JPH06503084A - Aromatic aldehydes and their derivatives and their pharmaceutical compositions useful in the treatment of skin diseases and arthritis - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] aromatic aldehydes and their derivatives, and pharmaceutical compositions thereof useful in the treatment of skin diseases and arthritis. due to accelerated cell proliferation (i.e., rapid and repeated reproduction by cell division) Diseases, such as dry skin, inflammatory diseases, rheumatic diseases and allergic skin This invention relates to aromatic aldehydes and derivatives thereof useful for treating diseases.

For example, translamina is a skin disease characterized by rapid turnover of the epidermis.

In addition, patients suffering from inuimaro are suffering from autoimmune and rheumatic diseases, e.g. They may also suffer from lupus and arthritis. Currently, transposition is Treatment with tisine derivatives, diLranole, and tar ointment However, in severe cases, for example, cytostatics, cyclosporins, or Patients are treated with immunosuppressants such as or their analogues. All of these treatments cause unwanted side effects.

According to the present invention, a compound known as an anti-cancer drug can be used as a result of abnormally accelerated cell proliferation. It has been found that it can be used for the purpose of combating the diseases that occur.

Compounds according to the invention have the following formula (I): where Y is H or D.

In the formula, Xl, 1' and X are the same and may be b-) or stomach, OR, 5R 5N　R,R: However, R, R, and R2 are Hi　r: is carbon number 1- 5 alkyl group)), or x1 and X2 are each a carbon atom Combined with C=0 group or cyclic acetal <20), thiosetal (0, S), dithiane (2S), aminal (2N), oxazoline (0,N) or chi Ajinshin (N, S) is built horizontally [,1 In the formula, Ar is represented by the following substituents at one or more positions: It is unsubstituted or monosubstituted phenyl, and the substituent is an alkyl group having 1 to 5 carbon atoms. group, carbon number 3-6 (7) alkyl group, halogen, nitro group, amino group, Mono-alkylamino, mono- or dialkyl-amino groups in which the alkyl group has 1-5 carbon atoms Min group, OR, where R may be 11 or an alkyl group having 1-5 carbon atoms,! And Hexaaromatic benzaldehyde or its derivatives, or pharmaceutically Those salts are acceptable.

In the present invention, the alkyl group may be linear or branched, but especially Preferred alkyl groups are methyl, ethyl, propyl and t-butyl. Halo Gen may be any of chlorine, bromine, fluorine and iodine.

Pharmaceutically acceptable salts include, for example, alkali metal salts such as sodium salts, e.g. Alkaline earth metal salts such as sium or calcium salts, ammonium salts, organic amino acids Salts with bases and analogs thereof may also be used.

Some features of the present invention are described in European Patent No. 215395 and Japanese Patent Laid-Open No. 6 3-564411, JP 63-009490, JP 55-06 951,0 and the specification of European Patent No. 283139, etc., it is used as an anticancer agent. It is known as

Prior art has shown that large doses of the compound of formula (1) over a long period of time can kill cancer cells. The compound of formula (1) is known to have an effect on protein synthesis in cells. It has a suppressive effect. The ratio of protein accumulation in cancer cells (-) is too low. Then, the deficiency of biological energy induced by treatment with a compound of formula (1) is: Causes cell death of cancer cells.

These monsters have a certain effect on cells with abnormally accelerated cell proliferation. According to this finding, according to the present invention, the compound of formula (+) For example, layer inversion, inflammatory diseases, rheumatic diseases, allergic skin diseases, etc. It can be used to treat.

Dermatological abnormalities such as monolayer are often characterized by rapid cellular metabolism .

Normal skin has approximately 27,000 cells, approximately 1250 cells per cm2 of skin per day. of new cells, whereas skin affected by inversion produces 52,000! from the cell Each cm' of skin produces 35,000 new cells per day. deer However, cells affected by these diseases also rapidly and repeatedly reproduce through cell division. These are "normal" cells that produce The cell cycle of normal skin cells is approximately 311 hours. In contrast, in skin affected by translaminarization, the progression of this division cycle takes about 10 to 36 hours. reduced.

Benzaldehyde and some of its acetal derivatives have been shown to be toxic to human cells. It is known to have an inherently reversible growth-inhibiting effect on These transformations The growth inhibition produced by the compound is essentially a reduction in protein synthesis by the cell. [Pettersen et al., Eur, J., Cl1n, 0 ncolo, 19.935-940 (1983) and Cancer Res , 45.2085-2091 (1985)], inhibition of protein synthesis is The fact is that these drugs only have an effect on cellular proteins present within the cell's microenvironment. Protein synthesis rapidly returns to normal within an hour after the drug is removed from the cell. Recover to level.

This means that normal cells are not damaged after treatment with the compound of formula (1). Furthermore, the inhibition of protein synthesis achieved is prolonged During treatment, a reduction in protein synthesis is equivalent to a decrease in protein synthesis. A reduction in cell production is achieved. Therefore, the cause of the symptoms is an accelerated cell proliferation rate. By treating a certain disease with the compound of formula (1), diseased cells undergo abnormal cell proliferation. Since the cells are normal cells with high speed, they do not cause cell death, which is an undesirable condition. can be treated.

Examples of diseases treated with compounds of formula (H) include rheumatoid arthritis, delaminated joints. inflammation, systemic lupus erythematosus (SLE), discoid lupus erythematosus <DLE), I have acne scars, Bechtelev's arthritis, systemic scleroderma, and seborrhea.

In the following in vitro tests, a compound with the representative formula (H), Silascope (" H) (Zilascorb['ll]) for cells with a short cell cycle time It has the effect of inhibiting protein '112-growth (Table 1), and the effect is reversible (Table 2). ), surprisingly showed that the cells were intact after treatment. protein synthesis Suppression of sion delay), Table 3), and other compounds of formula (+) , as shown in Tables 1 to 3, the protein inhibitory effect that induces the corresponding delay in cell division. It was also shown to have fruit (Table 4).

Biological materials and methods used to demonstrate efficacy The compound is 5,6-〇-benzylidene-mono-ascol represented by the following formula (n). Bin adi (Cirascope ["H]).

Cell culture techniques and cell synchronization NHIK302, an established cell line of human cells derived from uterine headache in situ 1 5 (Nordbye, K and 0ftebro, R,, Exp, Ce1 1les, 58: 458.1969゜0ftebro, R, and Nordbye, K, Exp, Ce1ll1es, 58: 45 9-460.1969> with 20% human serum (prepared in the laboratory) and [Grand Island Biological Co., Ltd. logical Co,)! ] E2a medium (Pu ck et al., J. Exp. Med, 106: 145-165.1957 ) was cultured in

These cells have relatively short cell cycle times and are tumor-resistant in nude mice. It is suitable for this study because it has some characteristics of malignant cells such as tumor formation and lacks epithelial cells. It was considered necessary.

The cells were routinely grown in monolayers in tissue culture flasks. These details Since the vesicles do not move around after adhering, they can be examined under a microscope for several generations. Cells can be observed. The cells are subcultured frequently, i.e. every 2 or 3 days. By continuously maintaining the logarithmic growth phase, cells in the mitotic phase are repeatedly selected and subdivided. cells were obtained (PeLLersen et al., Ce1l Ti5sue Kinet, 10:511-522.1977), during this entrainment procedure the cells are E2a In this study, all studies were carried out in a thermostatic chamber at 37°C. Under the growth conditions used for -NHIK 3025 cells, the average cell cycle time was 1 Does not exceed 8 hours, median time for 61st, 81st and 62nd periods is less than 7 hours each , within 8 hours, and within 2.5 hours.

Duration of cell cycle time (Table 3): For the purpose of detecting the effect of said drug on cell cycle movement, previously described methods ( Lindmo, T., and Pettersen, E., O., Ce1l.T. i5sue Kinet,, 12: 43-57.19V9 HPettersen et al., Eur, J, Cancer C11n, On co1. , 19: 507-514.1983; R4nn Amashi ■ et al., J., Ce11. Physiol, 109; 411-419.1 981> was used. The method is briefly described below. Cells in mitotic phase were placed in eight tissue culture flasks (25 cm”), 5 cells per flask. 000 cells were seeded. These cells divide within an hour and are deposited on the bottom of the flask. Glued heavily. Incubate the cells <ioomocytes> in the peripheral area of the flask under an inverted microscope. Observe again and determine when each cell enters the mitosis phase, similar to the 5-division leap. I recorded it.

Protein synthesis: The rate of protein synthesis was determined by a previously described method (R4nning et al., J. Ce. 1l Physiol.

107:47-57.1981). According to FJ Kiyoshi, it is an experiment. ["Cl valine and Cellular proteins were labeled and saturated during both two days of pre-incubation. tampa By using high concentration of valine, the labeling of protein molecules can be done by using intracellular valine and generated valine. [11C] 72, 1979) by valine to reduce specific radioactivity to a steady level. Achieved by keeping the bell. The rate of formation into proteins depends on the specific base running activity [' Calculated from the uptake of H]valine. The captured measurement values are displayed at the beginning of each measurement period. 10 per hour in relation to the total [+1C] radioactivity in proteins at Expressed as a percentage of 0 (RJnning et al., J.

Ce11. Physiol, 107: 47-57.1981).

result Protein if synthesis of H)-NHIK 3025 cells using Silascope (2H) A dosage of 0.5mM of said drug, whose essential effect on Protein synthesis per hour from about 37% to about 24? 1 enough to reduce it to J 1″CJ>, the higher the concentration, the more strongly protein synthesis was inhibited.

data: Todoroki 1 Protein synthesis rate during the first hour of treatment with Silascope (“H) 0 (control) 3.68±0.08 0.5 2.36±016 1, Ol, 73±0,06 1.5 1.38±0.02 2.0 1.40±0.08 3.0 1.21±0.11 Table 2 illustrates the reversibility of protein assembly inhibition. 4! 2m M cylinder in A cell. Administer Lascope (”) () and treat for 3 hours until the Silascope (2H) is removed. I understood.

Protein synthesis during treatment was 12-1.4% per hour; .

In the control, 4. -1l%. Sillascope (2H) removal? Negative, protein 1 It was rapidly increased to the level of control or control for 1'lL.

Table of contents 3 hours during 2mM Silascope (2H) treatment and the first time after removal of the drug. Protein W self-diagnosis speed between Measurement period ★ Protein synthesis (% 7' hours) Control 4.41 ± 0.08 0, during 1st hour processing 1.40±0.081 to 2nd hour processing 1.21±0 ．． 112 - 3rd hour during treatment 1.32 ± 0.023 - 4th hour after removal 2.57 ±0.064 to 5th hour after removal 432±0.08★Measurement is carried out in 1 hour period. and measure the uptake of ['H]valine shown just before the beginning and at the end. This was carried out by The time when Silascope (2H) was added was defined as 0 hours.

More details on the extent of cell damage due to limited amounts of Silascope (2H) treatment To conduct this research, we synchronized treated NHIK 3025M cells to , cells in the early S phase were treated with 1 mM Silascope (2H) for 8 hours. deer After cell division, the time of cell division was recorded.

K1 cells induced by 8-hour treatment of synchronized cells with 1mM Silascope (2H). Delaying median cell division; treatment started in early G1 phase of the cells.

Cilascope (21() treatment Median value of cell cycle period Table 3 shows that the delay in division is 6 ．． It was 5 hours.

Flow cytophotometric recording of treated cell DNA histograms revealed that these treated cells found that the initial onset of DNA self-control was delayed by approximately 6 hours compared to control cells.

Therefore, the progression of division in stages 8 and 02 of treated cells, i.e., silascope ( ``H) After removal, the rate of progression was almost the same as that of the untreated control.

The data in Table 3 shows that 1mM Silascope (2H) inhibited protein synthesis compared to the control. This shows that protein synthesis decreases from 3.68% per hour to 1.73% per hour. It should be evaluated based on the data in Table 1. NHIK 3025 cell tan Since protein degradation is usually much higher than 1% per hour, Protein accumulation I does not exceed 0.7% per hour, therefore protein doubling during processing Time is expressed by the following formula: The protein doubling time for these cells is typically about 18 hours, so the protein doubling time during processing is We conclude that the protein accumulation rate is reduced to approximately 18% of the control rate. According to the research of the present inventors, the initial suppression of protein synthesis Reduced cell cycle progression throughout the cell cycle to the same extent as the reduction in cell accumulation (i.e., the !fiI cycle time is equal to the protein doubling time). [R4nning et al., J. Cell Physiol, 1 09.411-418 (1981)], therefore 1mM Silascope (2 The cell cycle delay induced by 8 h treatment with H) was approximately 8 h-1,5 It is expected that the time (i.e. 18% of 8 hours) = 6.5 hours, but this value are exactly the same as the data obtained in this study. This delay is induced during processing and And since no extra delay accumulates after treatment, the effects of the drug-induced Cell cycle delay is reversible.

In general, cell cycle progression is a sensitive variable that is easily disturbed by various cellular insults. It is. The cell cycle was almost completely stopped during treatment with high concentrations of Silascope (2H). Even if the drug is stopped, this variable is so strong that the cell cycle is @iR in the residue after 8 hours of treatment with the drug. The fact that cells are not disturbed at all is strong evidence that cells are not harmed by this treatment. It is determined that the Therefore, this treatment may induce even sublethal damage. That's impossible.

■ An example measurement of a compound of formula (I) that induces inhibition of protein synthesis is N In HIK 3025 cells, the initial It was carried out for 1 hour.

For protein synthesis control Drug Chemical formula Concentration (mM) Relative velocity (%) The f-hyde compound according to the present invention is It can be administered in any pharmaceutical formulation suitable for local or systemic treatment. Wear.

Pharmaceutical formulations can be administered enterally, parenterally or topically.

When administered enterally, the compound of formula (1) may be administered, for example, as a soft or hard gelatin. latin capsules, tablets, granules, granules or powders, sugar coatings, syrups, suspensions It can be formulated into a suspension, solution, suppository, etc.

When administered parenterally, the compound of formula (1) may be prepared as an injection or infusion solution. It is appropriate to

When administered topically, compounds of formula (I) may be formulated into lotions, ointments (salv e.

ointment), emulsion, gel, tincture, dusting agent, or non-toxic inert A compound of formula (I) is incorporated into a warm solid or liquid carrier suitable for topical formulation. It can be formulated as analogs thereof containing. Also, air, water and the like It is particularly suitable to use formulations that protect the active ingredient from imitators.

The formulation may contain inert or biologically active additives.

Tablets or dragees can be prepared, for example, by a series of binders, filler materials, carrier substances or diluents. The liquid formulation may be, for example, in the form of a sterile solution.

Capsules may contain filler materials or thickening agents in addition to the active ingredient. Good, in addition, flavor improvers, preservatives, stabilizers, humectants and emulsifiers, osmotic pressure Substances commonly used as salt tablets, buffers and additives for such ponds to change Like quality, it may exist.

The dosage at which the preparation is administered varies depending on the patient's needs, method of use, and brand of use. It can be changed. Generally, the aim is to treat the whole body of a standard adult weighing 70 kg. The daily dosage is about 0.1-50 m87 kg for 7 days, preferably 1-15 mg/kg/day 0 suitable ointments for topical application may contain from 0.1 to 20% by weight of active ingredient, especially from 1 to 5% by weight.

The proportion of active ingredients in a pharmaceutical composition varies depending on the formulation type, but -4 , approximately 0.1-20% by weight for oral administration and absorption through the mucous membranes, and parenteral Dosing can range from about 0.60% to 10% by weight.

If desired, pharmaceutical formulations of compounds of formula (1) may contain, for example, tocopherols, N - Methylatocofelamine, butylated hydroxyanisole, ascorbic acid.

Alternatively, it may contain an antioxidant such as butylated hydroxytoluene.

Submission of translation of written amendment (Article 184-8 of the Patent Law) May 31, 1993

Claims (6)

[Claims] 1. The following formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, Y is H or D; In the formula, X1 and X2 are OR, SR, and NR, which may be the same or different. 1R2 (however, R, R1 and R2 are H or alkyl having 1 to 5 carbon atoms) or X1 and X2 are each bonded to a carbon atom so that C= O group or cyclic acetal (20), thiosetal (O, S), dithiane (2S ), aminal (2N), oxazolidine (O,N) or thiazolidine (N, Construct S); In the formula, Ar is substituted at one or more positions by one or more of the following substituents. Substituted or substituted phenyl, the substituent being an alkyl group having 1 to 5 carbon atoms. , C3-C6 cycloalkyl group, halogen, nitro group, amino group, alkyl A monoalkylamino group or dialkylamino group in which the group has 1 to 5 carbon atoms, R is an OR group which may be H or an alkyl group having 1 to 5 carbon atoms] compounds or their pharmaceutically acceptable salts due to abnormally accelerated cell proliferation. Use in the manufacture of drugs for the treatment of diseases. 2. Use of a compound of formula (I) according to claim 1 for the treatment of psoriasis. 3. Used in the treatment of rheumatoid diseases such as arthritis, lupus or systemic scleroderma , use of a compound of formula (I) according to claim 1. 4. The compound represented by formula (I) according to claim 1, which is used for the treatment of acne or seborrhea. Use of compounds. 5. The following formula (I); ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, Y is H or D; In the formula, X1 and X2 are OR, SR, and NR, which may be the same or different. 1R2 (however, R, R1 and R2 are H or alkyl having 1 to 5 carbon atoms) or X1 and X2 are each bonded to a carbon atom so that C= O group or cyclic acetal (20), thiosetal (O, S), dithiane (2S ), aminal (2N), oxazolidine (O,N) or thiazolidine (N, Construct S); In the formula, Ar is substituted at one or more positions by one or more of the following substituents. Substituted or substituted phenyl, the substituent being an alkyl group having 1 to 5 carbon atoms. , C3-C6 cycloalkyl group, halogen, nitro group, amino group, alkyl A monoalkylamino group or dialkylamino group in which the group has 1 to 5 carbon atoms, R is an OR group which may be H or an alkyl group having 1 to 5 carbon atoms] an unusual compound containing at least one compound or a pharmaceutically acceptable salt thereof A pharmaceutical composition for treating diseases caused by accelerated cell proliferation. 6. The following formula (I); ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, Y is H or D; In the formula, X1 and X2 are OR, SR, and NR, which may be the same or different. 1R2 (however, R, R1 and R2 are H or alkyl having 1 to 5 carbon atoms) or X1 and X2 are each bonded to a carbon atom so that C= O group or cyclic acetal (20), thiosetal (O, S), dithiane (2S ), aminal (2N), oxazolidine (O,N) or thiazolidine (N, Construct S); In the formula, Ar is substituted at one or more positions by one or more of the following substituents. Substituted or substituted phenyl, the substituent being an alkyl group having 1 to 5 carbon atoms. , C3-C6 cycloalkyl group, halogen, nitro group, amino group, alkyl A monoalkylamino group or dialkylamino group in which the group has 1 to 5 carbon atoms, R is an OR group which may be H or an alkyl group having 1 to 5 carbon atoms] compounds or their pharmaceutically acceptable salts due to abnormally accelerated cell proliferation. Use in the treatment of certain diseases.