrable, enters heart, through pulmonary circulation, to be reinjected mammary branches through arteria thoracica interna by large artery trunks, injects in breast thus.Apply magnetic field at each branch part to guide.That is, at the position by large artery trunks arteria thoracica interna branch, the root towards arteria thoracica interna applies magnetic field and guides anticarcinogen to flow into arteria thoracica interna by large artery trunks.Known to magnetic field intensity, from the result of cell culture experiments, if apart from short, adopt 1Tesla (intensity used by MR) just can guide.For resembling the breast carcinoma internal organs that distance skin is near like this, as long as 2Tesla is just enough.The magnetic field intensity of MR is generally about 1.5Tesla.As mensuration sensitivity, zooperal as a result, enough mensuration sensitivity can be obtained strengthen the condition of image at T1 under.
Then, the embodiment that medicine is obtained image to individual administration by MRI is described.Figure 19 be 9 week age of employing female rats (Japanese SIC Inc. ddy), the magnetic iron complex of tool being dissolved in pyridine (Fe-salen, two salicylidene ethylenediamine ferrum) (concentration 0.137mol/L) is carried out subcutaneous administrations to it after, use MR and the MRI image that obtains.When iron complex pyridine solution is carried out administration, compared with before administration, contrasting effects can be seen along the gap of internal organs and internal organs and abdominal cavity film.Arrow head part is the iron complex of the slotted section accumulated at small intestinal and small intestinal.Now, in the abdominal cavity of rat, attached to small-sized Magnet.In MRI analyzes, magnetic field intensity is set to 1.5Tesla.
In addition, Figure 20 shows the concentration dependent in MRI image with medicine.Left side is the series by water (No. 2 distilled water (DDW)) dilution pyridine stock solution, and right side is the series of the iron complex saturated solution with pyridine dilution pyridine.The concentration of the iron complex in pyridine is changed to 1/2 compared with above-mentioned ... 1/16, the change of its concentration can be gone out thus in mri by Image detection.Subsequently, when the state that rat L6 cell 30% merges, can visual observations be layered in culture medium to attraction iron complex powder to the amount on Magnet, after 48 hours, the state of culture medium be taken a picture.
Figure 21 represents the state making the rectangle bottle of the culture medium with rat L6 cell to be connected with bar magnet.Subsequently, take a picture to the other end from the one end at the bottom of rectangle bottle after 48 hrs, calculate the result of cell number as shown in figure 22.In fig. 22 apart from the near positional representation of Magnet in the projected area of the Magnet end face of rectangle bottle bottom surface, apart from Magnet positional representation far away on rectangle bottle bottom surface with the region of Magnet end face opposition side.Known as shown in figure 22, be attracted at the position iron complex near apart from Magnet, iron complex concentration increases, and the DNA inhibitory action due to iron complex makes cell number very low compared with amphi position.Its result, according to the present invention, relies on the magnetic medicine of tool and the system possessing magnetic generator, medicine can be concentrated the affected part or tissue that are present in as individual goal.
Next other examples of guiding device of the present invention are described.The pair of magnet 230,232 that this guiding device is relative on gravity direction is as shown in figure 23 supported by stand 234 and clamp 235, places metallic plate 236 between Magnet.By placing metallic plate, particularly iron plate between pair of magnet, magnetic field equally strong on local can be produced.
Replace Magnet with electric magnet, this guiding device can produce variable magnetic force.In addition, in order to a pair magnetic force generator that can move up in XYZ side, magnetic force generator can be moved to the solid target on desk.
By solid tissue being placed in this field region, medicine can be made to be concentrated to this tissue.To the metal complex (drug level is 5mg/ml (15mM)) that the mouse mainline of body weight about 30 grams is above-mentioned, open abdomen, mice is positioned on iron plate, right side kidney is placed between above-mentioned pair of magnet.
The Magnet used is the production number that Shin-Etsu Chemial Co., Ltd manufactures: N50 (neodymium system permanent magnet), residual flux density: 1.39-1.44T.The magnetic field now imposing on right side kidney is about 0.3 (T), the magnetic field imposing on left kidney be about its 1/10.With left kidney and do not apply magnetic field kidney (contrast) together with, applying magnetic field after 10 minutes to the right kidney of mice, under T1 pattern and T2 pattern, measuring SNR with MRI.Its result, as shown in figure 24, confirm to apply magnetic field right kidney (RT) and left kidney (LT) and compared with contrasting, can by drag residence in organizing.
Claims (3)
1.Fe-salen preparation can by introduction by magnetic field, the application undertaken by following method in the curative for the treatment of, described method comprises: when being applied to human body or animal, Fe-salen is guided to the region producing magnetic field by coming exogenic magnetic field partly, and remain on this region, play the medical benefit originally possessed in this region partly.
2. application according to claim 1, adopts magnetic force generator in the tissue of individuality or in affected part, makes Fe-salen be directed to this tissue or described affected part.
3. application according to claim 2, configures magnetic force generator in the way of the pathways such as the blood vessel in the described tissue body fluid of described individuality being supplied to described individuality or in affected part, makes Fe-salen be directed to dirty tissue or affected part.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP177971/2006 | 2006-06-28 | ||
| JP2006177971A JP2007091710A (en) | 2005-08-31 | 2006-06-28 | Drug, device for inducing drug, magnetic detection device and method for designing drug |
| JP056624/2007 | 2007-03-07 | ||
| JP2007056624 | 2007-03-07 | ||
| PCT/JP2007/063011 WO2008001851A1 (en) | 2006-06-28 | 2007-06-28 | Drug, drug induction device, magnetic detector and method of designing drug |
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| US9282923B2 (en) * | 2010-06-01 | 2016-03-15 | Ihi Corporation | Fluorochrome material and method for using the same |
| JP6280305B2 (en) * | 2013-02-05 | 2018-02-14 | 株式会社Ihi | Magnetic medicine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4737589A (en) * | 1985-08-27 | 1988-04-12 | Nippon Kayaku Kabushiki Kaisha | Platinum Complexes |
| US4871716A (en) * | 1986-02-04 | 1989-10-03 | University Of Florida | Magnetically responsive, hydrophilic microspheres for incorporation of therapeutic substances and methods of preparation thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4737589A (en) * | 1985-08-27 | 1988-04-12 | Nippon Kayaku Kabushiki Kaisha | Platinum Complexes |
| US4871716A (en) * | 1986-02-04 | 1989-10-03 | University Of Florida | Magnetically responsive, hydrophilic microspheres for incorporation of therapeutic substances and methods of preparation thereof |
Non-Patent Citations (1)
| Title |
|---|
| DNA cleavage by hydroxy-salicylidene-ethylendiamine-iron complexes;Sylvain Routier et al;《Nucleic Acids Research》;19991231;第27卷(第21期);4160-4166 * |
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