JPS6140282A - N_imidazolyl derivatives and manufacture - 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 The present invention relates to new N-imidazolyl derivatives of 3,4-dihydro-2H-1-benzothiopyran, processes for their preparation and pharmaceutical compositions containing them.

This invention is based on the following general formula (I) R+ (wherein each of R1, R2, R3 and R4 is the same,
or may be different, hydrogen, hydroxyl group, halogen,
Cyano group, self-C6 alkyl group, 01''-(+6 alkyl group, R2-R4 acyl fi4 or/
R' a2-o4 ar//l/amino group, -8R', -N
8Hp, /R'-aa2oR',-00OR', -0011, -c
u2n:R'\RRI 5 -PO(OR')2,-"'2COOR's Mataha-
cH2aoH-”.

- to R, where each of R' and R' may be the same or different and is hydrogen or an alkyl group of 01 to c6), and a pharmaceutically acceptable salt thereof It provides:

This invention covers all possible isomers of the compound represented by formula (1), such as diastereoisomers, enantiomers,
and mixtures thereof, metabolites, and pharmaceutically acceptable bioprecursors of compounds of formula (1).

Pharmaceutically acceptable salts of the compound of formula (1) include inorganic acids,
For example, salts with nitric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, organic acids such as acetic acid, propionic acid,
Glycolic acid, lactic acid, oxalic acid, malonic acid, malic acid,
maleic acid, tartaric acid, citric acid, benzoic acid, quinnamic acid,
salts with mannalic acid, fumaric acid, methanesulfonic acid, salicylic acid, inorganic bases such as alkali metals, especially sodium or potassium, or alkaline earth metals,
In particular salts with calcium or magnesium, and also salts with organic bases such as alkylamines, preferably triethylamine.

Alkyl, alkoxy and alkylthio groups may be branched or straight chain.

The halogen atom is, for example, fluorine, chlorine or bromine, preferably chlorine or bromine.

The 01-C6 alkyl group is preferably an 01-C4 alkyl group.

The alkoxy group of 01 and 6 is preferably an alkoxy group of 01 to C4, with methoxy, ethoxy, and impropoxy groups being particularly preferred.

The term acyl in 02-C4 acyl groups and 02-C4 acylamino groups refers to those derived from both saturated and unsaturated carboxylic acids, preferably from alkanoic acids such as acetyl, propionyl, butyryl.

When one or more of R1, R2, R3 and R4 is halogen, it is preferably chlorine or bromine.

When one or more of R1, R2, R5 and R4 is c1-c6 alkyl, it is preferably methyl, ethyl, isopropyl or t-butyl.

02-C4 acyl is an aliphatic carboxylic acyl group, such as C2-a4 alkanoyl.

When one or more of R4, R2, R3 and R4 is 02-C4 acyl, it is preferably acetyl or propionyl.

When one or more of R1, R2, R3 and R4 is 02-C4 acylamino, it is preferably acetylamino or propionylamino.

If one or more of R1, R2, R5 and R4 is -SR', it is for example -8H or -5(c1-04)alkyl, but especially methylthio, ethylthio, isopropyl It's Thio.

one of R1, R2, R5 and R4, or -
If RI is greater than or equal to -N, R, it is preferably -
NH2, -NHOH! l, -NHO2H5, -N(OH
5) 2 or -N(02H8)2.

When one or more of R1, R2, R5 and R4 is -OH2OR', it is preferably -0H20FK, -CHzOOH3, or -ca2oc
It is 2H5.

When one or more of R1, R2, R5 and R4 is 100OR', it is preferably carboxy or 01S-C4 flukoxycarbonyl, especially methoxycarbonyl or ethoxycarbonyl.

one of R1, R2, R5 and R4 or /
When R' is greater than or equal to -0ON, R, it is preferably aminocarbonyl or (01-C4 alkyl)aminocarbonyl, especially dimethylaminocarbonyl or diethylaminocarbonyl.

If one or more of R1%R2, R5 or R4 is 0H2000R', it is preferably carboxymethyl or alkoxy-carbonyl-methyl of 01-a2, especially methoxycarbonylmethyl or ethoxycarbonylmethyl .

one of R1, R2, R11 and R4 or/
If R' or more is 10H20ON, R, it is preferably aminocarbonylmethyl
) alkyl-aminocarbonylmethyl, especially dimethylaminocarbonylmethyl or diethylaminocarbonylmethyl.

When one or more of R1, R2, R3 and R4 is -PO(OR), it is preferably -PO(OH)2 or -po(ocas)2
or -PO(002H5)2. Preferably six of R1, R2, R3 and R4 are hydrogen.

Preferred compounds of this invention are compounds of formula (1) in which one of Etl, R2, It5 and R4 is /
R'100OR', -PO(OR2, -0H20ONO,
and -0H2C! and the remainder of R1, R2, R3 and R4 are hydrogen, and R' and R' are independently hydrogen or C1-04 alkyl; or a pharmaceutically acceptable salt thereof.

Examples of preferred compounds of this invention include 1) 2-(1-imidazolyl)-6-acetyl-3,4
-') Hydro-2H-1- is nzothiopyran 2-(1-imidazolyl)-6-carboxy-3
, 4-dihydro-2H-1-benzothiopyran 3) 2-(1-imidazolyl)-7-carboxy-3,
4-:) Hydro-2H-1-benzothiopyranly 2-(1-imidazolyl)-6-hydroxymethyl-3,4-dihydro-2H-1-benzothiobidi1 5) 2-(1-imidazolyl)-6 -Nitoxycarbonyl-3,4-dihydro-2H-1-benzothiopyra/6) 2-(1-imidazolyl)-6-carpamoyl-3
,4-dihydro-2H-1-benzothiopyran7) 2-(1-imidazolyl)-6-aminomethyl-5
,4-dihydro-2H-1-benzothiopyran8) 2-(1-imidazolyl)-6-phosphono-3,4
-dihydro-2H-1- includes nzothiopyran and pharmaceutically acceptable salts thereof.

The compounds of the invention and their salts have the following formula (IO (where Rls
R2, R3 and R4 are as defined above) with a reactive imidazole derivative and, if desired, converting a compound of formula (1) into another formula (1). and/or, if desired, convert the compound of formula (1) into its salt, and/or if desired, convert the salt to the free compound, and/or if desired, convert the compound of formula (1) into the free compound, and/or if desired, convert the compound of formula It can be produced by a method consisting of separating a mixture of isomers of the compound (1) into single isomers.

Reactive imidazole derivatives are, for example, N-(trialkyl-silyl)-imidazole, preferably N-(C1-06 trialkyl-silyl)-imidazole, more preferably N-()limethyl-silyl)-imidazole or N -(t-butyl-dimethyl-silyl)-imidazole.

The reaction of the compound of formula (IO) with the reactive imidazole derivative is preferably carried out at about 120°C to about 200°C,
More preferably in a temperature range of about 150°C to 175°C,
If necessary, it is carried out in the presence of a suitable aprotic organic solvent, preferably dimethylacetamide or dimethylformamide. Reaction times can range from about 2 hours to about 16 hours, preferably about 5 to 10 hours.

Alternatively, this method comprises a compound of formula (10) as defined above and an imidazole and a suitable silylating reagent, preferably bis- (Trimethyl-silyl)-urea or hexamethyldine dizan may be co-treated.

The compound of formula (II) is a known compound or can be synthesized from a known compound by a known method. For example, 3,4-9hydro-2H-1-benzothiopyran corresponding to formula (2), Ha4 (wherein R1, R2, R5 and R4 are as defined above), with a suitable oxidizing agent, Preferably with hydrogen peroxide in acetic acid in a temperature range of about -20°C to about +50°C, or with metaperiodic acid (IJum, or t-butyl hypochlorite) with a 01-C4 alkyl alcohol, especially In a suitable solvent such as methanol or water or mixtures thereof, preferably methanol/water, about -20
It is obtained by oxidation in the temperature range from °C to about +50 °C.

If desired, compounds of formula (1) can be converted to other compounds of formula (1).

These arbitrary conversions can be performed by known methods.

Thus, for example, a compound of formula (1) in which one or more of R1, R2, Rs and R4 is hydrogen,
Formula (1) wherein one or more of R1, R2, R3 and R4 is a halogen atom, such as chlorine, bromine
A Friedelkraff catalyst, such as AIL
in the presence of eng in a suitable solvent, e.g. oa2cn2
can be converted by reacting inside.

Compounds of formula (1) in which one or more of R4, R2, R5 and R4 are hydrogen can be prepared by alkylation, e.g. in a Friedel-Krach reaction, with compounds such as one of R2, R5 and R4
Formula (1
) can be converted into a compound.

a) 01-C6 alkyl halides, preferably chlorides, bromides, iodides.

b) C1-C6 aliphatic alcohol in a suitable solvent,
For example, nitrobenzene, 0H20J! Dissolved in 2.082.

In both cases (1) and (1), the reaction is hflcJ
ls, ZnOA2. It is carried out in the presence of a suitable amount of a Frieder-Schiff catalyst such as BF5. And 01~
When using C6 aliphatic alcohol, HF and lβ04
In the presence of a strong mineral acid such as concentrated sulfuric acid or without adding a solvent if desired, strain/acid from room temperature to 100 °C.
The reaction takes place over a temperature range of .

Compounds of formula (I) in which one or more of R1, R2, R5 and R4 are an alkoxy group of from to C6 can be prepared by preparing R1, R2, R3 by methods well known in the art of organic chemistry. and one or more of R4 is a hydroxyl group. For example, by treatment with a strong mineral acid such as aojL% HBr, HBr, preferably HBr, in the temperature range from 30°C to reflux temperature, preferably at reflux temperature, or by treatment with a Lewis acid such as JaJ15 or BF3. , 0H20 or nitrobenzene at a temperature range from room temperature to 80°C.

Compounds of formula (I) containing an esterified carboxy group or an esterified phosphono group can be converted into free carboxy or phosphono groups by hydrolysis with an acid or a base at a temperature range from room temperature to about 100°C. can be converted into a compound of formula (1) containing

Compounds of formula (1) containing free carboxy or phosphono groups are each esterified, for example via the corresponding acid halide, e.g. chloride, with an excess of the appropriate alkyl alcohol from 01 to C6. or by direct esterification in the presence of acidic catalysts, i.e. dry hydrogen chloride, or 5oci2, or BrF3-etherate, to give compounds of formula (I) containing esterified carboxy or phosphono groups. can be converted.

Compounds of formula (1) containing a carbamoyl group can be prepared by hydrolysis in a suitable solvent such as water, preferably with an acid, or with NaNO2 and a strong inorganic acid, i.e. H
Compounds of formula (I) containing free carboxy groups can be converted by Buber's method by treatment with an aqueous solution of 2SO4 at temperatures ranging from room temperature to 100°C.

The compound of formula (1) containing a free or esterified carboxy group/R' is -CON or 1. Formulas with groups (
It can be converted to the compound of 1). Here, R'
and R' are as defined above.

The conversion of this esterified carboxy group to the corresponding amide can therefore be achieved by direct reaction with ammonia or a suitable amine in a suitable solvent such as ether, benzene, or an excess of amine in the range from room temperature to reflux temperature. It is done by letting

Conversion of a free carboxy group to the corresponding amide can be carried out via intermediate reactive derivatives which may or may not be isolated.

Reactive derivatives of the intermediates include active esters such as no2-phenyl ester or N-hydroxysuccinimide ester, acid halides, preferably chlorides, mixed compounds such as ethoxycarbonyl or t-butylcarbonyl anhydrides. The anhydride or its reactive intermediate may be one obtained in the reaction of an acid and dicyclohexylcarbodiimidazole or carbonyldiimidazole.

The reactive intermediates are obtained by conventional methods such as those commonly used for the synthesis of peptides as described below, in which the reactive intermediates are heated in ammonia or a suitable amine in a suitable solvent or excess amine from about -10°C. The reaction is carried out in a temperature range of about 50°C.

O compounds of formula (1) in which one of R1, 'R2, R3 and R4 is a free or esterified carboxy group, especially a lower alkoxycarbonyl group, are R1
, one of R2, R3 and R4 is a -ca2oa group using LiAjlH4,
The transformation can be effected by conventional reduction in a suitable solvent such as ethyl ether or snow.

The optional conversion of the compounds of formula (I) into salts, and likewise the conversion of salts into the free compounds, and the resolution of mixtures of isomers into single isomers, may be carried out by conventional methods. I can do it.

In the compounds of formulas (1) and (10), if there is a functional group that needs to be preserved during the above reaction, such as an amino group, a hydroxyl group, or even a carboxy group, the functional group such as can be protected by conventional methods.

Examples of protective groups include those commonly used in the synthesis of peptides, such as acetyl, be/diyl, and t-butoxy-carbonyl groups when protecting an amine group.
The protecting groups are used: -meth)oxy-benzyloxy-carbonyl group, 0+nitro-7alesulfol, di-012 acetyl.

When protecting a hydroxyl group, a trialkylsilyl group such as an acetyl group, a benzoyl group, a benzyloxy group, a tetrahydropyranyl group, a β-methoxyethoxymethyl group (MKM), or a t-butyldimethylsilyl group is used. be able to. In order to retain the carboxy group, a t-butyl group, a benzhydryl group, or a p-methoxybenzyl group can be used.

After the reaction is complete, the protecting group is removed by known methods. For example, it is removed by mild acid hydrolysis or mild catalytic reduction, such as with a P(L/C catalyst) at atmospheric pressure.

The protecting groups for amino, carboxy, and hydroxyl groups are then usually removed by known methods after the reaction is complete. For example, if the amino protecting group is a monochrometetraacetyl group, it can be removed by treatment with thiourea.

Formyl.

and trifluoroacetyl groups can be removed by treatment with potassium carbonate in an aqueous methanol solution, and trityl groups can be removed by treatment with formic acid or trifluoroacetic acid.

For example, carboxy protecting groups can be removed by mild acid hydrolysis or catalytic hydrogenation, such as with P170 at atmospheric pressure.

For example, hydroxyl protecting groups can be removed by mild reaction conditions, such as acid hydrolysis.

The compounds of this invention are selective inhibitors of thromboxane A2 (TXA2) synthetase and therefore increase the ratio of thromboxane A2 (TXA2) to T3CA2 synthetase.

Activity on TxA2 and PG-2 synthetase has been evaluated in vivo. For example, rats are given an oral dose of this compound and killed 2 hours later.

Stable metabolite TxB from each of Txmu2 and PG2
Concentrations of 2- and 6-kedo-PGF1α are measured in serum and disrupted tissue, respectively.

For example, 2-(1-imidazolyl)-6-acetyl-
The compound 3,4-dihydro-2H-1-benzothiopyran markedly lowers serum TxB2 concentrations and markedly increases 6-cuto PGB'2α concentrations.

In many cells, the main product of arachidonic acid metabolism is T
-xA2 and PG-2, and their ratio plays an important role in vascular hemostasis. TXA2 exhibits a procoagulant effect (or coagulant effect) and vasoconstriction, whereas Pσ-2 exhibits an anticoagulant effect and vasodilation.

PG-2 synthetase enzyme is mainly located in endothelial cells,
Produce P ( ) work 2. PG-2, together with thrombin O products, prevents platelets from adhering to arterial walls and has a vasodilating effect.

The Tx mu2 synthetase enzyme is found primarily in platelets and is
Produces XA2. TXA2 prevents bleeding by forming platelet aggregates and vasoconstriction.

By balancing opposing forces, vascular hemostasis is regulated.

Compounds of this invention capable of selectively inhibiting the formation of TxA2 can be used as vasodilators and anticoagulants. For example, in the case of thrombosis, the peripheral pathway
ulopathy) and coronary artery diseases. In fact, inhibition of TXA2 production reduces the probability of thrombin generation and vasoconstriction with ischemic symptoms, while PE2 production remains unchanged (or increases).
Improves vasodilation, supplies blood to cells and protects blood vessel walls.

Another use of the compounds of this invention is for the treatment of migraine headaches. As is known, for example in the case of migraine, widespread vasoconstriction has been shown to be due to overproduction of platelet TxA2. [y.

C11n, Pathol, (1971), j2
, 250: J. Headache (1977), 17
, 101).

Overproduction of platelet TXA2 and MDA, such as malondialdehyde, has been shown in diabetes mellitus and correlates with microcirculatory defects due to the disease.

[Metaboliem, (1979), 28.39
4: mu, J, 01in.

Engineering Best, (1979), 9.233; Throm
bosis Haemost.

(1979), 42,983; J, Lab, 01in.
Med, (1981).

97.87’l.

Accordingly, the compounds of the invention are useful for diabetic capillary disease (micr).
oangiopathy).

Additionally, the compounds of this invention can be used as anti-inflammatory agents. As is known, for example carrageenin-1ncl.
cea) Fluid obtained from gr, anuloma converts arachidonic acid to TxA2 in the organism, in the synovial fluid of patients with rheumatoid arthritis and in fluid induced from carrageenan in rats with inflammation. increases TxA2 levels. [Pros taglands (19
77), 13, 17:5aana, J. Theum
, (1977).

Stand, 151:].

Recently, it has been demonstrated that overproduction of TxA2 is included in the pathogenesis of hypertension and that specific inhibitors of TXA2 production can be used to eliminate such factors in hypertension. (mu.

J, Pharmacol, (1981), 70.2
47]. In fact, the compounds of this invention can be used as antihypertensive agents.

Furthermore, a role for TzA2 in the pathogenesis of gastric ulcers due to the severe vasoconstriction effect has been shown, and inhibitors of TXA2 are also effective here. (Nat
ure (1981) eb deficiency A72]. In fact, the compounds of this invention show a need for the treatment of gastric ulcers. The compounds of this invention are also anticancer agents. for example,
Selective TxA2 inhibitors inhibit pulmonary metastase (me
thastases) and slow tumor growth. [Nature (198
2), 295, 188].

In view of the correlation between TXA2 and calcium transport, certain TXA2 synthetase inhibitors, such as the compounds of this invention, have recently been proposed by some authors to also inhibit osteoporosis (0θ
teoporosis), such as postmenopausal osteoporosis (p
ostmenopausal osteoporosis
It has been shown that it can be used to treat a).

[Prostaglandins (1981), 21
, 401].

Additionally, the compounds of this invention may be used to treat angina pectoris (anginap).
ectoris).

In this respect, for example Priltal
from angina patients [Prosta
grandinsandMed, (1979Ll, 2
431], and from patients with relapsed angina [811h engineering, congress
on Thrombosis, Monte Car
lo-October 1980AbθNa140]
It is known that high levels of TzB2 have been observed.

Compounds of this invention kltkt such as 2-(1-imidazolyl)-6-carboxy-6,4-dihydro-2H-
The appropriate dosage for oral administration of 1-benzothiopyran for adults is 3 times a day, from about 5 capsules to about 500"9 doses per dose.
s Dosing preferably 6 times a day, from about 20 miles per dose to 1501
v is common and depends on the disease, patient's age, and weight.

The toxicity of the compounds of this invention is negligible and therefore they can be safely used in therapy.

Mice and rats that had been deprived of food for 9 hours were given a single escalating dose of the drug orally, and then given home and food. Determination of acute toxicity (LD50) was evaluated 7 days after treatment and concluded to be negligible.

The compounds of this invention can be administered in a variety of forms. For example, oral tablets, capsules, sugar- or film-coated tablets, liquid solutions or suspensions, rectally
(rθeta:uy), in the form of suppositories, and parenterally, for example, in the form of intramuscular or intravenous infusion. In emergencies, intravenous treatment is better. As mentioned above, the exact dosage depends on the patient's disease, age,
Depends on weight, condition and route of administration.

This invention encompasses pharmaceutical compositions comprising a compound of this invention in combination with a pharmaceutically acceptable excipient (which may be a carrier or diluent).

Pharmaceutical compositions containing the compounds of this invention are usually prepared by conventional methods as described below and administered in a pharmaceutically stable form.

For example, solid oral forms contain the active compound, diluents such as lactose, dextrose, sucrose, cellulose, corn starch, starch, and lubricants such as silica, talc, stearic acid, magnesium or calcium stearate, or polyethylene glycols, and Binders such as starch, gum arabic, gelatin, methylcellulose,
carboxylethylcellulose or polyvinylpyrrolidone, dispersants such as starch, alginic acid, alginate or sodium starch glycolate, and foaming mixtures, dyes, sweeteners, wetting agents such as lecithin, polyturbate, diuryl sulfate, etc.
And generally, non-toxic and pharmaceutically inert substances are used in pharmaceutical formulations. The pharmaceutical preparations are manufactured by known methods, for example by mixing, granulating, tabletting, sugar-coating or film-coating processes.

Dispersed in liquids for oral administration are syrups,
It may be an emulsion or a suspension. The syrup may contain as carrier, for example saccharose, sucrose and glycerin or mannitol or sorbitol. especially,
Syrups given to diabetic patients must contain only carriers that are not metabolized to glucose or are only converted to glucose in small amounts, such as sorbitol. Emulsions and suspensions may be prepared using carriers such as natural rubber,
It may also contain agar, sodium alginate, k-cutin, methylcellulose, carboxyethylcellulose, or polyvinyl alcohol. Suspensions or solutions for intramuscular injection can contain the active compound and a pharmaceutically acceptable carrier such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol, and, if desired, lidocaine hydroxide. may be included at the same time.

Solutions for intravenous injection or infusion may contain as a carrier, for example sterile water or preferably sterile saline.

Suppositories may contain simultaneously the active compound and a pharmaceutically acceptable carrier such as cocoa butter, polyethylene glycol, polyoxymethylene sorbitan fatty acid ester surfactant or lecithin.

N, M, R, S is a solution of dimethyl sulfoxa, ido-(16, or 0DOj!5, 90 MH
2. Measured using a BrukerHFX device.

The Rf value was determined using a thin layer chromatograph using a silica gel plate coated with a thickness of 0.25.

The following examples illustrate, but do not limit, the invention.

Example 1 6-carboxy-3,4-dihydro-2H-1-benzothiopyran-8-oxide, m, p.

190-192°C, 1.1F (obtained by oxidizing thiochroman with hydrogen peroxide/acetic acid) (α0052 mo included) and 1.1 mg of trimethyl-silyl-imidazole (0.02
6 mol) was heated at 170°C for 8 hours.

After cooling, the mixture was poured into water, acidified with acetic acid and washed with ethyl acetate.

The aqueous solution was evaporated in vacuo and purified with pure ethyl alcohol (
2×50 m) was added and evaporated to dryness again.

The crude product was chromatographed on silica gel (eluent chloroform/methanol/acetic acid 90/10/1).
, CL65f c2) 2-(1-imidazolyl)-
6-carboxy-5,4-dihydro-2H-1-benzothiopyran, m, p, 256-258°C was obtained.

Actual elemental analysis value: 059.15: H4,70: N 1α6
5: S 12.15 calculated value 20 59.98: H4,
67; N 10.76; S 12.31 (01sH1
2n2o2s) TLC! : Eluent 0HOjL5 2 [! H30H
:CH5cOOH:90/10/1Rf-α38 N, M, R, (DMSO64) δp, p, m, :2
．． 45 (2H, m, CH2-9dan7-cHN)2
J37 (2H, m, %-C!■2-Crystal N)6j
7 (IH, t, 5-Qji-N) 6.95-7.
80 (6H, m, aromatic + imidazole) Using a similar method, the following compound was prepared =2-(1-imidazoly/I/)-6-promo3.4-sihydro2H-1
-Benzothiopyran, m-1), 131-166°C Elemental analysis actual value: c 4a84: H3y78: N
9.35 calculated value: 0 4a82: Hi75: N
9.49 (G12H11BrN2s) T, L, O,: Eluent Ac0Kt + 2% NH4
OHconc.

Rf-α56 N, M, R, (CDCHL5) δp, p, ms2.38
(2H, m, 0H2-Karagumi Issho N) 2.8Q
(2H, m, tn-0H2-OHN) 5.71
(IH, m, S-Cdan-N) 6.87-7.65 (
6H1ml aromatic + imidazole) 2-(1-imidazolyl)-3,4-dihydro-2H-1-benzothiopyran, m, p, 78-80°C Elemental analysis actual value: 066.69: H5,55; N 12.
92: S 14.73 Calculated value: 066.63; H
5,59: N 12.95: S 14.82 (01
2H12N2B) T, Il, [l! , :Eluent 0HOjL3:0H
sOH (195:5) P, f-[1,3H0M, R,
(ODOft3) δp, p-m.

2.1~&0 (4EI * mt Tsui 6ji) 575
(1a, m, s-Zan H-N) 6.9-7.73
(7H, m, aromatic ÷ imidazole) M, S,
m/c 216 (M) 149 (M-σ1) 2-(1-imidazoly/L/)-6-acetyl-3,4
-dihydro-2H-1-benzothiopyran m, p, 93
~95°C Actual elemental analysis value; c 64.15; H5,38: N 1α
37: S 12.09 Calculated value: O65,09: H
5,46: N 1 [L84: S 12.41 (01
4H14B120B) T, L, C! , two eluents Ac01[! t: 1%ZJ
H40Hconeuf=cL25 N, M, R, (CDQR5) δp@p-m-2.50
(2H, m, 0H2-side set-OEM) 257
(3Hj1tOHB) 2.90 (2”*m*insect-C■2-O2-0H,
81 (IH, aa, 5-ou-N) 7.20-7.70
(6H, m, aromatic + imidazo-/I/)2-(1-imidazolyfiv)-7-carboxy-s,4-:)hydro-2H-1-benzothiopyran, 2-(1-imidazolyl)-6 -Hydroxymethy1v-3,4-dihydro a-
2H-1-benzothiopyran, 2-(1-imidazolyl)-6-nitokiccarbonyl-3,4-dihydro-2H-1-benzothiopyran, 2-(1-imidazolyl)-6-carbamoyl-3,4
-dihydro-2H-1-benzothiopyran, 2-(1-imidazolyl)-6-aminomethyl-3,4
-dihydro-2H-1-benzothiopyran, and 2-(1-imidazolyl)-6-phosphono-3,
4-dihydro-2H-1-be/dithiopyran.

Example 2 A tub Vette weighing 1501 Ig and containing 50 η activated figurines was manufactured as follows.

Composition (10,000 tablets) 2-(1-imidazolyl)-6-acetyl-6,4-dihydro-2H-1-benzothiopyran 500 F Lactose 710 F Cornstarch 237.5 f Talc Powder 37.5 F Magnesium Stearate 15 f2
-(1-Imidazolyl)-6-acetyl-3,4-dihydro-2H-1-benzothiopyran, lactose, and half of the cornstarch were mixed. Add this mixture to 0.
It was passed through a 5 m sieve.

Cornstarch (18y) was suspended in warm water (180m). This paste was used to granulate the powder. The particles were dried and finely sieved through a 1.4 mm sieve, then the remaining amount of cornstarch, talcum powder, and magnesium were added and carefully mixed to form minced tablets with a diameter of 8/ξ.

Example 3 2-(1-imidazolyl)-3,4-:)hydro-6
-promo2H-1-benzothiopyran is treated with a stoichiometric amount of hydrogen chloride [,2-(1-imidazolyl)-6,4-:)hydro-6-pro11-2H-1-benzo Thiopyran hydrochloride was obtained.

Patent applicant: 7A2 Talia Calguchi Elver Societa Bel Atsuioji and 2 others

Claims (1)

[Claims] 1) The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (Here, each of R_1, R_2, R_3, and R_4 is the same or different. Hydrogen, hydroxyl group, halogen, cyano group, C_1 to C_6 alkyl group, C_
1 to C_6 alkoxyl group, C_2 to C_4 acyl group, or C_2 to C_4 acylamino group, and -S
R', ▲There are mathematical formulas, chemical formulas, tables, etc.▼, -CH_2
OR', -COOR', ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, PO(OR
')_2, -CH_2COOR', or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, where each of R' and R'' may be the same or different, and hydrogen or C
_1 to C_6 alkyl group), and pharmaceutically acceptable salts thereof. 2) In the compound of formula (I) described in item 1 above, R_
1. One of R_2, R_3 and R_4 is independently the acyl group of C_1 to C_4, -CH_2OR', ▲There is a mathematical formula, chemical formula, table, etc.▼, ▲There is a mathematical formula, chemical formula, table, etc.▼, - COOR', -PO(OR')_2,
▲There are mathematical formulas, chemical formulas, tables, etc.▼ and -CH_2C
a substituent selected from OOR' and R' and R
'' is independently hydrogen or an alkyl group of C_1 to C_4, and the remainder of R_1, R_2, R_3 and R_4 is hydrogen, and a pharmaceutically acceptable salt thereof. 3) The following compound group, namely 2- (1-imidazolyl)-6-acetyl-3,4-dihydro-2H-1-benzothiopyran, 2-(1-imidazolyl)-6-carboxy-3,4-dihydro-2H-1-benzothiopyran, 2-(1 -imidazolyl)-7-carboxy-3,4-dihydro-2H-1-benzothiopyran, 2-(1-imidazolyl)-6-hydroxymethyl-3,4-dihydro-2H-1-benzothiopyran, 2-(1- imidazolyl)-6-ethoxycarbonyl-3,4-dihydro-2H-1-benzothiopyran, 2-(1-imidazolyl)-6-carbamoyl-3,4-dihydro-2H-1-benzothiopyran, 2-(1-imidazolyl) )-6-aminomethyl-3,4-dihydro-2H-1-benzothiopyran, and 2-(1-imidazolyl)-6-phosphono-3,
A compound selected from 4-dihydro-2H-1-benzothiopyran and a pharmaceutically acceptable salt thereof. 4) Reacts with a compound of the following formula (II) ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (where R_1, R_2, R_3 and R_4 are as defined in Section 1 above) and, if desired, converting a compound of formula (I) into another compound of formula (I),
and/or if desired, converting the compound of formula (I) into its salt, and/or if desired converting the salt into the free compound, and/or if desired converting the compound of formula (I)
A method for producing a compound of formula (I) according to item 1 above, or a pharmaceutically acceptable salt thereof, comprising resolving a mixture of isomers of the compound of I) into single isomers. 5) A pharmaceutical composition comprising a suitable carrier and/or diluent and the compound of formula (I) of item 1 above or a pharmaceutically acceptable salt thereof as an active ingredient. 6) Compounds of formula (I) as defined in item 1 above other than those specified in item 3 above. 7) A compound of formula (I) as defined in item 1 above, or a pharmaceutically acceptable salt thereof, for use in a method of treating a human or animal body in therapy. 8) A compound of formula (I) or a salt thereof according to item 7 above for use as a selective inhibitor of thromboxane A2. 9) A process for preparing a compound of formula (I) as defined in paragraph 1 above, substantially as described in Example 1. 10) A process for preparing a pharmaceutically acceptable salt of a compound of formula (I) as defined in paragraph 1 above, which is substantially the process described in Example 3. 11) A pharmaceutical composition substantially as described in Example 2.