JPS58170778A - Benzoxathiin derivative and its use - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [R1 is H or a group shown by the formula II (at least one of R2 and R3 is H or lower alkyl and the other is lower alkyl)] or its acid addition salt. EXAMPLE:5-(3-Alkylamino-2-hydroxy)propoxy-3,4-dihydro-1,2-benzoxathiin 2,2- dioxide. USE:A drug for circulatory organs. Having more improved beta1 selectivity than well- known propranolol or cartorol. PROCESS:A 5-hydroxy compound shown by the formula VI is reacted with an epihalohydrin shown by the formula VII to give a mixture of 5-(2,3-epoxy)propoxy-3,4-dihydro-1,2-benzoxathiin shown by the formula VIII and 5-(3-halogen-2- hydroxy)propoxy-3,4-dihydro-1,2-benzoxathiin 2,2-dioxide shown by the formula IX, which is reacted with a primary or secondary amine to give a compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION A. BACKGROUND OF THE INVENTION The present invention relates to a new benzoxathiine derivative and its use as a pongee ring drug.

In the Near East, β-adrenergic receptors (β-adrenaline receptors) are used as a treatment for arrhythmia and angina pectoris.
Research and development of blocking agents against or) is actively being conducted. There are two types of blockers in this family: those that act selectively on the β2 receptors in the heart, and those that are non-selective and also act on the β2 receptors in the bronchi and blood vessels, but these drugs may cause complications in patients with heart disease. The former is considered to be more advantageous in that it is less likely to inhibit the action of bronchodilators (eg, isofroterenol), which are effective in treating bronchial asthma. However, the β-blockers developed so far still have much to be improved in terms of selectivity for βl receptors, side effects, duration, etc.

However, as a result of our research, the present inventors discovered that a new benzoxathiine (
Benzoxathin) compound is considered to have excellent β+* selectivity among known cutting agents.Propranolo!, the following formula R-1
) $ Rui (Cartrol, the following formula: This is a compound in which the hydroxyl group at the 5-position of the benzoxathiine ring is etherified with an r-primary or secondary amino-β-hydroxypropyl side chain.

i, , :+, Rz and R3 are methyl group, ethyl group, phytoI/M+isopropyl group, butyl group, isobutyl group, 2nd butyl group, 8th butyl group, amyl group, isoamyl group, Lower alkyl groups such as hexyl, either one of which can be hydrogen.

C [Process for producing the compound of the present invention] The compound represented by the above formula (1) is produced by using the known cyclohexane-1,8-dione (n) as a starting material.
Genoethanesulfonyl halide (Il+) was condensed in the presence of a salt and a dehalogenating hydrogen agent to form 2-oxa 8-
Thiabicyclo(4,4,0')deca-1111+1
Eun-7-one 8, S-dioxy F (lv) was extracted and this was blown with N-promosuccinimide (NBS) to give 6-alkoxy-8,4-dihydro-1,2-benzoxanaine. The corresponding 5-hydroxy compound (W) is obtained by boiling the 2.2-dioxy△ do (Y) with a mineral acid and oxidizing it. This compound (2) is the final target compound (i) above. It is an important intermediate for obtaining .

When the above intermediate (2) is reacted with shrimp halogenhydrin (2), 5-(2,8-epoxy)propoxy-8,
4dihydro-1,2-benzoxanaine 2,2-dioxide Hata and 5-(8-halo△ken-2-hydroxy)propoxy-8,4-dihydro-1,2-benzoxathiine 2,2-dioxide surfaces are obtained in the form of a mixture, which are both primary or secondary.
The final target compound (1) is derived by reaction with a class amine (Xa or xb). The scheme of the entire process outlined above is shown below.

(1) NBS @f, acid, 611. Forms stable water-soluble salts with succinic acid, fumaric acid, maleic acid, lactic acid, citric acid, tartaric acid and other physiologically acceptable inorganic and organic acids. These water-soluble salts can be used to prepare the compounds of the present invention in tablets, daily liquid preparations,
It is useful for making injections, suppositories, discounts, and other conventional preparations.

D [Pharmacological action of the compound of the present invention] The compound according to the present invention has an excellent β-blocking action. In particular, compounds in which one of R2 and R3 is hydrogen and the other is isopropyl group (sample number S LI N -1248 is
In a competitive test using isolated guinea pig atrium and guinea pig ventral trachea, the βl:β2 effect ratio was approximately 1500, and it has excellent β1 selective activity. Yet another compound, 5UN-1268 in R2 and R3) is also βI:β
2 ratio is considerably larger than that of the propranolol (R-I), which also has excellent selectivity. Below, the results of the β-blocking action measured according to the method described in Section F above are shown in Table 1.

(The following margins continue on the next page) Table 1 E [Identification data of the compound of the present invention] ill 5-(8-isopropylamino-2-hydroxy)propoxy-8,4-dihydro-1,2-benzoxathiin 2. 2-dione (Ia) hydrochloride (1) Infrared absorption (IR, Br, cs-')
: 8800 (OH).

maX.

81011 (NH), 1870.1165 (502),
1180.1155(i-Py□) (11) Nuclear magnetic resonance (NMR, DMSO-de-C
DC13, aW"): 1.04 (d, 5.7Hz,
6H,2XCH3), 2.81-8.04(m,,
8H.

CHz N CM<), 8.08-4.29 (m,
,9H,OCH2-CH.

2 x endocyclic CH2*NH,OH), 6.467.50
(m,,8H,φ-H)+21 5-(8-8th-butylamino-2-hydroxy)propoxy-8,4-
Dihydro-1゜2-benzoxathiine 2,2-dione (Ib) hydrochloride (i) IR (KBr, cy-'): 8860 (
OH), 8280 (NH).

max.

1870.1160 (S02), 1270.1225 (
t-Bu)(it) NMR(DMSO・daC
DCg3. δ, IP): 1.06 (a,,9H.

8 XCHs), 2.48-2.76(m,,
8H, CH2-N, Ofr or NH).

8.18-4.18(m,,8H,0-CH2-CH,
2x endocyclic CH2, NH or OH), 6.52-7.44
(m,,8H,φ-H)t3) 5-C8-isobutylamino-2-,hydroxy)propoxy-8,4-dihydro-1°2-benzoxathiine 2,2-dione (rc) hydrochloride ( 1) IR(shiKBr,cI'-')28100(
OH), 8100 (NH).

max.

1870.1160(502) (ii) NMR (CDC71!3.δF): 1.
91(d,,6.8H2,6H.

2 x CHs), 1.40-2.0? (m,,IH,C
H(田',), 2.46(d,, 6.8Hz, 2H,N
-CH2), 2.65 (wide 1..2H.

NH, OH), 2.68-2.91 (m, 2H
, CH2-N), 8.81-3゜50(m, , 4H,
2X endocyclic CH2), 8.90-4.20 (m,.

8H,0-CH2-CH), 6.52-7.40(m,
, 8H, φ-H)+41 5-(8-sec-butylamino-2-hydroxy)proxy8,4-dihydro-
1,2-pendaoxathiine 2,2-dione (Id)
Fumarate (+) IR (pKBr9cm-'): 8245 (O
H), 8100 (NH).

max.

1870.1165 (S02) (if) NMR (DMSO-ds CDCga, δ
F): 0.67-1.18 (m, 6H, 2xC
H3), 1.18-1.70 (m,, 2H, C
H2-Me), 2.24-2.87 (m,,
4H, CH2-N-CH<, OH or NH), 8.
12-4.28 (m,,8H,0-CH2CH,2X endocyclic CHr, NH or OH), 6.58-7.44 (m
,.

8H, φ-H) +51 5-(8-methylamino-2-hydroxy)propoxy-3,4-dihydro-1,2-benzoxathiin 2,2-dione (re) fumarate (i) IR( νK", cm-'): 8800 (OH
), 8040 (NH).

max.

1860.1155 (So□) (if) NMR (DMSO-ds-CDCga, δ
F): 2.88 (@,, 8H.

CH2), 2.562.82(m,,2H,CH2
N), 1104.21(m,,9H,・0-CH2-
CH, OH, NH', 2X intracyclic OH2), 6.54
-7.48(m,,8H,φ-H)+61 5-(8-
dimethylamino-2-hydroxy)propoquine-8,4
-Dihydro-1,2-benzoxathiine 2,2-dione (If) fumarate (1) IH (KBr, Cm-'): 8870
(OH), 1865.1160ax (502) (fi) NMR (CDC1s, δF): 2.2
5-2.59(m,,2H,CH2-N), 2.81(
a, , 6H, 2XCH3), 8.85-8.50 (m,
, 4H.

2 × endocyclic CHx), 8.68 (broad - Il!, 18
．． OH), 8.86-4.81(m,,8H,0-C
H2CH), 6.54-7.40<m, 8H.

φ-H).

G [Production example of the compound of the present invention] (1) 2-oxa-8-thiabicyclo l-4,4,0)
Preparation of deca-1(6)-en-7-one 3,8-dioxide' (■) Fuclohexane-1,8-dione (b) 10 (1) was added, and while stirring under water cooling, triethanolamine 845
A solution prepared by dissolving 1 ml of acetone in 100 ml of acetone was gradually added dropwise. After completion, the mixture was heated in a water bath at 80 to 90'C for 5 minutes and allowed to cool. The mixture was then made basic and extracted with chloroform.

The aqueous layer was extracted again with chloroform, the two chloroform layers were combined, washed again with a 10% aqueous potassium carbonate solution and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was chromatographed, eluted with a mixture of chloroform and ether (2=1), separated, and recrystallized from n-hexane to obtain the target compound 86.879. Yield 42.8%
.

[Identification materials]

(1) Shape: Colorless edge crystals (from CH2C12-cyclohexane) (11) Meltness: 101-102°C (i) Mass spectrum (Ms)''/e: 202 (
M+)BR (tV) IR('tcm-'): 1160
1640ax (C=C-C=9), 1870.

1180 (502) (V) NMR (CDC#a, δF): 1.81-
8.80 (m, 10H) (vO elemental analysis (C8H1o
(2) 5-methoxy-3,4 dihydro-
1,2-benzoxanaine 2,2-dioxide (V
Production of a) After removing anhydrous water containing 4% anhydrous methanol/L/L under moisture protection from IJ4, the furnace liquid was concentrated.

The above operation was repeated two more times using new raw materials, the resulting concentrates were combined, dissolved in acetone, filled with silica gel, and loaded onto the Tacolumn.1. Elute with benzene, n-
Recrystallized from hexane to obtain the target compound (Vi) 8.819
I got 2. Yield 86.2%.

[゛Identification materials]

(1) Shape: Colorless needle crystals (from CHIC12-n-hexane) (+D 8 points: 145.0-145.5°C (1)
MS 7. : 214(M+)(iv
) IR ('l:KB', Cm-'): 1860.1
180 (SO2) (nax.

(V) NMR (CDC1a+δp): 8.8
1-8.59 (m, 4H, 2xCH2).

8.85 (4,,8H,0CH3), 6.55 7.4
4(m,,8H,φ-H)(Vtl elemental analysis (C9
(as H1004S) (3) 5-hydroxy-8,4-
Production of dihydro-1,2-benzoxathiine 2,2-dioxide 1 (vl) After cooling, the precipitated compound (W) was taken out in a furnace, washed with water, and dried. Yield: 1.59 foMeanwhile, the furnace solution was diluted with water, extracted with ethyl acetate, the extract was washed with water, dried over anhydrous magnesium sulfate, the solvent was removed, and the fl distillate was mixed with dichloroethane-n-hexane. Recrystallized from compound (M) 0.251
I got y.

Total amount: 1.8411 (yield: 98.4%).

[Identified material]

(1) Shape: colorless edge-like crystals (from acetone-〇-hexysan) (II) Melting point: 160.0-160.5°C (iii
) MSm/e: 200(M÷)Br 0V) IR('9''-'): 8490(
OH), 1860, 1165max Kai (502) (V) NMR (DMSO・d 6 CDC (J3+
δF): 8.11-8.75(m,, 4H, 2X
, lJ, J(@), 6.887.8C1(m,,
8B, φ-H).

964 (wide 8., .1M, 0H) (vD elemental analysis (as Cs H80, S) (continued on next page in margin) +41 5-(2,8-epoxy)propoxy-8,4
-dihydro-1,2-benzoxathiine 2,2-dioxide (■) and 5-(8-chloro-2-hydroxy)
Production of propoxy-8,4-dihydro-1,2-benzoxathiine (Ha) Granular sodium hydroxide 816■ (
7.90mM) was dissolved in water 8-, and the compound (V
l) 1.059 f (5.29mM) was added and dissolved. While stirring this solution at room temperature, add epichlorohydrin (■a) 1.527 f (16,50mM)
was added and stirring continued for 41.5 hours. After completion of the reaction, the precipitate was collected, washed with water and dried to obtain compound (■) 548■.

After that, the solvent was distilled off. The residue was loaded onto a column packed with silica gel and filtered with chloroform. Yield: Compound (
■) Total 620■ (yield 45.7%), compound (I[a)
li7J14.1%.

[Identification materials]

tar compound (■) (1) Shape: Colorless needle crystals (CHI C12-n -
(11) Melting point: 128.5-125.5°C (III)
MS・r/e: 256 (M) Br 0V) IR (u, cm-'): 1860
．． 1180(802)ax M NMR (CDC4, δppm): 2.66
8.11 (m,.

-〇dan]n'), 8.48 (wide s,, 4H.

2 x endocyclic CH1, 8.78-4.58 (m,,
2)(.

0-CHg), 6.57-7.48 (m,,
8H, φ-H) (1) Shape: Colorless phyllodes (CHh
From C1*-1-hexane) (11) Melting point: 92.0-94.5℃] (ill
) MS m/e: 292 (M)KBr
−+ (lv) IRCv, cm): 852
0 (OH).

ax 1870, 11 @ I ('1M) M NMR
(CDCLm, δppm): 2.58-2
．． 85 (m,.

IH, OH), 8.85-8.54 (m,, 4H,
2X endocyclic CHt), 8.69-8.88 (m
, 2H, CHtCt).

4.05-4.44 (m,, 8H, O-CH2CH
).

6.58-7.44 (m,, 8H, φ-H)) Propoxy-8,4-silodrow 1,2-benzoxathiin 2, Production of 2-dioxide (I) Add granular soft sodium hydroxide to water. Dissolve the compound (V
1), and while stirring at room temperature, add compound (■) 4.
Continue stirring for 1-46 hours. The precipitate was collected by F, water and n
- Combine hexane with the previous precipitate and suspend in methanol, add amine and heat to reflux for 1.5-2.5 hours. After the reaction solution is allowed to cool, methanol and excess amine are distilled off, and the residue is made acidic by adding an aqueous solution of IOX hydrochloric acid, and then extracted with chloroform. Add the chloroform layer to 10
% aqueous hydrochloric acid solution, the aqueous layers were combined into one, made alkaline with aqueous ammonia, and extracted again with chloroform. The extract was washed with water, dried, the solvent was removed, and the residue was dissolved in n-hexane or dichloroethane-n-. When crystallized using a xane mixture, a refined product of I is obtained. Detailed data for each amine is shown in Table 2 below.

(The following is a blank space) Inspection F [Method for measuring the pharmacological action of the compound of the present invention] The compound of the present invention has an excellent selective β1 blocking effect as shown in Table 1 in the previous section. A summary of the pharmacological measurements is described below.

(1) β1-blocking effect (1) Experimental animal Nihadley male guinea pig (weight 400-500 g) (11) Drugs used: In addition to the test compound, DL-
Propranolol hydrochloride (manufactured by Gyudon Kagaku), carteolol (manufactured by Tenma Pharmaceutical), and bababerine hydrochloride (manufactured by rSigma) were used. In addition, L-isoproterenol-D-bitartrate was used as a β-stimulant. All drugs were dissolved in 0.9% physiological saline before use.

(11D Experimental method: After the guinea pig was exsanguinated to death, the right atrium was quickly removed and suspended in the tank of Magnus in a conventional manner.

Krebs-Henseleit solution was used as the nutrient solution, the amount of liquid in the tank was 10g/, the temperature was 38℃,
A mixed gas of 5% OQ and 5% COs was bubbled through. Cardiac motion and heart rate were converted into electrical output using a tension transducer and recorded using a polygraph K (manufactured by Nihon Kohden).

After the cardiac motion stabilized, 1xlO'y 8x10-" 11/l11 of isoproterenol was added to the
It was added cumulatively at minute intervals to obtain a melt-response curve for increasing heart rate, and then washed. Then, after the cardiac movement returned to the original level, the test compound and control compound were added and reacted for 15 minutes, and isoproterenol was further added to create a dose-response curve of heart rate increase in the presence of drug-isoproterenol. was determined, and the pAg value of antagonism was calculated from the difference in response.

(2) β1-blocking effect (1) Experimental animal = almost the same as (1) (body weight 840-50
01) (11) Drugs used: Almost the same as (1), except that histamine hydrochloride was used as a muscle constrictor.

(110 Experimental method: The trachea of a guinea pig was removed, the anterior surface of the trachea was incised, and the connective tissue between the cartilages was suspended in a Magnus tube containing 7 ml of Tyrode's solution at 37°C. After tracheal smooth muscle contraction peaks and stabilizes.

Cumulative administration of isoproterenol The concentration-effect curve of the relaxation response was determined.

The drug was applied 3 minutes before the addition of isoproterenol, and pAg values were calculated in comparison to when no drug was added. Note that recording was performed via a smooth muscle juicer.

G [Acute toxicity of the compound of the present invention] The test compound was administered into the tail vein using ddY male mice weighing 18-22 f, and LDse was calculated by the up-and-down method from the number of deaths within one week after administration. . The results are shown in Table 1 above.

The acute toxicity of all compounds of the present invention is weaker than that of propwanol, but except for If, the acute toxicity is slightly stronger than that of carteolol.

Patent Applicant: Suntory Co., Ltd. Procedural Amendments (Issued by 岨) July 31, 1980 Commissioner of the Patent Office Kazuo Wakasugi 1 Indication of the case 1981 Patent Application No. 54051 2 Title of the invention Benzoxathiin derivatives and Its use 3 Person making the amendment 4, agent 6 Number of inventions increased by amendment None 7, subject of amendment Column of patent application titled

Claims (1)

[Scope of Claims] A benzoxathiin derivative or its malic acid addition salt. (2t R2 & U Rs (f) - hydrogen,
G) A drug for the circulatory system containing i as a claimed component in which i is methtvg, iso'7'robyl group, tertiary butyl group, isobuna (3j Rj and R3 are both methyl groups. i51 R2 and R3) One is hydrogen and the other is a methyl group. Isopropyl group, tertiary butyl group, isobuty/l' and &
or 82-butyl group, the drug according to claim (4). +61 The drug according to claim 41, wherein both R2 and R3 are methyl groups.