JPH0353314B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel intermediate compounds used in the production of aminochromanols. More specifically, the present invention relates to intermediate compounds used in the production of aminochromanols that have a hypotensive effect and can be used to treat hypertension in mammals including humans. According to the invention, the formula () The compound represented by 2,2-dimethyl-3,4
-Epoxy-6-cyano-3,4-dihydro-
2H-benzo[b]pyran is obtained. Belgian patent No. 829611 specifies the formula (O) A group of antihypertensive agents represented by [where A ₁ is a hydrogen atom, a C ₁ to ₉ hydrocarbon group unsubstituted or substituted with a hydroxy or C ₁ to _{C 6} alkoxy group, and A ₂ is a hydrogen atom] or a _C1 - _C6 alkyl group, or _NA1A2 is _a 3- to 8-membered heterocyclic group unsubstituted or substituted with one or two methyl groups, and _A3 is hydrogen or halogen atom,
_C1-6 alkyl _{, C2-6} alkenyl _{, C1-6} alkoxy _{, C2-6} alkenooxy _{, C1-6} alkylthio _, bidroxy, amino, _{C1-6 alkylamino} , _{C1-6 6} dialkylamino, nitro, trifluoromethyl, _{C2-7 acylamino} ,
_{C1-6 alkoxysulfonylamino} , carboxy, nitrile, _{XOA7 , XSA7} , _XSO2A7 ,
XNHA ₇ , XNA ₇ COA, XNA ₇ SO ₂ A or
XNA ₇ CO ₂ A (wherein X is an alkylene group of 1 to 4 carbon atoms, A ₇ is an alkyl group of 1 to 4 carbon atoms, and A ₈ is an alkyl group of 1 to 4 carbon atoms). , A ₄ is a hydrogen or halogen atom, or A ₃ together with A ₄ is -CH=CH-
CH=CH−, −NH−CH=CH−, −CH ₂ −CH ₂ −
CH ₂ −CH ₂ − or −CH ₂ −CH ₂ −CH ₂ −CO−
A ₅ is a hydrogen atom, _a C _1-6 alkyl or phenyl group, and A ₆ is a hydrogen atom, a C _1-6 alkyl or phenyl group] and their acid addition salts are described _. ing. The present invention provides novel intermediate compounds for use in the production of novel aminochromanols that exhibit useful hypotensive effects belonging to groups different from those mentioned above. By using the intermediate compound of the present invention, the formula (') (wherein R ₁ is a hydrogen atom, an alkyl group of up to 4 carbon atoms, or an alkyl group of up to 4 carbon atoms substituted with a chlorine or bromine atom, hydroxy, an alkoxy group of up to 4 carbon atoms, or an acyloxy group of up to 4 carbon atoms) and R ₂ is a hydrogen atom or an alkyl group of up to 4 carbon atoms, or
5 in which R ₁ is unsubstituted or substituted with a methyl group together with the nitrogen atom bonding to R ₂ and connecting those groups;
(forming a 6-membered, 6-membered or 7-membered heterocyclic group) and their salts or O-acyl derivatives are obtained. Suitable R ₁ groups include hydrogen, methyl, ethyl, isopropyl, t-butyl, β-hydroxylethyl, β-acetoxyethyl, β-methoxyethyl, Υ-chloropropyl, and the like. Suitable _R2 groups include methyl, ethyl, isopropyl and t-butyl groups and hydrogen atoms. A suitable cyclic group NR ₁ R ₂ has the formula (a) A group represented by (in the formula, Z is a valency bonding two adjacent carbon atoms, or CH ₂ , CH ₂ , CH ₂ , CH ₂ .
CH ₂ .CH ₂ CH=CH, O, S or NCH ₃ group, R ₆ is a hydrogen atom or a methyl group, and R ₇ is a hydrogen atom or a methyl group). Particularly suitable NR ₁ R ₂ groups include NHCH ₃ , NH
(CH ₂ ) ₃ Cl, N(CH ₃ ) ₂ , NH.CH(CH ₃ ) ₂ , NH.C
(CH ₃ ) ₃ and formula (b) _{A cyclic} group _represented by
CH ₂ .CH ₂ .CH ₂ - or -CH=CH- group or oxygen atom). Further preferred NR ₁ R ₂ groups are piperidino and pyrrolidino groups. Preferred compounds of formula (') include formulas (') and (') Compounds represented by and salts thereof and O-
There are acyl derivatives. Suitable O- of compounds of formulas (') to (')
The acyl derivative is an O-acetyl derivative. Optimal O- of compounds of formulas (') to (')
Acyl derivatives are acyl groups represented by the formula -CO.R' (where R' is unsubstituted or substituted with a phenyl group).
n-alkyl group of ~6 carbon atoms). Acid addition salts of the amino compounds of formulas (') and (') can be prepared using acids according to conventional methods. Suitable salt-forming acids include hydrochloric acid, hydrobromic acid,
Examples include sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, propionic acid, succinic acid, citric acid, tartaric acid, mandelic acid, lactic acid, gluconic acid, and other organic and inorganic acids that can be used for medical purposes. These compounds exist in any active form. Those skilled in the chemical arts are well aware that racemic mixtures of amino compounds can often be resolved into pure optical isomers using techniques such as fractional crystallization, optionally using active acids, etc. ing. Pharmaceutical compositions suitable for the treatment of hypertension are obtained from these compounds. Although these pharmaceutical compositions may be suitable for parenteral or oral administration, oral compositions are generally preferred because of their convenience of administration. It is often advantageous to administer the compositions of the invention in conjunction with adrenergic beta-blockers. Preferably, the composition is in unit dosage form, such as a tablet or capsule. Such unit dosage forms usually contain 0.5 to 100 mg of the active ingredient, e.g.
The dose will be 100 mg 1 to 6 times per day. These pharmaceutical compositions can be formulated in conventional manner, similar to those used for known antihypertensive agents such as alpha-methyldopa, propranalol, guanethidine, and the like. As is customary, the compositions of the present invention may additionally contain other agents such as other antihypertensive agents, diuretics, and the like. The compound of formula (') is an amine represented by NR ₁ R ₂ [wherein R ₁ and R ₂ each have the meaning defined in (')] and formula () It can be produced by reacting with an epoxide which is an intermediate compound of the present invention shown in This reaction between amines and epoxides can be carried out at less extreme low, moderate or high temperatures, e.g.
It can be carried out at any temperature within 200℃, but
Generally, room temperature or a slightly higher temperature, for example 12 to 100°C, is optimal. The reaction is usually carried out in the presence of an alkanol or ketone solvent such as methanol, ethanol, propanol, acetone or methyl ethyl ketone. It has been found that reactions often run smoothly and satisfactorily when carried out in warm or refluxing ethanol. It has been found that the above reaction yields only the trans isomer containing virtually no cis isomer. Useful intermediate compounds of the invention of formula () can be prepared by a method analogous to that described in Belgian Patent No. 829,611. Preferred methods for producing these compounds are shown below. The reaction conditions for the conversion shown in the above reaction formula are commonly used conditions and are as described in Belgian Patent No.
This will be clear to those skilled in the art from available documents such as US Pat. No. 829,611. O-acyl derivatives of compounds of formula (') can be prepared by conventional acylation methods, such as reaction with acid anhydrides, acid halides, and the like. The following examples illustrate the invention. Example 1 3,4-epoxy-3,4-dihydro-2,2
-dimethyl-6-cyano-2H-benzo[b]
A 40% methanolic solution of 19.6 g of pyran 4-cyanophenol, 9.9 g of palletized sodium hydroxide, 40.83 g of 3-chloro-3-methylbut-1-yne and 34.5 g of benzyltrimethylammonium hydroxide in 150 ml of methylene chloride and 150 ml of water. at room temperature at 4
Stirred for days. After separation of the layers, the aqueous layer was extracted twice with chloroform, the combined organic extracts were evaporated, and the resulting residue was dissolved in ether, washed with water and 2N sodium hydroxide solution, and dried over anhydrous sodium sulfate. . Removal of the drying agent and solvent gave 15.72 g of an oil. Distillation was performed at 0.5 mmHg to obtain 10.13 g of 3-(p-cyanophenoxy)-3-methylbut-1-yne as a 96-102°C fraction. The cyclization of 9.77 g of the 3-(p-cyanophenoxy)-3-methylbut-1-yne compound was carried out by heating in diethylaniline at 210 DEG-220 DEG C. (in a stream of nitrogen). After purification by distillation and extraction with dilute hydrochloric acid, 6.84 g of a colorless oil of 2,2-dimethyl-6-cyano-2H-benzo[b]pyran was obtained. If this oily liquid is left to stand, it will gradually crystallize, and its nuclear magnetic resonance spectrum will be δ
= 1.46, 6.25 (double line, J = 10) 5.67 (double line, J
= 10), 6.74 (double line, J = 8), 7.18 (double line, J
= 2) and 7.34 (quartet, J = 8 and 2). While stirring a cold solution of 6.56 g of 2,2-dimethyl-6-cyano-2H-benzo[b]pyran in 65 ml of dimethyl sulfoxide and 1.30 ml of water,
To this was added 12.63 g of freshly crystallized N-bromosuccinimide in one portion, stirred for an additional hour, diluted with water, and isolated with ethyl acetate, trans-3-bromo-3,4-dihydro-
10.54 g of white crystalline solid of 2,2-dimethyl-6-cyano-2H-benzo[b]pyran-4-ol
I got it. When a small portion of it was recrystallized from petroleum ether with a boiling point of 60-80°C, the melting point was 128-128.5°C. This bromohydrin 5.63g and sodium hydroxide
0.80 g was stirred in 75 ml of dioxane and 18 ml of water at room temperature for 3 hours, diluted, and extracted with ethyl acetate.
4.35 g of a colorless oily liquid of 2,2-dimethyl-6-cyano-2H-benzo[b]pyran was obtained. Its nuclear magnetic resonance spectra are δ=1.26 and 1.54(−
CH ₃ ), 3.80 (double line, J=4, H-4), 3.40 (double line, J=4, H-3), 677 (double line, J=8,
H-8), 7.43 (quartet, J=8.2 and 4.7) and 7.58 (doublet, J=2, H-5). 3,4-epoxy-3,4-dihydro-2,2
- Dimethyl-6-cyano-2H-benzo[b]pyran 2.09 g and piperidine 0.86 g were treated in 60 ml of reflux-heated ethanol for 24 hours, and the yellow oil obtained by evaporating the solvent was dissolved in as little ethanol as possible. , treated with an ethereal solution of hydrogen chloride and left to stand, produces a trans-4-
Piperidino-3,4-dihydro-2,2-dimethyl-6-cyano-2H-benzo[b]pyran-3
-2.06 g of all hydrochloride was obtained. Similarly, trans-4-isopropylamino-3,4-dihydro-2,2-dimethyl-6-cyano-2H-benzo[b]pyran-
3-ol hydrochloride was obtained. Comparative Example 1 Test for unfavorable effects on the heart of the following compound (A) described in JP-A-51-1477 and the following final product compound (B) derived from the intermediate compound of the present invention. The results are shown below. Test method CD Sprague dawley (CD Sprague) with male and female weighing 130-200g.
Dawley) rats from Kent, England.
Obtained from Charles River. These were then divided into 8 groups (4 males and 4 females). Test compounds (A) and (B) each separately at 1% w/
ml of methylcellulose solution and was orally administered to separate groups of animals by gavage at a dose of 1 ml per 100 g of body weight. Animals were dosed once a day for two consecutive days. Both test compounds were 5
Administered at mg/Kg (free base). This dose showed the best estimate of an equally active dose for hypotension and tachycardia in normotensive rats of the same species.
Forty-eight hours after the first dose, each rat was deeply anesthetized with ether and exsanguinated from the spinal cord and abdominal aorta before removing the heart for microscopic examination. Each heart specimen was routinely processed prior to microscopy, sectioned (5 μm) and stained with hematoxylin and eosin. Simultaneously with this histophysiological examination, mortality, physical signs, body weight, gross post mortem findings, and organ weight analysis were recorded. Results Histophysiology With compound (A), small myocardial lesions were seen in the apex and subendocardium of the left ventricle in 6/8 rats of this group, which may be a result of the treatment. One of the remaining rats had a very slight lesion of little significance. According to compound (B), none of the rats in this group had any side effects related to cardiac treatment. and the lesions recorded were too small in magnitude and extent to be considered meaningful. The actual results obtained are shown in the table below.

[Table] Conclusion Histophysiological tests showed that Compound (A) caused focal muscle fiber degeneration at pharmacologically active doses. In contrast, compound (B) was shown to cause no cardiac effects at pharmacologically equivalent doses. Comparative Example 2 Blood pressure lowering effect of the following compounds (3) and (4) described in JP-A-51-1477 and the final products compounds (1) and (2) derived from the intermediate compound of the present invention The results of the comparison are shown below. Deoxycorticosterone acetate (DOCA)/
Each compound was orally administered to hypertensive rats treated with NaCl and evaluated for antihypertensive activity. Systolic blood pressure recorded directly from the tail was determined at various time intervals before and 6 hours after compound administration. The maximum blood pressure reduction obtained for each compound is shown in the following table.

【table】

[Table] As is evident from the above table, the final products compounds (1) and (2) derived from the intermediate compounds of the present invention are similar to those of compound (3) at the same dose (i.e. 10 mg/Kg) which is significantly lower. ) and (4) are about 10 times more active.

Claims (1)

[Claims] 1 Formula (): 2,2-dimethyl-3,4-epoxy-6-cyano-3,4-dihydro-2H-benzo[b]pyran. 2 Formula (): Formula () characterized by subjecting the compound represented by to basic hydrolysis A method for producing 2,2-dimethyl-3,4-epoxy-6-cyano-3,4-dihydro-2H-benzo[b]pyran represented by