WO1982002385A1 - N-(2-thiazolyl)carbamate derivatives,process for their preparation,and medicinal composition containing same - Google Patents

Abstract

N-(2-Thiazolyl)carbamate derivatives represented by the general formula (1):$(6,)$(wherein R represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a thienyl group, a furyl group, or a pyridyl group), a process for their preparation, and an immunity-controlling medicinal composition containing same, effective against chronic articular rheumatism, viral diseases, cancer, etc.

Description

 Name

N — (2 — Thiazolyl) Carbohydrate Inducer, its manufacturing method and the components of Ioi Aoi containing it

 The present invention relates to a novel chemical substance, an N- (2-thiazolyl) caprate derivative, a method for producing the same, and a pharmaceutical composition containing the same.

 More specifically, the present invention has immunomodulatory ability, and thus effectively acts against immune diseases such as rheumatoid arthritis rheumatism, and is effective for viral species. Also useful for diseases or anti-cancer immunotherapy: Pia] ?, N- (2-thiazolyl), which has a very desirable property as a medicinal product because it has only a weak toxic effect The present invention relates to a carbonate derivative, a method for producing the same, and a pharmaceutical composition containing the same. Conventionally, steroidal and non-steroidal anti-inflammatory drugs have been used clinically in many autoimmune diseases such as rheumatism. However, many of these drugs are still not satisfactory in terms of side effects, toxicity, etc., including the effects of Hexi-1. INDUSTRIAL APPLICABILITY The novel compound according to the present invention exerts a specific effect on cells related to an immune response, and has an effect of improving the immunity of a host. The present invention

(ο:.: π

' ^r As a compound having a relatively similar structure, a compound described in JP-A-54-61172 is known, but the novel compound according to the present invention is a pharmaceutically important thiazole ring. It has a specific substituent at the 4-position. DISCLOSURE OF THE INVENTION The present invention provides a novel chemical substance, an N- (2-thiazolyl) carbamate derivative, a process for producing the same, and a pharmaceutical composition containing the novel substance.

A novel chemical substance according to the present invention is a compound represented by the following general formula W.

(In the formula, R represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a carboxyl group, a furyl group, or a viridyl group.)

The lower alkyl group represented by R in the above formula means an alkyl group having 1 to 4 carbon atoms.

 All of the above-mentioned compounds according to the present invention exhibit tautomerism of amidin and imimine. Accordingly, the compounds of the present invention include all tautomers in the definition.

 O

 —Specific examples of the N- (2-thiazolyl) caparate derivative represented by the formula (1) are as follows.

, ' _L , hi It is.

2,2,2 one Application Benefits click opening port E Chi le N - (2 · - Chi A zone Li Le) Ca over Pas menu over preparative ₀

 2,2,2 One-trickle mouthpiece hole N — (4-Methorne hole zone-2-yl)

2,2, 2 one Application Benefits click b port E Chi le N - (4 over E Chi Le Chi A zone Lumpur one 2 one I le) Ca over Nog menu over preparative ₀

 2,2,2 1 Tric Mouth Methyl N — (4 1 n-7 ° π H. Norezazole 1 2 1) Carbamate.

2,2,2 1 Trichlorethylene Ν-(4 η-butyl azo radical 21) Car mate ₀

 2,2,2 One trick mouth! Ν Ν ((((((((((((((((((((((

 2, 2, 2 — Trichlore Ν — [4-1 (2 phenyl) thiazole 1 2 — yl] Carbamate.

 2,2,2-Trichlorethylene Ν — [4-(3-chenyl) thiazolone 2-yl] Kaha * Mate.

 2,2,2 Tricrole Ν — [4-1 (2-furyl) azole 2-yl] Carbamate.

 2,2,2 1 Trik mouth Mouth Ν — [4-1 (3-frill) razor 21-yl] Kaha * Mate.

 2, 2, 2 — Tricks π-ethyl — (: 4-1 (2-Ville)) Zol 2-yl) Carbamate.

2,2,2-Trick mouth π-ethyl Ν-[4-(3 ピ ヅ Chiazor 2-Ginore] Garha * Meet.

 2,2,2-Trichloroethyl N-[4-(4 1 pill))

The compound represented by the general formula (1) is represented by the formula (2)

(In the formula, the definition of R is the same as in the above formula (1).)

2-aminothiazoles represented by the formula: 2,2,2

-By the method of reacting with trichloroethyl ester]?

 In this reaction, the starting material represented by the general formula (2) (which may be present in the form of an appropriate acid addition salt) is dissolved or suspended in a solvent. , 2,2-Trik mouth Mouth ester can be added and dropped. Examples of the solvent used in this case include benzene, tonolene, xylene, acetate, ethylenol methyl ketone, 'quoxan, 1, 2 — キ Metixethane, Tetrahydrofuran, Ν, Ν — ヅ methylformamide, etc. are suitable. In carrying out this reaction, an organic base such as pyridin triethylamine or charcoal sodium is used for the purpose of removing hydrogen chloride generated by the reaction. Inorganic bases such as potassium carbonate and sodium bicarbonate can be used.

{-. This reaction proceeds at a temperature lower than room temperature, but the reaction can be heated to the boiling point of the solvent to accelerate the reaction.

 The starting material, 2-aminothiazoles represented by the formula (2) is a known compound, and is, for example, Jacques V. Metzger, ed. The Chemistry of Heterocyclic Com— pounds, Vol. 34: Thiazole And Its Derivatives, Part Two, John Wiley & Sons, (1979)). As another method for producing the compound represented by the general formula (1), the compound represented by the general formula (3)

RC -CH ₂ X (3) 0

(Wherein the definition of I is the same as that of the above formula (1), and X represents a halogen atom.)

 Reacts with 2,2,2-trik mouth and mouth N-chi talent Lubamoyl caramel There is a way. This reaction usually involves the conversion of these two compounds into alcohol, tetrahydrofuran, dixan, benzene, 1,2— —methoxine. Shetan, N, N — 'Mix in a solvent such as dimethylformamide. The reaction temperature can be freely selected usually from room temperature to the boiling point of the solvent. This reaction is usually completed in 1 to L0 hours.

The compound represented by Formula (1) of the present invention has useful and practical activities. Compounds of the invention are immunomodulatory ^ It has the special property of low toxicity and is extremely useful as a medicament. '

 Next, this will be explained using test examples.

 Numerous experimental systems are commonly used to test immunomodulatory ability using animals.The results of the most typical test, the delayed hypersensitivity test, which is the most prominent test, are described below in Test Example 1. An example is given below.

 Chloride. By applying Crill (2—Chlorol 1,3,5-trinitone-opening pen) to the skin]? Mouse-induced delayed 'hypersensitivity' Known as a typical cellular immune phenomenon

O] ?, one of the experimental systems that are widely used worldwide

, Asherson. G-. L. and Ptak, W .: Qontact and

delayed hype rs ensitivi y in the mouse I. Active

 sensitization and passive transfer. Immunolgy, 15,

405 one 416 (1968)) ₀

This experimental system was used in the delayed hypersensitivity test.

Test Example 1 Enhancement test of delayed type hypersensitivity reaction

 Test method: ICR male mice weighing around 30 ^ were used as 8 animals per group.

 Sensitization is a solution of olive oil and acetate in a 4: 1 ratio

After dissolving the salt in water so that it becomes 3

It was applied to the abdomen of the haired mouse.

 Simultaneously with the sensitization, the compound of the present invention was added for 0.2 ° h

The solution dissolved or suspended in the saline solution

/ ― 'Two u The mice were orally administered at a mouse body weight of 11 ^ ^ j ~ 50 ^. The control group was similarly administered with 0.2 ° h carboxymethylcellular saline.

 Delayed type hypersensitivity was induced 7 days after sensitization by applying a salt in which 1 saline solution had been dissolved and a felt impregnated with dissolved olive oil. The ears of the mouse were applied with a mouse. The thickness of the mouse ears was measured before and after the challenge, and the rate of increase in the thickness (average value of the eight ears of the eight mice) is shown in Table 1. '

 For comparison, the results of a similar test using levamisole hydrochloride are also shown.

 F. t test is performed on the test results, and the significance level is P <0.05 compared to the control group.

 Those are marked with **.

 Result: When the compound of the present invention was administered at the same time as sensitization, the delayed type hypersensitivity reaction induced by the challenge was enhanced.

The activity of the compound of the present invention was equal to or higher than that of levamisole used for comparison.

 According to this, the compound of the present invention is considered to have an action of regulating the mouse immune response (immunomodulation action). -'

… ^ Enhanced test of delayed type hypersensitivity reaction

次に、 ア ジ ュ パ ン ト 関節炎試験に よ る免疫調節能テ ス ト の結果を示す。

Next, the results of the immunomodulating ability test by the adjuvant arthritis test are shown.

 Rats with rheumatoid arthritis that develop U by injection of Mycobacterium tuberculosis adjuvant are frequently used as experimental models for rheumatoid arthritis.

Although the pathogenesis of this arthritis has not been fully elucidated, it is known that cellular immunity plays an important role. Using this known adjuvant arthritis test, The immunomodulatory ability of the light compounds was examined.

 Test Example 2 Adjuvant arthritis test (Table 2)

 Test method: Using an 8-week-old SD male rat, 0.4 dry dead bacterial cells of Mycobacterium um tuberculosis were flowed. It was suspended in raffin and injected into the cucumber of the right hind limb. The compound of the present invention was administered subcutaneously nine times before and after the injection of the compound. Compounds were dissolved or suspended in 0.2 calcium methyl π-salt saline and administered at a rate of 5 ^ per body weight.

 Until the end of the test, the volume of edema of the left hind limb was measured to calculate the swelling rate. For comparison, the results of tests using levamisole hydrochloride are also shown. F. t test was performed on the test results, and the risk factor P was significantly higher than that of the control group to which only 0.2 ° h carboxymethylcellulose physiological saline was administered, which was 0.05. Is marked with *.

 Result: By the compound of the present invention]? The secondary inflammation of adjuvant arthritis was strongly suppressed, and the effect was statistically significant compared to the control group.

 The activity of the compound of the present invention was equal to or higher than that of repamisol used for comparison. That is, the compound of the present invention has immunomodulatory activity and anti-arthritic effects.

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 2 Accuventer's flame test

本発明の化合物は試験例 1 と試験例 2 に示 した よ う に 免疫調節剤と しての活性が強力であ ])、 従って免疫機能 の低下ま たは異常が伴 う こ とが知 られている疾患、 例え ば墁性関節 リ ゥ マチ どの 自 己免疫疾患の治療に有効で ¾>る。

The compounds of the present invention have potent activity as immunomodulators as shown in Test Examples 1 and 2]), and are therefore known to be associated with decreased or abnormal immune function. It is effective for treating autoimmune diseases, for example, rheumatoid arthritis.

 Next, Test Example 3 shows the toxicity test of the compound of the present invention.

-two n

 Test example 3 Oral acute toxicity test

 Test method: ddY male mice were orally administered with a compound dissolved or suspended in physiological saline using 5 mice per group. After administration

For 7 days径過to篛察, it was determined the estimated LD ₅₀ value.

Result: The compound of the present invention had an estimated LD ₅₀ value of 1 000 w or more. This value is the estimated LD _{50 for} repamisol. Hydrochloride.

 Compared with 200 to 300 ^, it is much larger, and the toxicity of the compound of the present invention is considered to be weak.

 When the compound of the present invention is used as a medicament, it can be used as a raw material for a drug as a free-radical base, but as a salt of a kind acceptable as a medicament. Thus, it can be used as a raw material for a drug.

 When the compound of the present invention is used as a medical solution, it can be administered in the same dosage form and administration method as those of ordinary immunomodulators or anticancer agents. For example, oral preparations include capsules, granules, pills, fine granules, tablets, syrups

 It can be used in any way. Suppositories are suitable for rectal administration], and subcutaneous, intramuscular, or intravenous administration can be used for injection.

 The diseases to which the immunomodulator of the present invention is applied include diseases known to be accompanied by abnormal immune function, such as autoimmune diseases such as rheumatoid arthritis and polymyositis, and various types of diseases. Infectious diseases and various cancers can be expected to normalize the immune function of patients with such diseases.

？? 1 2)

 It is desirable that the administration method and dosage form of the medicament of the present invention be appropriately selected according to the type of the disease, the condition of the patient, and the like. The dose is 0.5 ^ or 100 W / day for oral administration, and is preferably 0.5 ^ or 100 W, or less preferably j9, or 100 for intrarectal administration. The appropriate dose is 10 for intravenous administration and 1 ^ or 30 ^ for subcutaneous or intramuscular administration, but the type of disease, patient condition, etc. It is desirable to select a more appropriate amount according to the situation. Also, depending on the type of the disease and the condition of the patient, use other drugs as necessary! ), It is also possible to increase the therapeutic effect of the compounds of the present invention. For example, chemotherapeutic drugs for cancer, such as alkylating agents and antimetabolites, which have side effects that reduce the patient's immunity, should be administered. In this case, the effective component of the present invention is used together! ) However, it can be expected to prevent the side effects of these drugs from appearing and enhance the therapeutic effect synergistically.

 Hereinafter, examples of the present invention will be described.

Example 1

2-1 Amino-141 (2-1-Chenanol) Thiazol 2.7 f and hydrocarbon sodium 1.8 were added to aceton, and then potassium oxalate 2, 2,2-Tric Mouth Ethyl ester 3.8 containing Acetate solution 15; ^ was added dropwise. After stirring at room temperature for 24 hours, the liquid separated from insoluble The residue was extracted with ethyl acetate and washed sequentially with a dilute aqueous solution of sodium hydrogen carbonate, dilute hydrochloric acid, and water. After the solvent was removed, the residue was applied to silica gel chromatography, eluted with chloroform, and further ethyl alcohol was added. Recrystallized from a mixed solvent of san and 2,2,2-trik-open-hole N- [4- (2- (2-chloro) -thiazole] 1 2 I got 2.7.

 Melting point: 133 ~: 135

Elemental analysis value: as C ₁₀ H ₇ CX ₃ N ₂ 0 ₂ S ₂

 C H N S

 Theoretical value ^) 33.58 1.97 29.74 7.83 17.93 experimental value) 33.58 1.84 29.65 7.88 17.94

cm- ¹ : 3420, 1760, 1740, 1570, 1300, 1230,

 1110, 1060, 820, 720

Awake ( ^δ δ ³ ppm): 4.72 (2H, s), 6.95-7-50 (4H,

m), 10.30 (1 H, br: disappeared in D ₂ 0) Example 2

1 ロ 1 mouth キ サ 2 «Kissanone 2.5 and 2,2,2 — Trichlorethyl N — Chile Luba Moir Caramel Parameter 5.1 In addition, the mixture was refluxed for 5 hours. Next, a large amount of water was added to the reaction solution, and then ammonia water (29 ml) was added to make the solution sufficiently alkaline, followed by extraction with an ether. The extract was washed with dilute hydrochloric acid and water, and the dried ether was evaporated to remove oil. The mixture was eluted with a mixed solvent of Shii-Dai-methylene-ether (20: 1), and recrystallized with n-hexane. There was obtained 2.4 f of the 2,1-trichloroethynole N- (41-n-peptinolethiazol-2-yl) canonome.

 Melting point: 79-81'C

Elemental analysis value: as a CioH ₁₃ CZs ₂ 0 ₂ S

 C H C. N S

Theoretical value) 36.21 3.95 32.07 8.45 9.67 Experimental value ^ 36.03 3.63 31.99 8.35 10.01 丽^R ^? Sl ppm) 0-.96 (3 H, t), 1.1 ~ 2.0 (4 H, m),

2..85 (2 H, m), 5.0 (2 H, s), 6.64 (l H, s), 12.05 (1 H, br: LOSS in D ₂ 0)

Example 3

 2—Amino-41 (thirdyl) thiazolone 1.89 was suspended in tetrahydrofuran 100 τη, and then triethylamine 4.2 J ^. The reaction was carried out at reflux temperature for 20 hours by using chloroformic acid 2,2,2-trik mouth mouth ester 2.1. The insolubles were separated from the reaction mixture, the solution was reduced, the residue was taken up in ethyl acetate, and washed with water. After removing the ethyl acetate under reduced EE, the obtained residual solid was recrystallized from tetrahydrofuran to give 2,2,2—tricycloethyl N—

C 4- (4-Billyl) thiazolone 2 —〕 レ 1.7 1.7? Obtained. Melting point: 265-275'C

 Elemental analysis value: CnHsC ^ sNsO ^

 C H N S theoretical ^ 37.47 2-29 30.16 11.92 9.09

 Experimental value () 37.33 2.40 29.94 11.97-07

) 5.03 (2H, s), 7.82 (2H, d),

 8.00 (1 H, s), 8.61 (2 H, d),

12.52 (1 H, t> r : disappeared in D ₂ 0)

 Following the same operation as in the first to third embodiments, the following example

 Four to seven compounds were prepared.

Example 4

 2,2,2 — Trichlorethylene N — (4-cyclohexyl thiazol-one 2-yl) Kaha * Mate.

 Melting point: 92-93

Elemental analysis: d ₁₂ H ₁₅ C ₃ N ₂ 0 ₂ S

 C H C-. N S

 Theory () 40.29 4.23 29.74 7.83 8.96

 Actual value) 40.21 4.43 30.02 7.86 9.06

NR (to ^{_{4 p p m): l~3 (}} llH, m), 2.84 (2 H, s),

6.46 (1 H, s). 11.5 (1 H, br: disappeared at D ₂₀ )

Example 5

2,2,2 Trichlorethylene N — (2 thiazolyl) force parameter. Otsuji Melting point: 167-168'C

Elemental analysis: C ₆ H ₅ C ₃ N ₂ 0 ₂ S

 C H C ^-N S

 Theoretical value) 26.15 83 38.60 10.17.64 Experimental value ^ 26.25 77 38.51 10.31 11.53

p _Om ): 4.8 ( _2H , s), 6.8 (1H, d), 7.42

(L H, d), 13.32 (1 H, s: LOSS in D ₂ 0)

Example 6

 2, 2, 2 — Trichlorethyl N — [4- (2-furyl) thiazol-2 yl] Carbamate.

 Melting point: 146.5 ~: L47.5'C

Elemental analysis value: Ci ₀ H ₇ CZ ₃ N ₂ 0 ₃ S

 C H C N S

 Theoretical value () 35.16 2.07 31.14 8.20 9.39

Experimental value) 34.99 1.99 31.07 8.18 9.37 R ( S 3 PP melon) 4.76 (2 H, s) 6.35~ 6.5 (1 H, m),

. 6.6~6.7 (1 H, m) , 7.10 (1 H, s) 7 · 38~7.42 (1 H, m), 10.58 (1 H, br: disappeared in D ₂ 0)

Example 7

 2,2,2 1 Tric Mouth Ethyl N-[4-1 (2 -Pyryl) thiazole-21 yl] Carbamate.

Point: 171 ~ 172'C Elementary analysis: CiiH ₈ C ₃ N ₃ as the 0 ₂ S

 C H CZ N S

Theoretical value ^ 37.46 2.29 30.16 11.92 9.09 Experimental value) 37.46 2.23 30.69 12.07 9.10 丽 R (§ ⁰ — ^d6 _ppm ): 4.82 (2H, s), 7-8.45 (5H, m), 11.8 (1H, br) : lost in D ₂ 0)

Claims

1) General formula (1) of as (wherein, R represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a thienyl group, a furyl group, or a benzyl group) )) N — (2 — thiazolyl) carbamate derivative o 2) — In general formula (1), R is cyclohexyl, 2 _ chloro group, 2 — A furyl group, 2 — a pyroxyl group, a 3-hydroxyl group or a 4-pyridyl group, a N- (2 Monothiazolyl) A canine derivative. 3) — General formula (1) (wherein, R represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a phenyl group, a furyl group, a pyridyl group) A method for producing an N— (2-thiazolyl) carbamate derivative represented by the general formula (2) (where R is defined in the case of the above formula (1)) The same as the above)). The above-mentioned reaction of reacting the 2-butyazoles with 2,2-, 2-trichloromethyl ethyl ester A method for producing an N— (2-thiazolyl) caprate derivative of the general formula (1). 4) One CC (1) (wherein, R represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a phenyl group, a furyl group, or a benzyl group) A method for producing an N- (2-thiazolyl) camet derivative represented by the following general formula (3): RC-CH2X (3) 0 (where R is defined by the above formula The same as in (1), where X represents a halogen atom), and a 2,22-trik π-roche N-tin A method for producing an N- (2-thiazolyl) came derivative of the above general formula (1), which comprises reacting an o-carbamol caramellate. 5) — Killing ceremony (1) (1)

CC (Wherein, R represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a chel group, a furyl group, or a benzyl group). Thiazolyl) camet induction A medical composition with immunoregulatory properties, characterized in that it contains the body as an active ingredient.  6) The pharmaceutical composition having immunomodulatory ability according to claim 5, which is combined with a diluent or carrier acceptable as a pharmaceutical.  7) The pharmaceutical composition having immunomodulatory ability according to claim 5, which is used for treating rheumatoid arthritis rheumatism.  8) The pharmaceutical composition having immunomodulatory ability according to Item 5, which is used for immunotherapy of cancer. Z-. ^