PL207979B1 - New compound - derivative of alcoholamine and its optically active enantiomers - Google Patents

Description

Description of the invention

The invention relates to a new chemical compound, an alcoholamine derivative in the form of a racemate and its R, S enantiomers, which is one of the compounds with affinity for β-blockers, the so-called β-blocker.

Beta-blockers are widely used in the treatment of diseases and conditions such as: arrhythmias, increased heart rate and ischemia, arterial hypertension, and angina. They are also used to treat glaucoma, anxiety attacks and migraines. They alleviate stress and symptoms of alcohol abstinence and drug craving in addicts. The receptor theory proposed by Alhquist, R.P. "A Study of Adrenotropic Receptors, American Journal of Physiology 1948, 153, 586-600, as well as subsequent studies aimed at the synthesis of new isoprenaline derivatives, contributed to the discovery of a new group of drugs - β-blockers, also known as β-blockers. These compounds contain a fragment of an alcoholamine in their chemical structure. They have an affinity for β-blockers, but unlike β-adrenergic drugs which agonists (ie stimulate) these receptors, they do not elicit a biological response and thus only block these receptors.

This group of compounds includes compounds known by common names such as propranolol described in Belgian patents No. 640,312 and 640,313 (1964) and in US patents No. 3,337,628 (1967) and 3,520,919 (1970), pindolol described in Swiss patents No. 469.002 and 472.404 (1969) or carvedilol described in German Patent No. 2,815,926 and US No. 4,503,067 (1979 and 1985). Their pharmacological action is well documented, for example for propranolol by Hansteen V. in Brit. Med. J., 284, 155, (1982); or carvedilol by Hirohashi M. ArzneimittelForsch. 40, 735, (1990). Also, Polish patent no. 195413 (2007) describes a new compound, an alcoholamine derivative with the chemical name 1- (1H-indol-4-yloxy) -3- (2- (2-methoxyphenoxy) ethylamino) propan-2-ol, which in the preliminary in vitro and in vivo tests showed an adrenolytic effect and can be used as a β-blocker. It is the lead structure for the subject of the new invention, just as isoprenaline was the lead structure for the first generation of β-blockers.

The subject of the invention is a new chemical compound which is an alcoholamine derivative of the general formula 1, where R1 is a residue derived from 7-methoxy-1H-indol-4-ol of the formula 2, R2 is a 2- (2-methoxy-phenoxy) ethyl fragment 3 and the stereogenic center has the R, S configuration and the subject compound is a racemate. Said compound in which the stereogenic center has the S configuration is its levorotatory enantiomer and when the stereocenter has the R configuration it is the right-handed enantiomer.

The R (rectum) and S (sinister) indices used in the specification and claims to denote absolute configuration are used in accordance with the Cahn-Ingold-Prelog principles described in Angew. Chemie., 5, 385, (1966).

The inventive compound and its enantiomers are new and have not yet been described in the literature.

The new derivative contains a structural unit found in β-blockers, the alcoholamine. Also the aryl groups appearing in the structure of the compound given by formulas 2 and 3 are structurally similar to those in known β-blockers, so the fragment of the unsubstituted indole in the para position given by the formula 2 is present in pindolol, and the fragment 2- (2 -methoxy) phenoxyethane formula 3 is present in the carvedilol structure. It can be assumed that the new compound will belong to the third generation β-blockers. The methoxy substituent in the indole fragment, formula 2, in the para position is capable of forming a hydrogen bond, thus this compound may have selective activity over β-adrenoreceptors. There are no known polycyclic drugs containing a substituent in the para position, selective for β-adrenoreceptors that can form hydrogen bonds, or those in which the role of the substituent forming the hydrogen bond is played by the methoxy group. In many of these compounds, the β-blocking effect occurs in parallel with the undesirable cardiodepressive effect. This is a disadvantage of drugs from this group, so new, better drugs are sought, i.e. drugs whose biological action will be selective, without any side-effects. The analysis of the mechanism of action of these drugs proposed in the literature shows that the new derivative, which is the subject of the application, will show such properties.

The new compound can be obtained by methods analogous to known methods in organic synthesis, starting from readily available raw materials. The key intermediate is 7-methoxy-1H-indol-4-ol, (marked as formula 2 ') which is obtained by reductive elimination

The corresponding styrene dinitro derivative has the systematic name 6-benzyloxy-3-methoxy-2, β-dinitrostyrene, formula 6. The key compound represented by the formula 2 'has not been described in the literature. This in turn is converted to the glycidyl derivative, formula 4, by the known condensation reaction with epichlorohydrin under basic conditions. If (+/-) racemic epichlohydrin is used for this transformation the end product will be a racemate. If an optically active (+) or (-) epichlohydrin is used at this stage of the synthesis, the final product will be its R or S enantiomer. The subject product (R, S) -1- (7-methoxy-1H-indol-4-yloxy) ) -3- (2- (2-methoxy-phenoxy) ethylamino) propan-2-ol is obtained by addition of a compound of formula 5 to the glycidyl epoxy moiety of formula 4.

Detailed examples of the preparation of the new compound and its enantiomers are given below.

P r z k ł a d 1.

Preparation of the subject compound (R, S) -1- (7-methoxy-1H-indol-4-yloxy) -3- (2- (2-methoxyphenoxy) ethylamino) propan-2-ol

Level 1.

Preparation of 7-methoxy-1H-indol-4-ol (formula 2 ')

In a round bottom flask with a capacity of 250 cm ³ with a side tap, equipped with a magnetic stirrer, were suspended 4.1 g of 6-benzyloxy-3-methoxy-2, e-dinitrostyrenu in 110 cm ³ of ethanol, 13 cm ^{3 of} acetic acid and 0.33 g of 10% palladium on activated carbon . Hydrogenation was carried out under slight overpressure. The progress of the reaction was checked by chromatography (TLC). The product was found to form after 8 hours. The catalyst was separated under reduced pressure on a pad of "Celite 545", rinsed copiously with methylene chloride. Water was added to the filtrate and, after phase separation, the organic was washed with sodium bicarbonate solution (to remove acetic acid) and water. The organic layer was dried over anhydrous sodium sulfate. After filtering off the drying agent and evaporating the solvent, the crude product was obtained, which was purified by column chromatography on silica gel (20 g; elution with hexane: acetone 4: 1). 1.63 g were obtained, 80% yield as a pale pink precipitate of 7-methoxy-1H-indol-4-ol, homogeneous by chromatography. For analysis, it was crystallized from methylene chloride / petroleum ether to obtain a fine crystalline precipitate with a melting point of 121.5-124 ° C.

Stage 2.

Preparation of 4- (2,3-epoxypropoxy) -7-methoxy-1H-indole (formula 4)

In a 25 cm ³ round-bottom flask equipped with a magnetic stirrer, 0.4 g of 7-methoxy-1H-indol-4-ol was dissolved in 4 cm ^{3 of} dioxane, then 3.2 cm ^{3 of an} aqueous solution of 3.2% sodium hydroxide was added dropwise. . After 15 minutes, 1.5 cm ^{3 of} racemic epichlorohydrin was added. The progress of the reaction was checked by chromatography (TLC). After approx. 18 hours, the substrate disappeared. The reaction mixture was poured into 120 cm ³ of distilled water, the product was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and after the desiccant was filtered off, the solvent was evaporated. The crude product was purified by silica gel column chromatography. 0.37 g, 69% yield, of an amorphous precipitate of 4- (2,3-epoxypropoxy) -7-methoxy-1H-indole was obtained. For analysis, it was crystallized from acetone / hexane to give a colorless crystalline precipitate, mp 96-98 ° C.

Stage 3.

Preparation of the racemate of (R, S) -1- (7-methoxy-1H-indol-4-yloxy) -3- (2- (2-methoxyphenoxy) ethylamino) -propan-2-ol

In a round bottom flask with a capacity of 25 cm ³ equipped with a magnetic stirrer, a reflux condenser protected with calcium chloride tube, was dissolved 0.36 g of 4- (2,3-epoxypropoxy) -7-methoxy-1H-indole in 1.5 cm ³ of acetonitrile, and 0.71 g of 2- (2-methoxyphenoxy) ethylamine. The reaction mixture was heated to the reflux temperature of the solvent. The progress of the reaction was checked by chromatography (TLC). After about 2 hours, the glycidyl derivative had reacted and 0.4 cm ³ of salicylaldehyde was added. The reaction mixture was stirred at room temperature for ca. 10 minutes and, without concentration, it was purified by silica gel column chromatography. 0.3 g of a chromatographically homogeneous precipitate of the (R, S) -1- (7-methoxy-1H-indol-4-yloxy) -3- (2- (2-methoxyphenoxy) ethylamino) propan-2-ol racemate was obtained with the yield 47%.

P r z k ł a d 2.

Preparation of levorotatory S (-) - 1- (7-methoxy-1H-indol-4-yloxy) -3- (2- (2-methoxyphenoxy) ethylamino) propan-2-ol

This derivative was prepared in an analogous manner to that described in Example 1 except that step 2 was carried out using levorotatory (-) epichlorohydrin instead of racemic epichlorohydrin.

With a purity of 99.9% enantiomeric excess. After standard work-up and purification, the chromatographically pure glycidyl derivative was obtained in the form of an oil with a yield of 16%. The spectral spectrum of proton nuclear magnetic resonance confirmed the structure of the derivative. Stage 3 was unchanged except that the glycidyl derivative obtained as above was used.

After isolation and purification of the crude product by column chromatography on silica gel and crystallization from methylene chloride, a crystalline product of 5 (-) - 1- (7-methoxy-1H-indol-4-yloxy) -3- (2- (2-methoxy-) was obtained. phenoxy) ethylamino) propan-2-ol in a yield of 77%.

P r z k ł a d 3.

Preparation of R (+) - 1- (7-methoxy-1H-indol-4-yloxy) -3- (2- (2-methoxyphenoxy) ethylamino) propan-2-ol

This derivative was prepared in an analogous manner to that described in Example 1 except that (+) epichlorohydrin with a purity of 99.0% enantiomeric excess was used in place of the racemic epichlorohydrin in step 2. After standard work-up and purification, the chromatographically pure glycidyl product was obtained in the form of an oil with a yield of 77%. The spectral spectrum of proton nuclear magnetic resonance confirmed the structure of the derivative. Stage 3 was unchanged except that the glycidyl derivative obtained as above was used.

After isolation and purification of the crude product by column chromatography on silica gel and crystallization from methylene chloride, the crystalline product R (+) - 1- (7-methoxy-1H-indol-4-yloxy) -3- (2- (2- methoxy-phenoxy) ethylamino) propan-2-ol in a yield of 62%.

T a b e l a

Characteristic data of new compounds

No. RELATIONSHIP TEM. TOP. [° C] HR-MS _M + Rotation [a] ²⁵ D Proton Magnetic Resonance Analysis; ¹ H-NMR (500 MHz); (acetone-d6); δ (ppm); J in Hz; 1. (R, S) -1- (7-methoxy-1H-indol-4-yloxy) - -3- [2- (2-methoxyphenoxy) ethylamino] - -propane-2-oI 133-133.5 (acetone) 386.18469 2.74 (bs, 2H, -OH and -NH aliph); 2.85 (dd, J = 6.7 and 12.0, 1H, 4-H); 2.97 (dd, J = 4.1 and 12.0, 1H, 4-H); 3.01 (m, 2H, 3-H); 3.78 (s, 3H, -OCH3); 3.86 (s, 3H, -OCH3); 4.05-4.10 (m, 5H, 1-H, 2-H, 5-H); 6.39 (d, J = 8.2, 1H, ArH); 6.49 (d, J = 8.2, 1H, ArH); 6.53 (dd, J = 2.2 and 3.0, 13-H); 6.84-6.91 (m, 2H, ArH, 8-H); 6.94 (dd, J = 1.9 and 7.8, ArH, 9-H); 6.97 (dd, J = 1.9 and 7.6, 1H, ArH); 7.16 (m, 1H, 12-H); 10.19 (bs, 1H, -NH). 2. (S) -1- (7-methoxy-1H-indol-4-yloxy) - -3- [2- (2-methoxyphenoxy) ethylamino] - -propan-2-ol 97-98 (chloride methylene) -8.5 ° (c = 1.11; 96% EtOH) 3. (R) -1- (7-methoxy-1H-indol-4-yloxy) - -3- [2- (2-methoxyphenoxy) ethylamino] - -propan-2-ol 96-97 (chloride methylene) + 5.1 ° (c = 0.44; 96% EtOH)

Patent claims

Claims (3)

1. A new compound, an alcoholamine derivative of formula 1 where R1 is a residue derived from 7-methoxy-1H-indol-4-ol of formula 2, R2 is a 2- (2-methoxyphenoxy) ethyl fragment of formula 3, and the stereogenic center is configuration R, S, and the compound in question is a racemate. 2. A compound according to claim Wherein the stereogenic center has the S configuration is the levorotatory enantiomer of the subject compound. 3. The compound according to p. Wherein the stereogenic center has the R configuration is the dextrorotatory enantiomer of the subject compound.