JPS6226273A - Isoquinoline derivative and use thereof - Google Patents

Abstract

NEW MATERIAL:The tetrahydroisoquinoline-3-carboxylic acid derivative of formula [R<1> is H, halogen, nitro, OH, etc.; X is CO or SO2; Y is direct bond, alkylene, vinylene, CHR<3>O or OCHR<3> (R<3> is alkyl); R<2> is phenyl or naphthyl, or R<2>-Y-CO is N-benzyloxycarbonylphenylalanyl, N-benzyloxycarbonyl-4- halogenophenylalanyl, etc.]. EXAMPLE:(3R)-2-[N-(4-methyl)-cinnamoyl]-1, 2, 3, 4-tetrahydroisoquinoline-3- carboxylic acid. USE:Agent for imparting absorbability of especially insulin. PREPARATION:The exemplified compound can be produced e.g. by reacting (3R)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride with 4- methylcinnamoyl chloride.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel tetrahydroine quinoline-3-carbic acid derivative and an absorption agent containing the same as an active ingredient. Its purpose is to impart or enhance the absorption of drugs such as insulin.

Prior art Absorption imparting agent V! Phenylalanine derivatives (%Refer to the specification of 1987-190926.)
, pencyl biperanone derivative (JP-A-59-5115
] and hydroquine benzoate derivatives (B
iochimlca et BlophyslcaAc
ta, 775 (I984) 269-271) et al., tetrahytroinquinoline-3- of the present invention
Carbic acid derivatives are different from these, and furthermore, among the existing tetrahydroinoquinoline-3-carbic acid derivatives, none are known to exhibit absorption-enhancing activity.

Problems to be Solved by the Invention When administered orally, polypeptide drugs such as insulin are not absorbed in the intestinal tract due to their inactivation by various proteolytic enzymes in digestive juices and their high molecular weight. Administration methods for such drugs are limited to injections. However, injection administration has drawbacks such as the great physical and mental pain it inflicts on patients during long-term treatment, and in recent years there has been a desire to develop absorbency-imparting agents with low toxicity.

The present invention provides a novel absorption-imparting agent or absorption enhancer containing as an active ingredient at least one of a novel tetrahydro-90-quinoline-3-carbic acid derivative represented by the following general formula (I) 2 and a non-toxic salt of this derivative. Regarding drugs.

However, in the formula, R1 is a hydrogen atom, a halogen atom such as a fluorine atom, a nitro group, a hydroxyl group, or an esterified-protected hydroxyl group, such as a dicarbonyloxy7 group in bennoluo, and X is a C
O or SO□, -Y- is a direct bond, a lower alkylene group, a substituted or unsubstituted vinylene group, such as a fluoroX-substituted vinylene group, or a formula -CnH2-0- or 10-CHR'-
Group represented by ) or an unsubstituted phenyl or naphthyl group, in formula (I), R
2-Y-C0iN-penzyloxycarbnylphenylalanyl, N-pendiheoxycarnonyl-4-octalode/(fil is fluoronephenylalanyl); liN
-(m-methquincinnamoyl)phenyl75nyl group, respectively.

That is, when the above-mentioned tetrahytroine quinoline-3-carbic acid derivative is administered, for example, together with a pharmaceutically active substance, the pharmaceutically active substance is absorbed orally or parenterally (for example, rectally), or its absorption is increased. .

Tetrahydroisoquinoline-3 represented by the above formula (I)
- Carganic acid derivatives may be specific, for example tetrahytroinquinoline-3-carboxylic acid itself or N-acetyltetrahydroisoquinoline-3-carboxylic acid, as well as the lower alkyl of the acid of formula (I). Neither esters nor amides are useful as absorbency-imparting agents.

Tetrahytroinquinoline-3 represented by formula (I)
-Carbic acid derivatives, some of which are known and some of which are new, can be prepared using conventional N-asolation reactions, salt formation processes, and the production examples described below.

Tetrahydroquinoline represented by the following general formula (II)
3-carboxylic acid derivatives or salts thereof are new compounds.

(However, in the formula, R1, R2, and Y have the same meanings as above.) In addition, the tetrahytroinquinoline-3-carbic acid derivative represented by the formula (IO and formula (I)) has an asymmetric carbon The atoms exist, but depending on the combination of substituents, they may be in any of the 8-, 8-, and R8-forms.

The above-mentioned tetrahuman 90-in quinoline-3-carbic acid derivative may be in the form of a salt. For example, metal salts such as sodium, potassium, lyticum, calcium, etc., or organic bases such as ammonia, synchlohexylamine, N-
Examples include salts with basic amino acids such as methyl-D-glucosamine, lysine, and arginine, and pharmaceutically acceptable salts are used for pharmaceutical purposes.

The above-mentioned tetrahytroine quinoline-3-carbic acid derivative or a pharmaceutically acceptable salt thereof may be used together with a pharmaceutically active substance to impart absorption properties, such as oral or parenteral administration.
For example, it can be administered rectally]. For example, in the case of incilin, it exhibits an oral or rectal absorption effect and an inhibitory effect on trinosine and/or chymotrinosine, which are proteolytic enzymes that degrade incilin.

In particular, among the incilin therapies for diabetes, oral or rectal administration of incilin has not yet reached the level of practical use, and there is a clinical need to develop agents that improve incilin administration absorption, which is highly safe even for long-term use. Therefore, there are extremely high expectations for the present invention.

Furthermore, the toxicity of the above-mentioned tetrahydroine quinoline-3-carboxylic acid derivatives is low, for example, (3R)-2-(N-(4-
'Methyl)-cinnamoyl:] -1,2,3゜LD5゜ when 4-tetrahytroinquinoline-3-carginic acid (S-2) was orally administered to mice was 3.01/A.
It is greater than or equal to y.

The above-mentioned pharmaceutically active substances include, for example, two or more substances that can form a spatial arrangement that allows non-covalent interaction with the adjuvant (tetrahytroine quinoline-3-carbic acid derivative or its salt). Examples include polypeptides or derivatives thereof in which hydrophobic amino acid residues are present in close clusters at one or more locations, and analogs of these regions.

Furthermore, as a specific example, water-soluble spherical tongue 1? Those that have a collection of hydrophobic amino acid residues on their surface (insulin, insulin-like growth factor I (IGF-I), insulin-like growth factor II (IGF-II), pancreatic polypeptide, etc.); two The above-mentioned hydrophobic amino acid residues exist adjacently or in close proximity to each other in a cyclic form9; Examples include those in which hydrophobic amino acid residues are located close to each other or clustered together at one or more locations.

The absorbability of the drug used in the present invention is 25 units of a drug, such as insulin. Q: 0.1 to 2.000n19, preferably 0.2 to 500.

The absorption agent and the pharmaceutically active substance can be used, for example, in the form of tablets, capsules, elixirs, microcapsules or suspensions.

The tetrahydroinquinoline-3-calanoic acid derivative of the present invention can be used in combination with the above-mentioned medicines for patients who require treatment. The dosage range of 50.1.1.0007# can generally be administered in several divided doses at a total daily dose of 0.2 to 2.000 Da per day. Dosage will vary depending on the severity of the disease, the weight of the patient and other factors recognized by those skilled in the art.

Typical combinations set forth above are formulated into pharmaceutical compositions as discussed below. The compound or admixture of the phenylalanine derivative or physiologically acceptable salt used in the present invention is a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavoring agent. and the like in unit dosage form as required by generally accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage within the indicated range will be obtained.

Specific drugs that can be mixed into tablets, capsules, etc. are shown below. Binders such as triglycerides, gum aragilla, cornstarch or gelatin; Excipients such as microcellulose; Leavening agents such as cornstarch, pre-gelatinized starch, alginic acid etc.; Lubricant such as magnesium stearate. sweeteners such as sucrose, lactose or saccharin; -2 flavoring agents such as permint, redberry oil or cherry; and when the dosage unit form is in a capsule, in addition to materials of the above type, liquids such as fats and oils; A carrier may be included. Various other materials can be present as coatings and to otherwise modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar or both. Sirot f''! or elixir contains the active compound, sucrose as a sweetening agent, methyl and f'' as a preservative.
+: Can contain 2-biruparaben, dyes and flavoring agents such as cherry or orange flavor.

In particular, it is preferable to use enteric-coated preparations for insulin, for example, 8% hydroxyphenylmethylcellulose.
An aqueous solution may be used as a coating pretreatment agent, and a 10% aqueous solution of hydroxyclovir methylcellulose phthalate 1.

Specific examples of the tetrahydroin and nolino-3-carboxylic acids used in the present invention are as follows.

S-7(3S)-2-(N-(I-naphthoxy)-acetyl]-1,2,3,4-tetrahyto90inquinoline-3-carboxylic acid The following examples describe the present invention in detail.MfJK explain.

Examples Example 1 (Production of -1, S-2, S-3, 8-4°S-5, 8-6, 8-9 and 5-10) (3R) -1,2, 3,4-Tetrahydroinoquinoline-3-carboxylic hydrochloride 8y and NaOH3-41 were dissolved in a mixed solvent of 220 ml of water and 180 tnl of acetone, and cooled at 10°C. 6.4 g of an acetone solution and 14 ml of a 10% NaOH solution were alternately dropped over 30 minutes. After stirring for 30 minutes at room temperature, the reaction solution was made acidic with hydrochloric acid, extracted with methyl acetate, and the resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained after distillation under reduced pressure was recrystallized with aqueous methanol to obtain the target product (S-1) as needle-like crystals of 6.79 (yield:
64%).

Other compounds were similarly produced.

Example 9 (Production of S-7,8-8,8-11 and 5-12) (3S) -1,2,3,4-tetrahydroisoquinoline-3-carzenic acid methyl ester hydrochloride 6.0
g1l-ethylamine 2.99 Tochloroform 12
01JK was dissolved, and 156ge of α-naphthoxyacetic acid hydroxythrinoneimide ester was added thereto. After stirring for 3 days at room temperature, the reaction solution diluted with ethyl acetate was diluted with IN.
It was washed successively with hydrochloric acid, 10% HaHCOs solution, and saturated saline, and dried over anhydrous sulfuric acid. The residue obtained after distillation under reduced pressure was separated and purified by silica gluchromatography,
From the toluene:ethyl acetate (9:1) eluate, (38)
-2-[N-(I-naphthoxy)-acetyl)-
1,2;3,4-tetrahydroisoquinoline-3-cal? 7.8 J of amorphous acid methyl ester was obtained.

Next, the above methyl ester 5.9! i is acetone 1
00ffL? Dissolve 401WJK in water and add 2N N in it.
Drop 9.5M aOH. After stirring at room temperature for 30 minutes, the reaction solution was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer obtained was washed with saturated brine and dried over anhydrous sodium sulfate.

The residue obtained after evaporation under reduced pressure was crystallized with acetone-ethyl ether to obtain 4.5J of the desired product (S-7) as prismatic crystals.

Other compounds were similarly produced.

Example 13 Activity test The activator according to the present invention shown in Example 1 was added to 0.5 liters of CMC.
Female ICR-CD
A predetermined amount was orally administered to -1 mice (5 to 7 weeks old), and after a predetermined time, the blood glucose lowering rate (%) and the fold increase in blood insulin compared to the control group were measured.

The results are shown in Table 2 below.

In addition, in Table 1, r4HIQcAJ in the structural formula is 1
．． 2,3.4-tetrahydroisoquinoline-3-carmenic acid. In addition, among the breaking values of effectiveness, the upper row shows 1) blood glucose lowering rate (@), and the lower row in parentheses shows 2) the incilin increase fold.

Although an example of oral administration has been described above, the activator according to the present invention exhibits the same activating effect when used in combination with insulin in the form of a normal suppository.

As described in detail above, the present invention opens the door to the practical application of oral or parenteral (for example, rectal) administration of insulin, and its effects are remarkable.

Example 14 Formulation example [Tablet example] Pocket insulin 0.577 g (I5,000 units,
After dissolving in 3011 Lt of 0.05 N hydrochloric acid (zinc content 0.5%), distilled water was added to dilute to 300 TRJ.

Compound S-4 was dissolved in 200 ml of 6F 0.1N sodium hydroxide, and then m pieces were dissolved with 0.1N hydrochloric acid.
．． Adjusted to 5. Next, add phosphate buffer (0.02M).

pH 7.5) was added to dilute to 600 mg.

The whole solution of s-4 was kept at 20° C. and stirred vigorously, and the entire Insuli-yg solution was added dropwise to the solution, and after adjusting the -value to 7.5, it was immediately subjected to freeze-drying.

A tablet was prepared containing 25 mg of the freeze-dried powder, 82 kg of pregelatinized starch, 82 ~ of fine cellulose, and 6 mg of magnesium stearate. Hydroxyphenylmethylcellulose (8%) aqueous solution was used as coating pretreatment 4J, then hydroxypropylmethylcellulose phthalate (I0%) aqueous solution and polyacetyl (3%
) An enteric preparation was prepared using the aqueous solution as coating 4j by a conventional method. In a similar manner, the above tetrahydroisoquinoline-3-cal? Other tetrahydroisoquinoline-3- as described above in place of the acid derivative (S-4)
A force kM7am conductor could be similarly formulated with pre-gelatinized dendon, fine cellulose and magnesium stearate.

[Example of capsule row]

Add 30% of the compound s-6 to 250μ of glacial acetic acid, dissolve by heating, cool to 20°C, and add 21% of s-6 to 250μ of glacial acetic acid.
(52,200 units, zinc content 0.5%) was added and dissolved in small quantities. At the same temperature, all acetic acid was distilled off under reduced pressure.

After pulverizing the solid residue obtained by adding 1 ounce of n-hexane, it was collected by filtration and washed, and the adhering n-hexane was distilled off under reduced pressure.

Further, it was subjected to vacuum drying in the presence of solid sodium hydroxide.

Dry-filled capsules containing 50 to 50 active ingredients? Prepared.

The above dry powder 5oIn9 lactose
149 ~ Magnesium stearate
1mg capsule (size AI) 200m
The ti dry powder (50 .mu.) was made into a 460 powder and then passed through a lactose and magnesium stearate A60 sieve cloth over the powder and then thoroughly mixed. This was filled into one dry gelatin capsule. A part or all of the powder mixed at this time can also be filled as an enteric preparation as described above.

Effects of the Invention From the above results, it can be seen that the tetrahydroisoquinoline-3-cargenic acid derivative used in the present invention is useful, for example, as an absorption-imparting agent or an absorption-enhancing agent for pharmaceutically active substances, particularly insulin.

Claims (1)

[Claims] 1. A tetrahydroisoquinoline-3-carboxylic acid derivative represented by the following general formula (I) ▲ Numerical formula, chemical formula, table, etc. ▼ (I). However, in the formula, R^1 is a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, or an esterified-protected hydroxyl group, X is CO or SO_2, and -Y- is a direct bond, a lower alkylene group, substituted or unsubstituted. vinylene group, or -CHR^3
-O- or -O-CHR^3-, R
^3 is hydrogen or a lower alkyl group, R^2 is a substituted or unsubstituted phenyl or naphthyl group, or formula (I)
In, R^2-Y-CO is N-benzyloxycarbonylphenylalanyl, N-benzyloxycarbonyl-4
-halogenophenylalanyl or N-(m-methoxycinnamoyl)phenylalanyl group, respectively. 2. The following general formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Absorption-imparting product containing at least one of the tetrahydroisoquinoline-3-carboxylic acid derivatives and nontoxic salts thereof as an active ingredient represented by (I) agent. However, in the formula, R^1 is a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, or an esterified-protected hydroxyl group, X is CO or SO_2, and -Y- is a direct bond, a lower alkylene group, substituted or unsubstituted. vinylene group, or -CHR^3
-O- or -O-CHR^3-, R
^3 is hydrogen or a lower alkyl group, R^2 is a substituted or unsubstituted phenyl or naphthyl group, or formula (I)
In, R^2-Y-CO is N-benzyloxycarbonylphenylalanyl, N-benzyloxycarbonyl-4
-halogenophenylalanyl or N-(m-methoxycinnamoyl)phenylalanyl group, respectively. 3. The absorbency-imparting agent according to claim 2, wherein the target compound to be absorbed is insulin.