JPS60120866A - Novel carbostyryl derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1>, R<4> and R<5> are H or alkyl; at least one of R<4> and R<5> is H; R<2> and R<3> are H, alkyl, aralkyl or cycloalkyl; the bond including dotted line is single or double bond). EXAMPLE:5-Isopropylaminoacetyl-8-hydroxycarbostyryl. USE:A synthetic intermediate of a compound having beta-adrenaline receptor stimulation activity, and is useful as a bronchodilator, peripheral vasodilator and hypotensor. PREPARATION:The compound of formula I can be produced by reacting the 1- substituted-8-substituted-carbostyryl or -3,4-dihydrocarbostyryl of formula II with the compound of formula III to obtain the novel intermediate of formula IV, and reacting the product with the amine of formula HNR<2>R<3> in a solvent or using the amine as the solvent, at 40-100 deg.C.

Description

[Detailed description of the invention] The present invention relates to novel carbostyril compounds.

More specifically, the present invention relates to the general formula (R% where R and R each represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and at least - of R and R is hydrogen). R and R may be the same or different, and may be a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a straight alkyl group having 1 to 4 carbon atoms in the alkyl moiety. an aralkyl group or a cycloalkyl group having 4 to 6 carbon atoms, including a chain or branched alkyl group, and R and R together with the nitrogen atom to which they are bonded represent 1 to 2 heteroatoms. (which may form a 5- or 6-membered substituted or unsubstituted heterocycle containing 2 nitrogen atoms, oxygen atoms, or sulfur atoms).

It is well known that certain carbostyril derivatives exhibit potent pharmacological activity. A typical compound of this type is Jo
unal of Medical Chemistry
Vol. 15, No. 3, pp. 260-266 (1972), Special Publication No. 1978-38789 Bulletin and Chemical Ab
structs Vol. 62, p. 16212e (1965)
etc. are disclosed. However, these prior art references suggest that the carbostyril structure or the 5-position (1-hydroxy-2
-rjjL-converted aminoaminokyl groups have not been shown to have excellent β-adrenergic receptor stimulating activity.

We have a 5-(1-hydroxy-2-substituted amino)-alkyl group at the 5-position of the carbostyril structure or 3,4-dihydrocarbostyryl structure and a substituent at the 1-position and/or the 8-position. Carbostyryl derivatives or 3,4-dihydrocarbostyryl derivatives and pharmaceutically acceptable acid addition salts thereof have β-adrenergic receptor stimulating activity and are therefore useful as bronchodilators and peripheral vasodilators. It has been found to be effective as a therapeutic agent, such as antihypertensive agents and similar agents, particularly as a drug for the treatment of bronchial asthma.

The object of the present invention is to create a novel 5-(1-hydroxy-2-
Substituted amino)alkyl-8-substituted carbostyryl compounds and novel 5-(1-hydroxy-2-
General formula 111 useful as an intermediate for substituted amino)alkyl-8-substituted-3,4-dihydrocarbostyryl structures
) An object of the present invention is to provide a novel carbostyril derivative represented by:

(In the above formula, R, R and R are each a hydrogen atom or 1 to
represents an alkyl group having 4 carbon atoms, R or R
At least one of them is a hydrogen atom, R and R may be the same or different, and a hydrogen atom, 1 to 4
an alkyl group having 1 carbon atoms in the alkyl moiety
an aralkyl group, including a straight-chain or branched alkyl group having ~4 carbon atoms, or a cycloalkyl group having from 4 to 6 carbon atoms, and R and R together with the nitrogen atom to which they are attached and form a 5- or 6-membered substituted or unsubstituted heterocycle containing 1 to 2 nitrogen atoms, oxygen atoms, or sulfur atoms as heteroatoms).

5-(1-hydroxy- of the formula (Ia) and formula (Ib)
2-substituted aono)alkyl-8-substituted carbostyril derivatives and -3,4-dihydrocarbostyril spindles and their acid addition salts exhibit β-adrenoceptor stimulating activity and are therefore useful as bronchodilators, peripheral Effective as a vasodilator or antihypertensive agent.

The phrase 1alkyl1 as used herein with respect to R, R and R means a straight-chain or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl. , isopropyl group, methyl group, secondary zotyl group, tertiary zotyl group, etc.

As used herein, the phrase 1 aralkyl 1 refers to aralkyl groups containing straight-chain or branched alkyl groups having 1 to 4 carbon atoms in the alkyl moiety, such as benzyl, α-methylindyl, α , α-dimethylbenzyl group, 7enethyl group, α,α-dimethylphenethyl group, etc.

As used herein, the phrase 1 cycloalkyl 1 is
Cycloalkyl agents having 4 to 6 carbon atoms, such as Schiff-4 butyl, cyclopentyl, cyclohexyl, etc. are meant.

As used herein, the term Ib-membered or 6-membered substituted or unsubstituted heterocycle 1 refers to 1 or 2 nitrogen atoms, oxygen atoms as a heteroatom such as a pyrrolidino group, a piperidino group, a morpholino group, a piperidino group. or a heterocyclic group containing a sulfur atom, or a similar group optionally substituted with an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, isopropyl, tert-butyl, etc., e.g. It means groups such as 2-methylpiperidino group, 3-methylpiperidino group, and 4-methylpiperidino group.

As used herein, the term 1hagen1 refers to fluorine,
Chlorine, bromic acid and iodine, preferably chlorine and bromine.

The compounds represented by formula (Ia) and formula (Ib) can be produced from the starting carbostyril compound of general formula (-) according to the following reaction schemes (1) to (VIE).

Reaction scheme■ Reaction scheme■ (If) (I) Reaction scheme■ Reaction scheme■ Reaction scheme■ Here, the prisoner expresses a contact reaction. Kugarasu represents reduction by a reducing agent.

Reaction scheme■ (Ib) (la) In the diagram, R4 and R5 are each a hydrogen atom or 1 It has the same meaning and may be the same as or different from X.

In the chemical structures shown in Schemes I and II above, and throughout the specification and claims, the dotted lines at the 3- and 6-positions of the carbostyril moiety represent the incidental lines between the 3- and 4-positions. represents a single bond or two hydrogen atoms bonded to the 3- and 4-positions. That is, it represents a carbostyryl moiety or a 3,4-dihydrocarbostyryl moiety having a chemical structure.

As shown in the above reaction scheme, one intermediate in the present invention, 1-substituted 1-5-heroacetyl-8-[1-substituted-carbostyryl or -3,4-dihydrocarbostyryl represented by the formula (M] Corresponding 1-substitution-8-R substitution-
Preparation of carbostyryl or -3,4-dihydrocarbostyryl by reacting it with haloacetyl halide, P, in the presence of a solvent or in the absence of a solvent in the presence of a well-known Lewis acid catalyst. (Route A)
.

Compounds of formula (M) in which R is a hydrogen atom can be prepared by the alternative route starting from 8-hydroxycarbostyryl or 8-hydroxycarbostyryl or 8-hydroxycarbostyryl of 2M in which R4 is a hydrogen atom () 1+(B') and (C)+(0) can be produced in the same manner. Route (B)+
(In B, the reaction between 8-hydroxycarbostyryl or 8-hydroxycarbostyryl M and an α-hap alkanoic acid halide of formula (■) is
This results in a novel 8-haloalkanoylcarbostyryl or -3,4-dihydrocarbostyryl in which X in formula (■a) is a halogen atom, which is then subjected to rearrangement of the acetyl group to form the intermediate. ■ Form.

In route (C) + (C'), starting material M and α-
The reaction between H and tetraalkanoic acid halides generates a novel 5-haloalkanoyl-8-haloalkanoyloxycarbostyryl or -3,4--, in which X of formula (Mb) is the same as defined above; 'Hydrocarbostyryl product results, which the 8-octaloalkanoyl group is then hydrolyzed to form the intermediate (M).

In fact, the reaction between 8-hydroxy-3,4-dihydrocamibostyryl and α-hap alkanoic acid halide,
The above three reaction routes, i.e. (8, (t)+(B')
and (C)+(0).Therefore, the reaction product is obtained as a mixture of compounds, (■a) and (lvb).Generally, when the reaction is carried out at a relatively low temperature In this case, the resulting product is a chemical compound (goods) and (I
I/a) and a small amount of compound 0Vb), whereas if the reaction is carried out at a relatively high temperature, the resulting product will be a mixture of compounds (M and (lVb)) and a small amount of compound (
■It would be a mixture of a).

The compound surface from the reaction product, (lVa) or (lVb
) can be advantageously carried out by well-known operations, such as fractional crystallization.

In one preferred embodiment for the separation, the solvent used is removed by distillation to obtain a residue or the reaction mixture is poured onto ice cubes to precipitate the crystals. The residue or core crystals are washed with hot water or cold methanol. Reconsolidation of insoluble materials from methanol yields 5-halalkanoyl-
8-substituted-carbostyryl or -3,4-dihydrocarbostyryl system is obtained. The remaining methanolic mother liquor was concentrated to dryness under reduced pressure, and the residue was recrystallized from acetone to give 8-haloalkanoyl-carbostyryl or -3,4-dihyP.
Locarbostyril (IVa) is obtained. The resulting acetone mother liquor is then concentrated to dryness under reduced pressure and the residue is recrystallized from acetone or acetic acid ethyl ester to give 5-haloalkanoyl-8-haloalkanoyloxycarbostyryl or -3
, 4-u hydrocarbostyryl (■b) is obtained.

The compounds having the formulas (Ia) and (tb) are the 5-(α-7S loalkanoyl)-8-hydroxycarbostyryl or -3,4-dihydrocarbostyryl derivatives of the formula (I) thus obtained. React with an amine of the formula ([0 (wherein R and R are the same as defined above), as shown in reaction scheme ⑐) C in the formula R', R2, R3 , R' and hiR' at
.

Thus, to obtain a new carbostyryl or 3,4-dihydrocarbostyryl having 5-haUalkanoyl-8-substituted monocarbostyryl or -3,4-dihydrocarbostyryl (prepared from M can do.

The method of the invention will be explained in more detail below.

1- or 8-substituted-3 used as starting material of the present invention,
4-Dihydrocarbostyryl is a known compound and is also described, for example, by George R, Rettit et al., J.
, Org, Chem, vol. 33, p. 1089 (19
It can be easily produced by the method described in 68).

The α-haloalkanoic acid halides that can be used in the present invention include α-chloropropionic acid chloride,
These include α-propropionic acid chloride, α-chlorobutylic acid chloride, α-bromobutylic acid chloride, α-bromobutylic acid prolide, α-chloropvaleric acid chloride, and the like.

In the reaction route (A), catalysts that can be used are conventional Lewis brewers, such as aluminum bromide, aluminum chloride, zinc chloride, ferric chloride, iron sternate, octafluoride trifluoride, and the like. 1 Shikuni t! 1 Hyaluminum. These catalysts are based on the starting carbostyril compound (■1
An amount of about 2 to 10 moles, preferably about 3 to 6 moles, is used per mole.

This reaction can be carried out without the use of a solvent, but the reaction runs much more smoothly and directly in an inert organic solvent. Suitable examples of solvents that can be used in this reaction include carbon disulfide, nitrobenzene, ether,
Dioxane and the like are preferred, and carbon disulfide is preferred. These reaction solvents are usually used in an amount of 0.5 to 20 times, preferably 2 to 10 times, the volume of the reaction reagent.

Reaction (A) is carried out in an equimolar amount to a large excess of α-haloalkanoic acid halide, preferably about 2 to 20 moles, most preferably about 2 to 10 moles per mole of starting carbostyryl compound(s). -0 reactions carried out with haloalkanonic acid halides proceed at room temperature to about 150<0>C, preferably at room temperature to about 80<0>C.

The reaction time varies depending on the reaction temperature used, but
Generally, the time is about 1 to 20 hours, preferably about 1 to 10 hours.

The reaction can be carried out using the same amount of the same catalyst used in reaction (A), in the same solvent used in the reaction, or without a solvent.

The reaction is carried out using an equimolar amount to a water excess of α-haloalkanoic acid halide, preferably about 2 to 20 moles, preferably about 2 to 10 moles of α-haloalkanoic acid halide per mole of starting carbostyryl compound. The process may be carried out for about 1 to 20 hours, preferably for about 1 to 10 hours, at a temperature of about room temperature to about 150'C, preferably about room temperature to about 80'C.

8-halalkanoyloxy(-3,4--,>hydro)carpostili #' obtained in reaction (B) as above
Reaction to obtain d-la-5-hafukualkanoyl-8-substituted-(3,4-dihydro)carbostyryl ('')Bs
The reaction, commonly known as the 7')-S rearrangement, can be carried out in the same solvent as in reaction (4) or without a solvent, using the same catalyst as in reaction (4)K. The temperature ranges from room temperature to about 150°C, preferably room temperature to about 80°C, and the reaction time ranges from about 1 to 2
0 hours, preferably about 1 to 10 hours. This reaction can be carried out in the presence of α-710 alkanoic acid halide remaining unreacted in the previous reaction system. In such cases, the presence of the α-haloalkanoic acid S:
It has been found that the yield of 4-hydro)carbostyryl(t) is improved.

Reaction (q) can be carried out in the same solvent as the good solvent used in reaction (A) or without a solvent, using the same catalyst and the same structure as that used in reaction (8). /Acid Halai r ranges from an equimolar amount to a large excess amount,
However, preferably from about 2 to about 20 moles, and most preferably from about 3 to 6 moles per mole of 8-1i-(3,+-thydro)carbostyryl, the reaction temperature used ranges from room temperature to about 150°C, preferably from room temperature to about 80°C,
The reaction time is about 1 hour to 20 hours, preferably about 1 hour to about 10 hours.

The reaction (σ) to obtain the compound (good) from the obtained 5-(α-alkanoyl)-8-tetraalkanoyloxy(3,4-dihydro)carbostyryl is carried out in a solvent such as water, methanol, ethanol. , in the presence of a lower alkanol such as isopropanol, a catalyst such as an alkali metal hydroxide or carbonate, a basic substance such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., or an inorganic acid such as This can be carried out using hydrochloric acid, sulfuric acid, phosphoric acid, etc. The amount of catalyst will vary depending on the type of catalyst used. For example, hydrochloric acid or sodium hydroxide can be used in amounts of 1 to 5 moles (per mole of 5-(α-haloalkanoyl)-8-haloalkanoyloxy-(3,4-hydro)carbostyryl). Generally, the process proceeds for about 0.5 to 5 hours at a temperature of about 0.degree. C. to 0.degree. C., but also at a temperature of 0.degree. If used, it is carried out at a temperature of 70°C to 100°C.

Amines that can be used in the reaction with the 5-(α-haloalkanoyl)-1- and/or -8-substituted-(3,4-dihydro)carbostyryl obtained above include alkyl amines such as Methylamine, ethylamine, n-propylamine, inpropylamine, n-butylamine, 2-butylamine, 3-butylamine,
Cycloalkylamines such as cycloditylamine, schifurentylamine, cyclohexylamine, aralkylamines such as benzylamine, α-methyl-benzylamine, α,α-dimethylbenzylamine, phenethylamine, α,α-dimethylphenethylamine, etc., and substituted or unsubstituted Substituted heterocyclic amines such as pyrrolidine, biylidine, cellforin, piperazine, 2-methyl-piperidine,
Includes 3-methylpiperidine, N-methylpiperidine, and the like.

This reaction between amines and 5-(α-haloalkanoyl)-1- and H-8-substituted-(3,4-dihydro)carbostyryls occurs at temperatures from about atmospheric pressure to about 10 atm. 5 in a suitable solvent or using the amine itself as a solvent at room temperature to the reflux temperature of the reaction system, preferably at a temperature of 40°C to 100°C, using an equimolar amount to a large excess of the amine. -(α-substituted-aminoalkanoyl)-8-
Substituted-(3,4-dihydro)carbostyryl (I[),
5-(α-Substituted-aminoalkanoyl)-8-alkoxy-(3,4-dihydro)carbostyryl (IIa)
Furthermore, 5-(α-substituted monoaminoalkanoyl)-8- and droxy-(3,4-dihydro)carbostyryl (nb
) can be obtained.

Alternatively, a carbostyryl compound or a 3,4-dihydrocarbostyryl compound (Ila) in which R represents an alkyl group
is dealkylated with hydrogen halide prior to reduction to form the formula (n
b) or by alkylating a carbostyril compound or a 3,4-dinicarbostyryl compound in which R represents a hydroxy group prior to reduction to obtain a compound of formula (IIa
) can be obtained as shown in the reaction scheme (■).

The hydrogen halides used in the above dealkylation include hydrogen bromide, hydrogen chloride, hydrogen iodide, and preferably hydrogen bromide. These hydrogen halides can advantageously be used in about 10-50% solutions, preferably 47% aqueous solutions of hydrogen halides, in solvents such as methanol, ethanol, alcohol, and preferably water.

This dealkylation reaction is generally carried out by heating the hydrogen halide to the compound (
It can be carried out using from an equimolar amount to IIa) to a large excess, preferably a large excess.

Alkylation of compounds of formula (Ilb) can be accomplished by reaction with alkylating agents well known in the art in the presence of basic compounds. Suitable examples of alkylating agents include alkyl halides such as alkyl iodides, alkyl chlorides, alkyl bromides, dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, and the like. Suitable examples of basic substances include alkali metals such as sodium metal, potassium metal and their hydroxides, carbonates, bicarbonates and alpretes, and aromatic amines such as pyridine, biridine, and the like.

The alkylation is advantageously carried out in an equimolar amount to a large excess of the alkylating agent, preferably 95 to 95% per mole of compound of formula (Ilb).
Using ~10 moles of alkylating agent, proceed in a solvent ranging from water, methanol, ethanol, lower alkanols such as isopropanol, % n-sitanol, acetone, methyl ethyl ketone or more. The alkylation generally proceeds at room temperature.

Formula (1) from 5-(α-substituted-aminoalkanoyl)carbostyryl of formula (I[a) or (I[b)],
Reduction of (Ia) or (Ib) to the compound, respectively.

Conventional reduction using reducing agents such as lithium aluminum hydride, sodium borohydride, etc., or conventional contact in the presence of hydrogen with catalysts such as palladium black, radium on carbon, nickel, platinum black, acidic platinum, etc. This can be done by reduction.

The reducing agent is added in a solvent at a temperature of about 0° C. to 100° C., preferably about 20° C. to 50° C., at atmospheric pressure, in a solvent per mole of carbostyril compound of formula (I[a)]. 2~
Amounts of 10 moles, preferably about 2 to 5 moles can be used. When sodium borohydride 2ide is used as the reducing agent, the solvent is preferably water or an alkanol such as methanol or ethanol, and when lithium aluminum Hytryr is used as the reducing agent, the solvent is anhydrous diethyl ether, Non-aqueous solvents such as ethyl acetate, tetrahydrofuran, etc. are preferred.

Catalytic reduction line, at a temperature of from room temperature to about 150° C., preferably from room temperature to about 120° C., under an atmosphere of hydrogen at a pressure of from atmospheric pressure to about 100 atmospheres, preferably from atmospheric pressure to about 50 atmospheres, in a solvent such as water, or methanol. , ethanol or isopro-A-ol in an alkanol such as ethanol or isopro-A alcohol.
Advantageously, the spreading reduction system is stirred using the above catalyst in an amount of from about 0.05 to about 1 mole, preferably from about 0.1 mole to 0.5 mole, per mole of carbostyryl compound of It can be carried out while The above catalytic reduction was carried out at atmospheric pressure for about 5
It is advantageous to carry out at a temperature above 0° C., or at a temperature above about room temperature under pressure.

The catalytic reduction and reduction with reducing agents that can be used in the process of the invention are shown in greater detail in Scheme V. These reactions can be carried out in the same manner as described above for the reduction of compounds of formula (n), (Ila) and (nb). Catalytic reduction of a compound of formula (II), (ITa) or (ub) having a double bond between the 3- and 4-positions is generally carried out to reduce the compound of formula (I) with saturated 3- and 4-positions. ,
C1a) or (It)) respectively, but catalytic reduction produces the corresponding 3,4-9 hydrocarbostyryls of -5; Only the 5-position of the carbostyryl compound of I[a) or (Ilb) is reduced to reduce the remaining double bond between the 3-position and the 4-position of the formula (I), (Ia) or (I
It should be noted that b) can be used to give the corresponding carbostyryl compounds. However, for reducing only the 5-position of the carbostyril compound, it is preferable to use the above-mentioned reducing agent.

The conversion or inverse transformation of a compound of formula (Ia) to a compound of formula (Ib), i.e. alkylation or dealkylation, may be performed by converting a compound of formula (Ia) into a compound of formula (Ib), i.e. alkylation or dealkylation
It can be carried out by the same methods as described for the alkylation or dealkylation of compounds la) or it (Ill)).

As shown in reaction scheme (2), the 3.4-:) hydrocarbostyryl compound can be converted to the corresponding carbosteryl compound at any stage of the process of the present invention.

The conversion of the compound of formula (Ib) to the compound of formula (Ia), i.e., dehydrogenation, releases hydrogen atoms from the 3- and 4-positions of the carbostyril structure, respectively, to form the 3- and 4-positions. This can be carried out by any known method capable of forming a double bond between. This dehydrogenation can be carried out using (1) a method using a dehydrogenating agent such as chloranil (tetrachloro-1,4-benzoquino/), dichlorodicyano-1,4-d-benzoquinone, etc., (2) a method using sulfur, selenium dioxide, etc. This can be achieved by a method using a dehydrogenating agent such as, and preferably by using the above method (1) or (2).

Both dehydrogenations are carried out in solvents such as aromatic hydrocarbons such as penzene, toluene, cyclobenzene, phenetol, chlorobenzene, methanol, ethanol, isopro/quinol,
The reaction can be carried out in a solvent such as a lower alkanol such as tert-butanol, an ether, a ketone such as dioxane or acetone, water, or acetic acid.

The dehydrogenation can advantageously be carried out from room temperature to the reflux temperature of the dehydrogenation system, preferably at or near the reflux temperature.

, p The compound of formula (I) obtained as above and the compound of formula (1)
) are both basic substances and can form acid addition salts with various organic or inorganic acids.

Particularly useful such salts are inorganic acids such as hydrochloric, sulfuric, phosphoric, hydrobromic, etc., or oxalic, maleic, fumaric, phosphorous! Acids are pharmaceutically acceptable acid addition salts formed with organic acids such as citric acid, tartaric acid, ascorbic acid, and the like. These acid addition salts can be prepared using well-known methods such as adding an equivalent to an excess amount of the acid to a solution of the compound dissolved in a suitable organic solvent such as methanol, ethanol, inopol, acetic acid, etc. can be easily manufactured by

Both the free base and the acid addition salt of the compound of formula (D) are
It exhibits stimulatory activity on β-adrenergic receptors and is therefore very effective as a drug for the treatment of diseases such as bronchial asthma.

As will be appreciated by those skilled in the art, the compounds of the present invention contain two asymmetric centers and may therefore provide four optically active forms.

The invention will be explained in more detail by reference to the following examples, which are given for illustrative purposes only and are not intended to limit the scope of the invention. It is not to be interpreted. Unless otherwise noted, all parts, percentages, percentages, etc. are by weight.

Example 1 27 g of 8-hydroxycarbostyryl and 37 g of chloroacetyl chloride were dissolved in 250 g of nitrobenzene,
After gradually adding 85.9% of aluminum chloride, at 70°C
0 hours - stirred. After adding 50011 d of 10% hydrochloric acid, dinitrobenzene was removed by steam distillation. From now on, the precipitated crystals were collected, washed with 300°C of hot water, and then recrystallized in methanol to form pale yellow crystals of 5-/l'l acetyl-8-hydroxycarbostyryl with a melting point of 285-287°C (decomposition). 14.0g was injected.

Example 2 20 g of aluminum chloride may be added to 5.09 g of 8-hydroxycarbostyryl, and after mixing, 10 I of chloroacetyl chloride was gradually added while cooling with ice water. 40-4
A heating reaction was carried out at 5° C. for 2 hours to produce 8-chloroacetoxycarbostyryl.

Next, the mixture was stirred at 70°C for 3 hours, and the precipitated crystals t-F were collected.
Water 300T! After washing with Ll and recrystallizing with methanol, pale yellow crystals (D
5-chloroacetyl-8-hydroxycarbostyryl 2
．． 6g was obtained. A part of the intermediately formed 98-μ-acetoxycarbostyryl reaction product was taken out and #1'N crystallized with acetone to obtain light yellow crystals, whose melting point was determined as i[I
The temperature at the zeta filter was 248-250°C (decomposition).

Example 3 0.5 g of 8-hydroxycarbostyryl (K-acetyl chloride)'1.5 II and 20 m of carbon disulfide were added, and 2 g of aluminum chloride was gradually added to Hyosui Teio. After mixing thoroughly, the mixture was gradually added. The mixture was warmed and refluxed for 30 minutes. Excess chloroacetyl chloride and carbon disulfide were then removed, and crushed ice was added to the residue to crystallize it. After washing with water, it was recrystallized with acetone to give a product with a melting point of 248-251°C (decomposed). 8-Chloroacetoxycarbostyryl in light yellow crystals 0.459
I got it.

Example 4 98-Chloroacetoxycarbostyryl 1 obtained in Example 3
．． 20 g of aluminum chloride and 109 grams of acetyl chloride were added to 0 g of the mixture, and the mixture was heated at 75 to 85° C. for 1 hour.

The precipitated crystals were collected by heating into crushed ice, washed with water, and then recrystallized from methanol to obtain 3.7 g of 5-chloroacetyl-8-hydroxycarbostyryl as pale yellow crystals with a melting point of 285-287°C (decomposed). .

Example 5 7.3 g of 8-hydroxycarbostyryl and 12.5 g of chloroacetyl chloride were added to nitrobenzene y70dK.
Then, aluminum chloride 3019 is gradually added while stirring with water cooling. After stirring at 50-55°C for 6 hours, the mixture was placed in ice water. Precipitated crystals were washed with tanol and then recrystallized with acetone, with a melting point of 239-241°C (decomposition).
3.5 g of pale yellow crystals of 5-/lolua-7tyl-8-chloroacetoxycarbosnaril were obtained.

Example 6 1.7 g of 5-chloroacetyl-8-chloroacetoxycarbostyryl obtained in Example 5 was added to 59 d of 10% hydrochloric acid and stirred at 95-100'C for 2 hours.

After that, the precipitated crystals were collected with F, washed with water, and then recrystallized with methanol to give a melting point of 285. 1.1 g of pale yellow crystals of 5-chloroacetyl-8-H)-#roxycarbostyryl with a melting point of 285 and 286°C (decomposition) were added. obtain.

Example 7 2.5 g of 5-chloroacetyl-8-chloroacetoxycarbostyryl obtained in Example 5 is added to 3 o's of 5% aqueous potassium hydroxide solution and stirred at 20 to 25°C for 30 minutes. While cooling, add dilute hydrochloric acid to adjust the pH to 2-3, wash the precipitated crystals several times with water, and then recrystallize with methanol to give a melting point of 28.
1.7 g of 5-chloroacetyl-8-hydroxycarbostyryl was obtained as light yellow crystals of 5-287°C (decomposed).

Example 8 20 g of aluminum chloride is gradually added to 4.5 g of 8-hydroxycarbostyryl and 1 og of chloroacetyl chloride while stirring under water cooling. Next, stirring is carried out at 55 to 60°C for 8 hours to produce 5-chloroacetyl-8-chloroacetoxycarbostyryl, and then 49 d of 5% potassium hydroxide is added and the mixture is stirred at room temperature for 30 minutes. then 10%
Add hydrochloric acid to make an acidic solution and collect the precipitated crystals. After washing with water, it is recrystallized from methanol to obtain 5-chloroacetyl-8-hydroxy-carbostyryl 2.3Ii as pale yellow crystals with a melting point of 285-286°C (decomposed). As mentioned above, VC
Before adding 5% aqueous potassium hydroxide, a portion of the reaction system was taken out and poured into ice water, and the precipitated crystals were washed several times with methanol and then recrystallized with ethyl acetate to give a melting point of 2.
Obtained pale yellow crystals of 5-chloroacetyl-8-chloroacetoxycarbostyryl at 38-241°C (decomposition).

Example 9 12.69 of 5-chloroacetyl-8-hydroxycarbostyryl obtained in Example 4 or 8 was added to Imp OzZ/-
Suspend the Impro♂Amine 2 in 130m of water and stir.
5.59 is added dropwise. Stir at 55-60"C for 3 hours. Add concentrated hydrochloric acid to make pa = 2-3. Remove the precipitated crystals, wash with acetone, and refill with methanol-dimethylformamide (volume ratio 1:1). Crystallized and melting point 286 ~
5-Isopyraminoacetyl-8- and thoxycarbostyryl hydrochloride in pale yellow crystals at 288°C (decomposed)6.
Get 511.

Example 10 The 5-aryl acetyl-8-hydrol obtained in Example 4 and 8
Suspend 8.09 of roxycarbostyryl in dinonol 100, and dropwise add 1 (l) of tart-butylamine while stirring. Stir at 55-60°C for 5 hours. Concentrate to about half the volume, then concentrate salt. Add wk to adjust pH to 2-3.

Precipitated crystals were taken from t-p, washed with acetate and methanol.
Recrystallize from ethanol (volume Jll ratio 1:1) to obtain a melting point of 2.
S-tert of light yellow crystals at 91-293°C (decomposition)
-butylaminoacetyl-8-hydroxycarbostyryl tatJi4.1.9 is obtained.

Example 11 Example 4 TFC is 5-chloroacetyl-8-hydroxycarbostyryl obtained in 8. 4.3 g't ethanol 50-
5 g of formula-butylamine are added dropwise under stirring. Stir at 60-65°C for 5 hours.

Afterwards, add concentrated hydrochloric acid to adjust the pH to -3. Precipitated crystals were recrystallized using methanol-ethanol (volume ratio 1:1) to give pale yellow crystals with a melting point of 289-291°C (decomposition).
2.9 g of 56cm butylaminoacetyl-8-hyP-roxycarbostyryl hydrochloride are obtained.

Example 12 10 g of 5-chloroacetyl-8-hydroxycarbostyryl prepared in Example 4 or 8 was suspended in 50 ml of benzene, and the suspension was charged with 10 mA of pyridine! was added, and the mixture was then heated under reflux and stirring for 6 hours. The reaction mixture was filtered to obtain the reaction product, which was then washed with inzene and then Improper Tool 50m. The resulting insoluble material was dissolved in 150 mJ of 2% hydrochloric acid.

The solution was concentrated to dryness under reduced pressure, and the resulting residue was recrystallized from ethanol to give a white amorphous 5-pidudinoacetyl-8-human p-xycarbostyryl hydrochloride solution having a melting point of 239-241°C (decomposed). 7.5 g of the compound was obtained.

Example 13 5-Chlodayacetyl-8-hydroxycarbostyryl 1oy1. produced in Example 4 or 8. Suspended in Banzen 60-, add morpholine 91 to this suspension,
Next, the mixture was allowed to react under reflux and stirring for 4 hours. The reaction mixture was cooled and the resulting precipitate was collected. This precipitate was dissolved in Improper Tool 60- and the solution was adjusted to pH 2-S with concentrated hydrochloric acid.

The resulting acidic solution was cooled with ice and the precipitate formed was filtered and then recrystallized from ethanol. This precipitated water 20
- Dissolve the solution with sodium bicarbonate to pH 7.5-8.
The temperature was adjusted to 0 and cooled in a water bath. The precipitate formed on cooling was collected by F and recrystallized from ethanol to give a melting point of 238-239.5°C.
4.2 g of white amorphous 5-morpholinoacetyl-8-hydroxycarbostyryl having (decomposition) was obtained. The product thus obtained was subjected to engineering R spectral analysis and N
This was confirmed by MR spectrum analysis and elemental analysis.

Example 14 fc5-chloroacetyl-ε- produced in Example 4 or 8
Hydroxycarbostyril 15g to benzylamine 12
0- was added and the mixture was stirred at room temperature for 1 hour. The precipitate formed by adding petroleum needles to the reaction mixture was dissolved by adding dilute hydrochloric acid, and the solution was filtered to remove any remaining insoluble material. Next, the hydrochloric acid layer was concentrated and dried, and the residue was recrystallized from methanol to give a melting point of 274-279.
A material 16.411 was obtained having a temperature of 16.411 °C (colored decomposition). The product thus obtained was confirmed to be 5-(1-phenethylaminoacetyl)-8-hydroxycarbostyryl hydrochloride by HMR spectral analysis, engineering R spectrum analysis, and elemental analysis.

Example 15 1. The precipitate formed by adding petroleum ether to the reaction mixture was washed with diethyl ether and dissolved in methanol solution of hydrochloric acid to remove insoluble materials. Methanol was distilled off and the residue was recrystallized from methanol to give a melting point of 246-247.
6.1 g of material having a temperature of 0.degree. C. (colored decomposition) was obtained. The product thus obtained was analyzed by NMR spectroscopy and mechanical engineering.
Spectral analysis confirmed the presence of 95-(1,1-dimethyl-7enethylaminoacetyl)-8-hyroxycarbomethylyl hydrochloride hydrate.

Example 16 8-hydroxy-3,4-dihydrocarbostyryl 24
．． 39 and 68 g of chloroacetyl chloride are added to 130 g of carbon disulfide, and 200 g of aluminum chloride is gradually added while stirring under ice water cooling.

After stirring at 60-70°C for 6 hours, carbon disulfide is distilled off. Pour the residue into 500 ml of ice water.

The precipitated crystals were collected in F, washed with water, and then recrystallized twice from methanol to obtain 8.0 g of 5-chloroacetyl-8-hyproxy-3,4-dihydrocarbostyryl as pale yellow crystals with a melting point of 189-191°C.

Example 17 8-Hroxy3,4-dihydrocarbostyryl 13
L chloroacetyl chloride y2oti is dissolved in 100 d of nitrobenzene, 40 g of aluminum chloride is gradually added, and the mixture is stirred at 70-75°C for 15 hours. Dinitrobenzene is removed by steam distillation. After that, the precipitated crystals were collected, washed with hot water, and then recrystallized from methanol to form pale yellow crystals with a melting point of 189-190°C.
8-Hydroxy-3,4-thydrocarbostyryl7.
Obtain 2g.

Example 18 17 g of 8-methoxy-3,4-dihydrocarbostyryl
Niri go acetyl chloride silide 66g nitrobenzene 3
0- was added. While cooling with water, 100 g of aluminum chloride was gradually added, and the mixture was stirred at room temperature for 30 minutes. After standing for 30 minutes, it was poured into 700 d of ice water. The precipitate was collected by F, then washed with ethanol, and recrystallized from methanol to give a melting point of 187-1.
20 g of white needle-like material at 88° C. was obtained. This thing is N
From the results of MR%IR and elemental analysis, it was confirmed that it was 5-chlorotetraacetyl-8-methoxy-3,4-dihydrocarbostyryl.

Example 19 8-methoxy-3,4-dihydrocarbostyryl 8.5
g, 33 g of chloroacetyl chloride, 30 g of carbon disulfide
- was added. While cooling with water, 50 g of aluminum chloride was gradually added, and the mixture was stirred at room temperature for 2 hours. After the carbon disulfide layer was removed by tilting, crushed ice was added to crystallize it. The resulting precipitated crystals were collected by F, then washed with ethanol, and recrystallized from methanol to obtain white needle-like substance 11 with a melting point of 187-188°C.
I got g. This product was found to be 5-chloroacetyl-8-methoxy-3, 5-chloroacetyl-8-methoxy-3,
It was confirmed to be 4-dihydrocarbostyryl.

Example 20 8-hydroxy-3,4-dihydrocarbostyryl 24
．． 3 g of chloroacetyl chloride P and 68 g of chloroacetyl chloride P were added to 130 ml of carbon disulfide, and 200 g of aluminum chloride was gradually added to the mixture under ice-water cooling and stirring. The mixture is reacted for 4 hours under water cooling to produce 8-polyacetoxy-3,4-dihydrocarbostyryl. Then, after stirring at 60 to 70°C for 2 hours, carbon disulfide is distilled off. Pour the residue into 500ml of ice water, separate the precipitated crystals in a furnace, wash with water, and then add methanol)
Recrystallization is carried out twice to obtain 8.0 g of 5-chloroacetyl-8-hydroxy-3,4-dihydrocarbostyryl as pale yellow crystals with a melting point of 189-191°C. A portion of the reactant 8-chloroacetoxy-3,4-dihydrocarbostyryl produced in the middle was taken out and recrystallized, and its melting point was confirmed to be 183 to 186°C.

Example 21 8-Hydroxy-3,4-uH)? locarbostiril 1
Add 40 g of aluminum chloride to 1.5 g, mix well, and then gradually add 21 g of chloroacetyl chloride to the ice water solution. After heating and stirring at 35-40"C for 2 hours, excess chloroacetyl chloride was distilled off. The residue was poured into crushed ice, and the precipitated crystals were collected in F, washed with water, and recrystallized from acetone to obtain mp.

5.6 g of 8-polyacetoxy-3,4-dihydrocarbostyryl is obtained as pale yellow crystals having a temperature of 182 to 184°C.

Example 22 8-Human Oxy3.4-9 Hydrocarbostyryl 13
p and chloracetylchlor2a) '20 fl'? : Dissolved in nitrobenzene 10 omJ, aluminum chloride 40
After gradually adding g, the mixture was stirred at 70-75°C for 15 hours.

Dinitrobenzene is removed by steam distillation. The precipitated crystals t-F were collected, washed with hot water, and then recrystallized with methanol to give pale yellow crystals of mp, 189-190°C, 5-Yuhiruacetyl-8-hydroxy-3,4-dihydrocarbostyryl7. Obtain 2g.

Example 23 8-Hydroxy-3,4-dihydrocarbostyryl6.
0g of aluminum chloride and 15.0g of chloroacetyl chloride were gradually added to 15.0g of chloroacetyl chloride while stirring with water cooling.Then, stirring was carried out at 55-60°C for 6 hours to obtain 5-chloroacetyl-8-chloroacetoxy-3,4. - generate dihydrocarbostyril, then 10% aqueous hydrochloric acid solution 50%
- and stirred at 95-100°C for 3 hours. The precipitated crystals were then collected, washed with water, and then recrystallized in methanol to give pale yellow crystals with a melting point of 189-190°C, 5-chloroacetyl-8-hyrroxy a, 4-9 hydrocarbostyryl. 'Get 1llt. Before hydrolysis, a part of the reaction system was taken out and separated into ice water, and the precipitated crystals were collected with F, washed with hot methanol, and then dimethylformamyl-methanol (volume ratio 1:1). The product was recrystallized to obtain pale yellow crystals of 5-chloroacetyl-8-chloroacetoxy-3,4-dihydrocarbostyryl with a melting point of 206-207°C.

Example 24 4 g of 5-chloroacetyl-8-hydroxy-3,4-dihydrocarbostyryl obtained in Example 23 was dissolved in Impropatol 50-, 20 g of isoprupylamine was added, and the mixture was stirred at 60°C for 3 hours. did.

After concentrating the reaction solution to 10 to 10 times its volume, it was saturated with dry hydrochloric acid gas. The precipitate was collected and recrystallized from ethanol to obtain 3.5 g of a colorless amorphous substance with a melting point of 274-275°C. This product was confirmed to be 5-inpropylaminoacetyl-8-hyroxy-3,4-dihydrocarbostyryl hydrochloride from the results of MMR, engineering R, and elemental analysis.

Example 25 5-chloroacetyl-8-hydroxy-a,4-S>hydrocarbostyryl 3S obtained in Example 23 was dissolved in isopropanol 4017, and 3 g of methylamine was dissolved in 60
The mixture was added dropwise over 30 minutes while stirring at ℃.

After the dropwise addition was completed, the mixture was heated and stirred for an additional hour. The liquid volume was concentrated to ten times the volume, and then concentrated hydrochloric acid was added to adjust the pH't to 1 to 2. The precipitate was collected and recrystallized from ethanol to a melting point of 254~
1.5 g of a colorless amorphous substance at 256° C. was obtained. This product was confirmed to be 5-methylaminoacetyl-8-hydroxy-3,4-dihydrocarbostyryl hydrochloride from the results of NMR, engineering R, and elemental analysis.

Example 26 5-ri-tetraacetyl-8-human ■ obtained in Example 23
Dissolve 2.549 xy-3,4-dihydrocarbostyryl in 30-isopropanol and 2.7 g of ethylamine.
was added dropwise over 20 minutes while stirring at 60°C. After the dropwise addition was completed, the mixture was heated and stirred for an additional 40 minutes.

The liquid volume was concentrated to ten times the volume, and concentrated hydrochloric acid was added to adjust the pH to 1-2. The precipitate was recrystallized from ethanol to obtain 1.9 g of a colorless amorphous substance with a melting point of 258 to 260"C. This substance was found to be 5-ethylamino based on the results of HMR, engineering R, and elemental analysis. acetel-8-hydroxy-3
, 4-dihydrocarbostyryl hydrochloride.

Example 27 To the 5-proacetyl-8-hydroxy-a,4-thydrocarbostyryl 4flk inproper tool 601117 obtained in Example 23, 20.9% of tert-butylamine was added under stirring at 60°C. , was added dropwise over 20 minutes. - After the completion of one drop, the mixture was further heated and stirred for 40 minutes.

The liquid volume was concentrated to 1 times the volume, and concentrated gold hydrochloride was added to adjust the pH to 1 to 2. The precipitate was collected in F and recrystallized in a mixed solvent of ethanol-acetone (volume ratio 1:1) until the melting point was 25.
Colorless amorphous substance at 3-255°C2. Obtained OIi. This product was confirmed to be 5-tert-butylaminoacetyl-8-hyroxy-3,4-dihydrocarbostyryl hydrochloride from the results of NMR, engineering R, and elemental analysis.

Example 28 5-chloroacetyl-8-human 0 obtained in Example 23
3 g of Roxy 3.4-0 hydrolubostyril was dissolved in Improper Tool 40- and the formula-ditylamine 10.9
The mixture was added dropwise over 20 minutes while stirring at 60°C. After the dropwise addition was completed, the mixture was heated and stirred for an additional 2.5 hours. After concentrating the liquid volume to ten times the volume,
It was saturated with dry hydrochloric acid gas. The precipitate t''F was collected and recrystallized from ethanol to obtain 1.8 g of a colorless amorphous substance with a melting point of 269-271°C. -Butylaminoacetyl-8-hydroxy-a,4-9hydrocarbostyryl hydrochloride was found to be 11!

Example 29 5-chloroacetyl-8 obtained in Examples 18 and 19
4 g of -methoxy-3,4-dihydrocarbostyryl was dissolved in 50 wLl of Impropatol, 20 g of isopropylamine was added, and the mixture was stirred at 60°C for 3 hours.

After concentrating the reaction solution to 10 to 10 times its volume, it was saturated with dry hydrochloric acid gas. Thereafter, the precipitate was collected and recrystallized from ethanol to obtain 3.5 g of a colorless needle-like substance with a melting point of 208-209°C. This product was confirmed to be 5-isopropylaminoacetyl-8-methoxy-3,4-dihydrocarbostyryl hydrochloride from the results of NMR, engineering R, and elemental analysis.

Example 30 5-chloroacetyl- obtained in Examples 18 and 19
Dissolve 3 g of 8-methoxy-3,4-dihydrocarbostyryl in Impropatool 40- and add 3 g of methylamine.
After one drop was added over 30 minutes under stirring at t-60° C., the mixture was further heated and stirred for 1 hour. The liquid volume was concentrated to ten times the volume, and then concentrated hydrochloric acid was added to adjust the pH to -1 to -2. The precipitate was collected and recrystallized in ethanol to obtain 1.5 g of a colorless needle-like substance with a melting point of 232-234°C. This product was confirmed to be 5-methylaminoa*fk-8-methoxy-3,4-dihydrocarbostyryl hydrochloride from the results of NMR, engineering R, and elemental analysis.

Example 31 2.54.9 of 5-riotiacef-8-methoxy-3,4-,'hydrocarbostyryl obtained in Examples 1B and 19 was dissolved in 39 m of Impropatol, and 2.54.9 of ethylamine was dissolved. 71 was added dropwise over 20 minutes while stirring at 60°C. After the dropwise addition was completed, the mixture was heated and stirred for an additional 40 minutes. Concentrate the liquid volume to ten times the volume and make salt i! ! was added to adjust the pH to 1-2. The precipitate eF was collected and recrystallized from ethanol to a melting point of 22.
1.911i of colorless needle-like substance having a temperature of 4-227°C was obtained. Based on the analysis results by LIMR, engineering R, and elemental analysis, this product was found to be 5-ethylaminoacetyl-8-methoxy-3,+-
It was confirmed that it was 0 hydrocarbostyril hydrochloride.

Example 32 5-chloroacetyl- obtained in Examples 18 and 19
8-methoxy-3,4-S) human tetracarbostyryl 4I
was dissolved in Impropatool 60111, and 20 g of tert-butylamine was added dropwise over 20 minutes while stirring at 60°C. After the completion of the dropwise addition, the mixture was further heated and stirred for 40 minutes. The liquid volume was concentrated to 7 times the volume, and concentrated hydrochloric acid was added to adjust the pH to 1-2. The precipitate was collected in a mixed solvent of ethanol-acetone (volume ratio 1:1) and recrystallized repeatedly until the melting point was 208-210°C.
A colorless amorphous product of substance 2.0.9'i was obtained. This product is 5-t based on the analysis results of NMR%E and elemental analysis.
ert-butylaminoacetyl-8-methocue 3.4
- It was confirmed that it was dihydrocarbostyril hydrochloride.

Example 33 5-rioOacetyl- obtained in Examples 18 and 19
Dissolve 3 g of 8-methoxy-3,4 mN hydrocarbostyryl in Impropatol 40, reduce-butylamine 1
The mixture was added dropwise with stirring at 120°C for 120 minutes. After the dropwise addition was completed, the mixture was heated and stirred for an additional 2.5 hours. After concentrating the liquid volume to ten times the volume, it was saturated with dry hydrochloric acid gas. The precipitate was collected and recrystallized from ethanol to obtain 1.8 g of a colorless needle-like substance with a melting point of 212-214°C. This product was confirmed to be 5-sec-ditylaminoacetyl-8-methoxy-3,4-dihydrocarbostyryl hydrochloride from the results of NMR, engineering R, and elemental analysis.

Example 34 5-isopropyl acetyl-8-methoxy-3,4-dihydrocarbostyryl hydrochloride obtained in Example 29 was dissolved in 10 d of a 47% aqueous hydrogen bromide solution and heated at a bath temperature of 120 to 130°C. The mixture was heated under reflux for .5 hours. 1011j of ethanol and 5 dt of water were added and concentrated. more water 2
01J? t and the pH was adjusted to 6.5-7.5 by adding sodium bicarbonate. Separate the precipitated crystals, wash with water,
After drying, it was dissolved in inproper tool and saturated with dry hydrochloric acid gas. The precipitate t-F was collected and recrystallized from ethanol to obtain colorless amorphous crystal substance 0.5S having a melting point of 274-275°C. This product was confirmed to be 5-impulpylaminoacetyl-8-hydroxy-3,4-dihydrocarbostyryl hydrochloride from the results of NMR, engineering R, and elemental analysis.

Example 35 5-methylamitubcetyl-8- obtained in Example 30
Methoxy-3,4-dihydrocarbostyryl hydrochloride 0.
71 was dissolved in a 47% aqueous hydrogen bromide solution at a bath temperature of 12
The mixture was heated under reflux at 0 to 130°C for 4 hours. Thereafter, the same procedure as in Example 30 was carried out to obtain a colorless amorphous substance o, sg6 with a melting point of 254 to 256°C. This product was found to be 5-methylaminoacetyl-8-
It was confirmed to be hydroxy-3,4-dihydrocarbostyryl hydrochloride.

Example 36 5-tert-methylaminoacetyl-8-methoxy-
3,4-dihydrocarbostyril hydrochloride 0.9g total 47
% hydrogen bromide aqueous solution and then operated in the same manner as in Example 34 to obtain 0.2 g of a pale yellow amorphous substance with a melting point of 252-255°C. This product was confirmed to be 5-tert-butylaminoacetyl-8-hydroxy-3,4-dihydrocarbostyryl hydrochloride from the results of NMR, IR, and elemental analysis.

Example 37 fc5-sec-butylaminoacetyl-8-methoxy-3,4-- obtained in Example 33, 'human tetracarbostyryl hydrochloride 0.511't-47% hydrogen bromide aqueous solution wL1
0d, and then operated in the same manner as in Example 34 to obtain a melting point of 2.
0.24 g of a colorless amorphous substance with a molecular weight of 69 to 271"C was obtained. This substance was found to be 5-sec-butylaminoacetyl-8-hydroxy-3,4-dihydrocarboxylic by NMR, engineering R, and elemental analysis. It was confirmed to be styryl hydrochloride.

Example 38 8-Hydroxycarbostyryl 20gKα-bromobutyric acid bromide 50y, anhydrous aluminum chloride 50g, carbon disulfide 4001Llt- were added and heated at 50°C for 13 hours, the carbon disulfide layer was removed by tilting, and crushed ice was added to the residue. After crystallization, it is subjected to the t-F-water extraction method. Furthermore, it was recrystallized from methanol to give 5-(α-bromobutyryl).
-8-Hydroxycarbostyryl 2711''?: obtained. Melting point 218-219°C (color decomposition).

Example 39 Add 25 g of α-zolomobutyric acid chloride and 259 t of anhydrous aluminum chloride to 10 g of 8-hydroxycarbostyril, heat at 17IO°C for 4 hours while mixing thoroughly, add crushed ice to crystallize, remove 1 kF of this, and wash with water. .

Further, it is recrystallized from methanol to obtain 12.6 g' of 5-(α-bromobutyryl)-8-hydroxycarbostyryl. Melting point: 218-219°C (color decomposition).

Example 40 10 g of 8-hydroxycarbostyryl, 2s 9 of α-bromobutyric acid, 100T of nitrobenzene
nl'f: Added and cooled anhydrous aluminum chloride 25#t
-Add. After heating at 70°C for 10 hours, the precipitated crystals were poured into crushed ice, washed several times in a tray, and then recrystallized from methanol to give 5-(α-bromobutyryl)-8-hydroxycarbostyryl 11,2.1. - get. Melting point 21
7-218.5°C (color decomposition).

Example 41 Secondary dithylamine 2001LlIC- was added to 5-(α-bromobutyryl)-8- obtained in Examples 38 to 40 and dorxycarbostyril 10I, heated at 60°C for 20 hours, and then concentrated to dryness. , crystals f precipitated by adding water
After removing i-F and dissolving it in 50% of ethanol, salt production @
Add to adjust the pH to 1. Next, the precipitated crystal eF is collected,
Recrystallized from methanol to give 5-(α-sec-zoluraminobutyryl-8-
8.39t of hydroxycarbostyril hydrochloride is obtained.

Example 42 Inopropylamine IQd and methanol 50*1 were added to 5 g of 5-(α-bromobutyryl)-8-hydroxycarbostyryl obtained in Examples 38 to 40, heated under reflux for 6 hours, and then concentrated to dryness. Thereafter, in the same manner as in Example 1, 4.2 g of 5-(α-i,soprobylaminoptyryl)carbostyryl-methanol solvate having a melting point of 136 to 137°C (foam decomposition) was obtained.

Example 43 50 g of α-bromobutyric acid bromide, 50 g of anhydrous aluminum chloride, and 400 g of carbon disulfide were added to 20 g of 8-hydroxycarbostyril, and after heating at 50°C for 13 hours, the carbon disulfide layer was removed by tilting, and the residue was Add crushed ice to precipitate crystals. The crystals were taken, washed with running water, and then recrystallized from methanol to obtain 27 g of 5-(α-)t-modityryl)-8-hydroxycarbostyryl [melting point 218-219°C].
(colored decomposition)], and this 5-(α-bromobutyryl)
Add isopropyladenone 100- to 5 g of -8-hydroxycarbostyril, heat at 50°C for 4 hours, concentrate to dryness, add water and precipitate crystals t-F, wash with running water and recrystallize from methanol. 4.6 g'i of hydroxy-5-(α-isopropylaminobutyryl)carbostyryl-methanol solvate are obtained.

Melting point: 136-137°C (foam decomposition).

Example 44 25 g of 2-7-ethylamine was added to Example 38.39 or 4.
It was added to 5 g of 5-(α-bromobutyryl)-8-hydroxycarbostyryl prepared in step 0, and the mixture was stirred at a temperature of 30° C. for 8 hours. A mixture of diethyl ether and petroleum ether was added to the reaction mixture, and the precipitated material was dissolved in dilute hydrochloric acid to remove insoluble material. Concentrate the hydrochloric acid layer, precipitate, and recrystallize from ethanol to obtain a melting point of 200-201
°C (color decomposition) t-substance that has! 5.3.9f, obtained.

The material thus obtained was subjected to NMR spectral analysis, engineering R spectral analysis and elemental analysis.
2-7enethylamino)]]butyryl-8-hydroxycarbostyryl hydrochloride dihydrate.

Example 45 Morpholine 5d was prepared in Examples 38 to 40 with 5-(α
-bromobutyryl)-8-hydroxycarbostyryl 5
g and the mixture was reacted for 4 hours at a temperature of 40° C. with stirring. The reaction mixture was then concentrated under reduced pressure, and 100 ml/l of water was added to the resulting residue. The mixture was stirred and heated, and then the mother F solution was concentrated under reduced pressure. The residue was dissolved in amethane, and the solution was exposed to F to remove insoluble materials. Then p
The liquid was concentrated under reduced pressure, the pH was adjusted to 2-3 with concentrated hydrochloric acid, and the precipitate formed by cooling in a water bath was recrystallized from ethanol to obtain a white amorphous 5-, having a melting point of 179-182°C (decomposed).
2.1 g of (α-morpholinobutyryl)-8-hyroxycarbostyryl hydrochloride monohydrate was obtained. The product thus obtained was confirmed by NMR spectral analysis, engineering R spectral analysis and elemental analysis.

Example 46 α-promopropionyl chloride t7.1.9', anhydrous aluminum chloride 27g and nitrobenzene 81111
t-8-methoxy-3,4-dihydrocarbostyryl 8
g and the mixture was heated at 50°C to 60°C for 1 hour while stirring.
The reaction mixture heated to a temperature of 200 mL was then poured onto 200 d of ice-water and the precipitate formed was washed with water. The precipitate was then recrystallized from ethanol to a melting point of 154°C ~
11.5 g of material having a temperature of 155° C. was obtained. The product thus obtained was confirmed to be 5-(α-bromopropionyl)-8-methoxy-3,4-dihydrocarbostyryl by NMR spectroscopy, engineering R spectroscopy, and elemental analysis. did.

Example 47 26.4 g of α-promozotyrylbromide, 17.5 g of anhydrous aluminum chloride and 5 d of nidogastric benzene were added to 5 g of 8-methoxy-3,4-dihydrocarbostyryl,
The mixture was heated to a temperature of 50-60 DEG C. for 1 hour with stirring. The reaction mixture was then poured into 100 d of ice-water and the precipitate formed was washed with water. The precipitate was then recrystallized from ethanol to yield 5 g of material with a melting point of 151-152°C. The product thus obtained was analyzed by NMR spectral analysis, engineering R spectrum analysis and elemental analysis) 5-
(α-promozotyryl)-8-methoxy-a,4-:)
It was confirmed that it was hypocarbostyril.

Example 48 5-(α-bromopropionyl) produced in Example 46
-8-methoxy-3,4-dihydrocarbostyryl 2g
T-improper tool 50 and suspension with 6
The mixture was stirred for 2 hours at a temperature of 0°C. The solvent is then distilled off,
The resulting residue was dissolved in 5011 liters of Improper Tool. This solution was then adjusted to pH 2-3 Kml with concentrated hydrochloric acid. The formed precipitate was added to the tF solution, a mixture of acetone and diethyl ether, every few minutes. Collect the formed precipitate tF,
Recrystallized from isopropanol, melting point 172-174℃
1.59 f of a white amorphous substance having (decomposition) was obtained. The product obtained in the above manner was determined to be 5-(α-
isopropylaminopropionyl)-3-methoxy-3
．． It was completely confirmed that it was 4-0 hydrocarbostyryl hydrochloride dihydrate.

Example 49 5-(α-bromopropionyl) obtained in Example 46
-8-Methoxy-3,4-dihydrocarbostyryl 51
After suspending it in isopropanol 50117, 16 g' of tert-butylamine was added, and the mixture was stirred at 60°C for 15 hours. The solvent is distilled off, the residue is dissolved in inopro2-nol 10-, and concentrated hydrochloric acid is added to adjust the pH to 2-3. Add precipitate t'' to the furnace. Add acetone to liquid F, and then separate the resulting precipitate further in a furnace. Add ether to liquid F and collect precipitate t-F. Recrystallize with inpro 2-nol-ether, melting point 207. ~2
A colorless amorphous substance 2.19f is obtained at 10° C. (decomposition). Based on the analysis results of NMR, engineering R, and elemental analysis, this product is 5-(α-tert-butyramidub is pionyl)-8
-Methoxy-3,4-dihydrocarbostyryl hydrochloride 1
Confirm that it is a hydrate.

Example 50 5-(α-promozotyryl)-8 obtained in Example 47
-Methoxy-3,4-dihydrocarbostyryl 2Ii'
After suspending the mixture in isopropanol 50-, isopropylamine 5II'e was added, and the mixture was stirred at 60°C for 4 hours. The solvent is distilled off and the residue is dissolved in isopropanol 51, and then concentrated hydrochloric acid is added to adjust the pH to 2 to 3.

The precipitate eF was collected and recrystallized from isopropanol-acetone to obtain a colorless amorphous substance with a melting point of 204-206°C (decomposition).1. 7 II'e get. This one is NMR. Based on the results of engineering R and elemental analysis, it was confirmed to be 5-(α-improbylaminozotyryl)-8-methoxy-3,4-dihydrocarbostyryl hydrochloride monohydrate.

Example 51 5-(α-Zolomozotyryl)-8 obtained in Example 47
-Methoxy-3.4-9 Hydrocarbostyryl 39 was suspended in Impropatool 5oR1, then 9 g of tert-butylamine was added and stirred at 60'C for 19 hours. After distilling off the solvent and dissolving the residue in Inproper Tool 51111, salt production is carried out! Add to adjust the pH to 2-3. Precipitate 1--Furnace separation Acetone is added to the F solution, and then the formed precipitate is further furnace-separated. Add ether to the F solution and collect the precipitate kF. A colorless amorphous substance that recrystallizes from Improper Tool and has a melting point of 160-162°C (decomposition).1. 6 Get 11f. Based on the analysis results of NMR%IR and elemental analysis, this product has a
It is confirmed to be (α-tert-dztylaminoptyryl)-8-methoxy-3,4-dihydrocarbostyryl hydrochloride monohydrate.

Example 52 5-(α-inpropylaminopropionyl)-8-me)-? obtained in Example 49 Sea 3. 1.5 g of 4-0 hydrocarbostyril in 15 wJ of 47% hydrobromic acid
1g dissolved in Ll 30 to 140"Cte1 Heat under reflux for 5 hours. Concentrate the reaction solution and add acetone to crystallize. Recrystallize from ethanol to 70% to give a melting point of 22
1.1 g of material at 3-226°C (decomposed) is obtained. This product was found to be 5-(
It is identified as α-isopropylaminopropionyl)-8-hydroxy-3,4-Q hydrocarbostyryl hydrobromide.

Example 53 5-(α-isopropylaminobutyryl)-8-medoxy 3.4-:)hydrocarbostyryl 1.59f:4
Dissolve 915ml of 7% hydrogen bromide at 130-140℃
The reaction solution was heated under reflux for 5 hours, concentrated, and acetone was added to crystallize it. Recrystallization from ethanol-acetone yields 1.11t of a substance having a melting point of 165-168°C. This product was found to be 5-(
α-Inpropylaminobutyryl)-8-hydroxy-
Confirmed as 3,4-dihydrocarbostyryl hydrobromide i-hydrate.

Example 54 5-(α-tert-butylaminopropionyl)-8-methoxy-3,4-dihydrocarbostyryl 1ge47% obtained from the hydrochloride monohydrate prepared as described in Example 49 Dissolved in hydrobromic acid 15-140-150
Heat to reflux for 15 hours at 20°C.

Reaction solution t- Concentrate and add acetone to crystallize.

Recrystallized from ethanol-acetone, melting point 224-227
Obtain 0.79f of material at °C (decomposition). This one is NMR,
From the analysis results by IR and elemental analysis, 5-(α-ter
tw7'thylaminopropionyl)-8-hydropoxy-
Confirmed as 3,4-s) hydrocarbostyryl hydrobromide monohydrate.

Example 55 5-(α-tert-butylamitunotyryl)- obtained from the hydrochloride monohydrate prepared as described in Example 51.
8-Methoxy-3,4-dihydrocarbostyryl 1. !
Dissolved in 1t47% hydrogen bromide 915m at 140-150℃
Heat under reflux for 19 hours.

Concentrate the reaction solution and add acetone to crystallize it.

Recrystallized from ethanol-acetone, melting point 144-146
1.11'i of material is obtained at °C (decomposition). This one is NMR
, 5-(α-te
rt-methylaminozotyryl)-8-hydroxy-3,
Confirmed as 4-dihydrocarbostyryl hydrobromide dihydrate.

Example 56 5-(α-promoprohionyl)-8-hydroxy-3
．． 5 g of 4-dihydrocarbostyryl were suspended in 30-mg of benzene, and this suspension was mixed with 4.2 d' of morpholine.
The reaction mixture was then reacted for 4 hours while heating under reflux.The reaction mixture was filtered, and the F solution was washed with water and concentrated under reduced pressure to remove remaining water.The resulting residue was diluted with inzolopanol. 50-, and the solution was adjusted to pH 2 ~ with concentrated hydrochloric acid.
Adjusted to 3. A viscous precipitate formed by water bath cooling was separated and dissolved under heating in acetone. After cooling the solution, the precipitate formed was dissolved in 30 mj of water and adjusted to pH 7.5-8 with sodium bicarbonate. Precipitate formed by water bath cooling? F was removed, dissolved in a 47% aqueous hydrogen bromide solution IQm, and then concentrated under reduced pressure. The residue thus obtained was washed with ethanol 10- and recrystallized from ethanol to give a white amorphous 5-
(α-morpholino)-propionyl-8-human aco-
3,4-dihydrocarbostyryl hydrobromide monohydrate 2.6. I got f'.

Example 57 Two days benzene 3 (Hrl and chloroacetyl chloride 7
0m+/1-1-Methyl-8-methoxycarbostyryl (40 g) and 130 Jl of aluminum chloride were gradually added thereto while cooling the mixture in a water bath, and then the mixture was allowed to react at a temperature of 60° C. for 4 hours with stirring. The reaction mixture was then poured into 11 g of ice water to precipitate the product. The precipitate t-F was collected, washed with diethyl ether, and recrystallized from a mixture of chloroform and ethanol (2:5 volume ratio) to give a white amorphous 1-methyl-5-chloro having a melting point of 204-205.5°C. 32.9 tons of acetyl-8-methoxycarbostyryl were obtained. The product thus obtained was confirmed by elemental analysis, R spectrum analysis and NMR spectrum analysis.

Example 58 Nitrobenzene 4-Od and monochloroacetyl chloride)
'12m was added to 7.4 g of 1-methyl-8-hydroxycarbostyryl, to which 20 g of aluminum chloride was gradually added while the mixture was cooled with ice water, and then the mixture was kept at a temperature of 60 °C for 18 hours with stirring. The reaction mixture was then poured into 500 ml of ice water to precipitate the product. The precipitate t-F was collected, washed with diethyl ether, and recrystallized from a mixture of ethanol and dimethylformamyl (x: volume ratio) to give white amorphous 1-methyl having a melting point of 287-289°C (decomposed). -5-chloroacetyl-8-
Hydroxycarbostyril 2.8p? Obtained.

The product thus obtained was confirmed by elemental analysis and IR and NMR spectroscopy.

Example 59 1-chloroacetyl-8-methoxycarbostyryl produced in Example 57 2.79 t Inproper Tool 40d
9gt of isopropylamine was dissolved in the solution and heated to a temperature of 55-60°C for 9 hours.
added. After the addition was complete, the mixture was stirred and allowed to react for up to 1 hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in isopropanol 4011j. Then the solution'k
Filter to remove insoluble substances, and adjust solution F to pH 2~ with concentrated hydrochloric acid.
Adjusted to 3. The mixture was cooled in a water bath and the precipitate formed
-F was collected and recrystallized from ethanol to obtain white amorphous 1-
Methyl-5-inpropylaminoacetyl-8-methoxycarbostyryl hydrochloride was obtained. The product thus obtained was confirmed by elemental analysis and engineering R spectrum analysis.

Example 60 Isopropylamine 10ml1'C Manufactured in Example 59 L7
1.11 of 'cl-methyl-5-chloroacetyl-8-hydroxycarbostyryl was added and the mixture was reacted for 2 hours at a temperature of 35° C. with stirring. The reaction mixture was concentrated under reduced pressure and dried by azeotropic distillation with ethanol. The resulting residue is dissolved in 20° C. of ethanol and the solution is filtered to remove the insoluble material, which is then dissolved in hot ethanol. The solution was adjusted to pH 2-3 with concentrated hydrochloric acid and cooled in a water bath. The precipitate formed was dissolved in 20'111 of water taken from ff1F. Adjust the solution to pH 6.5-7.5 with sodium bicarbonate,
The precipitate formed was recrystallized from ethanol to a melting point of 136~
1.1 g'i of white amorphous 1-methyl-5-isopropylaminoacetyl-8-hydroxycarbostyryl was obtained at 138°C (decomposed).

Example 61 1-Methyl-5-isopropylaminoacetyl-8-methoxycarbostyril hydrochloride prepared in Example 592.
0g' was dissolved in 47% aqueous hydrobromic acid and heated in an oil bath at a temperature of 120-130°C for 8 hours under reflux. 101 ml of water was added to the reaction mixture and then concentrated by distillation. 1 oil of water was added to the mixture again, and then concentrated. After the mixture was cooled, the precipitate tF formed was collected and dissolved by heating in 60 ml of water. The resulting solution was adjusted to 1H6,5-7.5 with sodium bicarbonate and a precipitate formed.
I took it. The precipitate was reconstituted from ethanol with a melting point of 136-1.
White amorphous 1-methyl-5- with 38°C (decomposition)
Isopropylaminoacetyl-8-hydroxycarbostyryl o, 4sl? -I got it.

Example 62 5-inpropylaminoacetyl-8 obtained in Example 54
-Hydroxy-carbostyril hydrochloride 1, Ogi water 40
ml, add 0.5 g of palladium on carbon as a catalyst, heat to 35-40'C, and completely absorb hydrogen while stirring.

When the reduction is completed, the catalyst YF is separated and the F liquid is completely concentrated to dryness under reduced pressure. Further, ethanol is added and the mixture is repeatedly concentrated to dryness to completely remove water, and then a7ton is added to the residue for crystallization. Residue tethanol-acetone (volume ratio 1:1
) recrystallized to give a pale yellow amorphous 5-(2-yn/!opyramid/-1-
0.4 g of hydroxy)ethyl-8-hydroxycarbostyril hydrochloride is obtained.

Example 63 5-(8)-Dithylaminoacetyl-8-hydroxycarbostyryl 2.0 p'i is dissolved in 100 d of methanol, and 0, sgv of sodium boron hydride is gradually added under water-cooled stirring. After stirring at the same temperature for 15 minutes, stir at room temperature for 1 hour. Add concentrated hydrochloric acid to pH 1.5-2
After that, the solvent gold was distilled off under reduced pressure. Add ethanol 301 to the residue
Add Llt- and dry under reduced pressure again to remove moisture. Anhydrous ethanol 501111 is added to the residue to dissolve it, and an ethanol solution of sodium hydroxide is added to adjust the pH to 7 to 8.5. The precipitate 't-F is separated, and the F solution is dried under reduced pressure. The residue is extracted with absolute ethanol 5017, and hydrogen chloride gas is passed through the extract. After concentrating to dryness under reduced pressure, the residue was recrystallized from inopropyl alcohol to give a melting point of 143-144°C.
(decomposition) of pale yellow amorphous 5-(1-hydroxy-2-
1.3 g of see-phthylamino)ethyl-8-hydroxycarbostyryl dihydrochloride monohydrate are obtained.

Example 64 5-tart-butylaminoacetyl-8-hydroxycarbostyryl obtained in Example 10 1.5. ! i't-
Dissolve in 100 methanol and gradually add 0.71 m of sodium boron hydride while stirring with water cooling. Stirring was carried out at the same temperature for 15 minutes and then stirred at room temperature for 1 hour.The same treatment as in Example 10 was carried out to obtain pale yellow amorphous 5 having a melting point of 242-244°C (decomposition) and recrystallized from ethanol. −
(1-Hydroxy-2-tart-butylamino)ethyl-8-hydroxycarbostyryl hydrochloride 0.9 g'i
obtain.

Example 65 2.0 g of 5-piperidinoacetyl-8-hydroxycarbostyryl hydrochloride prepared in Example 2 was dissolved in methanol 2001j!, and while cooling the solution in a water bath, sodium borohydride 2y2.oy+ Add then 2 parts of the mixture
Stir for hours. Adjust the mixture to pH 2-3 with concentrated hydrochloric acid,
The mixture was allowed to stand at room temperature for 1 hour and then treated with F. The treated reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 301 ml of ethanol. The solution was filtered to remove insoluble substances, and solution F was concentrated under reduced pressure.

These operations (dissolution in ethanol, filtration and concentration)?
Repeated 3 times. The obtained residue was heated and dissolved in acetone, and upon cooling, the precipitate eF formed was collected and recrystallized from isozorono (nol, melting point 146-148°C (decomposition)'f!:
White amorphous 5-(1-hydroxy-2-piperidino)ethyl-8-hydroxycarbostyryl hydrochloride with 1
- hydrate is obtained; the product thus obtained is IR
Confirmed by spectrum analysis, NMR spectrum analysis, and elemental analysis.

Example 66 5-morpholinoacetyl-8-hydroxycarbostyryl produced in Example 13 1. Ogt methanol 100-
Sodium borohydride y1 is dissolved in this solution.
．． 2y+ was added and the mixture was then reacted for 2 hours with stirring. 1. The reaction mixture was adjusted to pH 2-3 with concentrated hydrochloric acid, mixture f was left at room temperature for 1 hour, and then reaction mixture eF was added.
FW, t-concentrated under reduced pressure. The residue was dissolved in ethanol 2017, this solution was t-filtered to remove insoluble materials, and then F
fit-concentrated under reduced pressure. This operation (dissolving in ethanol,
Filtration and concentration) were repeated three times and the residue thus obtained was recrystallized from acetone. Precipitated crystal t-
The soluble substances are removed by filtration through a sieve with an aqueous solution of sodium bicarbonate @ 20°C, and the insoluble substances are washed with water and dissolved by heating in ethanol.

The resulting solution was adjusted to I)H2-3 with concentrated hydrochloric acid, and the precipitate formed by cooling was collected to obtain a solution with a melting point of 157-3.
White amorphous 5-(1-
Hydroxy-2-morpholino)ethyl-8-hydroxycarbostyryl hydrochloride IT hydrate was obtained. The product thus obtained was confirmed by IR spectral analysis, NMR spectroscopy and elemental analysis.

Example 67 Methanol 5 oyy is added to 5 g of the free base of 5-benzylaminoacetyl-8-hydroxycarbostyryl prepared in Example 14, and this solution is slowly added to it under water bath cooling and stirring. The mixture was then stirred at room temperature for 1 hour. The resulting mixture was adjusted to I)H1 with concentrated hydrochloric acid, and the precipitate formed was separated by F. Solution F was concentrated to dryness and crystallized from acecin. The pH of the obtained crystals was adjusted to g with an aqueous sodium hydroxide solution, and the formed precipitate was collected in F and washed with water. Adjust the precipitate to pH 1 with dilute hydrochloric acid.
and concentrated to dryness. The residue thus obtained was recrystallized from a mixture of methanol and acetone to a melting point of 1.
4.2 g'i of white amorphous material with a temperature of 20-121°C was obtained.

The product thus obtained was subjected to NMR spectrum analysis, engineering R spectrum analysis, and elemental analysis. 7% 5-(
It was confirmed that it was 1-hydroxy-2-benzylamino)ethyl-8-hydroxycarbostyryl hydrochloride dihydrate.

Example 68 1 g of 5-(1-7enethylaminoacetyl)-8-human xycarbostyril hydrochloride produced in Example 14? This solution was dissolved in 50-methanol and made weakly alkaline with a methanol solution of sodium hydroxide.Then, 0.5 gt of sodium borohydride was added to this mixture while cooling in a water bath, and then the mixture was heated for 1 hour at room temperature. I stirred it up. p
A precipitate formed by adding concentrated hydrochloric acid until H3 was separated from PF and PR' was concentrated and dried. The resulting residue was dissolved in pure ethanol and the solution was adjusted to pH 9 with an ethanolic solution of sodium hydroxide. Separate the precipitate t-F,
Solution F was concentrated and dried. The residue was crystallized from acetone,
Washed with water. The obtained crystals were dissolved in inproper tool, saturated with hydrochloric acid gas, and then cooled. The formed precipitate was collected by F and recrystallized from Improper Tool to a melting point of 16.
0.77 gt of white amorphous substance with a temperature of 2-164°C
Obtained. The product thus obtained was analyzed by NMR spectral analysis, engineering R spectral analysis and elemental analysis.
1-hydroxy2-(1-phenethylamino)]-
Ethyl 8-human 90 xycarpos f! It was confirmed that it was JktUR salt dihydrate.

Example 69 Platinum oxide 0. II and sQmg of water 0.5 g of 5-benzylaminoacetyl-8-hydroxycarbostyryl hydrochloride dihydrate prepared in Example 14 and the mixture was heated at room temperature under atmospheric pressure in a hydrogen atmosphere for 24 hours with stirring. It was returned in After completion of the reduction, the catalyst was separated from the furnace, and the aqueous layer was concentrated and dried. The residue was recrystallized from a mixture of methanol and acetone to give white amorphous 5-(1-hydroxy-2-amino)ethyl-, with a melting point of 261-262°C (decomposed).
0.25 gt of 8-hydroxycarbostyril hydrochloride was obtained. The product thus obtained was confirmed by MR spectroscopy, NMR spectral analysis and elemental analysis.

Example 70 5-(1,1-s>methyl 7enethylaminoacetyl)
5 g of -8-hydroxycarbostyryl L was dissolved in 50 ml of t-methanol, and 1 g of sodium bophydride was added to this solution while stirring under ice-water cooling, and stirring was then continued for an additional hour at room temperature. The resulting mixture was then pH-adjusted with concentrated hydrochloric acid and the mixture was concentrated to dryness. The residue was dissolved in ethanol and cine-soluble substances were removed by F separation. The ethanol layer was concentrated to dryness and the residue was dissolved in inopropanol. This isosolpanol layer was concentrated and acetone was added to crystallize the product. The product was recrystallized from methanol-acetone to give a white amorphous material 1.4.9'i with a melting point of 167-168°C (colored decomposition). The substance thus obtained has an NMRx-! ! #)5-(2-
It was confirmed that it was (1,1-dimethylphenethylamino)-1-hydroxy]ethyl-8-hydroxycarbostyryl hydrochloride dihydrate.

Example 71 Chloranil z, sy and xylene 20m! Jt"5-(
2.2 g of l-hyroxy2-amino)ethyl-8-hydroxy-3,4-syllocarbostyril were added and the mixture was heated under reflux for 24 hours. The reaction mixture was then concentrated to dryness and the residue was gently washed with carbon tetrachloride. The residue was then dissolved in 30 cJ of methanol and adjusted to pH 1 by introducing hydrochloric acid gas into the solution. The precipitated crystals 'ftF were collected and recrystallized from methanol to yield 1.5 ge of a substance having a melting point of 261-262 DEG C. (decomposed). The product thus obtained was analyzed by NMR spectral analysis, IRx-e spectral analysis, and elemental analysis.
(1-hydroxy-2-amino)ethyl-8-human90
It was confirmed that it was xicarbostyril hydrochloride.

Example 72 Water 2001R1, sodium hydroxide 0.9 g and Raney nickel 4.3.9ffi5-(2-(1,1-dimethyl7enethylami/-1-hydroxy)ethyl-8-hydroxy-a, 4-9hydrocarbostyryl 4.3 g of hydrochloride dihydrate were added and the mixture was heated at 80°C under reflux for 15 hours.
The reaction mixture heated to a temperature of 0 is then filtered to remove the catalyst, liquid F is concentrated, and the resulting crystal precipitate is recrystallized from water to produce a substance with a melting point of 167-168°C (decomposed). 2
．． I got 6g of gold.

The thus obtained dwarf product was analyzed by NMR spectroscopy, chemical reaction spectrum analysis and elemental analysis.
] It was confirmed that it was ethyl-8-human 90xcarbostyryl hydrochloride monohydrate.

Example 73 5-isopropylaminoacetyl-8-obtained in Example 34 was treated with 2.0. SF was dissolved in water at 40 rttlfC, and palladium black 0.59 was added as a catalyst and heated to 70-75°C.
9. Absorb hydrogen by stirring under normal pressure.

When the reduction was completed, the catalyst t-F was separated and concentrated to dryness over the F solution under reduced pressure. Further, after completely removing water by pouring ethanol all over, 70% gold was added to the residue and crystallized. Recrystallize with ethanol-acetone (volume ratio 1:1) to obtain a melting point of 19.
1.1 Jl of a colorless amorphous crystal substance having a temperature of 9 to 201°C was obtained. From the analysis results of NMR, IR and elemental analysis, this product was found to be 5-(2-inopropylamino-1-human 90x).
It was confirmed to be ethyl-8-hydroxy-3,4-dihydrocarbostyryl hydrochloride.

Example 74 1.511' of 5-tert-butylaminoacetyl-8-hydroxy-3,4-dihydrocarbostyryl hydrochloride obtained in Example 36 was dissolved in 35% of water and treated with $1.0 ft of palladium charcoal catalyst. Add as 50-60℃, 4-
Shake to 5 atmospheres! ? and absorbed hydrogen. When the reduction was completed, palladium on carbon tF was removed, and FM' was concentrated to dryness under reduced pressure. Add acetone to the residue to crystallize it, and recrystallize it from methanol-acetone (volume ratio 1:1) to give a melting point of 2.
A colorless crystalline substance o,sgt'' having a temperature of 40 to 241°C was obtained.

This product was found to be 5-(2-tart-methylamino-1-hydroxy)ethyl-8-hydroxy-a,4-S>hyrocarbostyryl hydrochloride from the results of NMR, IR, and elemental analysis. confirmed.

Example 75 The 5-sec-butylaminoacetyl-8-hydroxy-3,4-dihydrocarbostyryl obtained in Example 28 was dissolved in 2.0 gt of methanol and dissolved in sodium hydride with stirring under water cooling. o and sy were added gradually.

After stirring at the same temperature for 15 minutes, stirring was continued at room temperature for 1 hour. After adding concentrated hydrochloric acid to pH' (i-1, 5 to 2), the solvent was distilled off under reduced pressure.
was added and dried again under reduced pressure to remove water and gold. 5011 J'lt of absolute ethanol was added to the residue to dissolve it, and an ethanol solution of sodium hydroxide was added to adjust the pH'i to 7 to 8.5. The precipitate was separated in a t-furnace, and Fff' was dried under reduced pressure.

The residue was extracted with 50 d of total anhydrous ethanol, and hydrogen chloride gas was passed through the extract.

After concentrating to dryness under reduced pressure, the residue was recrystallized to 7 tons of total methanol (volume ratio 1:1) as a mixed solvent) with a melting point of 183.
A colorless amorphous material 1.3, f' was obtained at ~184°C.

Based on the analysis results of NMR, IR and elemental analysis, this product is 5-(2-sec-butylamino-1-hydroxy).
It was confirmed that it was ethyl-8-Hominid 3,4-dihyrocarbostyril hydrochloride.

Example 76 0.7 g of Flea Didium Black and 130 d of water were added to 1.5 g of 8-human 90x-5-(α-methylbenzylaminoacetyl) carbostyryl hydrochloride and the mixture was heated at a temperature of 60° C. with shaking. The reaction was carried out under a hydrogen pressure of 4 atm, and the catalyst was
Separated and the aqueous layer was concentrated to dryness.

Product by adding acetone to the residue? crystallized. The product was then washed with ethanol 100- and recrystallized from a mixture of methanol and ethyl acetate to give a white amorphous (2)5-(1
-roxy-2-insylamino)ethyl-8-hydroxy-3,4-thydrocarbostyril hydrochloride o,
The product thus obtained was IR
This was confirmed by spectral analysis, NMR spectral analysis, and elemental analysis.

Example 77 - 0.1 g of ξ radium black and 50 dt of water were added to 5-((1-hydroxy-2-benzylamino)ethyl-8-hyroxycarbostyryl hydrochloride dihydrate, and the mixture was stirred in a hydrogen atmosphere. The reaction was allowed to proceed for 8 hours at atmospheric pressure and room temperature. After the reaction was completed, the catalyst was separated and the aqueous layer was concentrated to dryness. The residue thus obtained was recrystallized from a mixture of methanol and acetone. white amorphous 5
-(1-Hydroxy-2-amino)ethyl-8-hydroxycarbostyryl hydrochloride 0.21- was obtained. The product thus obtained was confirmed by IR spectral analysis, HMR spectral analysis and elemental analysis.

Example 78 0.7 I of palladium black and 100 d of water were added to 4 g of 5-(α-benzylaminoacetyl)-8-hyperoxycyto-3,4-dihydrocarbostyryl hydrochloride, and the mixture was heated to 4 atm. Reduction at a temperature of 60"C under hydrogen pressure.

After completion of the reduction, the catalyst t-F is separated and the resulting aqueous Fgt-
Concentrate and dry. 77 tons of gold was added to the residue to crystallize the product. The crystals thus obtained were mixed with 100% ethanol.
d and recrystallized from a mixture of methanol and ethyl acetate to give white amorphous 5-(1-hydroxy-2-7mino)ethyl-8-hydroxy-a,4-9hirocarbostyryl hydrochloride. Obtained 0.711. The product thus obtained was confirmed by IR spectral analysis, NMR spectral analysis and elemental analysis.

Example 79 0.05 g of platinum black and 100 dffi of water were added to 5-((1'' nitroxy-2-7mino)ethyl]-8- and 1 g of deμxycarbostyril hydrochloride, and the mixture was heated at 50° C. for 10 min with shaking. The reaction mixture was reduced at 2 atmospheres of hydrogen pressure for 1 hour.

After completion of the reduction, the catalyst t″F was separated and the aqueous layer was concentrated to dryness. The precipitate thus obtained was recrystallized from a mixture of total methanol and acetone to give white amorphous 5 with a melting point of 270-272°C. -((1-Hydroxy-2-amino)ethyl-3,4-u human 0-locarbostyril hydrochloride 0.9 g in 8-hydrohydride was obtained. The product thus obtained was dIR spectral analysis and Confirmed by NMR spectroscopy and elemental analysis).

Example 80 Add 0.5 g of palladium black and water 5Qd'1z5-(1-hydroxy-2-opylamino)ethyl-8-human 90 chrysanthemum carbostyril 2I, shake the mixture,
while reducing at a temperature of 70° C. under a hydrogen atmosphere at atmospheric pressure. After completion of the reduction, the catalyst was separated by F and the aqueous layer was completely concentrated and dried. The precipitate thus obtained was recrystallized from a mixture of methanol and acetone to give a white amorphous 5-(1-
2-isopropylamino)ethyl-8-human-3,4-dihydrocarbostyril hydrochloride 1
．． 7gt-obtained. The product thus obtained is
Confirmed by spectral analysis, HMR spectral analysis and elemental analysis).

Example 81 Palladium black 0.1.9 and water 30wLtffi5-(
(1-human0roxy2-sec-butylamino)ethyl]
-8-Hiro was added to cicarbostyryl ig and the mixture was reduced with 3 atmospheres of hydrogen pressure at a temperature of 60C for 10 hours with shaking. After completion of the reduction, the catalyst t-F was separated and the aqueous layer was completely concentrated and dried. The resulting precipitate was recrystallized from a mixture of methanol and acetone to give 5-(1-hydroxy-2-sec-butylamino)ethyl-8-hydroxy-3,4-dihydrocarbostyryl hydrochloride. 67
I got 7 f.

The product thus obtained was subjected to industrial spectroscopy analysis, NMR spectroscopy analysis and elemental analysis.

Example 82 10% palladium on carbon 0.59 and water 50dt''5-
((1-hi)””?s/-2-MX-zofk7?/)ethyl]-8-)11 oΦcicarbostyril hydrochloride 1
．． 5pK was added and the mixture was incubated at 75°C for 16 hours with shaking.
was reduced at a temperature of 5 atmospheres of hydrogen pressure.

After completion of the reduction, the catalyst tF was separated, and the aqueous layer was concentrated and dried. The nine precipitates thus obtained were recrystallized from a mixture of total methanol and a7ton to form white amorphous 5-(1-hyroxy-2-sec-butylamino)ethyl-8 having a melting point of 240-241'Cff1. -Hydroxy-3,4-dihydryl carbostyril (1.1t) was obtained. The product thus obtained was confirmed by MR spectroscopy, 1'iMR spectroscopy and elemental analysis.

Example 83 Palladium black 100η and water 50μ Total 5-(1-Hroxy2-(x,
00 and the mixture t-2 for 8 hours at a temperature of 45-50 °C.
．． Reduction was carried out at a hydrogen pressure of 5 atmospheres. Catalyst t-F separate p
The liquid was concentrated and dried. The residue was recrystallized from water to give a melting point of 120.
A white amorphous material 2601111Pt-121°C was obtained. The product thus obtained was determined to be 5-1-hydroxy-2-(1,1-dimethylphenethylamino) by NMR spectral analysis, chromatographic analysis and elemental analysis.
It was confirmed that it was ethyl-8-hydroxy-3,4-S)hyrocarbostyril hydrochloride dihydrate.

Example 84 Platinum oxide 0.2, f and water 5 Q1111i5- (
1,1-tmethylphenethylaminoacetyl)-8-hydroxycarbostyryl hydrochloride-hydrate 1. lK added,
The mixture was reduced at a temperature of 80° C. and a hydrogen pressure of 5 atmospheres for 20 hours. After removing the catalyst tF, the F solution was concentrated and dried.

The resulting residue was recrystallized from water to give a melting point of 120-121"
A white amorphous substance having C1-O, Bt was obtained. The product thus obtained was determined by NMR spectroscopy, engineering R spectroscopy and elemental analysis.
-(1,1-dimethyl7enethylamino)ethyl-3,
It was confirmed that it was 4-dihydrocarbostyryl hydrochloride heptahydrate.

Example 85 1.59 t of cicarbostyril hydrochloride in 5-bisazinoacetyl-8-oxy 0 was dissolved in 100 d of water, 0.5 g of nocerazicum carbon and 0.2.91 g of palladium black were added to the solution, and then The resulting mixture was heated to 70°C with shaking.
Catalytic reduction was carried out under atmospheric pressure in a hydrogen atmosphere for 4 days at a temperature of . After completion of the reduction, the reaction mixture was filtered and the catalyst was concentrated and dried under reduced pressure. The resulting residue was dissolved in 70% of the solution by heating, and then the solution was cooled. Recrystallized from the precipitate formed on cooling, completely inpropatol, yields a white amorphous 5-(2-1veridino-1-and-droxy)ethyl-8-hydroxy having a melting point of 136-139°C (decomposition). 0.8 g of 3,4-dihydrocarbostyryl hydrochloride heptahydrate was obtained. The extended R spectral analysis and NMR spectrum of the product obtained in this way were confirmed by vector analysis and elemental analysis.

Example 86 47% aqueous solution of zopmic acid 10jljt5-(1-hydroxy-2-inopropylamino)ethyl-8-methoyaciccarbostyril hydrochloride monohydrate III and mixture t-
It was heated under reflux for 15 hours and then concentrated to dryness. A7tone was added to the resulting residue to crystallize the product, which was then adjusted to pH 8 with dilute aqueous sodium hydroxide solution. The precipitated crystals eF were collected, washed with water, and dissolved in ethanol. The solution was adjusted to pH 1.1 with concentrated hydrochloric acid and concentrated to dryness. The residue obtained was recrystallized from a mixture of ethanol and diethyl ether with a melting point of 210-212°C (
Decomposition) 0.79 f of material with t-t was obtained. The product thus obtained was confirmed to be D5-(1-hydroxy-2-isopropylamino)ethyl-8-hydroxycarbostyryl hydrochloride by NMR spectroscopy, R spectrum analysis, and elemental analysis. did.

In the same manner as described in Example 86, the corresponding 8-
The following compounds were obtained from the methoxy compound.

5-(l-2-isopropylamino)ethyl-8-hyaloxy-3,4-lyrocarbostyril hydrochloride with a melting point of 203-204°C (decomposition).

5-(l-Hydroxy-2-tert-butylamino)ethyl-8-hyro-Φcycarbostyryl hydrochloride ihydrate having a melting point of 244-246°C (decomposition).

White amorphous 5-(1- and do-4x-2-be/cylamino)ethyl-8-hydroxycarbostyryl hydrochloride dihydrate with a melting point of 120-121°C.

5-[1-Hydroxy-2-(1,1-dimethylphenethylamino)]ethyl-8-hydroxycarbostyryl hydrochloride monohydrate with melting point 167-168°C (decomposition) Melting point 270-272.5°C (decomposition) ) with 5-(1-
Hydroxy-2-7mino)ethyl-8-hydroxy-3
, 4-dihydrocarbostyryl hydrochloride.

Example 87 Methanol 40idf: 5-(α-isopropylaminobutyryl)-8- and r obtained in the same manner as Example 42 or 43
In addition to tetraxycarbostyril 2.9, the resulting solution was
? : 25.9% of sodium borohydride was added dropwise to the mixture under stirring while cooling in a water bath, and the mixture was further stirred at room temperature for 1 hour.Concentrated hydrochloric acid was added to the reaction mixture to adjust the pH to 1, and then this mixture was stirred. The precipitate was washed with acetone, dissolved in water, and adjusted to pH 8K1 with an aqueous sodium hydroxide solution to precipitate crystals. Obtained crystal 1
! -Recrystallized from ethanol with a melting point of 141-14
1.8 gK of 5-(1-human0roxy2-inopropylamino)dityl-8-hyroxycarbostyryl hydrate at 2°C (color decomposition) was obtained.

Example 88 5-(α-sec-butylaminozotyryl)-8-hydroxycarbostyryl produced in the same manner as in Example 41 1.51
301 t of methanol was added to the solution, and 2 y of sodium borohydride was added to the resulting solution while stirring under cooling in a water bath.
x, 5 g was added in small portions.

Stirring was continued for an additional hour at room temperature. The reaction mixture was then adjusted to pH 1 with concentrated hydrochloric acid and then concentrated to dryness. The precipitate was collected, washed with acetone, dissolved in water and adjusted to pH 8 with aqueous sodium hydroxide solution. The precipitated crystals tF were collected, washed with water and redissolved in dilute hydrochloric acid. The resulting solution was concentrated to dryness and recrystallized from precipitated ethanol to give a solution having a melting point of 182-183°C (foam decomposition).
(1-hydroxy-2-sec-butylamino)dityl-8
-Hiroxycarbostyryl hydrochloride monohydrate 1.39'
I got 1g.

Example 89 fc5-(α-
Tetrahyroalane 20d@: was added to 1 g of impro-2-hydraminobutyryl)-8-hydrocarbostyryl hydrochloride, and the resulting mixture t1 tetrahyrofuran 10- was added with 0.12 g of lithium aluminum ramino1iry! The suspension containing e was added dropwise to Fujicon at room temperature with stirring, and after one drop had been added, a small amount of water was added to the reaction mixture to decompose the excess lithium aluminum hytriyt.Next, the reaction mixture t50- The aqueous layer of the resulting solution was poured into ice water and the aqueous layer was separated and concentrated to dryness. The crystals were precipitated by tF and then recrystallized from ethanol to give a melting point of 141-1.
0.8 g of 5-(1-hydroxy-2-inopropylamino)dityl-8-hyroxycarbostyryl monohydrate having 42° C. (color decomposition) was obtained.

Example 90 1.59 ml of the free base of 5-α-(2-7enethylamino)butyl-8-hydroxycarbonyl prepared analogously to Example 44 was dissolved in 150 Il of methanol and the solution was stirred under ice-water cooling. To this, sodium borohydride 2) was gradually added, and stirring was continued for an additional hour at room temperature.The resulting mixture was then adjusted to pH 1 with hydrochloric acid, and the mixture was heated in an oven to form a mixture. The precipitate was removed.Fa
The mixture was concentrated to dryness and the residue was crystallized by adding acetone. Next, an aqueous solution of sodium hydroxide (M) was added to the crystals until the pH reached 8, and the formed precipitate was collected and recrystallized from ethanol to yield 13 g of a white amorphous substance having a melting point of 147-148°C (foaming decomposition). I got it. The substance thus obtained was analyzed by NMR spectroscopy, IR spectroscopy and elemental analysis.
It was confirmed that it was 2-7enethylamino)butyl-8-hydroxycarbostyryl trihydrate.

Example 91 In addition to 25 g of Chlora JS and 2.5 g of xylene, The mixture was heated for 24 hours. The reaction mixture was concentrated to dryness, the residue was gently washed with 50 ml of carbon tetrachloride, the residue was then dissolved in 39 ml of methanol, hydrochloric acid gas was introduced into this solution until the pH reached 1, and then it was cooled. Precipitated crystals t-F are taken and recrystallized from methanol to produce a substance having a melting point of 164-166°C (decomposed) 1.5. F
t- got it. The product obtained in this way was analyzed by 11 MR spectrum analysis, MR spectrum analysis and elemental analysis.
)5-(1-human0roxy2-inprepylamino)
It was confirmed that it was propyl-8-hydroxycarbostyryl hydrochloride hydrate.

Compound t below was also prepared from the corresponding 3,4-dihyrocarbostyryl compound in the same manner as described in Example 91 above.

5-(1-Hydroxy-2-M2zotylamino)butyl-8-hyto90xycarbostyryl hydrochloride l-hydrate with a melting point of 182-183°C (decomposed).

5-(1-human 0
Roxy-2-ditylamino)phthyl-8-hydroxycarbostyryl hydrochloride.

Example 92 A 47% aqueous solution of hydrobromic acid (1017') was added to 5-((1-HirO+C2-isopropylamino)propyl)-8-methoxycarbostyryl hydrochloride monohydrate II, and the mixture was refluxed. The mixture was heated for 15 hours and then concentrated to dryness. Acetone was added to the resulting residue to crystallize the product, which was then adjusted to pH 8 with dilute aqueous sodium hydroxide solution.

The precipitated crystals tF were collected, washed with water and dissolved in ethanol. This solution was adjusted to pH 1 with concentrated hydrochloric acid and concentrated to dryness. The residue thus obtained was recrystallized from a mixture of ethanol and diethyl ether with a melting point of 164 to
166°C (decomposition) yielded 0.777 t of material.

The product thus obtained was analyzed by NMR spectral analysis, engineering R spectral analysis, and elemental analysis.
hirroxy2-isopropylamino)propyl-s
-to-y roxycarbostyryl hydrochloride t-a
Approved.

In the same manner as in Example 92, the following compound was obtained from an 8-methoxy compound of the corresponding structure.

5-(1-human 0-roxy-2-inopropylamino)dityl-8-hydroxyfucarbostyryl hydrochloride with a melting point of 213-214°C (decomposed).

Example 93 5-(α-yne!ropylaminopropionyl)-8-hydroxy-3,4-dihydrocarbostyryl obtained from hydrobromide ihydrate prepared as described in Example 53. i, oy'l dissolved in methanol 50- and cooled with water. It- Add slowly and stir for 1 hour at room temperature. Methanol saturated with hydrogen chloride gas is added to adjust the pH to 1-2. By precipitate tP, F
Concentrate the liquid to dryness. Add IN sodium hydroxide aqueous solution Kw to pH 7.5-8 and collect the ridge precipitate 'ThF. The precipitate is dissolved in ethanol and then hydrogen chloride gas is blown into it. The precipitate tF was collected, recrystallized with ethanol, and the melting point was 21.
0.8Ii of material with a temperature of 1-213°C is obtained. This one is NMR
.

From the analysis results by engineering R and elemental analysis, 5-(2-yne7'0pylamino-niehtooxy)propyl-8-
Human Nikki 3,4-dihydrocarbostyryl hydrochloride I
Confirm that it is a hydrate.

Example 94 5-(α-isopropylaminobutyryl)-8-human carbostyryl 3.4--,'carbostyril 1.0Ii
Add ether/-#20m and 5g of platinum oxides and reduce at 60"C under 2 atmospheres of hydrogen pressure for 10 hours. After the reaction, separate the catalyst 'kF, add concentrated hydrochloric acid to solution F to adjust the pH to 1, and concentrate. Dry. Recrystallize the residue from ethanol to give a melting point of 196.
~198°C substance 0.9IIf: obtained. This one is NM
From the analysis results by R, IR and elemental analysis, 5-(2-inpropylamino-1-hyoxy)zotyl-8-
Hiroxy3.4-dihyrocarbostyril hydrochloride 1
Confirm that it is a hydrate.

Example 95 5-(α obtained from the corresponding monohydrate made in Example 54)
-tert-zotylaminopropionyl)-8-human o
To 1.0 g of dPcy 3,4-dihydrocarbostyryl hydrobromide were added 500 g of water and 0.2 pt of perdium black, and the mixture was reduced at 60° C. under normal pressure for 20 hours. Post-reaction catalyst tF
Separate and concentrate to dryness.

The residue was recrystallized from ethanol and had a melting point of 198-199°C.
0.75 g'i of (decomposition) material is obtained. This one is NMR
, 5-(l-hydroxy-2-tert-butylamino)propyl-8 from the analysis results by IR and elemental analysis.
-Hydroxy 3.4-dihydrocarbostyryl hydrobromide l-hydrate.

Example 96 95-(α
-tart-butylaminobutyryl)-8-human9px-3,4-0hirlocarbostyryl hydrobromide 1.
Add 50 kg of water and 0.29 kg of palladium black to 0 g, and reduce at 80°C under normal pressure for 10 days.

After the reaction, the catalyst 'tF was separated and vg, 'tm was condensed to dryness. The residue was recrystallized in ethanol and had a melting point of 164-166℃ [
0.7f/decomposition] was obtained. This one is NMR.

Based on the results of IR and elemental analysis, it was confirmed to be 5-(1-hydroxy-2-tert-butylamino)dityl-8-hydroxy-3,4-N human 0-locarbostyryl hydrobromide (ethanol solvate). .

Example 97 2 g of 5-(α-inpropylaminobutyryl)-8-hydroxycarbostyryl, 0.1 g of palladium black, and 5 QiA of ethanol! The mixture was stirred under a hydrogen pressure of 35 atm and at 75° C. for 15 hours to carry out the reduction reaction. Catalyst after reaction
-F is separated, and a prepared salt is added to adjust the pH to 1, and the mixture is concentrated to dryness. The resulting precipitate is recrystallized from ethanol to give 5-(i-hydroxy-2-inpropylamino)dityl-8-roxy-3,4-dihyrocarbostyryl hydrochloride hydrate with a melting point of 196-198°C. Get 1.7g1&.

Example 98 5-(α-inpropylaminobutyryl)-8-human 3
9.05 g of platinum black per 0,000 tg of cicarbostyril hydrochloride,
Add water IQQd and hydrogen pressure is 40 atm.

Mix and react at 60°C for 18 hours. After the completion of the reaction, the catalyst was removed and concentrated to dryness to give a precipitate, recrystallized from isopropanol, with a melting point of 196-19.
0.85.94' of 5-(l-hyroxy-2-inpropylamino)butyl-8-human90x-3,4-dihyrlocarbostyryl hydrochloride l hydrate is obtained at 8°C.

Example 99 0.5 g of 5-(α-1-butylaminobutyryl)-8-hydroxycarbostyryl and 0.025 g of radium black
g, 15 ml of ethanol was added, and the mixture was stirred and reacted at a hydrogen pressure of 50 atm and 80°C for 15 hours. After the reaction was complete, the catalyst was removed, and the resulting reaction solution was adjusted to pH 1 with concentrated hydrochloric acid, and then concentrated. The precipitate was dried and then recrystallized from ethanol to give 5-(l- and rμx-
2-butylamino)dityl-8-hydroxy3.
4-dihydrocarbostyryl hydrochloride-water 111 products 0.4
5 fl' is obtained.

Example 100 5-(l-hydroxy-2-tert-butylamino)
1511 L of 47% hydrogen bromide was added to 1.5 g of propyl-8-methoxy/-3,4-dihyrocarbostyryl, heated under reflux for 15 hours, concentrated to dryness, and acetone was added to crystallize. The crystals were recrystallized from ethanol-acetone and had a melting point of 198-199°C (decomposition), 1.4 gf.
Get f1. This one is NMR.

From the analysis results by IR and elemental analysis, 5-(1-hydroxy-2-tart-butylamino)propyl-8-
It is confirmed to be Hominid xy3.4-dihydrocarbostyryl hydrobromide l-hydrate.

The target compound of the present invention obtained by the same procedure as in Example 1OO is shown below.

5-[l-Hydroxy-2-morpholinobutyl-8-hydroxy-3,4-dihyrocarbostyril hydrochloride with a melting point of 127-129°C (decomposition).

5-1-hydroxy-, melting point 183-185°C (decomposition)
2-morpholinobutyl-8-human 90x-3,4-dihydrocarbostyryl hydrobromide.

Example 101 5-(α-tert-butylaminozotyryl)-8-hydroxy-3,4-dihydrocarbostyryl 1.09 to water 50
Add 0.2gt of gold and palladium black to the mixture t″80℃
It is reduced at atmospheric pressure for 10 days at a temperature of . After completion of the reduction, the catalyst t-F was separated, and the F solution was concentrated and dried. The resulting residue was recrystallized from ethanol to obtain 0.79f of a substance with a melting point of 164-166°C (decomposed). The product thus obtained: NMR spectral analysis, R spectral analysis and elemental analysis KLD5-(1-hydroxy-2-tert-butylamino)phthyl-8-hydroxy-3,4-dihydrocarbostyryl hydrobromide It was confirmed that it was a salt (as "-//-rualheit").

Example 102 5-(2-morpholinobutyryl)-8-human90x-
3,4-dihydrocarbostyryl hydrobromide 1.0g
i Dissolved in 701 ml of water and added 0.0 ml of palladium on carbon to this solution.
2 g of palladium black and 0.3 g' of palladium black were added and the mixture was then catalytically reduced under atmospheric pressure under a hydrogen atmosphere at a temperature of 70° C. with shaking for IO days. After completion of the reduction, the reaction mixture was filtered to remove the catalyst, and the solution F was concentrated and dried under reduced pressure.The resulting residue was dissolved in acetone by heating, and then the solution was cooled. A precipitate formed on cooling; recrystallized from ethanol; white amorphous 5-(1-hyroxy-2-morpholino)methyl-8-hyroxy-3,4-dihyde having a melting point of 183-185°C (decomposition); 0.7 g of tetracarbostyryl hydrobromide hydrate was obtained. The product thus obtained was confirmed by NMR spectroscopy and spectroscopy and elemental analysis. .

Example 103 0.45 g of the free base of cicarbostyryl in l-methyl-5-inzolobylaminoacetyl-8-hydro prepared in Example 59 was dissolved in methanol 501 and the WI
0.211" of sodium borohydride was slowly added to the solution while stirring under water bath cooling. Stirring was continued for an additional hour, and the resulting reaction mixture was brought to pH with concentrated hydrochloric acid.
Adjusted to 2-3. The formed precipitate is then removed by F.
Concentrate the liquid under reduced pressure.

The residue was dissolved in 20 liters of ethanol. The solution was filtered to remove other materials, the filtrate was concentrated under reduced pressure, and 2 ovt of ethanol was added to it and then filtered to remove insoluble materials. Solution F was concentrated under reduced pressure to remove the ethanol-soluble substances remaining in the residue in addition to the residue containing 400ml of ethanol.
Washed twice and recrystallized from ethanol, melting point 202~2 (
White amorphous l-methyl-5-(
0.3 g of (1-hydroxy-2-isopropylamino)ethyl-8-hydroxycarbostyryl hydrochloride was obtained. The product thus obtained was confirmed by IR spectroscopy, NMR spectral analysis and elemental analysis.

Example 104 1-Methyl-5-isopropylaminoacetyl-8-hyroxycarbostyryl hydrochloride 1 gt suspended in water, injected with radium carbon o, tg
The mixture was then polycatalytically reduced with hydrogen at a temperature of 60-70° C. and atmospheric pressure for 25 hours. After completion of the reduction, the reaction mixture was treated with f:F and concentrated and dried under reduced pressure with Fffe. The resulting residue was recrystallized from a7ton and then from ethanol to give white amorphous 1 with a melting point of 196-197°C (decomposition).
0.3 gt of methyl-5-((1-hydroxy-2-isopropylamino)ethyl]-8-hydroxy-3,4-dihydrocarbostyryl was obtained. The product thus obtained was It was confirmed by hard curl analysis, NMR spectrum analysis and elemental analysis.

Example 105 5-Impropylaminoacetyl-8-methoxycarbostyryl, og = i, dissolved in 50 methanol and gradually added 6 g of sodium borohydride to it with stirring under cooling in a water bath. Then, the mixture was stirred at room temperature for 1 hour, and the reaction mixture was diluted with concentrated hydrochloric acid.
The precipitate formed was separated by F. Liquid F was concentrated and dried, and crystallized from the obtained crystal t-acetone. Product t Recrystallized from ethanol, melting point 230-231"C (decomposition)
The substance o, 5IIt was obtained. The product thus obtained was determined by NMR spectrum analysis, IR spectrum analysis and elemental analysis of p5-(1-hydroxy-2-inopropylamino)ethyl-8-methoxycarbostyryl hydrochloride.
It was confirmed that it was a hydrate.

Example 106 5-inpropylaminoacetyl-8-methoxy-3,
4-dihydrocarbostyryl 21-methanol 70ml
Sodium fluorine/9) e-lye F'l gt'' was gradually added to the solution 1' while cooling with ice water, and then stirred for an additional L hour at room temperature.The reaction mixture was adjusted to pH with concentrated hydrochloric acid.
1, formed and separated into 9 plates. The filtrate was condensed and dried with tlI, and the resulting residue was recrystallized from ethanol to a melting point of 2.
06-208°C (decomposition) 1.5.9 't'' of substance was obtained. The product dNMR thus obtained was analyzed by chromatographic analysis, engineering R spectrum analysis and elemental analysis!!115-
(1-hydroxy-2-isopropylamino)ethyl-
It was confirmed that it was 8-methoxy-3,4-dihydrocarbostyryl hydrochloride.

Example 107 5-(2-inophtetrapylamino-1-hydroxy)ethyl-8-hydroxycarbostyryl hydrochloride 3 gt water 20
1111j and add 0 sodium hydroxide to this solution.
．． Added 99f. Next, 1.3 g of dimethyl sulfate was added dropwise while cooling the solution in a water bath, and the mixture was stirred for 1 hour.

The mixture was stirred for 2 hours at a temperature of 40-50°C and the reaction mixture was extracted with chloroform. The chloroform extract was washed with water, dried, and hydrochloric acid gas was introduced into the chloroform extract. The precipitated crystals were crystallized from a mixture of ethanol and acetone to yield 2.3 g'i of a material having a melting point of 235-237°C (decomposed). The product thus obtained was found to be 5-(l-hydroxy-2-isopropylamino)ethyl-8-methoxycarbostyryl hydrochloride hydrate according to 11MR spectroscopy, engineering R spectrum analysis and elemental analysis. I confirmed that.

Example tOS 5z(1-Hydroxy-2-isopropylamino)ethyl-8-hydroxy-3,4-dHydrocarbostyril 2.6 g' was dissolved in 30-ml of water and sodium hydroxide was added to this II. Added 0.459. While cooling the solution in an ice bath, 1.39 g of dimethyl sulfate was added dropwise to the solution, and the mixture was stirred for 1 hour. The reaction mixture was stirred at a temperature of t-40 to 50°C for 2 hours and extracted with chloroform. The chloroform extract was washed with water, dried, and hydrochloric acid gas was introduced into the chloroform extract. Precipitated crystals tethanol≠λ are recrystallized and have a melting point of 206-208°C (decomposition)%2
．． I got 211. The product thus obtained is NM
J5-(1-hydroxy-2-isopropylamino)
It was confirmed that it was ethyl-8-methoxy-3,4-dihydrocarbostyryl hydrochloride.

Example 1/9 47% aqueous hydrobromic acid solution 101/'tl-methyl-5-
(1-hydroxy-2-isopropylamino)ethyl-
8-Methoxy-3,4-dihydrocarbostyryl hydrochloride lhydrate IN was added and the mixture was heated under reflux for 15 hours and then concentrated to dryness. Acetone was added to the resulting residue to crystallize the product, which was then adjusted to pH 8 with dilute aqueous sodium hydroxide solution. The precipitated crystals eF were collected, washed with water and dissolved in ethanol. The solution was diluted to pE with concentrated hydrochloric acid.
I was adjusted to 1 and concentrated to dryness. The residue thus obtained was recrystallized from a mixture of ethanol and diethyl ether to obtain a substance having a melting point of 198-200°C (decomposed). The product thus obtained was identified as i-methyl-5-(1-eyroxy-2-inpropylamino) by NMR spectroscopy, XR spectroscopy and elemental analysis.
It was confirmed that it was ethyl-8-hydroxy-a,4-:)hydrocarbostyryl hydrochloride.

The excellent pharmacological action of compound (1) obtained from the novel intermediate according to the present invention will be specifically explained by the following examples.

Example 110 The stimulatory activity of compounds of the invention on β-adrenergic receptors was determined as follows. Mixed-breed adult males weighing 10-55 kg - Q, anesthetized with intravenous administration of bentoparbital sodium at 30#v/kg body weight
Six dogs were anesthetized, their backs were stabilized, and canicole tubes were inserted into their tracheas. 7)) - V Tsu*ler method (Kon
zett H, & Roessler R, “Vers.
uchsanordnug zn Untersuch
Ungen and Bronchial Mo5
Arch, Exp, Pat
H.

Pharmack, I 95. 71-74, 27
Artificial respiration was performed using a device according to 40 (1940). Air flow during inspiration was measured through a pulmonary velocimeter to determine bronchial resistance, and the resulting values were recorded on a pulse recorder.

In the above test, histamine was used as a bronchoconstrictor at a dose level of 9 body weight per 10 kg and an aqueous i'l sample containing each test compound and control as shown in Table IK below.
One minute prior to t-histamine administration, each anesthetized log was dosed through the femoral vein at various dosage levels as shown in the table below. Sodium intobarbicool was infused during the study at a dose level of 49/kg body weight to suppress spontaneous breathing and maintain anesthesia throughout the study period. The obtained crystals are shown in Table 1 below.

Table ■ Bronchial resistance compound 0.010° dose level (μm1/9) )3 0.1 0.3 1.0 3.0 10 30
1007.7 66.6 83.3 100 - -
- -5.5 78.6 90.4 100-- -
-0.0 47.5 87.8 Zoo ----1,
450,085,Otoo---8,785,51
00100---1,714,245,276,4100---1,13
0,563,387,3100---5,528,36
5,889,4100---Furthermore, 1 each before trial
Male rats (da species, body weight 18-20
Ii) Acute toxicity was tested for the test compounds shown in Table H below using 5-6 groups of 10 animals. Salcitamol and isoproterenol were used as upper controls. The LD (50% lethal dose) results were as follows:

Orally, intravenously, intramuscularly or by inhalation, preferably in combination with a carrier or excipient, in pharmaceutically customary dosage forms such as tablets, powders, granules, capsules, syrups, solutions, suspensions, inhalants, etc. It can be administered by any route of administration. Compounds of the invention and dosage forms containing at least one of the compounds of the invention can be administered in single or multiple doses.

Example 111 Prescription of pharmaceutical composition Lactose 55.9 Corn starch 22.9 Microcrystalline cellulose 22 g Methylcellulose-mace 0.8f1 Active ingredient 0.11I The above ingredients were mixed in a conventional manner and press-molded into tablets. 1000 tablets, 7 crops, 99.

Although the invention has been described in detail with reference to specific embodiments thereof, it will be apparent to those skilled in the art that the invention can be modified and expanded without departing from the spirit and scope of the invention. Patent Application Applicant: Yoshinari Higuchi

Claims (1)

[Claims] 1. General formula (wherein R, R and R are each a hydrogen atom, or 1 to 4
represents an alkyl group having 1 to 4 carbon atoms, at least one of R and R is a hydrogen atom, and R and Rd may be the same or different; an alkyl group having a carbon atom, an aralkyl group including a straight-chain or branched alkyl group having 1 to 4 carbon atoms in the alkyl moiety, or a cycloalkyl group having 4 to 6 carbon atoms, and R and R together with the nitrogen atom to which they are bonded form a 5- or 6-membered substituted or unstructured heterocycle containing 1 to 2 nitrogen, oxygen or sulfur atoms as heteroatoms; A novel carbostyril compound object represented by the formula (the carbostyril skeleton is represented by the formula)