JPH0141141B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to heterocyclic compounds represented by the general formula Het-CHOH-CH ₂ -NH-aralkyl. Substituted phenylaminoethanols represented by the general formula Ph-CHOH-CH ₂ -NH-aralkyl (where Ph is a substituted phenol group) are patented in the U.S.
No. 3,644,353 and US Pat. No. 3,705,233.
These compounds have random activity as β-adrenergic stimulants and β-adrenergic blockers. These compounds are taught to be useful as medicaments for the treatment of glaucoma and cardiovascular disorders such as hypertension and arrhythmia. Heterocyclic aminoethanols have been discovered that have medicinal uses. The present invention provides a compound having the general formula Het-CHOH-CH ₂ -NH-aralkyl (Het is a 6- to 10-membered N-heterocyclic ring) and their pharmaceutical uses. One embodiment of the present invention is a compound represented by the following general formula Het-R, its tautomers and pharmaceutically acceptable salts, where Het is or [In the formula, R ₁ is H or OH, and R is

[Formula] However, R ₃ is

[Formula] (where R ₄ and R ₅ are individually selected from H and C ₁ -C ₃ alkyl, and Y is CH ₂ , (CH ₂ ) ₂ , (CH ₂ ) ₃ or (CH ₂ ) ₄ )]. Pharmaceutically acceptable salts are salts of the chlorine of formula with a suitable organic or inorganic acid. Suitable organic acids include acetic acid, pamoic acid, pivalic acid,
These include carboxylic acids such as oxalic acid, lauric acid, pelargonic acid, citric acid, tartaric acid, maleic acid, oleic acid, propanoic acid, succinic acid, isobutyric acid, malic acid, and non-carboxylic acids such as isethionic acid and methanesulfonic acid. . Maleate salts are preferred. Suitable inorganic acids include hydrogen halides (e.g.
Hcl, HI, HBr), phosphoric acid and sulfuric acid. Hydrohalide salts, especially hydrochlorides, are preferred. These salts can be prepared by treating the free base with a suitable amount of the appropriate acid, usually in a solvent. R ₃ is a phenyl alkyl group. Each of R ₄ and R ₅ is C ₁ -C ₃ alkyl (e.g., CH ₃ ,
C ₃ H ₇ , C ₂ H ₅ , etc.) or hydrogen. CH ₃ and H are preferred R ₄ /R ₅ substituents, but it is more preferred that one or both of R ₄ /R ₅ is CH ₃ . Y
is CH ₂ or (CH ₂ ) _{1 to 4} , but CH ₂ and (CH ₂ ) ₂
is preferred. Among the heterocyclic groups, groups (a), (b), (c), (e), (g) and (h) are preferred, and (a), (b), (c), (e) and (g) are more preferred, and (a), (b), (e) and (g) are particularly preferred.
More particularly preferred are groups (b), (e) or (g). monocyclic group and bicyclic group is most preferred. Tautomers occur in heterocyclic groups and these are also included within the scope of the invention. Examples of such tautomers include:

[Formula] or Compounds of the general formula have one chiral center at the 1-position within the aminoethanol substituent, R ₃
If the R ₄ and R ₅ substituents within a group are different, it may have a second chiral center. These chiral centers confer optical activity to compounds of the general formula. All optical isomeric forms are included, ie mixtures of enantiomers or diastereomers, such as racemates, as well as individual enantiomers or diastereomers of the general formula. These individual enantiomers are usually represented by the symbols (+) and (-), (L) and (D), (1) and (d), or combinations thereof, according to their optical rotation. These isomers can also be designated according to their absolute spatial configuration by (S) and (R) representing left and right, respectively. Individual optical isomers can be prepared by using conventional decomposition operations, such as treatment with a suitable optically active acid, separating diastereomers and recovering the desired isomer. Compounds of the general formula are useful in treating glaucoma because they reduce intraocular pressure when administered topically to the eye. The ability to lower intraocular pressure is determined using in-vivo measurements in a rabbit model. It is preferably administered in the form of an eye drop composition suitable for topical application to the eye, such as a solution, ointment or solid insert. The formulation of this compound is 0.01-5%,
In particular, it can contain 0.5-2% of the drug. Higher doses, such as about 10% or less, can also be used if the dose is effective in reducing intraocular pressure. For the human eye, the unit dosage form is 0.001-5.0 mg, preferably. 005～
2.0 mg, especially 0.005 to 1.0 mg of compound is usually applied. Pharmaceutical compositions containing the compounds of this invention are conveniently mixed with non-toxic pharmaceutical organic carriers or non-toxic pharmaceutical inorganic carriers. Examples of pharmaceutically acceptable carriers include, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or aralkanols, vegetable oils, polyalkylene glycols, petroleum-based jellies, ethyl cellulose, ethyl oleate, carboxymethylcellulose,
Included are polyvinylpyrrolidone, isopropyl myristate and other commonly used acceptable carriers. Pharmaceutical preparations may also contain non-toxic auxiliary substances such as emulsifiers, preservatives, wetting agents, morphogens such as polyethylene glycol 200, 300, 400 and 600, Carbo Wax 1000, 1500, 4000, 6000 and 10000.
Bacterial components such as quaternary ammonium compounds, phenylmercury salts, thimerosal, methyl and propylparabens, benzyl alcohol, phenylethanol, sodium chloride, which are known to have pasteurizing properties and are harmless when used, etc. ,
Buffer components such as sodium borate, sodium acetate, gluconate buffer, and other conventional components such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, sodium dioctyl sulfosuccinate, monothioglycerol, It can contain thiosorbitol, ethylenediaminetetraacetic acid, etc. Additionally, suitable eye drop diluents can be used as carrier media for the purposes of the present invention, including conventional phosphate buffer diluent systems,
Isotonic boric acid dilution, Isotonic sodium chloride dilution,
Examples include isotonic sodium borate dilution.
Pharmaceutical preparations can also be in the form of solid inserts. For example, solid water-soluble polymers can be used as carriers for pharmaceuticals. The polymer used to form the insert can be any water-soluble, non-toxic polymer, including cellulose derivatives such as methyl cellulose, sodium carboxymethyl cellulose, (hydroxy lower alkyl cellulose), hydroxy ethyl cellulose, hydroxypropyl cellulose, hydroxy Acrylates such as polyacrylates, gelatin, alginates, such as propyl methylcellulose,
Natural products such as pectin, tragacanth, karaya, agar, agar, gum arabic, starch derivatives such as starch acetate, hydroxyethyl starch ether, hydroxypropyl starch, etc.
and other synthetic derivatives such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, neutralized carbopol and xanthan gum and compounds of these polymers. Preferred solid inserts are prepared from cellulose derivatives such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose or hydroxypropylmethylcellulose or other synthetic materials such as polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide or polyvinyl methyl ether. Hydroxypropylcellulose, one preferred polymer for insert preparation, is available in several polymeric forms, all of which are suitable for the preparation of these inserts. Namely, the name KLUCEL from Hercules, Inc. Wilmington, Delaware, for example, KLUCEL.
Products sold under HF, HWF, MF, GF, JF, LF and EF are particularly useful for food or pharmaceutical purposes. These polymers useful for the purposes of this invention have a molecular weight of at least
30,000 to about 1,000,000 or more. similarly
Up to 5000000 or more preferably 100000~
Ethylene oxide polymers with a molecular weight of 5,000,000 can also be used. Additionally, it is possible to use POLYOX, a polymer supplied, for example, by Union Carbide Co., which has a molecular weight of about 50,000 to more than 5,000,000, preferably from 3,000,000 to 4,000,000. Other useful specialty polymers range from about 10,000 to about
1000000 or more, preferably up to about 350000, especially about
Polyvinylpyrrolidone with a molecular weight of 20,000 to 60,000, about 30,000 to more than 1,000,000, especially 400,000 and polyvinyl alcohol with a molecular weight of about 100,000 to about 200,000, especially about about 10,000 to more than 1,000,000
Hydroxypropyl methylcellulose having a molecular weight of up to 200,000, especially about 80,000 to about 125,000, about
Examples include methylcellulose having a molecular weight of from 10,000 to more than about 1,000,000, preferably about 200,000, especially from 50 to 100,000, and CARBOPOL (carboxyvinyl polymer) represented by grades 934940 and 941 from BF Goodrich. It will be done. It is clear that for the purposes of the present invention the type and molecular weight of the polymer are not very important. Any water-soluble polymer having an average molecular weight that will cause the polymer to dissolve and thus the drug for the desired period of time can be used. The insert can thus be tailored to allow any desired length of residence and therefore effectiveness in the eye. Inserts can be square, rectangular, oval, circular, toroidal, semicircular, quarter-moon, etc. in shape. Preferably the insert is rod-shaped, donut-shaped, oval-shaped or quarter-moon shaped. Inserts can be easily prepared, for example, by dissolving the drug and polymer in a suitable solvent and evaporating the solution to form a thin film of polymer, which is then divided into appropriately sized inserts. Alternatively, inserts can be prepared by heating the polymer and drug and forming the resulting mixture into a thin film.
Preferably, the insert is prepared by known molding or extrusion techniques. The molded or extruded product is then divided into inserts of suitable size for administration to the eye. The insert may be of any suitable size so that it fits easily into the eye. For example, suitable inserts may be obtained by segmenting a casting or compression molded film having a thickness of about 0.25 mm to 15.0 mm.
A rectangular parallelepiped segment of cast or compression molded film having a thickness of approximately 0.5 to 1.5 mm is cut into 4×
A rectangular parallelepiped plate of 5 to 20 mm or an oval shape of similar size can be provided. Similarly, about 0.5~
An extruded rod having a diameter of 1.5 mm can be cut into appropriate sections to provide the desired amount of polymer. For example, rods with a diameter of 1.0-1.5 mm and a length of 20 mm have been found to be satisfactory. Inserts can also be formed by direct injection molding. Eye drop inserts containing the medicament of the invention are preferably formed so that they are smooth and do not have sharp edges or corners that could cause damage to the eye. Since the terms smooth and sharp edges or corners are subjective terms, these terms are used in this application to indicate that the use of the insert will not cause undue irritation of the eye. These eye drop inserts also contain plasticizers, buffering agents,
It may contain preservatives. Plasticizers suitable for this purpose must of course also be completely soluble in the lachrymal fluid of the eye. Examples of suitable plasticizers include water,
These include polyethylene glycol, propylene glycol, glycerin, trimethylolpropane, di- and tripropylene glycol, and hydroxypropyl sucrose. Typically, such plasticizers may be present in the eye drop insert in an amount of about 1 to about 30% by weight. A particularly preferred plasticizer is water, which is present in an amount of at least about 5% to about 40%. In practice, a moisture content of about 10% to about 20% is preferred as it is easily achievable and imparts desirable softness and flexibility to the insert. When plasticizing solid pharmaceutical products with water,
The product absorbs at least about 5% water and is contacted with air at a relative humidity of at least 40% until it becomes softer and more pliable. In a preferred embodiment, the relative humidity of the air is from about 60% to about 99% and the contact is continued until moisture is present in the product in an amount of from about 10% to about 20%. Suitable water-soluble preservatives that can be used in the inserts include sodium bisulfate, sodium thiosulfate, ascorbate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric borate, parabens, and benzyl alcohol. and phenylethanol. These reagents are available in solid inserts from 0.001 to 5
It may be present in an amount of % by weight, preferably 0.1-2%. Suitable aqueous buffers are alkali, alkaline earth carbonate phosphates, bicarbonates, citrates, borates, etc., such as sodium phosphate, sodium citrate, sodium borate, sodium acetate, etc. Examples include sodium bicarbonate and sodium carbonate. These reagents have a system pH of 5.5 to 8.0,
It can be used in sufficient amounts, especially from 7 to 8, and usually up to about 2% by weight of the polymer. The insert contains about 1 mg to 100 mg of water soluble polymer, more preferably 50 mg of water soluble polymer in an amount of 5 to 50 mg, especially 5 to 20 mg. The medicine is about 0.1 of the insert
Present at ~25% by weight. The ability of compounds of the general formula to lower intraocular pressure is determined using experimental glaucoma induced in rabbits by intraocular injection of α-chymotrypsin. Compounds of the general formula are effective in lowering intraocular pressure after topical application. Pressure is decreased in normal and glaucomatous eyes. The compounds of the invention (general formula) have β-adrenergic blocking activity. This β-adrenergic blocking activity is determined by measuring the ability of representative compounds to block the β-adrenergic stimulatory effects of isoprotenol in experimental animals. The compounds of the invention also have alpha-adrenergic blocking activity. This α-adrenergic blocking activity is shown in (a) in vitro methods to show that α-
(b) In an in vivo method, the α-adrenergic stimulatory effect of phenylephrine in anesthetized normotensive animals of representative compounds of the general formula was determined by measuring its ability to translocate adrenergic antagonists. This is done by measuring the ability to block the The compounds of the invention exhibit immediate onset antihypertensive activity. This rapid-onset antihypertensive activity is determined by administering representative compounds of the invention to rats with spontaneous hypertension (SH) and measuring the effect on blood pressure. The α- and β-adrenergic blocking activity of the compounds of the present invention demonstrates that these compounds can minimize tracheal constriction through α-adrenergic blockade in humans while minimizing cardiovascular conditions sensitive to β-blocking therapy (e.g. , angina pectoris, arrhythmia). This α/β-blocking effect is useful in the treatment of hypertension caused by chromaffin cells. For use as alpha/beta-adrenergic blockers and/or antihypertensive agents, the compounds of the invention may be administered in any suitable form, such as orally, by inhalation, by suppository or parenterally, i.e. intravenously, intraperitoneally. can be administered. The compound can be prepared in (1) a form for oral administration, such as a tablet or tablet combined with other commonly used ingredients (diluents or carriers) such as talc, vegetable oils, polyols, benzyl alcohols, starches, gelatin, etc.; (2) Dissolved, dispersed or emulsified in a suitable liquid carrier and encapsulated in a capsule or suitable encapsulating material, or (2) dissolved or dispersed in a suitable liquid carrier or diluent for parenteral administration. , in emulsified form, or (3) as an aerosol, (4) in the form of suppositories. The proportion of the active ingredient (compound of the invention) to the formulation ingredients will vary depending on the required dosage form. Conventional methods are used for the preparation of pharmaceutical formulations. Effective daily dosages using the compounds of this invention for uses other than eye treatment may vary from about 10 mg to about 3000 mg. Daily doses of about 100 mg to about 2500 mg are preferred, with doses of about 200 to about 1000 mg being a more preferred range. Oral administration is preferred. Depending on the unit dose, single or multiple doses can be administered each day. Compounds of the general formula also have bronchodilator activity. This is determined by measuring the effectiveness of a compound in antagonizing the slow reactant of anaphylaxis (SRS-A). These compounds are thus useful in treating conditions in mammals, particularly humans, that would benefit from bronchodilation, such as asthma. For use as a bronchodilator, the compounds can be administered orally or parenterally in conventional dosage forms such as tablets, capsules, solutions, dispersions, emulsions and the like. The compounds can also be administered as a spray or aerosol using a suitable delivery device and formulation. Oral administration is preferred. Sufficient compounds of the general formula can be administered to obtain the desired degree of bronchodilation. Daily dosage for oral or parenteral administration is approximately 1 mg/approximately 300 mg;
Preferably it ranges from about 2 to about 150 mg. Spray or aerosol administration as needed from approx.
Administered in metered doses of 1000mcg. Thus, the present invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of the general formula and methods of treating) hypertension, other cardiovascular conditions, or glaucoma;
It can be carried out as a method of 2) lowering intraocular pressure, or 3) a method of bronchodilation. Compounds of general formula can be prepared by any convenient method. One such useful method is illustrated by the following set of reactions:

[Table] Het' is a heterocyclic group a), b), c) or a suitable precursor thereof. Another method of preparing some compounds of the general formula is illustrated by the following sequence of reactions: The N-oxides of compounds of the general formula are prepared by the method illustrated by the following sequence of reactions: Another method of preparing some compounds of the general formula is illustrated by the following sequence of reactions: The following examples illustrate methods for producing representative compounds of the general formula. The method used is that shown in the reaction series above. All temperatures are in degrees Celsius. Example 1 7-[1-hydroxy-2-
(4-phenyl-2-butylamino)ethyl]
-2H-1,4-benzoxazine-3(4H)-
Preparation of onmaleate salt A 7-acetyl-2H-1,4-benzoxazine-3(4H)one (A) 17.7 g (0.117 mol) of 4-amino-3-hydroxyacetophenone (Eur.J.med.) stirred in a mixture of 350 ml of water and 350 ml of 2-butanone.
Chem., 9, 491 (1974)) and 35.4 g (0.42 mol)
14 ml (0.176 mol) of chloroacetyl chloride was added to the stirred mixture of NaHCO ₃ over 30 minutes at 25°C. The reaction solution was then stirred and heated at 90° C. for 5 hours, after which an additional 1 ml (0.013 mole) of chloroacetyl chloride was added and heating continued for 2 hours. TLC showed no starting material remaining.
The reaction solution was cooled and poured into 1500ml of water. After stirring for 1 hour, the precipitate was filtered and air-dried to obtain 16.3 g of A. Melting point 197-198°. An additional 4.5 g of A was obtained by extracting the aqueous phase with ethyl acetate. Overall yield 93%. B 7-bromoacetyl-2H-1,4-benzoxazine-3(4H)-one (B) 4 g (20.9 mmol) in 1000 ml ethyl acetate
of 7-acetyl-2H-1,4-benzoxazin-3(4H)-one and 8.9 g (39.9 mmol) of finely ground second bromide were stirred and refluxed for 18 hours.
Further 3.6 g (16 mmol) of second bromide were added,
It was refluxed for 6 hours. The reaction solution was filtered, decolorized with charcoal, and concentrated to obtain 3.8 g (68% yield) of B. Melting point 217~
219° (disassembly). C 7-azidoacetyl-2H-1,4-benzoxazine-3(4H)-one (C) In a suspension of 270 mg (1 mmol) of 7-bromoacetyl-2H-1,4-benzoxazin-3(4H)-one in 20 ml of methanol, 78 mg dissolved in 2 ml of water adjusted to pH 5 with acetic acid. A solution of (1.2 mmol) sodium azide was added. After stirring for 20 hours at 25° C., the precipitate was separated, washed with water, and air-dried to obtain 137 mg (59% yield) of C. Melting point: 180℃ (decomposition). D 7-(1-hydroxy-2-azidoethyl)
-2H-1,4-benzoxazine-3(4H)-
On (D) 5.6 g (24.1 mmol) in 750 ml methanol
of 7-azidoacetyl-2H-1,4-benzoxazin-3(4H)-one at 50°C.
4.56 g (120 mmol) of sodium borohydride was added in portions (intense gas evolution). After the addition is complete, stir the reaction solution for 1 hour and add 50 ml of water and 1.5 ml.
of acetic acid was added and the mixture was evaporated to dryness. 100ml
Three portions of methanol were evaporated from the residue, which was then treated with 200 ml of water. PH to 5 with acetic acid
After adjusting the aqueous suspension, the aqueous suspension was extracted with 3 x 200 ml of ethyl acetate. Combine the organic extracts and add 0.5N acetic acid, 5
Washed _with % _NaHCl3 , dried and evaporated ( _Na2SO4 ). The residue was triturated with 50 ml of ether and filtered to give 4.5 g (80% yield of D, mp 121-123
°C (decomposition). E 7-(1-hydroxy-2-aminoethyl)
-2H-1,4-benzoxazine-3(4H)-
On hydrochloride (E) A solution of 4.5 g (19.2 mmol) of D dissolved in 120 ml of methanol containing 1 ml of 12NHCl was heated at 25° C. in a Parr vessel at 50 psi (approx.
cm ² ) for 18 hours on 10% PD/C. Filtration and evaporation gave 4.5 g of crude E, which was combined with 5.0 g of crude D from the second hydrogenation to give 10.2 g of crude E. The free base of E is aqueous solution (100 ml) of crude E in 130 ml of acid form.
It was obtained by passing through AG-50W-X8 cation exchange resin (100-200 meshes) and eluting with 1.5N _NH4OH . After evaporation, 5.2 g of crude E was obtained as free base, which was crystallized from 300 ml of ethanol to obtain 3.62 g containing 1/4 of 1 mole of water.
Melting point 179-182℃. Elemental Analysis Values C H N Theoretical Values 56.47 5.88 13.18 Actual Values 56.26 5.83 13.17 The hydrochloride salt (E) was prepared in ethanol and had a melting point of 228° C. (decomposition) after recrystallization twice. Elemental analysis value C H N Cl Theoretical value 49.09 5.35 11.45 14.49 Actual value 49.19 5.63 11.32 14.31 F 7-[1-Hydroxy-2-(4-phenyl-2-butylamine)ethyl]-2H-1,4
-Benzoxazine-3(4H)-olemaleate (F) 2.5 g (17 mmol) of 4-phenyl-2- in a solution of 2.3 g (11 mmol) of the free base of E and 1.5 g (6 mmol) of E in 100 ml of methanol.
Butanone and 1.07 g (17 mmol) of sodium cyanoborohydride were added and the mixture was stirred for 18 hours at 25° C. in the presence of 4A molecular sieves. TLC showed no starting material present and one major new product. Dilute the reaction solution with 12NHCl
, stirred for 20 minutes, perevaporated and the residue slurried with ether. The insoluble hygroscopic solids were separated by filtration, suspended in 100 ml of 1N NaHCO ₃ and the mixture was extracted with 3×100 ml of ethyl acetate. The organic extracts were combined, washed with water, dried and evaporated to yield 4.2 g of solid crude F free base. Slurry this with 200ml of ether four times,
2.85 g of purified free base was obtained. 0.97 g (8.38 mmol) of this free base in a heated solution in ethyl acetate
A heated solution of a minimum amount of maleic acid in ethyl acetate was added (total volume 200ml). Crystallization and cooling yielded 3.6 g of crude F. This was recrystallized from 250 ml of heated acetonitrile by adding ether and cooled to obtain 2.6 g (5.7 mmol, 34% yield) of F. Melting point 132-137℃. Elemental analysis value C H N Theoretical value 63.14 6.18 6.14 Actual value 63.33 6.32 6.13 Example 2 6-[1-hydroxy-2-
(4-phenyl-2-butylamino)ethyl]
-2H-1,4-benzoxazine-3(4H)-
Preparation of onmaleate salt 6-chloroacetyl-2H-1,4-benthuxazin-3(4)-one (CRAcad.Sci., C.270,
1601 (1970)) as the starting material, C of Example 1,
Substantially following steps D, E and F, the following compounds were successively obtained. A 6-azidoacetyl-2H-1,4-benzoxazin-3(4H)-one: Melting point 177-178℃ (decomposition) 85% Yield: Elemental analysis value C H N Theoretical value 51.72 3.47 24.13 Actual value 51.55 3.48 23.90 B 6-(1-hydroxy-2-azidoethyl)
-2H-1,4-benzoxazine-3(4H)-
on: Melting point 137-138℃, 79% yield Elemental analysis value C H N Theoretical value 51.28 4.30 23.92 Actual value 51.37 4.35 24.07 C 6-(1-hydroxy-2-aminoethyl)
-2H-1,4-benzoxazine-3(4H)-
on: Melting point 175-178℃, 78% yield Elemental analysis value C H N Theoretical value 57.68 5.81 13.46 Actual value 57.50 5.91 13.30 D 6-[1-Hydroxy-2-(4-phenyl-2-butylamino)ethyl]-2H -1,4
-Benzoxazine-3-(4)-onmaleate : Melting point 125-130℃, 83% yield Elemental analysis value C H N Theoretical value 70.56 7.11 8.23 Actual value 70.57 7.40 8.33 Maleic acid: Melting point 154-157℃, 96% yield Elemental analysis value C H N Theoretical value 63.14 6.18 6.14 Actual measurement value 63.25 6.19 6.20 Example 3 2,3-dihydro-α- expressed by the following formula
Preparation of {[(1-methyl-3-phenylpropyl)amino]methyl}-2-oxo-6-benzoxazole methanol maleate: 6-chloroacetyl-2,3-dihydro-2-
Oxo-benzoxazole (Eur.J.Med.Chem.,
9, 491 (1974) as the starting material, Example 1
The following compounds were sequentially obtained by substantially following the procedures of Steps C, D, E and F of . A 6-azidoacetyl-2,3-dihydro-2
-Oxobenzoxazole: Melting point 250°C (decomposition), 78% yield. Elemental analysis value C H N Theoretical value 49.55 2.77 25.68 Actual value 49.71 2.90 24.14 B 2,3-dihydro-α-(azidomethyl)-
2-oxo-6-benzoxazole methanol: Melting point 119-121.5℃, 78% yield Elemental analysis value C H N Theoretical value 49.09 3.66 25.44 Actual value 49.01 3.76 23.47 C 2,3-dihydro-α-(aminomethyl)-
2-oxo-6-benzoxazole methanol/Hcl Melting point 315℃ (decomposition), 60% yield Elemental analysis value C H N C Theoretical value 46.86 4.81 12.14 15.37 Actual value 47.10 4.89 11.75 15.15 D 2,3-dihydro-α {[(1-methyl-3-
phenylpropyl)amino]]methyl}-2-
Oxo-6-benzoxazole methanol maleate Melting point 163-165°C, 31% yield Elemental analysis value C H N Theoretical value 62.43 5.92 6.33 Actual value 62.75 6.03 6.34 Example 4 6-Amino-α-{[(1-methyl-3-ph) enylpropyl)amino]methyl}-3-pyridinemethanol dihydrochloride A 6-Acyltetrazole[1,5-a]pyridine (A) 8.4g in 150ml ethanol and 150ml water
To a stirred solution of (51.6 mmol) of 2-chloro-5-acetylpyridine and 8.4 g (129 mmol) of sodium azide was added 75 ml of 10% HCl over 20 minutes. The reaction solution was then heated to reflux for 18 hours, cooled in an ice bath, and the resulting crystals were separated to yield 6.0 g of the first product. 1.0 g of second product was obtained, giving a total of 7.0 g of A (84% yield), melting point
159-160℃. Elemental analysis value C H N Theoretical value 51.85 3.73 34.56 Actual value 52.01 3.91 34.40 B Bromoacetyltetrazole [1,5-a]
Pyridine (B) 1500ml saturated with HBr and cooled in an ice bath
In a solution of 55.4 g (0.34 mol) of Part A in glacial acetic acid,
A solution of 57 g (0.32 mol) bromine in 500 ml glacial acetic acid was added over a period of 2 hours. The reaction was evaporated to dryness and the residue was taken up in ethyl acetate. A small amount of insoluble material was separated and the ethyl acetate was washed with water, 1N NaHCO ₃ solution and dried (Na ₂ SO ₄ ). 82.4g after evaporation
A crude product was obtained containing 80% B. A portion of the crude material (71 g) was slurried twice with 500 ml of 10% ethyl acetate in ether to yield 56 g of B (79%) pure enough for further use.
yield). The sample recrystallized from ethanol is 110~
It had a melting point of 113°C. Elemental analysis value C H N B Theoretical value 34.88 2.09 23.24 33.15 Actual value 35.05 2.12 23.14 33.36 C 2-(tetrazole[1,5-a]pyrido-
6-yl]oxirane (C) To a suspension of 37 g (154 mmol) of B in 280 ml of methanol was added 1.85 g (49 mmol) of sodium borohydride with stirring at 20° C. over a period of 30 minutes. The reaction was evaporated to dryness and thoroughly stirred with a mixture of 500 ml ethyl acetate and 500 ml 1N NaOH. The organic layer was separated, washed with water, decolorized with charcoal, dried and evaporated to give an oily solid. This was chromatographed on silica gel using ethyl acetate. The partially purified material thus obtained was crystallized from 130 ml of ethanol and 18.2
g of C (73% yield), melting point 108-110°C. Elemental analysis value C H N Theoretical value 51.85 3.75 34.56 Actual value 51.71 3.53 34.34 D α-[(1-methyl-3-phenylpropyl)
Amino] thyl-6-terazol [1,5-a]
Pyridine methanol (D) 10 g (61.7 mmol) C and 10 g (67.1 mmol) 4-phenyl-2 in 50 ml ethanol
-Aminobutane was heated under reflux for 1.5 hours. The reaction was evaporated and the residue was crystallized first from a minimum amount of ethyl acetate and then recrystallized from 100 ml of ethanol to give 11.4 g of D. Chromatography of the mother liquor yielded 2.3 g of second product, totaling 13.7 g.
D was obtained (71% yield), melting point 117-120°C. Elemental Analysis C H N Theoretical 65.57 6.80 22.48 Found 65.57 6.95 22.48 The maleate salt was prepared in ethyl acetate: mp 121-124°C. Elemental analysis value C H N Theoretical value 59.00 5.90 16.39 Actual value 59.29 6.13 16.31 E 6-amino-α-[(1-methyl-3-phenylpropyl)amino]methyl-3-pyridinemethanol dihydrochloride (E) 11 g (35.4 mmol) of D in 60 ml of 12NHcl
and 24 g (106 mmol) of stannous chloride dihydrate were heated to reflux for 2 hours. The reaction solution was evaporated to dryness, the residue was suspended in 150 ml of methanol, and concentrated.
Made basic with _NH4OH . Separate the precipitated salt,
The product in the liquid was transferred onto 600g of silica gel.
Chromatography was performed eluting with a mixture of CH ₂ Cl ₂ :CH ₃ OH: concentrated NH ₄ OH (15:5:4) and the eluate was evaporated to give 6.8 g of the free base of E (67 %yield). Dihydrochloride from free base in ethanol 12NHCl
(65% yield), melting point
156-158℃. Elemental analysis value C H N C Theoretical value 56.98 7.03 11.73 19.79 Actual value 56.58 7.32 11.29 19・96 Product E consists of four isomers S, S; S, R; R,
It is a racemic mixture of diastereomers containing S; and R, R. By using a particular isomer of the amine reactant in Step D, such as S-4-phenyl-2-aminobutane, two isomers of E, namely the S,S-E free base and the R,S-E free base. A mixture is obtained. This mixture is conveniently separated, e.g. by chromatography,
Individual isomers i.e. S,SE free base and R,S
-E free base is obtained. R-4-phenyl-2
-If aminobutane is used, the corresponding S,R and R,R isomers of the free base of E are obtained. This procedure for preparing individual isomers can be used to prepare compounds of any general formula involving the reaction of epoxides and aminos. Example 5 6-amino-α-{[1,1-dimethyl-3-
phenylpropyl)amino]-methyl}-3-
Preparation of pyridine methanol dihydrochloride hemihydrate: Using 4-phenyl-2-amino-2-methylbutane and the product C of Example 4 as starting materials,
Substantially following the procedures of Steps D and E of Example 4, the following compounds were successively obtained. A α-{[(1,1-dimethyl-3-phenylpropyl)aminocomethyl}-6-tetrazole[1,5-a]-pyridinemethanol (A) Melting point 126-127℃, 76% yield. Elemental Analysis C H N Theoretical 66.44 7.12 21.52 Actual 66.70 7.20 21.37 The maleate salt was prepared in ethyl acetate. Melting point 167-168℃, 98% yield. Elemental analysis value C H N Theoretical value 59.85 6.16 15.86 Actual value 59.98 6.35 15.74 B 6-amino-α-{[(1,1-dimethyl(-
3-phenylpropyl)amino]methyl}-3
-Pyridine methanol dihydrochloride hemihydrate Melting point 185-188°C (decomposition), 54% yield. Elemental analysis value C H N C Theoretical value 56.69 7.14 11.02 18.60 Actual value 56.96 7.18 11.04 18.54 Example 6 6-amino-α-{[1-methyl-3-phenylpropyl)amino]methyl-3-pyridinemethanol-1 -Oxide dihydrochloride A A solution of 2.0 g (7.02 mmol) of the free base of the product of Step E of Example 4 in a mixture of 20 ml of pyridine and 10 ml of acetic anhydride was stirred at 20° C. for 18 hours. Excess reactants were evaporated and the residue was partitioned between 150ml water and 150ml ethyl acetate. organic layer
Washed with _{1NNa2CO3 solution} , dried and evaporated to 2.6
g (90% yield) of triacetylated intermediate was obtained. This protected intermediate was dissolved in 30 ml of chloroform and 1.4 g (25% excess) of m-chloroperbenzoic acid was added. After stirring the solution for 3 hours at 20° C., 2 g of Ca(OH) ₂ powder was added and stirring continued for 30 minutes. The reaction was filtered, the liquid was evaporated and the residue (2.3 g) was chromatographed on 400 g of silica gel, eluting with 10% methanol in ethyl acetate. Two fractions were obtained: (a)
0.50g, single diastereoisomer (b) 1.71g, 1:
Mixture of diastereoisomers of 1 (2.21 g, 82%
yield). The material from fraction (b) was dissolved in 25 ml of 6NHCl;
After heating under reflux for 3 hours, the reaction solution was then evaporated to dryness. The residue was dissolved in methanol, basified with concentrated NH ₄ OH and evaporated again to dryness. The residue containing the free base was chromatographed on 100 g of silica gel using methanol-methylene chloride-conc. NH ₄ OH (20:80:3) as eluent. The fractions containing the desired product were combined and dissolved in 10 ml of ethanol.
Treated with HCl. The residue after evaporation was triturated with ether to give 1.0 g of A (67% yield), melting point 203-210°C (decomposition), 49% overall yield. Elemental analysis value C H N C Theoretical value 54.56 6.73 11.23 18.95 Actual value 54.46 6.93 11.10 18.95 Example 7 5-{1-hydroxy-2-[1]-methyl-
3-phenylpropyl)-amino]ethyl}-
2(1H)-pyridinone phalate hydrate A 5-acetyl-2-fluoropyridine (A) 20 g (142 mmol) of 2 in 750 ml of ether
-Fluoro-5-pyridinecarboxylic acid (J.Am.
Chem. Soc., 71, 1125 (1949)) was stirred and, while cooling in ice, 225 ml of a 1.6 M methyllithium ether solution (360 mmol) was added over 1 hour. After stirring the reaction solution for an additional 2 hours
300ml of ice water was added. The aqueous layer was washed with 2 x 100 ml of fresh ether, acidified and extracted with ether to extract 5.0 g (25%) of unreacted acid. The original ether solution was washed with water, dried and evaporated.
12.2 g of crude crystal A containing approximately 15% of the corresponding t-alcohol was obtained. Chromatography on silica gel eluting with 5% ethyl acetate in methylene chloride gave 7.81 g of A (52% yield). A sample crystallized from hexane gave a melting point of 43-44°C. Elemental analysis value C H N F Theoretical value 60.43 4.35 10.07 13.65 Actual value 60.17 4.33 9.97 12.96 B 5-bromoacetyl-2-fluoropyridine
(B) 7 according to the method described in Example 4, Step B, using 14 g (100 mmol) of A as starting material.
18.6 g of crude B was obtained, consisting of % A, 82% B and 11% dibromoketone. This material was used in the next step without further purification. C (2-fluoropyrid-5-yl)oxirane (C) Using 18.6 g of crude B as starting material and following the procedure of step C of Example 4, 13.4 g of crude C was obtained. This was suitable for use in the next step without further purification. D 6-fluoro-α-{[(1-methyl-3-phenylpropyl)amino]methyl}-3-pyridinemethanol (D) 15g crude C (contains about 67% epoxide)
was used as the starting material and after chromatography substantially following the procedure described in Example 4, Step D.
10.04 g (48% yield) of D was obtained. Melting point 81-86℃. Elemental analysis value C H N F Theoretical value 70.81 7.34 9.71 6.59 Actual value 70.61 7.45 9.69 6.43 E 5-{1-Hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl}-
2(1H)-pyridinone fumarate hydrate (E) 2.03 g (7.0 mmol) of D in 25 ml 2NHCl
The solution was heated to reflux for 6 hours. The reaction was evaporated to dryness, redissolved in water and basified with _NaHCO3 .
The resulting mixture was evaporated to dryness and the residue was thoroughly extracted with hot ethyl acetate and after drying the ethyl acetate was evaporated to give 1.9 g of an oil (free base of E). The crystallized sample had a melting point of 85-89°C. The base (3.15 g) was dissolved in equal volumes of acetonitrile and methanol (250 ml total), and to this was added fumaric acid (1.4 g) dissolved in methanol (15 ml).
The salt was prepared by adding the solution of g) and evaporating the solution to approximately 50ml volume. After 2 hours, the resulting crystals were filtered to obtain 3.7 g (75% yield) of E. Melting point 185~
189℃ (decomposition). Elemental analysis value C H N Theoretical value 59・99 6.71 6.66 Actual value 59.49 6.33 6.41 Example 8 5-{1-Hydroxy-2-[(1,1-dimethyl-3-phenylpropyl)-amino]ethyl}- 2(1H)-pyridinone dihydrochloride Using epoxide C of Example 7 as a starting material and reacting it with 4-phenyl-2-amino-2-methylbutane, following substantially the procedures of Steps D and E of Example 7, the following compounds were prepared: I got it one after another. A 6-fluoro-α-{[(1,1-dimethyl-
3-phenylpropyl)amino]-methyl}-
3-Pyridinemethanol (A) Melting point 116-118℃, 48% yield. Elemental analysis value C H N F Theoretical value 71.50 7.66 9.26 6.28 Actual value 71.46 7.74 9.08 6.04 B 5-{1-Hydroxy-2[(1,1-dimethyl-3-phenylpropyl)amino]ethyl}
-2(1H)-pyridinone dihydrochloride Melting point 179-181℃, 65% yield. Elemental analysis value C H N C Theoretical value 57.35 6.97 7.43 19.74 Actual value 56.91 6.94 7.73 19.93 Example 9 1-hydroxy-5-{(1-hydroxy-2
- Preparation of [(1-methyl-3-phenylpropyl)amino]ethyl}-2(1H)-pyridinone hydrochloride: A 6-methoxy-α-{[(1-methyl-3-phenylpropyl)amino]methyl}-3-pyridinemethanol (A) To a solution of 5.9 g (20.5 mmol) of the product D obtained in Example 7 in 200 ml of methanol was added 2 ml of
12NHCl was added and the reaction was stirred at 20°C. Analyze the reaction solution regularly by NMR and TLC.
Additional 12NHCl was added until the reaction was complete as follows: 6 days - 2 ml; 11 days - 2 ml;
17 days - reaction complete. Evaporate the reaction solution to dryness,
Partitioning between 1N NaHCO ₃ and ethyl acetate and evaporation of the organic layer gave 4.8 g of A (79% yield). melting point 80
~83°C, containing a small amount of the corresponding pyridone. B 6-methoxy-α-{[(1-methyl-3-phenylpropyl)amino]methyl}-3-pyridinemethanol-1-oxide-O,N-diacetyl derivative (B) 4.6g in 250ml pyridine and 20ml acetic anhydride
A solution of A (15.3 mmol) was stirred at 20° C. for 18 hours. The reaction was then evaporated to dryness and the residue was taken up in ethyl acetate, washed with 1N NaHCO ₃ and water and evaporated. The residual oil (~6.6g) was dissolved in 500ml of chloroform and 6g (~34mmol) of metachloroperbenzoic acid was added at 20°C with stirring. After 4 days the reaction was complete and 5.3 g of Ca(OH) ₂ was added to the mixture. After 30 minutes, the reaction solution was filtered and evaporated to give 8 g.
An oil was obtained which was chromatographed on silica gel using 10% methanol in methylene chloride as eluent. Approximately 2.7 g (45%) of unoxidized O,N-diacetyl derivative was recovered and then
0.4 g (6.5%) of the single form of B was recovered. Melting point 139-140°C Elemental analysis C H N Theoretical value 65.98 7.05 6.99 Actual value 66.00 7.18 7.03 Further elution yielded 2.1 g (34% yield) of B as an oily mixture of diastereoisomers, which was Well, it was used in the next step. C 1-hydroxy-5-{1-hydroxy-2
-[(1-methyl-3-phenylpropyl)amino]ethyl}-2(1H) pyridinone hydrochloride (C) A solution of 2.6 g (6.5 mmol) B in 100 ml of 2NHCl was heated to reflux for 20 hours. Analysis by NMR indicated that hydrolysis and cleavage were complete.
The solution was treated with charcoal, extracted with ether and evaporated to dryness to give a very hygroscopic solid. This was dissolved in methanol-water and neutralized with concentrated _NH4OH .
The free base solution was adsorbed onto an ion exchange column (AG50W x X8, 100-200 mesh, H ⁺ form) and then eluted with 5% _NH4OH . Evaporation of the eluent gave 1.8 g of crude C as free base. 1.5 g free base of C and 0.265 g NH ₄ Cl dissolved in 50 ml methanol were evaporated to give the hydrochloride salt. The residue was slurried in 25 ml of acetonitrile for 3 days, filtered, and air dried to give 1.3 g of C.
(58% yield). Melting point: 188℃ (decomposition).

Claims (1)

[Scope of Claims] 1 Compounds represented by the following general formula, tautomers, pharmaceutically acceptable salts thereof, and individual enantiomers: or [In the formula _, R ₁ is H _{or OH} , R is _[ Formula] However, R ₃ is [Formula] CH ₂ , (CH ₂ ) ₂ , (CH ₂ ) ₃ or (CH ₂ ) ₄ )]. 2. A compound according to claim 1 having formula (a) (R ₁ is H), (b), (c), (e), (g), or (h). 3. The compound according to claim 2, wherein Y is CH ₂ or (CH ₂ ) ₂ . 4. The compound according to claim 3, wherein Y is (CH ₂ ) ₂ . 5. The compound according to claim 4, wherein R ₄ and R ₅ are either CH ₃ or H. 6. The compound according to claim 5, wherein R ₄ is H. 7 R ₃ is [formula] or The compound according to claim 5, which is 8. A compound according to claim 2 having formula (a), (b), (e) or (g). 9. A compound according to claim 2 having formula (b). 10th equation or The compound according to claim 9, which has the following. 11. A compound according to claim 2 having the formula (c). 12th equation The compound according to claim 11, having the following. 13. A compound according to claim 2 having the formula (g). 14th equation or A compound according to claim 1 having the following: and a tautomer thereof. 15th equation A compound according to claim 14 having the following: and a tautomer thereof. 16. Compounds according to claim 1 having the following formula, their maleates or hydrochlorides,
Individual enantiomers and tautomers: or 17 (a), (c), (d) described in claim 16
and the compound of (e). 18. Compound (a) according to claim 16. 19 Compound (c) according to claim 16. 20. Compound (d) according to claim 16. 21 Compound (e) according to claim 16. 22 Claim 15 which is S,S isomer
Compounds described in Section. 23 Claim 15 which is S,R isomer
Compounds described in Section. 24 Claim 15 which is R,S isomer
Compounds described in Section. 25 Claim 15 which is R,R isomer
Compounds described in Section. 26 Compounds of formula a) according to claim 1, wherein R ₁ is OH.