JPS60199892A - 2,4-dioxa-6,8-dithiabicyclo(3,3,0)octane derivative, its preparation, and its use - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [R<1> is H, its salt-forming residue, alkyl, or alkenyl; R<2> is COOH, its salt-forming salt, alkyloxycarbonyl, alkylcarbonyl, etc.; R<3> is alkyl(oxy), cycloalkyl, or (substituted)phenyl; R<4> is H, or alkyl(oxy); R<3> and R<4> are linked to form alkylene]. EXAMPLE:A 7-bis(sec-butoxycarbonyl)methylene-2,4-dioxa-6,8-dithia-3-methylbicycl o[3,3,0]octane. USE:An activator for liver function, and a remedy for hepatic diseases. PREPARATION:A compound shown by the formula III is reacted with a carbonyl compound shown by the formula IV preferably in an inert organic solvent such as benzene, etc. in the presence of an acid such as p-toluenesulfonic acid.

Description

Detailed Description of the Invention The present invention relates to the general formula (I): (wherein 1 represents a hydrogen atom, a salt-forming residue thereof, an alkyl group or an alkenyl group, R2 represents a carboxyl group, a salt-forming residue thereof, , represents an alkyloxycarbonyl group, an alkenyloxycarbonyl substrate, or an alkylcarbonyl group, R3 is an alkyl group, an alkyloxy group, a cycloalkyl group, a phenyl group, or a substituted phenyl group, and R4 is a hydrogen atom, an alkyl group, or an alkyl group. (represents an oxy group, or R3 and R4 together represent an alkylene group)
The present invention relates to a 6,8-dithiabicyclo(3,3°0)octane derivative, a method for producing the same, and a therapeutic agent for liver diseases containing the compound as an active ingredient.

General formula tI], the alkyl group defined in Kl, the alkyloxycarbonyl group defined in R2, the alkylcarbonyl group, the alkyl group defined in R3, the alkyloxy group, the alkyl group defined in R4, the alkyl in the alkyloxy group The group is a lower alkyl group such as a methyl group, an ethyl group, an n-propyl group, '2
Ovir group, n-butyl group, i-butyl group, S-butyl group, t-butyl group, n-amyl group, 1-amyl group, S-amyl group, activated amyl group, t-amyl group and n- Includes hexyl group, etc.

The alkenyl group defined in R1 and the alkenyl group in the alknyloxycarbonyl group defined in R2 are lower alkenyl groups, such as allyl group, n-butene-
2-yl group, 2-methyl-3-buten-2-yl group, 3
-penten-2-yl group, 2-methyl-2-propenyl group, 2-butenyl group, 3-methyl-2-butenyl group, 3
-Methyl-3-butenyl group, 1-methyl-5-butenyl group, etc.

Examples of the substituent in the substituted phenyl group defined in R3 include a halogen atom, a lower alkyl group, a lower alkyloxy group, a hydroxy group, a nitro group, a phenoxy group,
Methylenedioxy groups etc. are strictly prohibited.

2,4-dioxa-6゜8- coated with general formula (1)
Dithiabicyclo(3,5°o)octane derivatives are novel compounds that have not been described in any literature and have liver function-activating effects, and are therefore useful as liver function-activating agents and liver disease therapeutic agents for humans or animals.

Further, in the general formula txt, R1 represents a salt-forming residue means that the compound represented by the general formula 11) represents a carboxylate salt. Similarly, when R2 represents a salt-forming residue, it also means that the compound represented by the general formula (1) represents a carboxylate salt.

These salts are pharmaceutically acceptable salts, preferably metal salts or ammonium salts, such as alkali metal or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts, as well as ammonia or suitable organic salts. Ammonium salts formed by reaction with amines are mentioned.

The compound represented by the general formula (11) can be synthesized, for example, according to the reaction route shown schematically below. , Ill, IV, R1, R2, R
3 and R4 have the same meanings as defined in formula I above, and R5 represents an alkyl group. ), that is, 2,4-dioxa-6,8- represented by general formula (1)
Dithiabicyclo(3,s,o)octane derivatives are
It can be obtained by reacting a compound represented by the general formula tn> with a carbonyl compound represented by the general formula R3-C-R4(1) in an inert solvent, preferably in the presence of an acid.

Furthermore, 2,4-dioxa-6,8-dithiabicyclo(3,
5,0:) The octane derivative is prepared by combining the compound represented by the general formula (II) in an inert solvent, preferably in the presence of an acid.
It can also be obtained by reacting with an orthoester compound represented by the general formula. Examples of acids that can be used in these reactions include inorganic acids such as sulfuric acid and hydrochloric acid, and organic acids such as para-toluenesulfonic acid.

Although water can be used as the solvent, it is generally preferable to use an inert organic solvent.

Any inert organic solvent may be used as long as it does not interfere with this type of reaction, such as aromatic hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as carbon tetrachloride, chloroform, and dichloromethane; diethyl Ethers such as ether, tetrahydrofuran, dioxane;
Vinegar, *esters such as ether; dimethylformamide,
Dimethyl sulfoxide and the like can be mentioned. Particularly preferred are organic solvents that are soluble in water, such as penzene, toluene, chloroform, and carbon tetrachloride.

The reaction proceeds if the reaction temperature is room temperature or higher, but heating is particularly preferred, for example, at the reflux temperature of the solvent used.

The reaction molar ratio is desirably selected appropriately from the range of equimolar to slightly 1fftA51!11 mole of the compound represented by the general formula tnl or the general formula (Vl).

The compound represented by the general formula (ill) can be synthesized according to the following scheme.

(Vl (U) (wherein R1 and R2 represent the same meanings as above, M
represents an alkali metal atom or an ammonium group. ) That is, the compound represented by the general formula (II) has the general formula (
The compound represented by V) can be obtained by reacting with glyoxal in an inert solvent in the presence of an acid.

Representative examples of the compounds represented by the general formula (II) are shown in Table 1 below.

NMR value CDcl.

Note 1) PMRTMsδppm: a93. (6H,t
), 1.3 (6H, d).

1.56 (3H,d), 1.4. ,ZO(4H,
m).

4.97 (2H, m), 5.37 (IH, q).

to3(2H,S) 1.4-15 (4H, m) 4.26 (aH, q).

5.23 (1Ht), &03 (2H, 5) co (i3 Notes) PMREPPm: 1.0 (6H, t)
,' 1.25-2,2 (6 above (m).

TMδ 2.4 (3H,s), 4.2 (2H,t C5,
2 (I H, t), 6. o (2H,s).

1.23 (6H, d), 1j7 (3H, S).

1.4-2.3 (6f(, ml, 4.92 (2H
, ml.

11s (2H, 5) CDα3 Notes) PFIRT,, J(rPys: as+s
< 6m, t),? , 3 (6a d).

1.5-10 (aH, m), 1.2 (3H, t)
.

365 (2Hq), 4.4 (2H, m).

1.4-2 [(aH, ml, 1.6-1.75 (3
H,s).

! L28. i35 (5H,s), 4.95 (2H
, ml.

6.3 (2H, S).

ocL3 Note y) PMRT,, J rrw+: 0.95 (
6H, t), 1j (6H, d) 1.6 (4H, m
l, 5.1 (2H, m) 6.3 (IH, sl,
6.6 (2H, s) 7.45 (4H, s).

coCi, 3 Notes >PF1RTPs'P""'α93(6H,t
), 1.3 (6H,d)1, C1~2.2 (14
n, m), 50 (2H, m).

4.9 (IH, d), 6.05 (2H, s) The compound represented by the above general formula fI) has low toxicity to warm-blooded animals.

The compound represented by general formula (1) is particularly useful as a therapeutic agent for liver diseases. For example, it is known that various drugs such as carbon tetrachloride can be administered to healthy test animals to experimentally cause liver damage in the animals.

The compound represented by the general formula (1) can be administered orally or parenterally (e.g., by injection) to test animals with various experimentally created pathological models of liver damage. 4 (1) It has been found that the effect of suppressing or improving liver function decline is brought about.

Therefore, the compounds represented by the general formula (11) are useful as human and veterinary medicines for the treatment or prevention of liver diseases. It can be used as a therapeutic agent for alcoholic hepatitis, hepatitis, toxic liver disorder, congestive liver disorder, cholestatic liver disorder, or liver cirrhosis, which is the terminal stage thereof.Compounds represented by general formula (1) can be used as a treatment for liver diseases as it is, or can be formulated as a mixture with pharmaceutically acceptable diluents and/or other pharmacologically active substances according to pharmaceutical practice, and the dosage It may also be composed in unit form.Pharmaceutical forms include: powders, granules, tablets, dragees, capsules, tablets, suspensions, solutions, emulsions, ampoules, injections, isotonic such as liquids and suppositories.

When the compound of the present invention is prepared as a medicine, it includes an embodiment in which the compound represented by general formula +1) is contained in a mixture with a pharmaceutically acceptable diluent.

Here, the diluent means a material other than the compound represented by the general formula (Il), and may be a solid, semi-solid liquid, or an ingestible capsule, and includes various substances such as excipients. , fillers, binders, wetting agents, disintegrants,
These include surfactants, lubricants, dispersants, buffers, flavoring agents, flavoring agents, color patches, fragrances, preservatives, solubilizing agents, solvents, coating agents, and sugar coating agents. However, stuttering is not limited to these. They may also be used as a mixture of one or more units. Such pharmaceutically acceptable diluents may also be used in mixtures with other pharmacologically active substances.

A medicament based on the compound of the present invention may be produced by any of the methods mentioned above. For example, the active ingredient is mixed with a diluent, eg, into granules, and the composition is then shaped, eg, into tablets. Parenterally administered preparations should be sterile. It should also be made isotonic with blood if necessary.

In the present invention, since the compound represented by the above general formula (11) can itself be a therapeutic agent for liver diseases, the active ingredient in the composition is generally 0.01 to 100% (N amount).
included.

In the case of dosage unit preparations, the individual formulation parts forming the super-preparation may be in different forms or the same, for example the following forms are often adopted: Tablets, granules, pills, powders, dragees, capsules, ampoules, etc.

The therapeutic agent for liver diseases according to the present invention can be applied to humans and animals for the treatment of liver diseases by methods commonly used in the field. It is administered orally or parenterally. Oral administration includes sublingual administration. Non-oral administration is by injection (
Examples include subcutaneous administration, intravenous injection, and intravenous drip).

The dosage of the medicament of the present invention depends on whether the subject is an animal or a human, sensitivity differences, age, sex, body weight, administration method, administration timing, interval, medical condition, properties of the medical condition pharmaceutical preparation, and preparation. It varies depending on various factors such as type and type of active ingredient.

Therefore, in some cases, it may be sufficient to administer a dose lower than the lowest dose shown below, and in other cases, it may be necessary to administer a dose exceeding the upper limit shown below.

In addition, in the case of large-dose administration, it is preferable to divide the administration into several times a day.

In order to obtain effective results in animals, the active ingredient must be administered orally at a dosage of 0.1 to 50 per 91 days per body weight.
071+1i1, preferably in the range 0.1 to 251 ng, for parenteral administration, ic (1
A range of 01 to 250 mg, preferably 01 to 25 mq is advantageous.

The dosage required to obtain effective results in humans is
Considering the effective dose, sensitivity difference, safety, etc. in animals, for example, the following dose range is advantageous. In the case of oral administration, 0.5 to 250 q, preferably 0.5 to 50 lv per g per body weight, in the case of parenteral administration, α01 to 100 q/day per body weight, Preferably 0.
It is 1-25m9.

Next, a synthesis example of the compound of the present invention will be shown.

Synthesis Example 1 Synthesis of 7-pis(tJ>'?''leuptoxycarbonyl)methylene-2,4-dioxa-6,8-dithia-3-methylbicyclo(5,5,0)octane (compound 1) Secondary Pter 4,5-dihydroxy-1,3-
Dithiolane-2-ylidene malonate 2.0? , acetaldehyde dimethyl acetal 12.02, benzene 1
A mixture of 0,12 N p -) luenesulfonic acids was heated on a hot plate with stirring and refluxed for 10 hours. After cooling, the reaction mixture was transferred to a separating rotor, washed with water, dried (anhydrous magnesium sulfate), and the solvent was distilled off to obtain a crude oil. This was subjected to silica gel column chromatography and sheath # (ethyl acetate/n-hexane (1
Elution with a mixed solvent of :6) yielded 1.4 f of the desired product as a colorless oil. Yield 25 65.2%6"D~1.5382 PMRCD"! δppm': a93 (6H, t),
1.5 (6H, d).

MS 1.56 (AH, d) 1.4~ZO (4H, m),
4.97 (2H, m).

5.37(IH,q), 6.03(2H,S) Synthesis Example 2 7-bis(ethoxycarbonyl)methylene-4-dioxa-6,8-dithia3-n-propylbicyclo(
3,3,0) Synthesis of octane (compound-5) Diethyl 4,5-dihydroxy-1,3-diteolane-
A mixture of 2-ylidene malo 4-) 1.5 f, butyraldehyde 1.5 f, benzene 100 ml, nokuradolene sulfonic acid Q, and 1 F was placed in a flask equipped with a condenser and a fractionator receiver for moisture measurement. , heated to reflux on a hot plate. After reacting for 10 hours, let it cool.
The reaction mixture was transferred to a separatory funnel, washed with water, and dried. The solvent was distilled off under reduced pressure, and the resulting crystals were recrystallized from a mixed solvent of ether and hexane.

Yield i 1.05 f (yield 56.7%), tn, p
, 5AO~54.00P-CDCI TMS'δppm: 0.93 (3H, t), 0.
5 (6H, t).

1.4-2.15 (4H, m), 4.26 (41
(,q), 5.23 (11(,t).

Modified as(zH,S) Synthesis Example 6 2.4-Dioxa-6,8-dithia-7-(methylcarbonyl, n-propyloxycarbonyl)methylene-3-n-propylbicyclo[3,3,0]octane (compound -11) -N-propyl 4,5-dihydroxy-1,3-dithiolan-2-ylideneacetoacetate 1.51, butyraldehyde 1.5f, benzene IQQm.

Para-toluenesulfonic acid a1jP was synthesized in a completely different manner from Example (2).

Yield 1. astt (yield 77.4%), lightning, p, 74
．． 5~°C (recrystallized with a mixed solvent of ether and hexane).

PMRCDCl, δppm: 1.0 (6H,t
), 1.25-2.2 (6H, m).

MS 2.4 (3H, s), 4.2 (2H, t), 5
．． 2 (IH, t), &0 (2H, s).

Synthesis Example 4 7-bis(bhndarybutyloxycarbonyl)methylene-2,4-dioxa-6,8-dithia-6-ethyl-3-methylbicyclo Ij, 3.0) octane compound 2
5) Synthesis of secondary protein, 4,5-dihydroxy-1,3
-dithiolane-2'-ylidene malonate 2.02, methyl ethyl ketone z02. Benzene 100-p-toluenesulfonic acid 0.12 was synthesized in exactly the same manner as in Example (2). The crude product was subjected to silica gel column chromatography (dry) (eluted with ethyl acetate: normal hexane - 1:6) to give a colorless oil [1L7
5f (yield 32.5%), n2D25=1.531
9-shoulder lareta. Ph/B%”J-ppm: [L9 (6
Ht ), (197(AH,t), 1.23 (6
H,d) 1.37 (5H,s).

ta ~2.3 (6H, ml, 4.92 (2g m)
,b,13(2H,s).

Synthesis Example 5 Synthesis of 7-bis(sec-butyloxycarbonyl)methylene-2,4-dioxa-6,8-dithia-7-ethoxybicycloC5,3,0)octane (compound 36) di-sec-butyl 4,5 -Dihydroxy-13-dithiolane-2-ylidenemalonate 2.0? , ortho ant bun ethyl 5.09. A mixture of benzene 5O-1p-1 luenesulfone 11O, 1f was heated on a hot plate and refluxed for 20 hours. After cooling, the solvent was distilled off, the residue was subjected to silica gel column chromatography (dry type), and washed out with a mixed solvent of ethyl acetate/n-hexane (1:3).
0 1.12 oily substances were served. Yield 47.2%, nDl, 5
269°1.3~2.0 (4H, m), 1.2 (
3H,t), s, 6s (2Hq), 4. a
(2H, ml, 5.9 (IH, s), 6.2
(2f(,s) Synthesis Example 6 Tubis(sec-butyloxycarbonyl)methylene-2,4-dioxa-6,8-dithia-3-methyl-6-medoxybicyclo(3,3°0)octane (compound Synthesis of 67) di-sec-butyl 4,5-dihydroxy-1,3-
Dithiolane-2-ylidene malonate 2.02, methyl orthoacetate 51. Benzene 5occ.

p-Toluenesulfonic acid (conducted from LOllF)
It was synthesized in exactly the same manner as (6) and purified by silica gel column chromatography to obtain a paste-like target product of 1.25y.
(yield 5!hQ%). PMRCD"I
sδppm: MS 0.9 (6H, t), 1.25 (6M, d
), 1.4-2.0 (4H, m), 1.6-1.
75 (+H,s), 528.5.55 (5H,s
), 4.95 (2H,m)6.3(2H,s) Synthesis Example 7 Tubis(secondarybutyloxycarbonyl)methylene-2,4-dioxa-6,8-dithia-3-parachlorophenylbicyclo[3 ,3,0] Octane (Compound 46) Synthesis of di-sec-butyl 4,5-dihydroxy-1,3-
Dithiolane-2-ylidene malonate 1. .

2. Synthesized in the same manner as in Example (2) from 0.44f of parachlorobenzaldehyde, o and osf of paratoluenesulfonic acid. ztor (yield 74.6%). nlp.

59.5℃. PMRCDC15δppm: Q, 95
(6H, t), 1.3 (6H.

MS d), 1.6 ('a ml, 5.1 (2H, m
), tz5 (IH,s), 6.6 (2H.

s), 7.45 (an, s) Examples of formulations are shown below. All parts in this example are parts by weight. The types and proportions of the ingredients can vary widely.

Example 1 Compound 22 10 parts Heavy magnesium oxide 10 parts Lactose 80 parts Mix them uniformly to make a powder or fine granules.

Example 2 Compound 26 10 parts Synthetic aluminum silicate 10 parts Calcium hydrogen phosphate 5 parts Lactose 75 parts to prepare a powder according to Example 1.

Example 5 Compound 5 50 parts Starch 10 parts Lactose 15 parts Crystalline cellulose 20 parts Polyvinyl alcohol 5 parts Water 30 parts are uniformly mixed and kneaded, then crushed, granulated, dried and sieved to obtain granules.

Example 4 99 parts of the granules obtained in Example 3 were mixed with 1 part of calcium stearate and compressed to form tablets with a diameter of 10 m.

Example 5 Compound 6 95 parts Polyvinyl alcohol 5 parts Water 60 parts Granules were prepared in the same manner as in Example 3 using .

10 parts of crystalline cellulose is added to 90 parts of the obtained granules and compressed to form tablets with a diameter of 8 squares.

Further, appropriate amounts of syrup gelatin, a mixed suspension of precipitated calcium carbonate, and a coloring agent are added to the tablets to form sugar-coated tablets.

Actual IM example 6 Compound 12 α5 part Nonionic surfactant 2.5 parts Physiological saline 97 parts After mixing at a temperature of 100 ml, the mixture is evaporated and used as an injection.

Implementation 07 Actual 211i The powder obtained in Fig. 1 is filled with light into a commercially available capsule container to form a capsule.

Examples of biological tests are shown below.

Test example 1. Carbon tetrachloride liver damage inhibitory effect test method The test compound was dissolved or suspended in olive oil and orally administered to mice (6-week-old DD male) at a rate of 250η24ψ or No. 30.6 hours later, carbon tetrachloride was dissolved or suspended in olive oil. 0.0
The liver was orally administered at a ratio of 5 tal/9 to 9 tal, and 24 hours after administration of carbon tetrachloride, the liver was sacrificed and the degree of liver damage was examined with the naked eye.

On the other hand, blood was collected during sacrifice, plasma was obtained by centrifugation, and plasma glutamic birvic transaminase (GPT) activity was determined using Reitman-Frankel (&itman-Fr
The activity was measured in accordance with the Ankel method, and the activity was expressed in carmen units (K, U,). The liver damage index is as follows.

Liver damage index Liver symptoms 0 Healthy liver 2 Slightly affected 4 Obvious damage 6 Severe damage 1 group of 5 mice were used, and the average values are shown. The results are shown in Table 2.

Effect on carbon tetrachloride liver injury As shown in Table 2, the compound of the present invention has a
It is found that it significantly modifies the liver damage index and P-GPT and has a liver damage suppressing effect.

(11ro profanity)

Claims (4)

[Claims] (1) General formula (I): (wherein R1 represents a hydrogen atom, a salt-forming residue thereof, an alkyl group or an alkenyl group, R2 represents a carboxyl group,
The salt-forming residue represents an alkyloxycarbonyl group, an alkenyloxycarbonyl group or an alkylcarbonyl group, and R3 is an alkyl group, an alkyloxy group,
It represents a cycloalkyl group, a phenyl group or a substituted phenyl group, and R4 represents a hydrogen atom, an alkyl group or an alkyloxy group, or R3 and R4 together form an alkylene group. ) 2,4-dioxa-6°8-dithiabicyclo[s,s,o)octane derivative. (2) General formula (1): (wherein I!1 represents a hydrogen atom, its salt-forming residue, an alkyl group or an alkenyl group, Rz represents a carboxyl group, its salt-forming residue, an alkyloxycarbonyl group, represents an alkenyloxycarbonyl group or an alkylcarbonyl group, and R3 represents an alkyl group, an alkyloxy group, a cycloalkyl group, a phenyl group or a substituted phenyl group, and R4 represents a hydrogen atom, an alkyl group or an alkyloxy group, or R3 and R4 together represent an alkylene group. Disease treatment agent. (3) General formula (ID: (wherein, R1 represents a hydrogen atom, an alkyl group, or an alkenyl group, and R2 represents a carboxyl group, an alkyloxycarbonyl group, an alkenyloxycarbonyl group, or an alkylcarbonyl group). and the general formula (% formula %) (wherein R3 represents an alkyl group, alkyloxy group, cycloalkyl group, phenyl group or substituted phenyl group, and R4 represents a hydrogen atom, an alkyl group or an alkyloxy group). or R3 and omi together represent an alkylene group), and optionally, the resulting compound is reacted with a base to form a salt. 2,4-dioxa-6,8 represented by the general formula (1): (wherein, R1, R2, R3 and R4 have the same meanings as above)
- A method for producing a cyclo(3,5,0)octane derivative in dithia. (4) General formula (■): (In the formula, Kl represents a hydrogen atom, an alkyl group, or an alkenyl group, and R2 represents a carboxyl group, an alkyloxycarbonyl group, an alkenyloxycarbonyl group, or an alkylcarbonyl group.) and the general formula □□□: R'C(OR1) s (y) (wherein, R3 represents an alkyl group, an alkyloxy group, a cycloalkyl group), an enyl group or a substituted phenyl group, and R5 represents an alkyl group It represents wo. ) and optionally reacts the obtained compound with a base to form a salt: (wherein gl, R2, R3 and 2,4-dioxa-6,8- represented by R5 has the same meaning as above.)
A method for producing a dithiabicyclo[3,3°0]octane conductor.