JPS584749A - Aminobenzylamine derivative, manufacture and use as drug - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed Description of the Invention] The invention relates to aminopencil, amines, and uses thereof, more specifically, novel 4-aminobenzylamine derivatives, analogous compounds 2, salts thereof, methods for producing these compounds, and compounds containing these compounds. The present invention relates to pharmacological compositions and the use of these compounds as medicines, especially hyperglycemic agents.

The present invention is particularly applicable to the formula [■]: [wherein R1 is hydrogen, halogen, 01-C4 alkyl or 01-C4 alkoxy, R2 is hydrogen, halogen, 01-C4 alkyl, C1 (where A is oxygen, sulfur, carbonyl or a direct bond, R8 and 9 each individually represent water, halogen, C
1-C4 alkyl ti is C1-C4 alkoxy), R3 is hydrogen-! Take01~C4 alkyl, n is 0.1 dimension or 2. 1 (4 is C4, -C24 alkyl, R5 is hydrogen, 01-C24 alkyl or a truncated group physiologically decomposed to a hydrogen atom, R6 and 7 are each individually hydrogen, 01-here B
(6C, ~C6 alkylene' 10 and R11 each independently represent hydrogen, halogen, 01-C4 alkyl or 01 to 04 alkoxy), or a vine group that is physiologically decomposed into hydrogen atoms. Each nitrogen-containing thread is mutually exists in the meta or puff position.] or its pharmacologically acceptable acid addition sound, and a pharmacological composition containing it mixed with a pharmacologically acceptable carrier or diluent. It is something that provides something.

Haloken includes fluoro, chloro or pro-7, and the alkyl moiety may be any branched or unbranched group.

Compound CI of the present invention exhibits pharmacological activity. In particular, these compounds have been shown to be effective in hyperglycemia, especially in oral starch tolerance tests.
As shown in Table 1, postprandial hyperglycemia can be suppressed.

The above test was conducted on a male winter nut (Mkollie Wistar).
Royal-Hart 1-71-dozen (Royal-Hart 1-71-dozen in New York)
3reeders). ) is used. Before using the test animals - fast overnight (16 hours).

One hour after orally administering the carrier (05% carpogysimethylcellulose (CMC) or water) - (control administration substance consisting of carrier or carrier and drug 125 to 200 to 9) to the foot, Give a starch load (2.5 g/9 of boiled wheat starch in 5% water).

Thirty minutes after starch administration, the foot is anesthetized by intraperitoneal injection of Thorium Heginbarbital (1207I'&/KS'), followed by cardiac puncture and heparin (1,000 unit/me) 0.1mt
CV blood is collected by collecting blood in a test tube containing -2.

Using this heparin-treated blood, the blood sugar concentration is measured using an automatic analyzer. The mean value of change in blood sugar after oral starch loading (Flu-4 to 8 animals/treatment group) is compared with the mean value of change in the control group, and the bar seven points of blood sugar change are calculated. In this test, the I': D5o value (dose to suppress hyperglycemia by 50% after starch loading) of Compound Pool 1 (described later) was determined to be 93.7 "!?/ It was 9.

Because it has the above-mentioned active properties, the uninvented compound is useful as a hyperglycemic agent, particularly as an inhibitor of postprandial hyperglycemia in diabetic patients.

Suitable daily doses indicated for treating hyperglycemia (particularly postprandial hyperglycemia) are about 200-300011'
fl', which is divided into 50 to 1500ηl.
-gfJ divided into 92 to 4 doses per day or delayed-release administration -tg type, especially in the case of postprandial hyperglycemia, administered appropriately in three divided doses after meals.

Therefore, the invention is not based on a method for suppressing hyperglycemia by administering the compound CI), and for use as a drug for reducing hyperglycemia (in particular, as an inhibitor for postprandial hyperglycemia). Compounds can be provided for therapeutic treatment of reeds/moss or animals.

The compound CI) of the present invention can be administered in the free base form or in the form of a wide range of pharmaceutically acceptable acid addition salts, such as its hydrochloride. The η-yucal salt has the same degree of pharmacological activity as the free base.

As mentioned above, the uninvented compound CI) can contain a group that can be decomposed biologically into a hydrogen atom. Such a group converts the tertiary amino moiety into a ni-amino moiety, such as 7J1]water)ヅ"drug" under the conditions encountered in the patient's gastrointestinal tract. 1 (which may be of the J:jIf class known to form scientifically acceptable derivatives. Conversion of such groups occurs particularly in the stomach, by hydrolytic enzymes such as esterases and amidases. Representative examples of such groups include carboxymethyl, 11kM alkanoyl, succinyl, 1-striasulfo(low i)alkyl, 1-(sodiumsulfo)polyhydroxyalkyl, and 1,3-vinu(striium). sulfo)aralkyl (herein, aryl may be phenyl, naphthyl, alkanoyl, or a group having a prime number of 2 to 6). They can be introduced into the final product sequentially or simultaneously, thereby providing reactive amino group protection for selective introduction.

Uninvented compounds [■] or their chemically acceptable acid addition salts can be mixed with chemically acceptable diluents or carriers, and if necessary, other excipients. It can be administered in the form of oral preparations such as tablets, elixirs, capsules, and suspensions, or as solution injections or suspension injections.

Preferred pharmacological compositions from the standpoint of ease of drug manufacture and administration are solid compositions, particularly tablets and solid-filled or liquid-filled capsules.

4-(N-methylhexadecylamine) in the present invention
Benzylamine has not, to the best of our knowledge, been shown to have a useful medicinal activity.

Therefore, the novel compounds in the present invention are limited to the compounds represented by the following formulas [■,] among the compounds [■]. The present invention relates to compounds such as '1J)71) and their salts (
In particular, acid addition salts) can be provided.

[In the formula, 1 (1 is hydrogen, halogen, 01-C4 alkyl'! * Irl C1-C4 alkoxy, R' is hydrogen, halogen, C1-C4 alkyl, C1 group (where A is oxygen, sulfur, carbonyl or direct bond, R8
and R9 are hydrogen, halogen, 61~C
4 alkyl or C4 alkoxy), 3 is hydrogen or C] ~C4 alkyl, n is 0.1 or 2, / R4 is C4 alkyl or C4 alkyl or R'62 and ■ ('7 are each individually hydrogen, CI''2
4] 3 is 01-C6 alkylene, "10 and R11
each individually represents hydrogen, halokene, C1-C4 alkyl (41), C1-C4 alkoxy), or a group that is physiologically decomposed to a hydrogen atom. Each of the nitrogen-containing threads exists in the meta or nogu position with respect to each other. However, when R4 is Kahegizadecyl, R5 is methyl, and n = Q, RR'
Less of RR and R7 ■I 21 3+
6 At least one is a group other than hydrogen. ].

This unexploded new compound [T,] has the formula [■]: [wherein, k
and I ('7 has the same meaning as above.) and an amine represented by the formula [■]: [wherein k'1 to l ('5 and n have the same meaning as above.
represents a group that can be eliminated. ] By reacting the compound shown in ! :V can be obtained.

This reaction operation can be carried out under the usual conditions for such types of reactions. Examples of groups that can be eliminated include halogen (for example, chloro, bromo or iodo), and alkyl ti is arylsulfonyl (for example, l-syl).

Also, /R/ and 1 (7 is hydrogen, n is Or,
616 The novel compound [■,] has the formula (lv) [wherein R'i, R'2. R', i Okobigin has the same meaning as above. ] It can be obtained by reducing the compound shown below.

The aromatic nucleus of the above compound CIV) is treated with a metal hydride to avoid total reduction of the 21-lyl functional group, for example by treatment with a metal hydride, taking into account any changes in other substituents on the ring, or Alternatively, it is possible to perform a catalytic hydrogenation treatment to reduce the compound [1v) (r) to the corresponding compound [■,].

The method for producing the compound [IV
l, in an inert organic medium (e.g., a cyclic ether such as TrlF) under substantially anhydrous conditions at moderate temperatures (e.g., about 10-70'C1).
In particular, a method of treating with a hydrogen-containing metal reducing agent such as an alkali metal aluminum hydride derivative (for example, lithium aluminum hydride) at a temperature of about 20 to 30''C is preferred.

Compounds [TO> and [■] are known or can be produced by conventional methods.

Compound [1v] is disclosed in the literature, for example Belgian Patent No. 87
No. 0.687゛, Derwent Apse 1-Lak I (
DerwenL AbsLracL) 23,959
4r! is known from B or, if not known, in the literature regarding the production method of known compounds. It can be manufactured by a method similar to the method of slicing. For example, compound (IV:
l can be manufactured.

It is understood that compounds having primary amines 3i can be converted into the corresponding secondary and tertiary amine compounds, for example by reductive amination and then optionally introducing further alkyl groups according to conventional methods. Should.

Known compounds of formula CI] can be prepared similarly:
Wear.

The compound CI)- or [], ] of the present invention can be purified to a slightly higher degree by a conventional method. The compound of Kouen et al. may be recovered as its acidic acid 11 salt. Yuma II'? 、A阜；ノf't
! - f or acid addition salt type compounds are
They can be manufactured or converted into each other and pushed one forward.

All preferred r substituents in compound CI) of the present invention are as follows: R1-(a) CH3, (+)) I-1+t2-r-
t R3-(a) CH3, (b) H n = (al O, (1) l 1 R4-(a) 64-C24 alkyl, (b) C8-C2
o alkyl, (C)012-018 alkyl R5-(al ■, (1)] CI-C47 alkyl,
(C) 64-C24 alkyl, (d) C8-C2o alkyl, (e) C12-C18 alkyl R6-(a) I-1, (+) Ic8-C2o argyl R
7-(a)111(1))08-C2o Alkylalkyl group is preferably a non-branched group.

A preferred group that is physiologically degradable is C1-C4 alkanoyl (eg acetyl). If R5 and/or R7 are physiologically decomposable groups, these groups (preferably only one) are at the same time alkanoyl.

The two nitrogen-containing groups of compounds CI) and [■,] are preferably present in alternate positions with respect to each other.

Combinations of these favorable groups are of particular interest.

In the compound of the present invention [f,], U, R2, Ra, R6 and 7 are hydrogen, n is 0.1 (4 is alkyl having 4 to 24 carbon atoms, R5 is hydrogen, or physiologically equivalent to a hydrogen atom). Compounds that are non-degradable groups are specific compounds.

Within this group of compounds, preference is given to those compounds in which R1 is hydrogen and/or 4 is an unbranched group having 8 to 20 carbon atoms and 7 or 5 is hydrogen.

These groups can be applied to the preferred CI1 (compound CI) as described above, and if appropriate, these groups can be added to the compound [■,
] can be applied.

The following two compounds are particular compounds of interest: 4-
Hexdecylaminobenzylamine and 4-(N-methylhegisadecylamino)benzylamine.

Next, a method for producing a preferred non-inventive compound will be described in detail with reference to Examples.

Example 1 4-Decylaminobenzylamine (Compound 1)
(i) Preparation of 4-hegisadecylaminobenzyl bromide (4) Into a solution of 3.47 y of [N-n-hexadecylamino]benzyl alcohol and 50% of dry tetrahydrofufurine,
Triphenylfomefine 526y and tetrabromomethane 666y are added at 0°C and the mixture is stirred at room temperature for 2-3 hours. Water was added to this and the resulting mixture was extracted five times with methylene chloride.

Combine the methylene chloride extracts, wash twice with water, and add 1 ml of anhydrous sulfuric acid.
- Dry with aluminum, filter, and evaporate the '/p solution to dryness. The resulting residue was purified by flash chroma I from methylene chloride.
4-hexadecyl aminobenzyl bromide is obtained by processing Kufufi.

ji) Preparation of 4-hexadecylaminobenzylamine Add 4.109 drops of 4-hexadecylaminobenzyl bromide to a solution of 100 methanol saturated with ammonia (containing about 3.49 ammonia) and add 7 JIl of the mixture. 18-241R at room temperature? Stir for a while. The solvent was evaporated under reduced pressure to obtain 1 crude product. The product is purified by rapid filtration of the salt in 1-methylene over silica gel. Melting point 67-70'C.

Example 2 4-hexadecylaminobenzylamine (compound 1)
Preparation of 4-hexadecylaminobenzoni I. In a 21 four-headed round-bottomed flask equipped with a mechanical stirrer, a 41 inlet and a nitrogen inlet tube, dimethylamide amide (1 ) MA ) 600 m/" After adding 21.0 g (0.43 mol) of 1150% sodium hydride,
50 g (0.42 mol) of 4-aminobenzonitrile D
Add MA2QQm/solution. After stirring the mixture at room temperature for 05 hours, 129.2 g of 1-bromohexadecane (
A solution of IIMA3QQmZ (0.42 mol) is added dropwise and the mixture is stirred for a further 16 hours.

The reaction mixture was poured into water, and the precipitate kP was collected and air-dried.

The air-dried solid material is dissolved in methylene chloride, dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. The resulting brown solid solid is recrystallized from hexane and purified to obtain 4-hexadecyl aminobenzonitrile.

Melting point 60-61.5 °C0 (iil) Preparation of 4-hexadecyl aminobenzylamine Two units attached with a knee addition funnel, reflux cooling heat and mechanical stirrer
1. In a 4-necked, 9-bottomed flask, add 1 lithium aluminum hydride.
2.0. f (0,31 mol) and T I (F 1000,
．． 1: Put it in. This was then stirred and P-hexadecylaminobenzonitrile 55y (016 mol) was added.
Add all drops of r 11 F 5 Q Q mt solution gf.

The mixture is refluxed for 5 hours and stirred for a further 16 hours at room temperature.

The reaction mixture was decomposed by adding 400 g of a saturated aqueous solution of sulfuric acid, and extracted several times with ether.

The ether extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure.
The resulting residue (title crude product) was crystallized from acetonitrile to obtain pure title product.

Melting point: 67-70°C6 Using appropriate starting materials to prepare compounds having the substituents shown in Table 1, they were treated according to the general method described above and the same procedure as in Example 1 or 2, and the compounds shown in Table 1 were obtained, respectively. The following compound [1] was obtained.

In the table, the two nitrogen-containing groups (R4) (''5) N-groups in the product [[] shown in the left column are present at the 4-position, and are at the para-positions of each other.

Claims (1)

[Claims] Formula 1 CI, ): [wherein R' is hydrogen, halogen 7, C1-C4 alkyl or C1-C4 alkoxy, k' U hydrogen, halogen, C1-C4 alkyl, C1
2. (where A is oxygen, sulfur, carbonyl or a direct bond, Rs 2 and 9 are each independently hydrogen, halogen, 61-C4 alkyl or 01-C4 alkoxy)
, R' is hydrogen or 01-C4 alkyl, n is 0, IY
m is 2; k'4 is C4NC24 alkyl; R5 is hydrogen; , C1-C24
B is C1-C6 alkylene, Rlo and R11 each individually represent hydrogen, Hiffgen, C1-C4 alkyl or C1-C4 alkoxy), or a radical that can be physiologically decomposed into a hydrogen atom. . Each nitrogen-containing group is present in the meta or para position with respect to each other. If R4 is hexadecyl, I (5 is methyl, n-0, R1, R2,
At least one of R3, R6 and R7 is a group other than hydrogen. ] Compounds represented by or their acid salts. 2. R2, R3, R6 and R7 are each hydrogen, n is 0, R is an alkyl having 4 to 24 carbon atoms, and R5 is hydrogen or a vine group that can be physiologically decomposed into a hydrogen atom, Claim 1 Compound of record 1 defeat. 3. The compound according to claim 2, wherein 3I is hydrogen, R4 is an unbranched group having a prime number of 8 to 20, and/or R5 is hydrogen. 44-hexadecylaminobenzylamine. Formula 5 [■]: An amine represented by: [In the formula, k1 to R7 and n have the same meanings as in the first term. X represents a group that can be eliminated. ] React the compound represented by the formula, or reduce the compound represented by the formula [■] when R′3゜ and R′7 are each hydrogen and n is O, and liberate the obtained compound. 2. A method for producing the compound according to item 1, wherein the compound is recovered in the form of a base or an acid addition salt thereof. Formula 6 [■]: [In the formula, kl is hydrogen, halogen, C1-C4 alkyl or 01-C4 alkoxy, R2 is hydrogen, halogen, 01-C4 alkyl, C1 group (where A is oxygen, sulfur, carbonyl) or a direct bond, R8 and 9 are each individually hydrogen, halogen, C
N6 alkyl or C1-C44 alkoxy), R3 is hydrogen or C1-C4 alkyl, n is 0.1 or 2, R4 is 04-0247'' and 5 is hydrogen, C1-C24 alkyl or physiologically hydrogen atom R6 and R7 are each individually hydrogen, 01 to B here
represents C1-C6 alkylene, R10 and R11 each independently represent hydrogen, halogen, 01-C4 alkyl or 01-C4 alkoxy), or a radical that can be physiologically decomposed to a hydrogen atom. Each nitrogen-containing group is present in the meta or para position with respect to each other. A pharmaceutical composition comprising a compound CI) or a pharmacologically acceptable acid addition salt thereof, mixed with a pharmacologically acceptable carrier or diluent. 7. A compound according to any one of claims 1 to 3 or a composition according to claim 6 for use as a drug. 8. A compound according to any one of claims 1 to 3 or a composition according to claim 6 for use in suppressing hyperglycemia, especially postprandial hyperglycemia. 9. The composition according to claim 6, or the compound according to claim 7, wherein the compound used is 4-hexadecylaminobenzylamine or ff1fc4-(N-methylhexadecylamino)benzylamine.