JP2000290181A - Intracerebral migration potentiator for encephalopathy therapeutic agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject potentiator having potent activity helping resolve a current problem of the intracerebral migration limitation of encephalopathy therapeutic agents, therefore useful in clinically new effective therapy by including a specific quinoline derivative. SOLUTION: This potentiator is obtained by including a quinoline derivative of formula I A is nitrogen or carbon; B is a direct bond, C=O or (CH2)m (m is 0-3); E is a group of formula II (R1 to R3 are each H or phenyl) or formula III [D is (CH2)n(n is 0-3), CH=CH or a group of formula IV (R4 and R5 are each H or a halogen)]} (e.g. a compound of formula V). This potentiator is orally or parenterally administrable, its daily dose being 10-2,000 mg/adult either singly or in several portions.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to quinoline derivatives having an activity of enhancing the transfer of a therapeutic agent for brain diseases into the brain, which is a clinically important problem, and a drug composition thereof.

[0002]

2. Description of the Related Art It has long been known that drugs existing in blood are extremely hard to reach brain tissue as compared with other peripheral tissues. This phenomenon is histologically based on the characteristic structure of brain capillary endothelial cells and surrounding tissues, and is called the blood-brain barrier (BBB). The blood-brain barrier permeability of most drugs is determined by the lipid solubility and molecular weight of the drug, and the higher the lipid solubility and the smaller the molecular weight, the higher the permeability. Also has a significant effect. Glucose, neutral and basic amino acids, etc., which are required as nutrients of nerve cells that occupy most of the brain tissue, are selectively taken into the brain by an independent transport system, but other substances are cerebral capillaries. It is permeated by simple diffusion in endothelial cells. However, some anticancer drugs, such as vincristine, have fat-solubility and significantly lower blood-brain barrier permeability than expected from their molecular weight, and it is estimated that a mechanism that specifically blocks the transfer of these drugs to the brain. Was.

[0003] Recently, expression of MDR-1, one of the multidrug resistance genes, or P-glycoprotein encoded thereby has been confirmed in the luminal membrane of brain capillary endothelial cells. Pumps have been found to function as the blood-brain barrier (Cardon-Cardo et al .: Proc. Natl.
Acad. Sci. USA, 86, 695 (1989), Sugawara et al .: Jpn.J.
Cancer. Res., 81, 727 (1990)). In 1994, Schinkel et al. Reported vinblastine and iverm after intravenous administration in mice knocked out of the P-glycoprotein mdr1a in the brain.
ectin translocated to the brain about 30 times and 8 times in normal mice, respectively.
Increase of more than 0 times (Cell, 77, 491
(1994)). By the way, it is known that P-glycoprotein has an ATP-dependent pumping action and discharges various intracellular drugs out of cells. P-glycoprotein is a causative protein of a phenomenon called multidrug resistance in cancer, that is, a phenomenon called multidrug resistance, in which when a drug acquires resistance to a certain anticancer drug, it simultaneously becomes resistant to other structurally different anticancer drugs. Also known as To remove this resistance,
Many studies have been made, and among them, a group of drugs called calcium antagonists represented by verapamil
It is also well known that it inhibits the function of glycoproteins and exhibits a resistance overcoming action (BIOmedica, 6, No. 5 (1991)). Tsuruo et al. Reported that mouse brain capillary endothelial cell line MBEC4 was cultured in a monolayer culture medium in a permeation filter culture cup, and active excretion of [3H] vincristine was detected. (J. Biol. Chem., 267, 2
0383 (1992)).

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to find a compound having a potent transfer-enhancing effect on the brain transfer restriction of a therapeutic agent for a brain disease at present and a drug composition thereof, It offers clinically new and effective treatments.

[0005]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have found that among the P-glycoprotein inhibitors, a therapeutic agent for a brain disease, which has a strong effect of enhancing the translocation into the brain, is a highly safe clinical indication. As a result of intensive studies on possible compounds, the present inventors have found that a certain quinoline derivative has a very strong potentiating activity of a therapeutic agent for brain disease into the brain, and completed the present invention.

That is, the present invention provides: [1] The following general formula (1)

[0007]

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Wherein A represents a nitrogen atom or a carbon atom, B represents a direct bond, C ＝ O or — (CH ₂ ) m-
(M represents an integer of 0 to 3), and E represents the formula (2)
(Wherein R ₁ , R ₂ and R ₂ independently represent a hydrogen atom or a phenyl group) or formula (3) (formula 8) wherein D is — (CH ₂ ) n -(N represents an integer of 0 to 3), -CH = CH-, or formula (4)

[0009]

Embedded image

[0010]

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(Wherein R ₄ and R ₅ independently represent a hydrogen atom or a halogen atom). Represents｝]
Or a biologically acceptable salt thereof, wherein the quinoline derivative is a therapeutic agent for brain disease, wherein the quinoline derivative is represented by the following formula (5): A brain disease therapeutic drug according to claim 1, which is a brain transfer enhancer,

[0012]

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[3] The therapeutic agent for brain disease according to claim 1, wherein the quinoline derivative or a biologically acceptable salt thereof has the following formula (6):

[0014]

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[4] A therapeutic agent for brain disease is a therapeutic agent for brain tumor, HI
The therapeutic agent for brain disease according to claim 1, which is one or more drugs selected from the group consisting of a therapeutic agent for V, a central nervous system acting agent, a cerebral circulatory agent, and an anti-inflammatory agent.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail.

The quinoline derivative according to the present invention is represented by the general formula (1) and is described by Fukasawa and Suzuki in JP-A-3-101662, JP-A-6-1768 and J. Med. Chem. Vol. .204
7 (1997) and the like, and is known to exhibit an action of overcoming the resistance of resistant cancer by inhibiting the action of P-glycoprotein. However, there is no description of the effect of a therapeutic drug for brain disease on the brain, which counteracts the action of the BBB and enhances the ability of useful drugs acting on the brain to move into the brain. Has been demonstrated and disclosed for the first time by the present inventors' earnest studies. These compounds generally have the above-mentioned actions, and among them, the compounds called MS-209 and MS-073 shown in claims 2 and 3 show particularly strong actions.

In the present invention, the halogen atom represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom,
The biologically acceptable salt is not particularly limited, but includes salts with inorganic acids such as hydrochloric acid and sulfuric acid, and salts with organic acids such as acetic acid, oxalic acid, fumaric acid, maleic acid and tartaric acid. Further, the compound according to the present invention has an asymmetric carbon,
Although optical isomers exist, the present invention naturally includes all these isomers.

In the present invention, when a quinoline derivative is clinically applied, it can be administered alone or in combination or mixed with an existing drug. The administration timing is effective before or after the administration of the existing drug, or even when administered simultaneously, and is determined by the characteristics of the drug used, the state of the patient, and the like. As an administration method, it is possible to administer orally or parenterally. There are no particular restrictions on existing drugs to be used in combination, as long as they are drugs for treating brain diseases.
HIV treatment drugs, central nervous system drugs (psychotropic agents, antiparkinson agents, antipyretic analgesics and anti-inflammatory agents, hypnotics and sedatives, anticonvulsants, central muscle relaxants, anti-dementia drugs, etc.), cerebral circulation improving drugs, blood Anticoagulants, cerebral protective agents, hormonal agents, antibiotics and the like are conceivable.

The dose of the compound of the present invention varies depending on the condition, age, sex and the like of the subject to be administered, but 10 to 2000 mg per day for an adult is administered once or in several divided doses. In some cases, it may be mixed with a concomitant drug and administered simultaneously with a new drug.

When administered orally, tablets, granules,
Dosage forms such as powders, suspensions, capsules, syrups and the like are possible. For example, in the case of a tablet, crystalline cellulose, soft silicic anhydride or the like as an adsorbent, corn starch, lactose, calcium phosphate as an excipient,
Crystalline cellulose and the like, and if necessary, a binder, a humectant, a lubricant and the like can be used.

In the case of parenteral administration, intravenous injection,
Forms such as subcutaneous injections, intramuscular injections, suppositories, transdermals and the like are possible. For example, in the case of an injection, an aqueous solution obtained by making the quinoline derivative isotonic or sterilized, or a suspension aqueous solution using cottonseed oil, corn oil, olive oil, or the like, or a surfactant such as HCO-60 is used. Used as an emulsion.

The compound of the present invention has acute toxicity in rats,
It has a very low toxicity of LD50 of 1000 mg / kg or more in dogs orally, has good oral absorbability, has a long drug action time in the body, is safe and easy to use, and is a highly clinically useful drug.

[0024]

[Examples] The effect of the agent of the present invention on the enhancement of brain drug recruitment into the brain was examined using the drug excretion effect held by brain capillary endothelial cells as an index. Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto. Example 1 Vincristine (hereinafter abbreviated as VCR) widely used clinically as an antitumor agent was used as a model drug. The drug excretion inhibitory effect was evaluated using an in vitro blood-brain barrier model system constructed by Tsuruo et al. In the mouse brain capillary endothelial cell line (MBEC4) used in this system, the expression of P-glycoprotein has been specifically confirmed in the apical membrane, and a monolayer cell layer is formed while maintaining the polarity. From the basolateral side to the blood side (apical side)
Detection of active drug transport to the drug.

Method: After culturing the above cell line in a D-MEM medium (containing 10% fetal bovine serum, 100 μg / ml kanamycin), the lower chamber (lateral bottom membrane) of a 6-well plate containing a transmission filter type culture cup was included. 2.6 ml of a medium was placed in the side (brain side), MBCE4 was seeded in each upper chamber (apical membrane side; blood side) at 2.5 × 10 6 cells / 1.5 ml, and cultured in a CO ₂ incubator for 16 hours. After membrane formation of vascular endothelial cells, [3H] VCR was added to the upper chamber or lower chamber, and unlabeled VCR was added from the opposite side to a final concentration of 200 nM. Fumarate salt of [3- {4- (2,2-diphenylacetyl) piperazin-1-yl] -2-hydroxypropyl] quinoline, molecular formula C30H31N3O3 / 3/2
C4H4O4, molecular weight 655.7 (claim 2, compound MS
-209) dissolved in DMSO was added in the same concentration to both the upper and lower chambers to a final concentration of 3 μM.
Only the same amount of SO was added and cultured in a CO ₂ incubator. In addition, from the side where the unlabeled VCR was added simultaneously with the same concentration in both upper and lower chambers, 1
/ 13 were collected and radioactivity was measured. Immediately after collection, equal volume of 200 nM unlabeled VC to balance upper and lower chambers
The medium containing R was supplemented.

Results: As shown in [FIG. 1], in the control experiment, transport from the apical membrane side (blood side) to the basolateral membrane side (brain side), whereas the basolateral membrane side (brain side) → Although transport to the apical membrane side (blood side) exceeded and active drug excretion was observed, active drug excretion was clearly suppressed in the inhibition experiment with the agent of the present invention. In other words, it clearly showed the effect of various drugs to increase the ability to enter the brain.

[0027]

From the above examples, it has been clarified that the quinoline derivative according to the present invention suppresses the active elimination of a therapeutic agent for brain diseases by P-glycoprotein expressed in brain capillary endothelial cells. Therefore, when the agent of the present invention is used in combination with a therapeutic agent for brain disease, it can be expected to enhance the translocation of the therapeutic agent for brain disease into the brain, which is a major clinical problem, and to enhance the therapeutic effect of the therapeutic agent for brain disease. The agent of the present invention provides a new clinically effective therapeutic agent and method, and is a very useful invention.

[Brief description of the drawings]

FIG. 1 is a graph showing the inhibitory effect of a quinoline derivative on [3H] VCR excretion using a mouse brain capillary endothelial cell line (MBEC4). The vertical axis indicates the permeation amount of the VCR through the monolayer culture membrane, and the horizontal axis indicates the time elapsed. (a) is a control experiment, (b) is MS-
209 is an inhibition evaluation experiment. Open circles represent transport from the apical membrane side to the basolateral membrane side, and solid circles represent transport from the basolateral membrane side to the apical membrane side.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification FI theme coat ゛ (Reference) // C07D 215/20 C07D 215/20 (72) Inventor Hideo Fukui 1900 Togo 1900 Togo, Mobara City, Chiba Mitsui Pharmaceutical Industries Co., Ltd. (72) Inventor Takashi Tsuruo 3-36-6 Miyasaka, Setagaya-ku, Tokyo F-term (reference) 4C031 DA05 4C084 AA24 NA05 NA13 NA14 ZA021 ZA022 ZA362 ZB112 ZB262 ZC552 ZC751 4C086 AA01 AA02 BC28 GA07 GA07 MA01 MA02 MA03 MA04 NA13 NA14 ZA02 ZC41 ZC75

Claims (4)

[Claims] 1. A compound represented by the following general formula (1): [In the formula, A represents a nitrogen atom or a carbon atom,, B is a direct bond, C = O or - (CH ₂₎ m- (m is 0-3
Represents an integer. And E is a compound of the formula (2) (wherein R ₁ , R ₂ and R ₃ independently represent a hydrogen atom or a phenyl group) or a compound of the formula (3) {the D in the formula _{- (CH 2) n-, (} n represents an integer of 0 to 3.) - C
H = CH-, or formula (4) Embedded image (In the formula, R ₄ and R ₅ independently represent a hydrogen atom or a halogen atom.) Which represents a quinoline derivative or a biologically acceptable salt thereof. 2. The therapeutic agent for brain disease according to claim 1, wherein the quinoline derivative is represented by the following formula (5). Embedded image 3. The therapeutic agent for brain disease according to claim 1, wherein the quinoline derivative is represented by the following formula (6): Embedded image 4. The brain disease according to claim 1, wherein the brain disease therapeutic agent is at least one drug selected from the group consisting of a brain tumor therapeutic agent, an HIV therapeutic agent, a central nervous system acting agent, a cerebral circulatory agent, an anti-inflammatory agent and the like. Therapeutic agent for brain entry.