JPS62155291A - 3-amino-4, 5-dihydroxypiperidines and production and use thereof - 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 present invention relates to 3-7 minnow 4,5-dihydroxypiperidines, a method for producing them, and particularly a method for lipid and carbohydrate metabolism (1).
lipid and carbohydrate
their use in drugs for metabolism).

1-deoxynojirimycin (ideoxynojir)
It is known that E. Torscheid (E.
Truscheit), Goubry 70mer (W, Fr.
ommar), B, Junge, L, Muler, De Schmidt (
D. Schmidt), D. Schmidt (LW)
ingender), Amp Bunch Chemie-ΔngeI
II, Chem, ) 93-1738 (1981)
].

The present invention relates to the general formula (1) in which R1 represents hydrogen, alkyl having up to 8 carbon atoms, aralkyl having 7 to 14 carbon atoms, or the following formula (wherein R4 represents up to 8 carbon atoms). straight-chain or branched alkyl having up to 8 carbon atoms or straight-chain or branched alkoxy having up to 10 carbon atoms) represents hydrogen or represents a group of the following formula % (wherein R5 has the same meaning as R' and is the same as or different from R''), provided that in all cases R2 or R' 3-7 minnow 4,5-dihydroxypiperidines and physiologically acceptable thereof, wherein one substituent of R2 or R3 shall represent hydrogen and the other substituent of R2 or R3 shall represent NHR5. Regarding salt.

Preferred compounds are those of the general formula (1) in which R1 represents hydrogen or alkyl having up to 6 carbon atoms or represents pencil or the following formula (wherein R4 is a linear chain having up to 4 carbon atoms). or branched alkyl, straight-chain or branched alkoxy or benzyloxy having up to 4 carbon atoms, and R2 and R3 represent hydrogen or has the same meaning as R' and represents a group (same or different from R'), provided that in all cases one of the substituents of R2 or R3 represents hydrogen and one of the substituents of R2 or R3 The other substituent shall represent NHR', the compounds and their physiologically acceptable salts.

Particularly preferred compounds are compounds of the general formula CI) in which R' is hydrogen, alkyl having up to 4 carbon atoms, benzyl,
Represents acetyl or benzyloxycarbonyl, and
R2 and R3 represent hydrogen, or the following formula (in the formula, R5
has the same meaning as R' and represents a group (same or different from R1), provided that in all cases one substituent of R2 or R3 represents hydrogen and the other of R2 or R3 The substituents shall represent NHR5, the compounds and their physiologically acceptable salts.

In general, physiologically acceptable salts are salts of the compounds according to the invention with inorganic or organic acids.

Preferably hydrochloride, hydrobromide, sulfate, hydrogen sulfate, hydrogen phosphate (1+hydrogen pbosphn
tes), bicarbonates, carbonates, phosphates, acetates, maleates, citrates, hepmalates, oxalates or benzoates.

General formula (I) within the scope of the present invention has a D-man/configuration (
Ia) (D-1Ilanno configura
tion (Ia)) and D-gluco configuration (r b) (D-gluco configur
cation (lb)).

Derivatives having the Mann 7 configuration represent, according to the invention, compounds of the -do notation (]a). Derivatives having the gluco configuration represent, according to the invention, compounds of the following formula (Ib):

General formula (Ia) in which R1 represents hydrogen, alkyl having up to 8 carbon atoms, aralkyl having from 7 to 14 carbon atoms, or straight-chain or branched alkyl, straight-chain or branched alkoxy with up to 8 carbon atoms or aralkoxy with up to 10 carbon atoms) and R5 has the same meaning as R' The derivatives having the same or different manno configuration as R1 and their physiologically acceptable salts can be synthesized under reducing conditions in an inert solvent.
Formula (■) where R1 represents an amino protecting group, preferably benzyloxycarbonyl, benzyl or tert, -butyloxycarbonyl and does not represent hydrogen, and R5 is an amino protecting group different from R', preferably Cyclize the compound representing acetyl, remove the necessary protective groups, introduce new protective groups as necessary, and then prepare the corresponding salt using an acid as necessary! ! ! It can be obtained by leaving behind something.

The method can be illustrated, for example, by the diagram below.

The above reductive cycliz
ation) is generally carried out in the presence of a reducing agent and optionally a catalyst.

Cyclization is preferably carried out using hydrogen as reducing agent. Catalyst brushes suitable for this purpose include metal catalysts such as Pd and Pd.
t, preferably Pd on animal charcoal.

Suitable solvents for this are water and all inert organic solvents which do not change under the reaction conditions. Preferably these include alcohols such as methanol, ethanol, propatool or inpropyl, ethers such as diethyl ether, nooxane, tetrahydroctane or glyfur dimethyl ether, dimethylformamide or glacial acetic acid. It is likewise possible to use mixtures of the solvents mentioned.

Generally, the above reaction is carried out at 1 to 150 bar, preferably 1 to 150 bar.
It is carried out under 100 par hydrogen pressure.

Generally, the reaction is carried out between 20 and 150°C, preferably between 20 and 10°C.
It is carried out in a temperature range of 0°C.

Additionally, suitable reducing agents include alkali metal cyanol/borohydrides.
+orol+ydrides), dialkylaminoboranes (dialkyla+einoboranes) or alkali metal borohydride phytes (alkali met
al L+orohydrides).

Solvents that can be used are the same as in the case of cyclization with hydrogen. Particularly suitable for this are mixtures of water and alcohols or dimethylformamide.

Reductive cyclization is generally carried out at 0 to 150°C under atmospheric pressure.
Preferably it is carried out at a temperature range of 20 to 100°C.

The process according to the invention generally comprises from 1 to 11, preferably from 4 to 9, p Performed in the H range.

Removal of a protecting group and introduction of a new protecting group are generally carried out using, for example, Houben-Weyl (1-1 ouben -W Cy l
)'s ``Methods of Organic Chemistry'' (MeLhoden der
OrganishenChemie” (Method
s of 0rFIanic Chemistry))
XV/1 and 2 and by methods familiar to those skilled in the art.

The compounds of general formula (II) used as starting materials are new. These can be produced by methods known per se, for example according to the scheme described below.

■■ Step a of this formula is carried out in an inert solvent such as water, an alcohol such as methanol, ethanol, propatool or isopropyl alcohol, or a mixture of said solvents, in the presence of a catalyst such as Raney nickel. In the presence of Nia,
implies hydrogenation of N-acetylglucosamine II at a temperature of 20 to 200 °C, preferably 20 to 150 °C, and a pressure of 1 to 200 bar, preferably 1 to 150 bar, so that the IJII ring Open-chain isomerie com
(pounds) IV and ■ are obtained. In step 6, without isolation, the mixture is treated with a base, e.g. in an inert solvent, e.g. water or an alcohol, e.g. -20 to +80°C, preferably O to +80°C in the presence of sodium carbonate or potassium carbonate
It is reacted with benzyloxycarbonyl chloride at a temperature of +40"C and the mixture of products 1 and 2 is isolated by a conventional chromatographic step. Final step C
Finally, the isomer having the Man7 configuration is obtained by methods known per se, preferably for example G.
(G, Kinast), M Schedel (M, 5cb)
Amp Bunch Chem International Edition (＾ngeu, Chem,
IntJd, )-40(9) 805 (1981).
oxidation by a microbiological process using Bacter cells) to obtain compound (Ila).

General formula (Ib) wherein R1 represents hydrogen, alkyl having up to 8 carbon atoms, aralkyl having from 7 to 14 carbon atoms, or straight-chain or branched alkyl, straight-chain or branched alkoxy with up to 8 carbon atoms or aralkoxy with up to 10 carbon atoms), and R5 has the same meaning as R1. and have the same or different gluco configuration as R' and physiologically acceptable salts thereof, in an inert solvent, in the presence of a reducing agent, optionally in the presence of a catalyst. to reduce the at compound of the formula (■), where R1 represents an ami7 protecting group, preferably benol, and remove the protecting group if necessary,
It can be obtained by introducing a new protecting group R5 if necessary and then preparing the corresponding salt using an acid if necessary.

The above reduction is generally carried out by conventional methods for reducing azide to amine 7 groups.
or optionally an acid such as ebasulfonic acid (for example methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid) in the presence of a catalyst such as PT (optionally over animal charcoal).
or inorganic acids (e.g., ICI, H2SO, or HBr)
) or a carboxylic acid (acetic acid or trifluoroacetic acid), an inert solvent such as water, an alcohol such as methanol, ethanol, propyl or inpropyl 7
reduction with hydrogen as reducing agent in -ol, dimethylformamide or mixtures thereof, or inert solvents such as water, alcohols such as methanol, ethanol,
Hydride such as sodium borohydride, lithium alanate or sodium borohydride (sodiu
These include reductions using mcyanoborohydride (1de), optionally with niekel salts, and reductions with hydrogen sulfide in birinone.

Other methods of reduction of anodides that can be used according to the invention are described in Holuben-Heyl's "Methods of Organic Chemistry".
rganisl+en Chemie")X/3.82
2, XI/1.539.

The separation of a protecting group and the reintroduction of a new protecting group are described, for example, in John Houben-Weyl's ``Method of Organic Chemistry J''.
XV/1 and 2 and Baker and Ollis'
Comprehensive Organic Chemistry” (Co + n p r e h e
n 5ive organic CI+e+aist
ry") 5, 714. These methods are known and familiar to those skilled in the art.

The azide of formula (■) used as starting material is new. However, these can be prepared in a manner known in principle and according to the scheme shown below. ! I can leave something behind.

AY
or p-methoxy-bennol According to this formula, in step A, deoxynojirimycin (which is described in European Patent No. 947
Benzyl bromide and potassium carbonate to give X. In step B, after removing the potassium carbonate, the benzyl compound
and 2-methoxypropene or 2,2-dimethoxypropane in dimethylformamide to give XI;
Convert to I.

Reaction of XII with NaI/Zn in dimethylformamide (step D) gives olefin XIII, which is then converted into OsO,/N-methylmorpholine N
-oxide (N-IIlethyllIlorphor
Hydroxylation (Step E) with 1ncN-oxide) gives XIV. In step F, the derivative
X
■ Get. In step G, x is converted to XVI using fluoromethanesulfonic anhydride at -20 °C in CH2Cl2/pyrinone, then cH,C
XVI is stereoselectively converted to the azide Villa by inversion of the C-2 position using Li N= in a l 2 /dimethylformamide mixture at −40° C. (step ①).

The compounds according to the invention have interesting pharmacological actions.

These are involved in the metabolism of extracellular and intracellular carbohydrates, glycosyltransferase (glycosyltransferase),
erase) and glucosidase (glucosida
se). Furthermore, they act on glycoprotein and chitin biosynthesis and have fungicidal effects.
action), bacterial action
atic action) and immunomodulatory action (imm
unomodulatory action).

Owing to this property, the compounds according to the invention may be useful, for example, in the following diseases: prediabetes, gastritis, constipation, caries, atherosclerosis, obesity, diabetes or hyperlipidemia.
It can be used as a therapeutic agent for C. proteinacroia.

The compounds can be administered undiluted, eg as a powder or in a gelatin container □Heliatin casr:), or in combination with a vehicle in a pharmaceutical acid. Pharmaceutical compositions can contain large or small amounts of the active compound, for example from 0.1% to 99.5%, in combination with a pharmaceutically acceptable non-toxic inert vehicle. The vehicle here includes one or more solid, semi-solid or liquid diluents, excipients and/or non-toxic, inert pharmaceutically acceptable formulation adjuvants.
rmulatiBauxiliaries). Pharmaceutical preparations of this type are preferably dose units, i.e. physical units containing a defined amount of active compound and representing a fraction or multiple of the dose required to produce the desired effect. separate units,
It is in the form of A dose unit can include 1.2.3.4 or more times a single dose, or 1/2, 1/3 or 1/4 times a single dose.

A single unit preferably comprises:
administration according to a predetermined dosage regimen of one or more dosage units;
Usually all main meals of the day
1.1/2.1 of the daily dose administered at the time of a snack.
/3 or 1/4 times the dose, containing an amount of active compound sufficient to achieve the desired effect.

Other medications may also be taken. Each dose and regimen should be carefully considered by applying sound professional judgment and taking into account the patient's age, weight and condition as well as the nature and severity of the disease. be. However, the dosage is usually about 1 to 1 per day.
It will be in the range of about 1×10′ SIU/kg (body weight). In some cases, a suitable therapeutic effect may be achieved with lower doses; in other cases, higher doses may be necessary.

Oral administration includes solid and liquid dosage units, such as powders, tablets, coated tablets,
It can be carried out by using capsules, granules, suspensions, solutions and the like.

Powders are produced by comminution of the material to a suitable size and mixing it with a pharmaceutical vehicle in which it is also comminuted. edible carbohydrates
hydrates), such as starch, lactose, sucrose or glucose, are commonly used for this purpose and may be utilized in this example, but it is preferable to utilize non-metabolized carbohydrates such as, for example, cellulose derivatives.

Sweetening agents, flavoring agents, preservatives, dispersing agents, and coloring agents may also be used.

Capsules can be manufactured by preparing the powder mixture described above and introducing it into a pre-formed gelatin container. The powder mixture is mixed with a lubricant (l) during the introduction process.
for example silica gel, talc, magnesium stearate, calcium stearate or solid polyethylene glycol.

This mixture can likewise be mixed with disintegrants or solubilizers, such as agar-afar, calcium carbonate or sodium carbonate, in order to improve the effectiveness of the active compound when taking the capsule. .

Tablets can be prepared, for example, by preparing a powder mixture, coarse or fine grains, and adding lubricants and disintegrants! ! !
! be left behind. Tablets are formed from this mixture. Powder mixtures are prepared by mixing the finely divided materials in a suitable manner and supplementing with diluents or other vehicles as described above. Binders such as carboxymethylcellulose, alginate, gelatin or polyvinylpyrrolidone, solubility inhibitors
ion retardnnnt), such as puffins, absorption enhancers
or), such as t54 salts and/or adsorbents such as bentonite, kaolin or dicalcium phosphate (dic
aleium phosphate) as necessary. The powder mixture may contain binders, such as syrups, starch pastes, acacia mucila
ge) or granulate using liquid formulations of cellulosic or polymeric materials. The product is then passed through a coarse sieve.

Alternatively, the powder mixture can be passed through a tablet machine (tnbletti).
The irregularly shaped pieces obtained can be comminuted to the size of grains by passing through a Bmachine.

To prevent the resulting granules from sticking to the nozzle, they can be mixed with a lubricant, such as stearic acid, stearate, talc or mineral oil. This lubricated mixture is then applied to the tablets. Compress into form. The granulation and comminution steps were omitted and the C-active compound was left free (
+a! tC conversion is also possible. The product may be coated with a clear or opaque protective coating.
opaque protective coating
), for example covering of shellac
5bellac), a sugar or polymeric material covering and a polished wax coating. Coloring agents can be added to these coverings to distinguish individual dosage units.

Preparations for oral administration in dosage units, such as solutions, syrups and elixirs, can be prepared so that a specified amount of the product contains a specified amount of active compound. A syrup may be prepared by dissolving the active compound in an aqueous solution containing a suitable flavoring agent. Elixirs are obtained by using non-toxic alcoholic vehicles. Suspensions can be made by dispersing the compound in a non-toxic vehicle. 'rIj solubilizer and? L-forming agents, such as ethoxylated instearyl alcohols (ethoxylated lsostea
ryl alcohol.

Is) and polyoxyethylene sorbitol esters, preservatives, flavor-impro
It is also possible to add additives such as peppermint oil or saccharin.

You can instruct the capsule on which thrust to throw. Additionally, the active compound may be delayed, for example by tethering the active compound to polymeric substances, waxes, etc.
manner) administration 4it can be protected to release.

In addition to said pharmaceutical composition, food products containing this composition,
For example, it is also possible to produce sugar, bread, potato products, fruit juices, beer, chocolate or other items of candied fruit and conserves of fruit, such as noyam. In this case an effective amount of at least one active compound according to the invention is added to these products.

Food products prepared using the active compounds according to the invention include:
Diet for patients suffering from metabolic disorders and nutrition for preventing metabolic disorders 1! Ma is suitable for one person's nutritional intake in the sense of a nutrition method.

Furthermore, the compounds according to the invention are suitable for use in lean meat (leau
It shows the property that it has a large effect on the ratio of undesirable fat parts to desirable low-fat meat parts of the animal. This is especially important in keeping and managing other useful ornamental animals. Furthermore, the use of active compounds results in considerable savings in terms of time, quantity and quality when feeding animals. These have a constant digestion time W'7 questions are delayed -t 17)
t', the residence time of nutrients in the digcstive tract is reduced, which allows for ad libitum feeding with less effort. Furthermore,
When using the material according to the invention, considerable savings in protein feed, often expensive, result.

In this way, the active compound is delivered to the animal! It can be used as a drug to reduce obesity and conserve protein in feed in virtually all areas of ingestion.

The efficacy of the active compounds for this purpose is substantially independent of the species and sex of the animal. The active compound may be present endogenously (intrin).
sicnl ly) or ゛, a relatively large number of fatty deposits (heavy f+ujy
to dep+: IX9/,/tMIτMC Yu East
1h No. 1 Ruu Shirizuku Shi High Egg (You can see that there is a 1st place stone value.

2-7ceto7mido-1-amino-1,2-dideoxy-
D-Mannitol 221g (1 mol) of 7cetylglucosamine was dissolved in 2p of methanol, 20g of Raney nickel and 250m
β concentrated N 2 Hs is added and the mixture is hydrogenated at 100° C. with 100 pars H 2 for 5 hours. For finishing, the catalyst is removed by suction and the batch is evaporated to dryness. The obtained ffl product was further subjected to M
! l! ! React as shown in Example 2.

X11'' 2-7 cetamido-1-bennoloxycarponylamine/-1,2-dideoxy-D-manni)-. 11 concentrated HSO, dried thoroughly under reduced pressure over N
The crude product of Example 1 without H, at 250 +oA
Dissolved in water, cooled with water, stirred, and boiled for 150y (1
, 1 mol) of benyloxycarbonyl chloride and 1
50 g (1.1 mol) of 2CO, are added and the mixture is stirred for 18 hours at room temperature. The precipitate was then removed by suction filtration, the filtrate was evaporated to dryness, and the residue was evaporated to dryness.
Fractionate on P8 (laboratory column supplied by Merck, C size). For this, two columns were connected in series, the residue of 209 was dissolved in about 200 ml of H2O, the resulting solution was applied to the column and then 1.51
1□O/CH, CN=90/10 and (71,51 H2
Elute using 0/CH, CN=80/20 at an outflow rate of about 15 mJ2/min. 7 lactation by HPLC (column: Li Chrosorb)/RP
8 (10μm), 2LLl12/min, $1 buffer pH
7/CH3CN = 80/20.210 rua) with a retention time of 3.35 minutes, the a7tonitrile is removed by evaporation to a vacuum of 1 and the residue is lyophilized. 1-2 g of pure product are obtained from the 20 g of residue used.

Example 1 - 5-acetamido-6-benzyloxycarbonylamine/-5+ 6-sideoxy-D-fructose 4 g of Glucobacter cells were mixed with 100 IIβ of ptI of 4.5 in 0.1 M phosphate buffer (raw water). (prepared above) and add 1.2 g of 7cetamido-1-bennoloxycarbonylamide/-1,2-dideoxy-D-mannitol. Shake this mixture overnight at 32°C. 30 hours removed, this is centrifuged #! The residue was washed twice with 100 methanol each. The supernatant and this methanol extract are combined and evaporated to dryness. This crude product is further processed without finishing.

0.6 g of the product of Example 3, 1.1 g of Pd/C(
5%) and 3 mg of 2CO3 to 25 d of H□O and 5
Dissolve in 0 mβ methanol and hydrogenate at 60° C. and 50 atm for 4 hours. For finishing, the catalyst was removed by filtration and washed with acid ion exchanger (acid 1onexch
aBer) (Lewa Teit S P 112 (Lewa
The iP solution was passed through a column containing H, COH/conc.
7 lactation (TLC) containing the product, eluted with H,
Series 20MCI 3/CH30H/? Agriculture NH, = 4:
3: Evaporate 1) with a rotary evaporator,
)-120/H3COH-.

Yield: 0.21 g
After stirring in H for 2 hours, the product was neutralized with 2N ICI and purified on an acid ion exchanger as shown in Example 3.

Yield: 0.2g [Kai N-benzyl-1,5-nobuoxy-1,5-imino D-glucitol] 63.2y
(1.0 mol) of deoxynojirimycin is dissolved in 2.51 parts of dimethylformamide.

76.0 g (0.55 mol) of potassium carbonate are added to this solution. After cooling to O″C, 188.1g (1°1
mol) of benzyl bromide are added dropwise over a period of 30 minutes.

The starting material was completely reacted after about 120 minutes. The product is further processed in situ.

A small aliquot was taken for characterization and after removal of the solvent, chloroform:methanol=4. : Purification by column chromatography and togelaf treatment on 1-system silica gel to obtain a crystalline solid.

Melting: 181°C Lα eny 483゛ (methanol) u N-bentrue 4,6-0-inpropylidene-1.5
-Dideoxy-1,5-imi/-D-glucitol After removing the precipitate from the reaction mixture of Example 6 by filtration, sufficient p-)luenesulfonic acid was added and LIH
Adjust to 1.5. Then a mixture of 2082 (2 mol) of nomethoxypropane and 14/l@(2 mol) of 2-methoxy-propene is added. After reacting at 30°C for 2 hours, thin layer chromatography (toluene: ethyl/-
Le = 3: Confirm that the reaction ends in January.

Work-up is carried out by stirring for several hours with a suspension of sodium bicarbonate 2109 in water 100. After removing the solvent by evaporation, the residue is incubated with chloroform, the chloroform phase is washed, dried over sodium sulfate, and after removing the solvent by evaporation, the residue is recrystallized from ethyl acetate/petroleum ether.

Yield: 249.3g Melting point: 117°C [α] = -100,3° (methanol) Example 8 N-bentrue 4,6-0-inpropylidene-2,3
-di〇-mesyl-1,5-dideoxy-I+5-imy/-D-glucitol The product 240FI (0.81 mol) of Example 7 was added to 2°0
00mβ acetone and 300-triethylamine (
2.1 mol). 13 in 600- acetone
8mj! A solution of (1,8 moles) of methanesulfonyl chloride is slowly added dropwise to this while cooling with ice. The water bath is then removed and the mixture is stirred at room temperature overnight. After the reaction is completed ("l'Lc) luene: 7 setone = 4
1) The precipitated salts are first removed by filtration, then the excess mesyl chloride is hydrolyzed with a little water and the mixture is evaporated in a rotary evaporator. The crystalline residue is taken up in methylene chloride, the organic phase is washed with water and N
Dry over a25O and evaporate.

Although the product has sufficient purity for the next reaction (≧97
%), which can be recrystallized from ethyl acetate/petroleum ether.

Length: 354s (97% of theoretical value) Melting point: 162°
C [aJf=-44,8°C (CHCI 3) and (Renko N-pencil-4,6-0-inpropylidene-1,2
,3,5-tetradeoxy-1,5-imi/-D-erythro-2-hexenitol The product sog (o, 2 mol) of Example 8 was added to 1,600
Dissolved in dimethylformamide of Jt, 149°9g (
After adding 1,0 mol) of Mar and 130.8 g (2,0 mol) of Zn powder, the mixture was heated at 135 °C for 3 hours.
(TLC) Luene:EA=3:1
). After cooling, the salts are removed by suction, the entire batch is evaporated, the residue is taken up in CH2Cl2 and the solution is washed several times with water. The organic phase was dried over NuSO and
Evaporate and filter the remaining syrup through silica sol (230-400 mesh, fluid phase: toluene, toluene/acetone = 30/1).

Yield: 36.31? (70% of i!Ii theoretical value) [al
i=51.4"(CHCI:l) bundle 1u Kai"-N-benzyl-4,6-0-impropyritine-1,5
-Nobuoxy-1,5-imino D-mannitol 40 g (0,154 mol) of the product of Example 9 was added to 1°20
0-acetone, 300-120 and 1()Omj
2 to 78M in tert,-butanol, 27. Og(
0.2 mol) of N-methylmorpholine N-oxide and 400 mg of 0f10. After addition of the mixture, the mixture is stirred until completion of the reaction is observed by thin layer chromatography (toluene:acetone=1:1). then 1
Add 0-cyclohexene to the reaction mixture and continue stirring for 2 hours (black color). The solution is then filtered through Celite and evaporated.

The syrup residue is taken up in CH, c I□ and the organic phase is washed several times with water, dried over N250 and evaporated again. This residue was chromatographed on a 7-layer chromatograph on silica sol.
E (flash chromoLIlatogrnp
by) (fluid phase: toluene/ethyl acetate = 1/1 to 1
．． 3) and crystallized from ethyl acetate/petroleum ether.

Yield: 33.9g (75%) Melting point: 123-125°C [(7Jfff=122.8° (CHCI,) East Kyokusho I
J11 N-Benzyl-3-0-benzyl-4,6-0-impropylidene-1,5-nobuoxy-1,5-imino D
- 15 g of the compound of Example 10 in 300 g of anhydrous toluene in which 14 g (56 mmol) of mannitol butyltin oxide are suspended (
A solution of 519 mol) was immersed in a protective atmosphere of N2F using a water separator until no water separation was observed.
The mixture is heated to reflux under (at+nosphcre). The temperature is then lowered to 100°C and a countercurrent flow of nitrogen (couu
1.64y (5.1 mmol) of tetofbutylammonium bromide is added to this solution. Then 9.58. (56 mmol) of benzyl bromide is slowly added dropwise over a period of 5 hours. )1rJ
Thin layer chromatography (toluene:acetone = 5
:1i) is confirmed after 8 hours and finished.

This work-up is carried out by removing the solvent by evaporation, taking up the residue in chloroform, and subsequently washing the organic phase with saturated hydrogen carbonate solution.

The tin salt obtained from this is removed by centrifugation. From the crude product obtained after drying over sodium sulfate and removing the solvent by evaporation, 7 tons of toluenia = 40
: Incidental by-products are removed by i-based cuff chromatography treatment.

Yield: 14.3 g (37 mmol, 73% of theory)
[Q'J H=-55,3°, C=0.85 (ethanol) real ↓'' UN-benzyl-3-0-benzyl-4,6-〇-isopropylidene-2-to17 Fluoromethanesulfonyl
1,5-nobuoxy-1,5-imi/-D-mannitol Compound 14y (37 mmol) of Example 11 was added to 140-
of anhydrous dichloromethane. 6.9 g (88 mmol) of birinone was heated at -20'C under an inert gas atmosphere.
Add to the solution kept at a constant temperature.

In this condition f, 10.4. dissolved in anhydrous dichloromethane at 60 mA. (37 mmol) of 1 triple olomethane sulfonic anhydride is added dropwise over 60 minutes. After reacting for 1 hour, the starting material was converted to the final product (R(=0.3, 7 tons of toluenia=10:1).

Work-up is carried out by adding 50-saturated sodium bicarbonate solution. After stirring vigorously for 3 Oe at 0° C., the organic phase is dried over +7 μm of sulfuric acid and evaporated. A product of 18.1y (35 mmol, 95%) is obtained which is immediately subjected to the next reaction step.

ShakuMJLLL 2-azido-N-pencil-3-〇-bentrue 4.6
-0-inpropylidene-1,2,5-trideoxy-
1,5-Imi/-D-glucitol Compound 18.11 of Example 12? (35 mmol) in a protective gas atmosphere
0- dissolved in anhydrous dichloromethane. Temperature -40℃
Add 100-anhydrous dimethylformamide slowly keeping the value constant. Then 8.6y (0,175 mol)
Add the anonymized chikum. The mixture is stirred at -40°C under protection. After about 8 hours the precursor can no longer be detected by thin layer chromatography (spray reagent: 7 tresorcin).

Evaporate to about 1/4 of the original volume under high vacuum at a bath temperature of 30°C, take up the residue in toluene, and finish by washing the f# solution several times with a dilute solution of NaCl. After drying over sodium sulfate and purifying the product by column chromatography in a 50:1 toluene:ethyl acetate system, 10.6 g (26.5 mmol, 74%) of crude product are obtained.

Lα1 back = + 78.86゜ fruit 14 and 15 2-ami/-N-benzle-3-0-penkuru-4.6
-inpropylidene-1,2,5-trideoxy-1,
5-Imino-D-glucitol ■ and 2-7cetamido N-benzyl-3-〇-bentrue 4,6-imbropylidene-1,2,5-trideoxy-1,5-imino-D-gluci(- 7) Take the compound io,e,, (26 mmol) of Example 13 in a 4% ethanolic NiC12 solution of 100-
□ Saturated ethanolic NaBH= while stirring at 0℃?
8 liquid is added until the black coloration, which was initially reversible, becomes permanent. The complete conversion of the precursor to the 2-amino compound 14 was then shown by confirmation by thin layer chromatography (toluene:ethanol=io:i) and visualization with Ninhydrin.
The solvent was distilled off using a rotary evaporator under high vacuum at a bath temperature of 30°C, and then added to an acetylation mixture 50 consisting of acetic anhydride:pyridine = 1:2, and acetylated on the spot. After reaction for 2 hours at 40° C., 14 was completely converted to 15 (the product was no longer red due to ninhydrin).

The mixture is evaporated to dryness under high vacuum and the residue is taken up in toluene/H20.

Semi-saturated Na C
The nickel and boron salts are removed by several extractions with 1 solution, the toluene phase is dried over sodium sulfate, evaporated and the product is chromatographed on silica sol in 50 mβ of toluene:methanol.

Yield + jij: 9.43g (87%) - [α]
Di=-3.3° (CHCl, ) Melting point: Suitable for 40℃ m 2-7 Cetamido 4.6-0-Impropylidene-1
, 2,5-trideoxy-1,5-imino-D-glucitol acetate 2 g (15 mmol) of the compound of Example 15 in 50 mβ of methanol with 2 mβ of glacial acetic acid and 5 g of 10% palladium/charcoal were added at 3 bar to 24 Hydrogenate for an hour. Compound 15
is quantitatively converted into the acetate salt of the final product, from which it is obtained pure by evaporation several times with triethylamine. Yield: 1.1 g (quantitative) Melting point of acetate: 166-169°C (decomposition)
[alpha] = -4,35° (pyridine, C = 0.58) No. 0, 1-2-7cetamido 1,2-dideoxy-/silimycin Compound 1.1y (5 mi'7 mol) in 20 mjt of a mixture of glacial acetic acid:N20=3:2 and the solution is heated at 60° C. for 8 hours. After evaporating the hydrolysis mixture, the product is dried and evaporated several times with methanol/triethylamine to obtain the final product in quantitative yield.

[α]l=+9.9@(N20) Melting point: 220.5-221.7°C Example 18 N-bentrue 3-0-p-methoxybenzyl-4,6
-0-inpropylidene-1,5-dideoxy-1g5
-Imi/-D-mannitol dibutyltin oxide 55g
A solution of 58.6 g of the compound of Example 1o in anhydrous toluene 700 suspended in anhydrous toluene is heated to reflux using a water separator under a protective atmosphere of N2 until no more separation of water is observed. . The temperature is then lowered to 100'C and 6 g of tetrabutylammonium bromide are added with a flow of nitrogen. Then 34.5I? of p-methoxypencil chloride is slowly added dropwise over a period of 5 hours. Complete reaction of the precursor is confirmed by thin layer chromatography (toluene:acetone=4:IM) after 12 hours. Work-up is carried out by evaporating the solvent and taking up the residue in chloroform, followed by washing the organic phase with saturated sodium bicarbonate solution. The tin salt obtained from this is removed by centrifugation. The accompanying by-products are removed from the crude product obtained after drying on a V ram and distilling off the solvent by column chromatography using a toluene:acetone=40:1 system. After crystallization from ethyl acetate/hexane, 36 g of the title compound are obtained.

M point 288°C [αJ = -70.9° (chloroform, C = 0.9) 5.3 m'j mol) of potassium carbonate by stirring 1.6 y (11.6 mmol) of potassium carbonate
of! Dissolve in cloudy dimethylformamide. 900 μ (5.3 mmol) of benzyl bromide are added to this mixture at 0°C. The reaction is complete after 8 hours. After removing the precipitate by filtration and evaporating the solvent,
The product is isolated in quantitative yield.

Rr=0.3'(CHCIy: Me
0H=4: 1) l of acetate (21 bamboo=+2
5. ．． 0" (H2O, C=1°0 Example 20 2-7 Cetamido N-・Methyl-1,2-dideoxy-nojirimycin The compound of Example 17 *1 g (5.3 mmol) was mixed with formic acid:methyl=2:1 Dissolve 30 mj! of the (V/V) mixture and heat the solution at 80"C for 12 hours.

After distilling off the solvent, the isolated residue was taken up in methanol and added to Amberlit) CG4001 type (^mberlit).
type CG 4001) Basic ion exchanger (ba
Remove the salt on a sic ion exchanger.

Yield: Quantitative Rr=0,44 (CHCl-: MeO14,
"N IJyH20=4: 3: 1 thread) [aJ=+10,72°

[Brief explanation of drawings]

Figure 1 shows the IHNMR spectrum of the compound of Example 4 (
250MHz/D20). Figure 2 shows the IHNMR spectrum of the compound of Example 11 (9)
(200MHz, CD CL) Figure 3 is the IR spectrum of the compound of Example 11. Figure #5 is the IHNMR spectrum of the compound of Example 13 (300M
Hz, CDCI-). FIG. 6 shows the IR spectrum (C to IC+) of the compound of Example 13. Figure 7 shows the 'HNMR spectrum of the compound of Example 15 (
300MHz, CcDs). FIG. 8 shows the IR spectrum of the compound of Example 15. FIG. 10 shows the IR spectrum of the compound of Example 16. Figure 12 shows the 'IINMR spectrum <300 MHz, D20) of the compound of Example 17. FIG. 13 shows the IR spectrum of the compound of Example-17. The fjI115 diagram shows the ' HN M of the compound of Example 18.
The R spectrum (300 MHz, CD CL) is shown. FIG. 16 shows the IR spectrum of the compound of Example 18. FIG. 18 shows the IHNMR spectrum (300 MHz, D20) of the compound of Example 19. Figure 19 shows the It (spectrum) of the compound of Example 19.
KBr). FIG. 20 shows the 'HNMR spectrum (300M l-1z, D20) of the compound of Example 20. Figure 1jS21 shows the IR spectrum of the compound of Example 20 (
KBr).

Claims (1)

[Claims] 1. General formula (I) ▲ Numerical formula, chemical formula, table, etc. ▼ (I) In the formula, R^1 is hydrogen, alkyl having up to 8 carbon atoms, carbon atoms 7 to 14 or the following formula ▲ mathematical formula, chemical formula, table, etc. ▼ (wherein R^4 is a linear or branched alkyl having up to 8 carbon atoms, represents a straight-chain or branched alkoxy having up to 10 carbon atoms or an aralkoxy having up to 10 carbon atoms) and R^2 and R^3 represent hydrogen or the following formula NHR^5 (in which: R^5 has the same meaning as R^1 and represents a group (same or different from R^1), provided that in all cases, one substituent of R^2 or R^3 is hydrogen. and the other substituent of R^2 or R^3 is NHR^5
3-Amino-4,5-dihydroxypiperidines and physiologically acceptable salts thereof, represented by: 2. In the general formula (I), R^1 represents hydrogen or alkyl having up to 6 carbon atoms, or represents benzyl, or the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^ 4 represents a straight-chain or branched alkyl having up to 4 carbon atoms, a straight-chain or branched alkoxy having up to 4 carbon atoms or benzyloxy), and R^2 and R ^3 represents hydrogen or a group of the following formula NHR^5 (wherein R^5 has the same meaning as R^1 and is the same or different from R^1), provided that in all cases One substituent of R^2 or R^3 represents hydrogen, and the other substituent of R^2 or R^3 represents NHR^5
Compounds according to claim 1 and physiologically acceptable salts thereof. 3. In the general formula (I), there are ▲mathematical formulas, chemical formulas, tables, etc.▼(I) R^1 represents hydrogen, alkyl having up to 4 carbon atoms, benzyl, acetyl or benzyloxycarbonyl, and R^ 2 and R^3 represent hydrogen or a group of the following formula NHR^5 (wherein R^5 has the same meaning as R^1 and is the same or different from R^1), but all In the case where one substituent of R^2 or R^3 represents hydrogen and the other substituent of R^2 or R^3 represents NHR^5
Compounds according to claim 1 and physiologically acceptable salts thereof. 4. Claims 1 to 4 of the following formula (Ia) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(Ia) in a form having a manno configuration
Compound according to item 3. 5. Claims 1 to 1 of the following formula (I b) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I b) in the form having the gluco configuration
Compound according to item 3. 6. General formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) A compound in which R^1 and R^5 have the meanings described in claim 1. 7. The following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R^1 represents hydrogen, alkyl having up to 8 carbon atoms, aralkyl having 7 to 14 carbon atoms, or the following formula ▲ Numerical formula , chemical formulas, tables, etc. aralkoxy having up to carbon atoms), and R^5 has the same meaning as R^1, and R^5 is the same or different from R^1 and has the manno configuration of formula (I) In the method for producing compounds and physiologically acceptable salts thereof, the formula (II) ▲ includes a mathematical formula, a chemical formula, a table, etc. ▼ (II) where R^1 is an amino protecting group, preferably benzyloxycarbonyl, represents benzyl or tert-butyloxycarbonyl and does not represent hydrogen, and R^5 represents an amino protecting group different from R^1, preferably acetyl, under reducing conditions in an inert solvent. A method characterized by: converting the protective group into a compound, removing a protecting group if necessary, introducing a new protecting group if necessary, and then producing a corresponding salt using an acid if necessary. 8. The following formula (I b) ▲Mathematical formula, chemical formula, table, etc.▼(I b) In the formula, R^1 is hydrogen, alkyl having up to 8 carbon atoms, aralkyl having 7 to 14 carbon atoms or the following formula ▲ Numerical formula, chemical formula, table, etc. or branched alkoxy or aralkoxy having up to 10 carbon atoms), and R^5 has the same meaning as R^1, and is the same or different from R^1, and represents a glucosteroid of In the method for producing compounds of formula (I) and their physiologically acceptable salts having the configuration, formula (VIII) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VIII) In the formula, R^1 is amino An azide compound representing a protecting group, preferably benzyl, in an inert solvent in the presence of a reducing agent,
It is characterized by reducing in the presence of a catalyst if necessary, removing a protecting group if necessary, introducing a new protecting group R^5 if necessary, and then producing a corresponding salt using an acid if necessary. How to do it. 9. under hydrogen pressure of 1 to 150 bar and water, alcohol,
8. Process according to claim 7, characterized in that the cyclization is carried out using hydrogen in the presence of Pd or Pt in ether, DMF or glacial acetic acid. 10. Process according to claim 9, characterized in that the cyclization is carried out at a temperature of 10, 20 to 150<0>C. 11. The method according to claim 7, characterized in that the cyclization is carried out in the presence of an alkali metal cyanoborohydride, dialkylaminoborane or alkali metal borohydride. 12. The method according to claim 11, characterized in that the cyclization is carried out at a temperature of 0 to 150° C. under atmospheric pressure. 13. General formula (I) for use in therapeutic treatment methods for human or animal bodies ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) In the formula, R^1 is hydrogen, having up to 8 carbon atoms Alkyl, aralkyl having 7 to 14 carbon atoms, or the following formula ▲ Numerical formula, chemical formula, table, etc. ▼ (wherein R^4 is a linear or branched alkyl having up to 8 carbon atoms) , straight-chain or branched alkoxy with up to 8 carbon atoms or aralkoxy with up to 10 carbon atoms) and R^2 and R^3 represent hydrogen or NHR^5 (in the formula, R^5 has the same meaning as R^1 and is the same or different from R^1), provided that in all cases R^2 or R^3 One substituent represents hydrogen and the other substituent of R^2 or R^3 is NHR^5
3-Amino-4,5-dihydroxypiperidines and physiologically acceptable salts thereof, having the following formula. 14. General formula (I) ▲Mathematical formula, chemical formula, table, etc.▼(I) In the formula, R^1 represents hydrogen, alkyl having up to 8 carbon atoms, aralkyl having 7 to 14 carbon atoms. or the following formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^4 is a straight chain or branched alkyl having up to 8 carbon atoms, a straight chain or represents a branched alkoxy or aralkoxy having up to 10 carbon atoms) and R^2 and R^3 represent hydrogen or the following formula NHR^5 (wherein R^5 is R^ has the same meaning as 1 and represents a group (identical or different from R^1), provided that in all cases one substituent of R^2 or R^3 represents hydrogen and R^2 or The other substituent of R^3 is NHR^5
3-Amino-4,5-dihydroxypiperidines and physiologically acceptable salts thereof, having the following formula. 15. General formula for the production of drugs (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) In the formula, R^1 is hydrogen, alkyl with up to 8 carbon atoms, carbon atoms 7 to 14 or the following formula ▲ mathematical formula, chemical formula, table, etc. ▼ (wherein R^4 is a linear or branched alkyl having up to 8 carbon atoms, represents a straight-chain or branched alkoxy having up to 10 carbon atoms or an aralkoxy having up to 10 carbon atoms) and R^2 and R^3 represent hydrogen or the following formula NHR^5 (in which: R^5 has the same meaning as R^1 and represents a group (same or different from R^1), provided that in all cases, one substituent of R^2 or R^3 is hydrogen. and the other substituent of R^2 or R^3 is NHR^5
The use of 3-amino-4,5-dihydroxypiperidines and their physiologically acceptable salts, which represent the following.