JP2000086519A - Medicine for reinforcing effect of antirheumatic wedicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject effect-reinforcing agent having an action for reinforcing the effect of an antirheumatic medicine against antirheumatic medicine resistance which has become a problem in the clinical treatments, by adding a specific quinoline derivative. SOLUTION: This medicine for reinforcing the effects of antirheumatic medicines contains a quinoline derivative of formula I A is N or C; B is a direct bond, C=O or the like; E is a group of formula II (R1 to R3 are each H or phenyl) or a group of formula III [D is (CH2)n ((n) is 0-3), CH=CH or a group of formula IV (R4, R5 are each H or a halogen)]}, preferably a compound of formula V. The quinoline derivative may be administered singly, together with an existing medicine (for example, an antirheumatic medicine such as sodium aurothiomalate, auranofin, bucillamine or D-penicillamine) or as a mixture with the existing medicine. The medicine for reinforcing the effects of antirheumatic medicines is preferably administered at a daily dose of 10-2,000 mg for an adult.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a quinoline derivative having an effect of enhancing the effect of an antirheumatic drug on antirheumatic drug resistance, which has become a clinically serious problem, and a drug composition thereof. In particular, the present invention relates to an effect-enhancing agent for an antirheumatic drug such as a gold agent and busilamine.

[0002]

2. Description of the Related Art In the treatment of rheumatoid arthritis (hereinafter sometimes abbreviated as RA), it is considered to be important in the treatment of RA to correct an immune abnormality causing RA inflammation. Antirheumatic drugs (DMARDs: disease
Modifying antiarthritic drugs are drugs that are expected to correct immune disorders. Because it can be introduced into remission in some cases, it is used aggressively in addition to nonsteroidal anti-inflammatory drugs for patients with a reliable diagnosis of RA. However, these antirheumatic drugs often require several months to develop their effects (slow effect), and if the effect is temporarily seen after initiation, the effect gradually decreases and acquires resistance (escape phenomenon)
There are many problems such as the presence of non-responders, and often severe side effects, and more effective drugs are needed. Of these, the acquisition of resistance to antirheumatic drugs (escape phenomenon) has become a major problem in the treatment of rheumatism as well as ineffective cases. Many antirheumatic drugs, once effective, eventually become resistant and lose their effectiveness. Especially RA
In the pyramid therapy, which is a general treatment strategy, the effects of gold drugs and bucillamine, which are frequently used in mildly affected patients, are significantly reduced. At present, relapse of inflammatory symptoms has to be dealt with by changing the drug, and multidrug combination of antirheumatic drugs and additional therapy have been tried, but reliable results have not been obtained . On the other hand, the use of steroids is difficult to withdraw, and clinicians are struggling to cope with them. In addition, it is difficult at present to discriminate invalid cases, and invalid cases vary depending on the drug, but it is said that several to 10% correspond.

[0003] Although a method for distinguishing invalid cases in RA has not been established and the mechanism of acquiring resistance has not yet been elucidated, recently, lymphocyte in peripheral blood and synovial fluid of RA patients has a multidrug resistance gene. MDR-1 (multi drug r
esistance-1) or P- encoded by it
Glycoproteins are strongly expressed, and their expression is reported to be positively correlated with the number of resistant antirheumatic drugs, the amount of steroid used, or the duration of use (C. Jorgan et al .: Rheumat. Int., 15, 83).
(1995), JF Maillefert et al .: Br. J. Rheumatol., 3
5, 430 (1996); Tsukasa Matsubara et al .: 1997 Annual Meeting of the Japanese Society of Rheumatology, Kazuo Yudo et al .: The 42nd Annual Meeting of the Japanese Association for Rheumatology (May 1998
Mon)), it was suggested that a multidrug resistance gene including MDR-1 may be involved in an invalid case in RA or one of the mechanisms of acquiring resistance. In addition, Matsubara et al. Treated patients with strong expression of MDR-1 in peripheral blood lymphocytes and patients with low expression of MDR-1 with sodium gold thiomalate or auranofin for 4 to 5 months to change the Landsbury index. As a result of the comparison, it was reported that the improvement was significantly lower in the group in which MDR-1 was strongly expressed than in the weak group (the 42nd Annual Meeting of the Japanese Association for Rheumatology (May 1998)).

[0004] It is known that P-glycoprotein has an ATP-dependent pumping action and excretes various intracellular drugs outside the 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 Many studies have been conducted to eliminate this resistance, but it is also well known that a group of drugs called calcium antagonists, represented by verapamil, inhibit the action of this P-glycoprotein and exert an action of overcoming the resistance. (BIOmedica, 6, No. 5 (1991)). Matsubara et al. Used peripheral blood lymphocytes from RA patients in which MDR-1 was strongly expressed, and were previously treated with a low-concentration calcium antagonist or cyclosporin A having a P-glycoprotein inhibitory action encoded by MDR-1. Analysis of the effect of gold on lymphocyte blastogenesis after treatment showed that the blastogenesis was significantly suppressed in the pretreatment group compared to the group treated with gold alone (FY 1998) Japanese Rheumatology Association).
However, these p-glycoprotein inhibitors have drawbacks such as strong side effects such as lowering of blood pressure, high toxicity, poor oral absorbability, and poor effect of the drug, and have many problems in clinical use. . Therefore, a new drug that is strong and safe has been strongly desired.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to find a compound and a drug composition having a potent effect of enhancing the effect of an anti-rheumatic drug which is currently in question on ineffectiveness or the acquisition of resistance. It provides a new and effective treatment.

[0006]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have developed a compound having a strong effect of enhancing the effect of an anti-rheumatic drug among P-glycoprotein inhibitors and a highly safe clinically applicable compound. As a result of intensive studies, they have found that a certain quinoline derivative has a very strong effect-enhancing effect, and completed the present invention.

That is, the present invention provides a compound represented by the following general formula (1):

[0008]

Embedded image [In the formula, A nitrogen atom, also represents a carbon atom, B is a direct bond, C = O or _{- (CH 2) m- (.} M is an integer of 0 to 3) represents a, E mother Wherein R 1, R 2, and R 3 independently represent a hydrogen atom or a phenyl group, or formula (3)

[0009]

Embedded image {Wherein, D _{is, - (CH 2) n- (} n represents an integer of 0~3.), - CH = CH- or the formula (4) (formula 8) (wherein, R4, R5 are each other Independently represents a hydrogen atom or a halogen atom.). ｝

[0010]

Embedded image Or a biologically acceptable salt thereof represented by the formula (1):

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail. The quinoline derivative is represented by the general formula (1), a typical compound of which is represented by the formula (5) (Formula 9),
The fumarate is called MS-209 and is particularly preferred.
Further, a compound represented by the formula (6) (formula 10) is also preferable.

[0012]

Embedded image

[0013]

Embedded image Here, the quinoline derivative is a part of a compound previously reported by the present inventors as a compound having an effect of enhancing the effect of an anticancer agent. That is, JP-A-3-101662, JP-A-6-1788, J. Med. Chem. 40 2047 1997 and the like. Among them, it has been found that the following compounds exhibit particularly strong effects. The previous report does not describe anything about the effect enhancing effect of the antirheumatic drug shown in the present invention.

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, naturally all of these isomers are included in the present invention.

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. The existing drugs to be used in combination are not particularly limited as long as they are drugs used for rheumatism, but sodium gold thiomalate, auranofin, busilamine, D
-Anti-rheumatic drugs such as penicillamine, lobenzarit, actarit and salazosulfapyridine, as well as drugs such as a wide range of anti-inflammatory drugs and therapeutic drugs for autoimmune diseases are considered. The dose varies depending on the condition, age, sex, etc., of the patient to be administered.
Is administered once or in several divided doses.

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.

When administered parenterally, an 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 suspending 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.

[0019]

EXAMPLES The effect of the agent of the present invention to enhance the effect of an antirheumatic drug was examined using the cell killing effect of the antirheumatic drug 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 Gold thioli widely used in clinical practice as an antirheumatic drug
Sodium malate (hereinafter abbreviated as GST) as a model drug
A human myeloid leukemia cell line (K562) and P-glycoprotein
A strain that expresses white matter and has acquired multidrug resistance (K562 / AD
R) to the cell growth inhibitory effect in vitro
Was. Method: Each of the above cell lines was transformed into RPMI 1640 medium (10%
Fetal calf serum, 20 μM 2-mercaptoethanol, 10
After containing 0 μM streptomycin).
1.5-2 × 10 in a 6-well plate^Threecells / well
And sowed. Next, a drug solution obtained by serially diluting GST with a culture medium
And further added to each well as a representative of the quinoline derivative
dl-5- [3- {4- (2,2-diphenylacetyl)
Le) piperazin-1-yl} -2-hydroxypropyl] quinol
Fumarate, molecular formula C₃₀H ₃₁N_ThreeO_Three・ 3/2 C_FourH_Four
O_Four, Molecular weight 655.7 (MS-209) at 0 or 10μ
M. After 96 hours of culture, the MTT assay
The cytotoxicity was measured in a. Results: As shown in [Fig. 1], the parent strain (K562)
Difference in proliferation rate between GST alone and MS-209 combined system
No MS-209 was observed in the resistant strain.
The cell proliferation was suppressed more in the system in which was added in combination. other
Similar effects are observed with compounds.

Example 2 In the same manner as in Example 1, the effect of the agent of the present invention on the cell killing effect of GST was examined. However, as the cells, a human myeloid leukemia strain (HL60 / R) which has acquired resistance by expressing MRP having a pump function similar to that of P-glycoprotein and its parent strain (HL60) were used. Method: Same as in Example 1. Results: The results are shown in FIG. GST for HL60
There was a tendency for MS-209 to be added in combination rather than alone to slightly suppress cell growth. On the other hand, the resistant strain HL60
/ R clearly showed strong growth inhibition in the system to which MS-209 was added.

[0022]

The quinoline derivative according to the present invention has been found to enhance the effect of an antirheumatic drug on cells that have acquired resistance. Therefore, by using the quinoline derivative according to the present invention in combination with an anti-rheumatic drug, a therapeutic effect can be expected in a case showing ineffectiveness and resistance acquisition of the anti-rheumatic drug, which is a major clinical problem. 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 effect of a quinoline derivative on enhancing GST. (A) shows the growth inhibitory effect of a human myeloid leukemia cell line, and (b) shows the growth inhibitory effect of a human myeloid leukemia cell line that has acquired multidrug resistance. The white circle is MS
The combination of -209 and GST is shown, and the closed circles show administration of GST alone.

FIG. 2. Human myeloid leukemia (HL60) with acquired resistance
/ R) and the enhanced effect of MS-209 on the cell killing effect of its parent strain (HL60). The white circle is MS
The combination of -209 and GST is shown, and the closed circles show administration of GST alone.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Yoshimitsu Kimura 1900-1, Togo, Mobara City, Chiba Prefecture Inside Mitsui Pharmaceutical Industry Co., Ltd. (72) Inventor Hideo Fukui 1900, Togo, Togo, Mobara City, Chiba Mitsui Pharmaceutical Industry Co., Ltd. F term (reference) 4C031 AA01 DA05 4C086 AA01 AA02 BC28 BC50 DA30 EA02 GA07 GA08 MA01 MA02 MA04 MA10 NA05 ZB15 ZB21 ZC75

Claims (4)

[Claims] 1. A compound represented by the following general formula (1): [In the formula, A nitrogen atom, also represents a carbon atom, B is a direct bond, C = O or _{- (CH 2) m- (.} M is an integer of 0 to 3) represents a, E mother Wherein R 1, R 2, and R 3 independently represent a hydrogen atom or a phenyl group, or a compound represented by the following formula (3): {Wherein, D _{is, - (CH 2) n- (} n represents an integer of 0~3.), - CH = CH- or the formula (4) (Chemical Formula 3) (wherein, R4, R5 are each other Independently represents a hydrogen atom or a halogen atom.). ｝ (3) Or a biologically acceptable salt thereof represented by the formula (1): 2. The antirheumatic drug effect enhancer according to claim 1, wherein the quinoline derivative is a compound represented by the following formula (5). Embedded image 3. The anti-rheumatic drug effect enhancer according to claim 1, wherein the quinoline derivative is a compound represented by the following formula (6). Embedded image 4. An antirheumatic drug comprising sodium gold thiomalate, auranofin, bucillamine, D-penicillamine,
2. The anti-rheumatic drug effect enhancer according to claim 1, which is one or more compounds selected from the group consisting of lobenzarit, actarit, and salazosulfapyridine.