JPS5919545B2 - New tricyclic cage-shaped amine compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to tricyclic cage amine compounds.

That is, the present invention relates to a new tricyclic cage-shaped amine compound represented by the general formula [I] useful as a pharmaceutical and its acid salt. [In the formula, l is 0 or 1,
m and n represent 1 or 2.

] The compound of the present invention represented by the general formula [I] is, for example, influenza virus, influenza virus X. influenzae.

Herpessimplexvirus
It has an antiviral effect against U. General formula of the present invention [
The novel tricyclic cage-like amine compound represented by [I] was synthesized for the first time using the fabric of the present invention, for example, by the method shown below.

l) In the case of a compound of general formula [I] where 1=0, for example, formula 1
It can be synthesized by the method shown in . Formula 1, n and m have the same meanings as before.

] That is, cyclopentadiene or cyclohexadiene (1) and diethyl methylenemalonate (2) or itaconic acid anhydride (j) were reacted with Diels-Alda, and compound (3) was reacted with water. :Hydrolyzed with caustic soda in a mixed solvent of methanol and tetrahydrofuran, and compound (4) was obtained by heating and refluxing compound (3) in water. Compound (4) was converted into an iodolactone using 12-KI in an aqueous solution of NaHCO. , Compound (9) is obtained, compound (5) is converted into acid chloride with thionyl chloride, and then reacted with sodium nitride in an acetone monowater solvent, or compound (5) is converted into a mixed acid anhydride and nitrided with this. Acid azide was obtained by reacting with sodium, and this product was further reacted with ethanol to obtain compound (6). Compound (6) was reacted with tri-n-butyltin hydride to obtain compound (7), and then calcium was dissolved in ethanol. Reduction with boron hydride yields compound (8). Compound (8) is etherified with tosyl chloride in pyridine to yield compound (9).
The target amine can be obtained by hydrolysis by heating an aqueous solution of caustic soda under reflux. 1) In general formula [1], l=
In the case of compound 1, it can be synthesized, for example, by the method shown in formula 2.

V[In the formula, m and n have the same meanings as above, and TS represents a tosyl group.

] Compound (3) or (3) was reduced with lithium aluminum hydride in tetrahydrofuran to obtain compound (self).

The compound (self) was made into a compound (self) on which N-bromosuccinimide was reacted in a mixed solvent of chloroform and tetrahydrofuran, and then reduced with tri-n-butyltin hydride to obtain the compound (self). Compound (self) can also be obtained by reacting compound (self) with mercury acetate and sodium borohydride. Compound (self) was tosylated with tosyl chloride in pyridine to give compound (self), then brominated with lithium bromide in methyl ethyl ketone solvent to obtain compound (self), and condensed with phthalimide potash to obtain compound (self). . The target amine (5) can be obtained by decomposing the compound (self) with hydrazine. 111
) A compound of general formula [1] where m=1 can be synthesized, for example, by the method shown in formula 3.

[In the formula, n has the same meaning as above, and R is C1~\24' Compound (self) is obtained by a Diels-Alda reaction between compound (1) and α-cyanoacrylic acid ester, and Q( (g) can be reduced to obtain 09, and (19 can be reacted with N-bromosuccinimide in the same manner as before to obtain compound 1.

Compound 1 can be subjected to a debromination reaction to obtain compound (20). Also, in the same manner as before (Ll is treated with mercury acetate and NaBH)
(21) can be obtained by reacting with 4. Compound (2
Compound (22) can be obtained by reducing the cyano group of 1). Further, the cyano group of compound (21) was hydrated to form compound (23), and then compound (23) was subjected to Hoffmann reaction (H
Ofmann reaction) to obtain compound (24). The compound group obtained by the present invention will be named using the following names. That is, the prentane derivative has the following structure. The homoprentane derivative has the following structure, the isotwistane derivative has the following structure, and the D homoisotwistane derivative has the following structure.

According to the present invention, for example, the following compounds can be obtained.

~υ! The compound of the general formula [1] obtained by the present invention is:
Since it is an amine derivative, various physiologically harmless inorganic and organic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, fumaric acid, succinic acid, etc. can be used as desired. Acid addition salts can be formed.

EXAMPLES The present invention will be specifically illustrated below with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Example 1 21.59 methylene diethyl malonate was dissolved in benzene 200
ml, and 9.89 g of cyclopentadiene was added dropwise.

After stirring at room temperature for 1 hour, concentrate. 85-9 by distillation
11.89 of an oily substance 2,2-diethoxycarbonyl-5-norbornene was obtained at 0°C/0.2mlH9. Similarly, diethyl methylenemalonate 47.3f! and cyclohexadiene 209 to oily 2,2-diethoxycarbonylbicyclo[2,2,2]oct-5-ene 65f
I got 1.

Example 2 Methyl α-cyanoacrylate 359 and 20 g of cyclopentadiene were stirred and concentrated in benzene at room temperature to obtain oily exo-12-cyano-endo-2-methoxycarbonyl-5-norbornene 569.

(This product contains about 30% exo-12-methoxycarbonyl-endo-2-cyano-5-norbornene.)
Similarly, from methyl α-cyanoacrylate and cyclohexadiene, oily exo-1-2-cyano-endo-2-2
Methoxycarbonylbicyclo[2,Z2,2]oct-5-ene was obtained.

Example 3 2,2-diethoxycarbonyl-5-norbornene2.
38f! , 10% monocaustic soda aqueous solution, 12Tn, 11 tetrahydrofuran, and 12d of methanol are mixed and stirred at room temperature for 24 hours.

After the reaction, the mixture is concentrated, and after distilling off tetrahydrofuran and methanol, the mixture is acidified to pH=2 and extracted with ether. After distilling off the ether, an oily product of 2,2-dicarboxy-5-
1.639 of norbornene was obtained. Similarly, 2,2-diethoxycarbonylbicyclo[2,2,2]octo-5
Oily 2,2-dicarboxybicyclo[2,2,2]oct-5-ene was obtained from -ene 209.

Example 4 1.639 ml of 2,2-dicarboxy-5-norbornene is dissolved in 60 ml of 0.5N sodium bicarbonate.

Iodine-Yoka potash solution (122.549, KI9.9
69) was added dropwise, the container was surrounded with aluminum foil, and the mixture was stirred overnight. After the reaction is complete, remove excess 12 with sodium thiosulfate.
is reduced, adjusted to pH=2 with HC2, and extracted with ether. After distilling off the ether, the solid 9-iodo-5-oxa-4-
1.89 oxo-13-carboxy blendan was obtained.
Recrystallization from benzene gave a white solid with a melting point of 171-172°C. The following compound was obtained in the same manner as in 0.

2,2-dicarboxybicyclo[2,2,2]oct-5-ene 10.59 to 10-iodo-5-oxa-3
- Crystals of carboxyisotwistane 6.29 were obtained.

Melting point: 198-200°C (recrystallized from benzene, exo-2-carboxy-endo-2-carboxymethyl-5
-10-iodo-6-oxa-5-oxo-3-carboxyhomoprenetane was obtained from norbornene. Melting point 2
12.5-2143C (reconsolidated from ethanol? Exo-12-carboxy-endo-2-carboxymethylbicyclo[2,2,2]oct-5-ene to 11-iodo-
6-oxa-5-oxo-3-carboxyhomisotwistane was obtained.

Melting point 205-210℃ (recrystallized from ether) Example
5 9-iodo-5-oxa-4-oxo-3-carboxy blendan 1.09 to thionyl chloride 20wLI
3 and heated under reflux for 3 hours.

After the reaction, it is concentrated and further azeotroped with benzene to remove remaining thionyl chloride. Next, add acetone 207711 and add 0.232% sodium azide while stirring under cooling.
Add 9 and stir overnight. After the reaction is complete, acetone is distilled off, ethanol is added, and the mixture is heated under reflux for 2 hours. After concentration, extraction with chloroform was performed to obtain 0.85f of solid 9-iodo-5-oxa-4-oxo-13-ethoxycarbonylamino blendan! I got it. Recrystallization from benzene gave a white solid with a melting point of 165-167°C. The following compound was obtained in the same manner.

Crystals of 10-iodo-5-oxa-4-oxo-3-ethoxycarbonylaminoisotwistane 8.51 from 10-iodo-5-oxa-4-oxo-3-carboxyisotwistane 9.79 Obtained.

10-iodo-6-oxa-5-oxo-3-carboxyhomoprenetane to 10-iodo-6-oxa-5-
Oxo-13-ethoxycarbonylaminohomobretan was obtained.

Melting point 112-114.5°C Obtain 11-iodo-6-oxa-5-oxo-3-ethoxycarbonylaminohomoisotwistane from 11-iodo-6-oxa-5-oxo-3-carboxyhomisotwistane Ta.

Melting point: 139-140°C Example 6 4.59 g of 9-iodo-5-oxa-4-oxo-3-ethoxycarbonylamino blendan is dissolved in 100 g of tetrahydrofuran.

A solution prepared by dissolving 7.89 g of tri-n-butyltin hydride in 50 g of ether is added dropwise, and 50 g. of azobisisobutyronitrile is added thereto, followed by stirring at room temperature for 2 hours. The reaction solution is concentrated and crystallized by adding n-hexane to remove the Sn compound. 2.89 g of white solid 5-oxa-4-oxo-3-ethoxycarbonylaminoprene was obtained. n
-Recrystallized from hexane-benzene mixed solvent, melting point 1
A white solid was obtained with a temperature of 57-159°C. The following compound was obtained in a similar manner.

5.2 g of 5-oxa-4-oxo-3-ethoxycarbonylamino-isotwistane was obtained from 8.19 g of 10-iodo-5-oxa-4-oxo-3-ethoxycarbonylamino-isotwistane.

Recrystallized from isopropyl ether, melting point 128-13
Crystals at 1°C were obtained. 6-Oxa-5-oxo-3-ethoxycarbonylaminohomoprenetane was obtained from 10-iodo-6-oxa-5-oxo-3-ethoxycarbonylaminohomoprenetane.

Melting point: 90.5-92.0°C (recrystallized from benzene-hexane) 11-iodo-6-oxa-5-oxo-3
-Ethoxycarbonylaminohomoisotwistane to 6
-Oxa-5-oxo-3-ethoxycarbonylamino homoisotui female tongue was obtained.

Melting point: 118-120°C (recrystallized from benzene-hexane) Example 7 1.469 g of calcium chloride is added to 30 g of dry ethanol and dissolved.

Next, 1.0 g of 5-oxa-4-oxo-3-ethoxycarbonylamino blendan was added and cooled to 2-5°C, and then 0.6719-ml of sodium borohydride was added.
Allow time to react. After the reaction, add saturated aqueous NH4Cl solution,
Chloroform extraction was carried out to obtain extract material endo-5-hydroxy-endo-3-hydroxymethyl-exo-3-ethoxycarbonylaminonorbornane 0.99%. This compound crystallized when left at room temperature for one week. The following compound was obtained in the same manner with a melting point of 115-116.5°C.

5-Oxa-4iOxo-3-ethoxycarbonylamino-isotwistane 4.21 to oily endo-5-hydroxy-endo-3-hydroxymethylexo-3-
4.19 ethoxycarbonylaminobicyclo[2,2,2]octane was obtained.

Endo-5-hydroxy-endo-3-β-hydroxyethyl-exo-3-ethoxycarbonylaminonorbornane was obtained from 6-oxa-,5-oxo-3-ethoxycarbonylaminohomoprenetane.

This compound crystallized when left at room temperature for one week.

Melting point 136-1.38℃ 6-oxa-5-oxo-3-
Ethoxycarbonylamino homoisotwistane to endo-5-hydroxy-endo-3-β-hydroxyethyl-exo-3-ethoxycarbonylaminobicyclo [
2,2,2]octane was obtained.

Example 8 Endo-5-hydroxy-endo-3-hydroxymethyl-exo-3-ethoxycarbonyla! 0.99 of minorbornane was added to 5 ml of pyridine, stirred under ice-cooling, and 0.9979 of P-toluenesulfonyl chloride was added at once. After stirring for 1 hour, the mixture was returned to room temperature and stirred overnight.

After the reaction was completed, 10% HCl water was added to make PHL, the mixture was extracted with chloroform, washed with saturated sodium bicarbonate water and saturated brine, and dried over magnesium sulfate. After concentration, the oily substance was purified by column chromite, and 0.349 of oily 5-oxa-3-ethoxycarbonylamino blendan was obtained from the chloroform eluate. The following compounds were obtained in the same manner. endo-5-hydroxy-endo-3
-Hydroxymethyl-exo-3-ethoxycarbonylaminobicyclo[2,2,2]octane 4.19 gave 2.29 of an oily 5-oxa-3-ethoxycarbonylaminoisotwistane.

This compound crystallized when left at room temperature for one week.

Melting point 73-74.5 weeks .45g was obtained.

Endo-5-hydroxy-endo-3-β-hydroxyethyl-exo-3-ethoxycarbonylaminobicyclo[2,2,2]octane to oily 6-oxa-3-
Ethoxycarbonylaminohomisotwistane was obtained.

It became.

Melting point: 87-88.5° C. Example 9 5-oxa-3-ethoxycarbonylamino blendan 19 was added to 40 ml of a 15% KOH aqueous solution and heated under reflux for 7 hours.

After the reaction, the reaction mixture was extracted with chloroform, dried over magnesium sulfate, and concentrated to obtain 0.839 of an oily substance, 5-oxa-3-aminoprene. 5-oxa-3-aminobrendan and 2 equivalents of HC2-methanol solution are added, concentrated, and washed with isopropanol to obtain white crystalline hydrochloride of 5-oxa-3-aminobrendan.

The melting point was 250°C or higher. The following compound was obtained in the same manner.

1.09 of oily 5-oxa-3-amino-isotwistane was obtained from 2.29 of 5-oxa-3-ethoxycarbonylamino-isotwistane.

From 0.459 of 6-oxa-3-ethoxycarbonylamino-homobrendan, 0.259 of 6-oxa-3-amino-homobrendan was obtained as an oil.

From 0.89 g of 6-oxa-3-ethoxycarbonylamino-homisotwistane, 0.5 g of 6-oxa-3-amino-homisotwistane was obtained as an oil.

) Example 10 2,2-dicarboethoxy-5-norbornene was reduced with lithium aluminum hydride in tetrahydrofuran and treated in a conventional manner to obtain crystals of 2,2-dihydroxymethyl-5-norbornene.

Recrystallized from isopropanol, melting point 108-110
It was warm at ℃. Similarly, exo-2-carboxy-5-
Norzel i So 1 Sodo 2 Monoacetic acid value hydrate 3.569 to oily Exo 2-hydroxymethyl Endo 2-
1.99 of β-hydroxyethyl-5-norbornene was obtained.

Example 11 The following compound was obtained in the same manner as in Example 7.

From 50 g of exo-12-cyano-endo-2-methoxycarbonyl-5-norbornene, 40.29 g of oily exo-12-cyano-endo-2-hydroxymethyl-5-norbornene was obtained. exo-2-cyano-endo-2-
Methoxycarbonylbicyclo[2,2,2]octo-5
An oily exo-12-cyano-endo-2-hydroxymethylbicyclo[2,2,2]oct-5-ene was obtained from the -ene.

Example 12 2,2-bishydroxymethyl-5-norbornene5.
59 and chloroform 93d1 tetrahydrofuran 627
! After charging Ll, 7.09 g of N-bromosuccinimide (NBS) was added while stirring at room temperature, and the mixture was stirred for 1 hour to promote the reaction.

After decomposing excess NBS with hypo, THF is distilled off, washed with water, washed with saturated NaC, and dried over magnesium sulfate. Concentrate to give 7.99 white crystals of 9-bromo-5-oxa-3
-Hydroxymethyl-Brendan was obtained.゛ether-
Recrystallization from a hexane mixed solvent gave a solid with a melting point of 72-73°C. The following compounds were obtained in the same manner.

exo-2-cyano-endo-2-hydroxymethyl-
5-norbornene 309 to 9-bromo-5-oxa-
3-cyanoprene 429 was obtained.

Melting point 45-46.5C exo-2-cyano-endo-
2-Hydroxymethylbicyclo[2,2,2]oct-5-ene 1.09 to 10-bromo-5-oxa-3-
Cyanoisotwistane 1.29 was obtained.

Melting point 108.5-109 Oily 10-bromo-6-oxa-3-hydroxymethyl-homobrendane from exo-2-hydroxymethyl-endo-2-β-hydroxyethyl-5-norbornene 1.09W9
I got it.

Example 13 In the same manner as in Example 6, 9-bromo-5-
From 9.79 g of oxa-3-hydroxymethyl-brendan, 5.69 g of oily 5-oxa-3-hydroxymethyl-brendan was obtained.

The reaction solution was treated by extracting water with n-hexane, re-extracting the n-hexane layer with water, combining the aqueous layers, and extracting with chloroform.
Dry over magnesium sulfate and concentrate. The following compound was obtained in the same manner.

9-bromo-5-oxa-3-cyanoprene 259
From this, oily 5-oxa-3-cyanoprene 109 was obtained.

10-bromo-5-oxa-3-cyanoisotwistane 1.29 to 5-oxa-3-cyanoisotwistane 0
．． I got 79.

Melting point: 105°C Example 14 637 η of mercuric acetate was added to a mixed solution of 20 d each of water and tetrahydrofuran, and 316 η of 2,2-bishydroxymethyl 5-norbornene was added at room temperature while stirring in a suspension state. Add 1f.

After stirring for 1 hour, 5.69% of caustic soda was added, and sodium boron hydride 380719 was added at room temperature.
and stirred for 2 hours. Next, Hf in decantation! After distilling off THF, the mixture is extracted with water and chloroform, and dried over magnesium sulfate. Concentrated, oily 5-
Oxa-3-hydroxymethyl-brendan 300m9
I got it. This product was obtained by the previous Example 13 and the IR. They matched in NMR.

Example 15 5-oxa-3-hydroxymethyl-brendan 5.0
9. P-toluenesulfonyl chloride 7.49 and benzene 30 ml were charged, and under ice water cooling, pyridine 13 ml
1 dropwise to stimulate the reaction.

After stirring overnight, the mixture was extracted with 10% HCI water, monoacetic acid, washed with saturated sodium bicarbonate water, dried over magnesium sulfate, and concentrated to obtain 9.6θ crystals. This was purified by column chromatography, and crystals of 5-oxa-3-P-toluenesulfonyloxymethyl-brendan 6.6θ were obtained from the benzene eluate. Example 165
-Oxa-3-P-toluenesulfonyloxymethyl-Brendan 430Tnf7 and lithium bromide monohydrate 40
After refluxing 0TI19 in methyl ethyl ketone solvent for 3 hours, the solvent was distilled off, H2O and CHCl3 were added to the residue, and the organic layer was separated.

The solvent was distilled off to obtain the desired 5-oxa-3-prommethyl-brendan 300Tf19 as an oily substance. Example 175-oxa-3-prommethyl-Brendan 3
00~ and potassium phthalimide 250TI9 were heated at 150°C for 2.5 hours in dimethylformamide.

After cooling, chloroform and water were added to the reaction solution, and the target product was extracted with chloroform. The chloroform was washed with a 5% aqueous Na2cO3 solution and water (3 times), and then dried.

The mixture was concentrated to obtain the desired 5-oxa-3-phthaliminomethyl-brendan 300~ as crystals. Recrystallization from isopropanol gave a product with a melting point of 135-137°C.
Example 18 5-oxa-3-phthaliminomethyl-brendan 30
Dissolve 0mf7 in 2ml of ethanol, add hydrazine.1
Hydrate 100Tf1f7 was added and heated for 5 to 10 minutes.

White crystals were precipitated, so they were cooled and added with 10% HCI (2
Added soybean paste and heated for 10 minutes. The precipitated crystals were filtered and washed with a small amount of ethanol. The filtrate and washing solution were combined and concentrated, made alkaline by adding 10% NaOH, and extracted with chloroform. After washing with water, dry and concentrate to form an oily 5
-Oxa-3-aminomethyl-Brendan 100? ! 1
I got a 9. Example 1910%H2O25Oml and 6N
-20 g of an ethanol solution of 49 g of 5-oxa-3-cyanoprene was slowly added dropwise to 2.8 g of the aqueous NaOH solution, stirred at 40 to 50° C. for 30 minutes, and further refluxed for 2 hours.

The reaction solution was concentrated, and the target product was extracted with ethyl acetate. The crystals obtained by concentrating the solvent were recrystallized from benzene to obtain 3.8 g of 5-oxa-3-carbamoylprentane. melting point
138-139.5℃ Similarly, 5-oxa-3-cyanoisotwistane 21
5-oxa-3-carbamoylisotwistane from 1.
I got 69.

Melting point: 166.5-167.5 Example 20 5-oxa-3-carbamoylprentane 1θ was dissolved in a dry tar solution containing sodium ethoxide, and bromine was added dropwise according to a conventional method.

After stirring at room temperature for 10 minutes, the mixture was heated for 10 minutes. Treatment was carried out in a conventional manner to obtain 1.29 5-oxa-3-ethoxycarbonylaminoprentane. This was consistent with that obtained in Example 8. Example 21 1 g of 5-oxa-3-cyanoprene obtained by the method of Example 13 or Example 14 was reduced with lithium aluminum hydride in anhydrous tetrahydrofuran, water was added, and the target compound was extracted with ether.

It was treated in a conventional manner to obtain 0.8f1 of 5-oxa-3-aminomethylprentane. This was consistent with the compound obtained in Example 18.

Similarly, 5-oxa-3-cyanoisotwistane 2.
2.09 of oily 5-oxa-3aminomethylisotwistane was obtained from 09.

Film. I Rν. 3400, 3300, 1030, 1010m
ax Hydrochloride Melting point>250°C Example 22 Dissolve 2 g of caustic soda in 20 g of water and add 0.6 g of bromine under ice cooling.
Added mj.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, l represents 0 or 1, m and n represent 1 or 2. ] A novel tricyclic cage-shaped amine compound and its acid salt.