JPS5942398A - 1-deazaadenine nucleoside compound and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula (when X is halogen, R is OH, Y is beta-hydroxyl and Z is H; when X is amino, R is OH, Y is beta-hydroxy or H and Z is H, or R is alkylthio or aminoacylthio, Y is H and Z is alpha-hydroxy). EXAMPLE:6-Chloro-1-deazapurine arabinoside-3',5'-disiloxane-2'-acetate. USE:Antiviral agent and antitumor agent. PROCESS:For example, 6-chloro-1-deazapurine riboside is made to react with 1,3- dichloro-1,1,3,3-tetraisopropyldisiloxane to obtain 6-chloro-1-deazapurine riboside- 3',5'-disiloxane, and a strong electron-attracting group, e.g. trifluoromethanesulfonyl group is introduced to the 2'-position. The product is made to react with a nucleophilic reagent such as sodium acetate to invert the 2'-OH configuration, and the protecting groups are removed to obtain the objective 6-chloro-1-deazapurine arabinoside.

Description

DETAILED DESCRIPTION OF THE INVENTION S-adenosylmethionine (hereinafter referred to as SAM)-dependent methyltransferase is m-RNA.

SAM is an important enzyme responsible for the methylation of macromolecules such as proteins and phospholipids, and the methyl donor involved in this enzyme reaction is SAM. SAM is produced by this reaction) S-adenosylhomocystine
tein) (hereinafter referred to as SAH (Xf')), and since this SAH is a strong inhibitor of SAM-dependent methyltransferase, it is thought that this substance controls the in vivo methylation reaction. SAH is S-adenosylhomocysteinas (3)ase.
e) (hereinafter referred to as 5AIIα8e), it is broken down into eriadenosine and homocystine and regulated. Since this methylation reaction is one of the basic reactions of cell proliferation, it is thought that it is possible to regulate the proliferation of cells or viruses by regulating 5AHase.

Incidentally, 8-deazaadenosine is a competitive inhibitor of 5AHase, but it also inhibits Rous sarcoma virus (Rows sarcoma virus).
5arco gourd virus), Sindopis virus C
3ind, vis virys), boliomaui/l
/X (Polyoma virus), Herpes virrbs (ty
It shows the growth inhibitory effect of peO.

On the other hand, S-adenosylmethionine, which is decarboxylated by SAM, is an amine donor for the synthesis of Szerumidins lumin, which is a biological polyamine. Polyamines are important factors for cell proliferation, and it is thought that it is possible to suppress the proliferation of cancer cells by regulating polyamine biosynthesis. (X, C.

(4) 7'ang et al. J, Mec1. Chem,, vol. 24, 1
277 (1981)).

In particular, adenosine derivatives 5'-methylthioadenosine and 5'-ethylthioadenosine inhibit spermidine synthase and spermine synthase.

Furthermore, 5'-methylthio-7-diazaadenine inhibits sulfurumin synthesis. (J.Couard, et al., J.Med.Chem, vol. 17, 1286-'!-ji (1974): H9Ilibasarni et al.Bi
ochem, J., vol. 187, p. 419 (1980)) The present inventors conducted intensive research to synthesize a derivative of deazaadenosine (1) and screened for active substances using BAHα8e inhibitory activity as an index. Since we observed strong inhibitory effects on deazaadenosine derivatives, we considered them to be promising as antiviral and antitumor agents, and thus completed the present invention.

The present invention provides novel l-deazaadenosine derivatives (I
) and its manufacturing method.

α) General formula (I) (5) (wherein, when X is halogen, R and Y are β-hydroxyl group,
Z represents a hydrogen atom, and when X is an amino group, R is a hydroxyl group, Y represents a β-hydroxyl group or a hydrogen atom, and Z represents a hydrogen atom, or R is an alkylthio group, an aminoacylthio group (
, Y represents a hydrogen atom, and Z represents an α-hydroxyl group. ) A method for producing the compound of general formula (I) will be explained.

General formula (I) OZ (wherein, X represents a halogen or an amine group, and Y represents β-
The hydroxyl group and Z represent a hydrogen atom. ) of 6-chloro-1-deazapurine riboside, s/, 5
/In order to selectively protect both hydroxyl groups, for example, 1,8-dichloro-1,1,3゜8-tetraisopropyldisiloxane is reacted with a tin group such as pyridine to protect 6-chloro-
1-deazapurine riboside-s/,5/-disiloxane is used as 7, then a strong electron-withdrawing group such as trifluoromethanesulfonyl group is introduced into the 2' position, and then hexamethylphosphotriamide, dimethylformamide, etc. By reacting with a nucleophile such as acetic acid, sodium benzoate, etc. in a non-aqueous polar solvent to invert the coordination of the 2'-position hydroxyl group, and then removing the protecting group, One of the target products, 6-chloro-1-deazapurine arabinoside, can be obtained. When aminating this 6-chloro-1-deazapurine arabinoside, 6-amino-1-de(7) azapurine arabinoside is Sid can be obtained in high yield.

Also, general formula (I) (In the formula, X represents an amino group, and Y and Z represent a hydrogen atom.

) for l-deazaadenosine 8
/, 5/'% For example, 1.8 to selectively protect hydroxyl groups.
-Dichloro-1,1,8,8-tetraisopropyldisiloxane is reacted in a base such as pyridine to form 1-deazaadenosine-ff,5'-disiloxane, and then in the presence of a base such as triethylamine or diethylaminopyridine. , phenoxythiocarbonyl chloride is reacted with 2'
The 927th position can be deoxylated by phenoxythiocarbonylation and reduction (with tributyltin hydride), followed by deprotection to give 1-de(8)aza-2'-deoxyadenosine. .

In addition, in producing the general formula (I) (wherein, X is an amino group, R is an alkylthio group or an aminoacylthio group, Y is a hydrogen atom, and Z is an α-hydroxyl group), l-deaza The 5'-position hydroxyl group of adenosine is selectively converted into chloride, and then alkyl mercaptans such as methyl mercaptan, butyl mercaptan, isobutyl mercaptan, or L-homocysteine are added in a non-aqueous polar solvent such as dimethylformamide or hexamethyltriamide phosphate. The desired product can be produced by reacting with profitable amino acids such as

(9) of the 1-deazaadenosine derivative obtained here When examining its harmful effects, it showed relatively strong inhibitory activity.

Furthermore, the compound of the present invention exhibits resistance to adenosine deaminase and has the effect of having a sustained action. Therefore, the compounds of the present invention can be expected to be used as antiviral agents and anticancer agents. The present invention will be described in detail below with reference to Examples, but the present invention is not limited thereto.

6-Chlor-1-deazapurine riboside 1.00? (
8.5 mmol) was dissolved in pyridine lQm/, and tetraisopropyl dichlorodisiloxane 1.199 (8,8
mmol) was added under stirring, 5μ of the drained water that had been reacted for 8 hours was added, and 5QT! of chloroform was added. Extract with Llx3. After drying the chloroform layer with anhydrous sodium sulfate,
Concentrate to dryness. The residue was applied to a column (φ1.4 x 41.2 cm) packed with silica gel 80R and developed with chloroform, and the corresponding two fractions were collected and concentrated to obtain dirowchloro-1-deazapurine riboside-8', 5'.
-Disiloxane 1.66r (89.5 units) (10) was obtained.

Mass spectrum (K/Z) 52g15so (Af+1), 5271529 (foundation),
485/487 (A/+1-41.484/486CM
-48) NMR spectrum (δρ voice, TMS/CDCl5.20
0MHz) 1.0-1.2 (m, 285 1sp) 4.0-4.
2 (m, 8 H, H-4'&H-5') 4.59
(dd, LH, H-2' J=1.5.5.4)4.
78 (sbr%LH,0H-2'), 5.04Cdd
, LH, H-8' J=5.9.6.6), 6.09
(d.

iff, H-1' J=1.0), 7.80 (d
, IH.

H-I J=54), 83B (d, LH%H-2J
=5.4>, 8.2 (S IH, H-8) Example 2 6-chloro-1-deazapurine riboside-aS5/-disiloxane 1.55 f (2,94wnol) was dissolved in dimethylaminopyridine. 895F119 (8,24 飄 o1)
) 0.45 d (8,81 ml) of ethylamine was dissolved in 14 ml of dichloromethane, trifluoromethanesulfonyl chloride was added dropwise under water cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, and insoluble materials were extracted with chloroform 1oodX3. The chloroform layer was dried with anhydrous sulfuric acid) After drying with IJum, it was concentrated to dryness, and then transferred to a column packed with 30 f of silica gel (φ1.4 x 42.2 c).
m), eluted with chloroform, collected and concentrated the corresponding two fractions, and a colorless candy-like substance 6-chloro-1 was obtained.
-deazapurine riboside-8', 5'-xan-2/-)su7) 1.64t (84,4,chi) was obtained.

Mass spectrum (Shu/Z) 617/619 (A/+1-48), 616/61
8 (Af-48), 484/486 (&-48-188
+1) NMR:x! vector (δppm, TMS/CDC15,
200MHz) 1.0-1.2 (m, 28H%isp), 4O
-48 (Raku, 8H, H-4'&H-5') 5.28
(dd,'J-H,H-8J=4.9.9.1),5.
79 (d.

1H% H-2' J=4.9), 6.22(8,
14H-1'), 1.84 (d% iH,,7=4.
9), 8.22 (d% 18% H-2J=5.4)
, 8.27 (8,18% H-8) Example 8 6-chloro-1-deazapurine ribocyto°-5r5/-
Disiloxane-2/)su7v-)1.2?
r(1,98rrwnol) in sodium acetate 81 ? in hexamethyltriamide phosphate 8d? tty
(8.86 mnol) at room temperature for 6 hours with stirring, using five silica gel plates for preparation, benzene-
It is developed with ethyl acetate (5:1) and the corresponding bands are eluted with chloroform-ethanol (10:1). By collecting the eluate and concentrating to dryness, a colorless and transparent candy-like substance 6-chloro-1-deazapurine arabinocyto-a was obtained.
/, 51-disiloxane-21-acetate 852■
(77.7%) was obtained.

Mass spectrum (m/Z) 5701572 (M+1), 5691571CM), 5
271529 (A/+1-48), 526 (13) 7528CM-48), 277/279 (Af-812
) NMR7,”!cuttle(δpptn, TMP;/CD
C1B, 200MHz) 1.0-1.2 (m, 28H, i8p), 1
．． 64 (s, 8H, AC), 8.97 (97+,, lH
, H-4'), 4.14(d&ABχ 2H,H-5'
), 4.91 (t% lH%H-8' J = 8.8
．． 8.8), 5.60 (dd% lH%H-2', 7=
6.4.8.1), 6.59(d, IH%H-1' J
=6.4), 7.29(d, IH, Ij, -1,
7=5.4), a25(d, IH, H-2J=4.9>
, 8.50 (s, IZf.

H-8) Example 4 6-chloro-1-deazapurine arabinoside 2'-〇-acetyl-8',5'-disiloxane 8521Q (
1,497trvnol) to methanol51) + jlC
Dissolve, add 1 OWit triethylamine, seal and store overnight (18 hours). The reaction solution was concentrated to dryness, the residue was dissolved in tetrahydrofuran 1QmJ, and tetrabutyluane 1AX monium fluoride 81411'? (8,29 mmo
Add 1) and leave to stir at room temperature for 20 minutes. Pour water and extract with chloroform 59m x 8. The aqueous layer was dried and developed twice with chloroform-ethanol (:l) using 8 silica gel plates for adjustment.

The corresponding bands were extracted with chloroform-methanol (8:1).
The eluate was concentrated to dryness, and the residue was polycrystallized from ethanol to obtain 6-chloro-1-deazapurine arabinosites 890-(91,71).

Melting point 196-197°C Mass spectrum (m/Z) 285/257 (M), 254/256 (M-81),
212/214 (M-78), 152/154 (B+8
0), 15B/155 (B+1), 152/154 (B
) NMR spectrum (δppmDMEO/DMSO-da
, B 00 MHz) 8.66 (Ji, 2H%H-5'), 8.81 (q%l
H%H-4' J=4.5.9.1), 4.15 (regular 8H, H-2'&H-8'), 5.10 (t, L
H.

0H-5'), 5.62.5.56 (each d
, 2H1OH-2'&8'), 6-42 (d,
14. H-1'J=44), 7.44(d, 18% H
-1, J=5.4), 8.29 (d, LH, H-2J
=4.9>8.59 (s, IH, H-8) 6-chloro-1-deazapurine arabinosite 580 m
9 (1,88 rrvnol) was added with 7.0 l of hydrazine hydrogen chloride and refluxed for 1 hour under a nitrogen stream. After concentrating the reaction solution to dryness, it was azeotropically distilled off with water to remove hydrazine hitrad. Raney nickel 21 and deaerated water 71
Reflux for 1 hour under a nitrogen stream.

The nickel was removed by washing with water, the F solution was concentrated to dryness, and the residue was crystallized from water to obtain 1-deazaadenine arabinosite 2821119 (65,6) as white needle crystals. . Decomposition point 261-262℃ Mass spectrum (?7L/Z) 266/267 (M+), 249/250 (J/-17
), 286-28? CM-80), 168/164(
B+80), 184/135 (B+l) NMR spectrum (appm, DMSO/DMSO-d6.200 M
Hz) 8.62 (m, 2H%H-5'), 8-74 (tn,
IH, H-4'), 4.10 (m, 2H, H-2'&
8'), 5.14 (t, IH,,OH-5'
), 5.48.5.58 (eachd, 2H, 0H-
2'&8'), 6.28-6.85 (apprehension, 4H
%H-1', NH7-6, H-1), T, '1TCd,
IH%H-2, J=5.4), 8.09 (s, IH,
H-8) Example 6 500 # of 1-deazaadenosine (1,88 ml) was dissolved in 5 wl of pyridine, and 650 # of tetraisopropyl dichlorodisiloxane (2,07 ml) was added at room temperature for 4 hours. Stir. After the reaction, 6N water is poured and extracted with chloroform 5011jX8. The extract is dried over Glauber's salt and then concentrated to dryness. The residue was eluted with 2% methanol-chloroform through a column packed with silica gel SOt (φ1.8 x 2.7 on), and the corresponding fractions were concentrated to dryness to give 1-deazaadenosine-a/, S
/-disiloxane 888119 (98.0(17)%) was obtained.

Mass spectrum (inert/g) 5081509 (A/), 465/466 (A/-4
8), 168/164 (B+80), IJ15/186
(B+2) NMR spectrum (δpp, TMS/CDCj
s, 200 MHz) 1.0-1.2 (m, 28H, 1sp), 4.18
(m, 8H%H-4'&5"), 4.58 (FJI,
d, 2H.

H-2'&OH-2') 5.10 Cdd,
IH, H-8'), LO8 (1, lH, H-1' J=
1.5), 6.48 (d, LH%H-1, J=5
．． 4), 7.97 (d, IH, H-2, J=5.9)
, 7.98 (s, IH%H-8) Example 2 1-deazaadenosine-a/, S/-disiloxane 8
80 da (1,78 flo l), dimethyl annoviridine 21119,) ethylamine 0.51 was dissolved in a7tonitrile l0IK (4C1) and stirred at room temperature under a nitrogen stream to phenoxythiocarbonyl chloride. Lido (1
8) Add 568 ml (8.46 mmol) and react for 3 hours. Pour the reaction solution into ice water and add 10 ml of chloroform.
Extract at 0m/X3. After washing the organic layer with water, it is dried over anhydrous sodium sulfate to dryness to gkm. Treat the residue with silica gel 492
Column packed with (φ1.6 x 58.8CF!L)
The light reddish brown 1-deazaadenosine-8' was obtained by elution with chloroform and concentration of the corresponding fractions.
, 907 da (81.8%) of 5'-disiloxane-27-phenylthiocarbonate was obtained.

Mass spectrum (normal/g) 644/646 (M+), 601/602 (M-43
), 5411542 (M-108), 168/164
(B+80), 184/185 (B+1) NMR spectrum (δ1) p'In, TnoWElCDC et al., 200
MHz) 1.0-1.2 (bait, 28H%1sp), 4.08-
4.21 (m, 8H, H-4'&5'), 4.8
9 (j, br.

2d%MHz -6), 5.87 (dd, iH, H-8
' J = 5.2.8.2), 6.22 (d, IL
H-1' J=1.0), 6.40 (dd, IHS
H-2' J= 1.0.5.8) 6.44 (d
,, LH,II-I J=5.6), 7.1-
7.5 (m, 5H, aromatic origin), 7.96c d
, 14. H-2, y=5:er), 8.00
(g, 18% H-8) Example 8 ■-Deazaadenosine-s/, 5/-disiloxane-2
'-Phenylthiocarbonate 547■ (1,82wn
o l) is refluxed with 3.0 d of tri-n-butyltin (tin) hydride and a catalytic amount of azobisisobutyronitrile in a nitrogen stream for 8 hours. Concentrate the reaction solution as much as possible.
, a column packed with silica gel 501 (φ2.2 x 8
2.8 cm) and chloroform-ethanol (
30:1). Both the corresponding fractions were concentrated and the residue was subjected to preparative thin layer chromatography in chloroform.
1-deaza-2'-deoxyadenosine-a/, 5/ - 652 m9 of disiloxane were obtained.

Mass spectrum Cm/Z) 492/498 (A/+), 449/450 (M-48
), 168/164 (B-+lO), 184/'13.
5 CB+2) NMR spectrum (δppm, TMS/CDCl, 2
00MH2) 1.0-1.1 (m%2.8 H,'1s7i),
2. '65 (m.

'2. H, H-2'), 3.90 (q, 14.
H'-4'J=8.5.7.4), 4.05 (m, 2
1LH-5'), 4.91 (7?L, lH,H-
3'J=1.9.1'5[), 5.02 (s
br, 2H%NH2-6), 6.87 (dd.

14, H-'1' J=8.8) δ6.48 (
d, LH.

H-I J=5.0), 8.0'l (d, 14.
'H-2, J=5.4), 8.01 (a, lH, H-
8) ■-Deaser 2'-deoxyadenosine-8/, 5
/-Disiloxa76 '40 mli (1,80mm
ol) in 1QmJ of tetrahydrofuran and diluted with 640μ of tetrabutylammonium fluoride (2,-'60
Add 1) water and stir for 20 minutes at room temperature.
After adding 0d, extract with chloroform 10 Q+n/x 8. The aqueous layer was treated with P(21) and the v liquid was concentrated to dryness. The resulting candy-like residue was subjected to preparative silica gel thin layer chromatography and developed with chloroform-methanol (5:1). The corresponding bands are eluted with chloroform-methanol (8:1) and the eluate is concentrated. The resulting residue was Doweyc I
8 (OR-type) 100 m column packed with resin (φ
2.2 x 41.0 cWL) and bathed with 60% methanol-water. The corresponding fractions were collected and lyophilized, and the residue was crystallized from ethanol to obtain needle-like 1
-Deaza-27-dioxyadenosine I B 61v
I got it.

Decomposition point = 207-208°C Mass spectrum (mouse/g) 250/251 (M+), 220/221 (A/-80
), 168/164 (B+80), 162/164 C
B+29), 184/185 (B+1) NMR spectrum (δppm, DME O/DME O-δ6.2
00MHz) 2.18 (trL, IH, H-2'α), 2.77 (
trL, IH.

H-2'b), 8.56 (m, 2H, H-5'
), 8.88 (22) (m, IHSH-4'), 4.88 (m, iH, H-8
') 5.29 (S, br, IH, 0H-8'), 5.
72 C8゜bτ, IH, 0H-5'), 6.84 (
dd, IH, H-1'J=5.9.8.5), 6.8
4 (d, LH, H-1, J=5-5), 6.42 (,
S', 2H%NH, -6), 7.75 (d, LH, H-
2, J=5.5), 8.28 (S, IH.

H-8) Example IQ 1-deazaadenosine 1. Of (8,75m mol
) in advance with phosphoric acid hexamethyltriamide5. On/+c
Thionyl chloride 1.511Ll (20.8m ma
Add t) to the mixed solution and stir at room temperature in a nitrogen stream for 20 hours. After the reaction, water was added and concentrated, neutralized with 1N ammonia, and concentrated again.
Column packed with H+ type) 100+117 (φ2,2 x
After washing with water and eluting with 1M aqueous ammonia, the eluate was concentrated to dryness, and the residue was crystallized from ethanol to give white needle-shaped crystals, 1-deaza-5'-deoxy-5'. -Chloradenosif 877
m9 (70.9%) was obtained.

Melting point 127-125°C Decomposition point 185-187°C NMR S'! vector (δppm, DMSO/DMSO-
tla, 200 MHz) 8.25 (s, IH, H-8), 7.80 (d, LH
, H-2J=5.7), 6.86 (d, 14°H
-IJ=5.7), 5.87 (s br, 2HN
H2-6), 5.95 (d, LH, H-1' J-
5,9), 5.52.5.89 (d, 2 II,
0H-2'&8'), 4.76 (q, 14.
H-2'), 4.20 (Q, 1.#, H-8'
), 4.05 (ps q, IHlH-4'), 8.9
0 (m, 2 H, H-5') elemental analysis value: Cn
HIsN40sc l-%CJfs OH theoretical value: C,
47,02;H,5,44;N,17. '78; (j,
11.25 Actual value: C, 46,84; H, 5,68; #, 17.6
2; (J, 11.45 Example 11 ■-Deaza 5'-deoxy-5'-chloradenosine l 10 m? (0.89 mmol) in advance isobutyl mercaptan 0.201111 (1.85 mmol)
), sodium hydrogen 60 m9 (1,50 mmol)
dimethylformamide2. The mixture was added to the solution mixed and adjusted in Od under cooling with water and allowed to react at 0°C for 5 hours. The reaction solution was concentrated to dryness, and the residue was subjected to preparative silica gel thin layer chromatography, developed with chloroform-methanol (7:1), and the corresponding band was eluted with chloroform-methanol (5:1). The concentrated residue was crystallized from ethanol to obtain needle-like crystals, which gave 1-deaza-5'-deoxy-51-isobutylthioadenosine 1.
07m9 (81.4%) was obtained. Melting point 187-188°C Mass quictor (m/Z) a 38/839 cM+), 281/282 (Af-
57), 249/250 (Af-89), 168/16
4 (Z?+80), 185/186 (Z?+2) NMR spectroscopy (δppm DMSO/DMEOc
16.200MHz) 0.85 (q, 6Hs 1so-Bu), 1.67
(m, LHl(25) i-Bu), 2.86 (dd, 2Hiso -1
ht, CH2J = 2.2.6.6), 2.80
(m, L H, H-2'), 4.42.5.50
(br, d, 2H, 0ff-2'&8'), 5.90
(d% LH, H-1' J=5.9), 6.84
(8, br, 2H, N & 6), 6.86 (d,
LH.

H-I J=5.4), 7.79 (d, 14.H
-2,7=5.4), 8.24 (s, IH, ll-8
) Elemental analysis value' C+ y H2JV < O, S Theoretical value: C, 5B, 28; H, 6, 55; #, 16-55; S
, 9. ．． 47 Actual measurement value: C, 58,06; H, 6,45; #, 16.6
2;S, 9.41 Example 12 In a sealed tube, 880 Da (1,28 mmol) of L-homocystine was added while cooling in a dry ice-acetone bath.
Liquid ammonia 2511Lt, metallic sodium 0.11
Mix to obtain a dark colored liquid. Add a small amount of ammonium chloride to this to make a colorless liquid, and
7-chloradenosine 400m9 (1,41mmol)
was added and stirred for 1 hour, then returned to room temperature (2F'+ ' and allowed to react for another day. After the reaction, ammonia was gradually evaporated, the residue was dissolved in water 2011Z, neutralized with 10% acetic acid, and Dowez 50WX 8 (NH4 type) was adsorbed on a 60g column, washed with water, eluted with 1N ammonia water, and the corresponding two portions were lyophilized.
280 m9 (42.6%) of -deaza-5'-deoxy-5'-homocystenyl adenosine was obtained. Decomposition point:)1
78°C NMR spectrum (62%, DMSO/DMfF; 0-
do, 200 MHz) 1.7 g (Ji, 2H, H-β), 2.55 (t,
2H.

H-r J=7.8), 2.96 (2HSH-5'
), 8.22 (dd, IH, H-α), 4-84
(dd, IHSH-4'), 4-89 (t, IH
, H-8'), 4.84 (t, IH, H-8'),
6.08 (d, iH, H-1'J=6.5), 6.
68 (d, IH, H-1, J=5.8), 7.96
(d, IHlH-21,7=5.8), 8.85
C8, IH, H-8) Oni-ttu Shadow Yellow Ruby/Seeds (Yellow Lupin
S-adenosylhomocystenase (adanoglhomoeystminasg) (S
AHass) (A, Gxranowskt and J.
, PawalkigwiezrEur-J, Bio
chem, + vol. 80, p. 517 (1971)
) was incubated in the presence of the 1-deazaadenosine obtained in Example 5, which is a representative compound of the present invention, and a certain amount of it was collected at intervals and added to the BAH synthesis system. The SAH thus produced was measured by high performance liquid chromatography to determine the residual activity of 5AHas-.

The results are shown in Figure 1.

As is clear from FIG. 1, l-deazaadenosine and 1-deazaadenosines such as 1-deazaadenine arabinocyto and 2/-deoxy-1-deazaadenosine, which are the substances of the present invention, are as follows: BAHα8e activity is irreversibly (or over time) inactivated.

(References: P., Chiwrg et al., Arch, E.
iochmn.

Biophyg, vol. 207, p. 175 (1981
Year)).

[Brief explanation of the drawing]

FIG. 1 is a graph showing the residual activity of BAHα8g. The symbols in the cough drawings are explained as follows.・rd: Control Δ dc"Ado: 2'-deoxy-1-deazaadenosine 45gM ατac'Ado: 1-deazaadenine arabinocyto 90μM ○ C"Ado: l-deazaadenosine 60gM Patent Applicant Sun) IJ-Co., Ltd. Agent Patent Attorney Kyozo Yu Asa (29) Bottom/V21 Inc., ll-to time 1'W'l (亦) Procedural Amendment 1980, October 22 Kazuo Wakasugi, Commissioner of the Japan Patent Office, 2, Title of the invention 1 - Deazaadenine nucleoside compound and its manufacturing method 3, Relationship with the case of the person making the amendment Address and name of the patent applicant (190) Suntory Ltd. 4, Agent 5, Subject of amendment 1, the scope of claims is amended as follows. "(1) General formula m (wherein, when X is halogen, R", Y is a β-hydroxyl group,
Z represents a hydrogen atom; when X is an amino group, R is a hydroxyl group, Y is a β-hydroxyl group or a hydrogen atom, Z is a hydrogen atom, or R is an alkylthio group, an aminoacylthio group, and Y is The hydrogen atom and Z represent an α-hydroxyl group. ) A 1-deazaadenine nucleoside compound represented by: (2) In producing general formula (I) (wherein, X is a halogen, R is a hydroxyl group, Y is a β-hydroxyl group, and Z is a hydrogen atom), 3',5'-protected 6-chloro-1 -(1) 1-deazaadenine nucleoside characterized by converting the 2'-position hydroxyl group of deazapurine riboside into a triflate, then inverting the coordination using an appropriate nucleophilic reagent, and then deprotecting it. Method of manufacturing compounds. (3) In producing the general formula (■) (wherein, X is an amine group, one group in front of R, Y is a β-hydroxyl group, and Z is a hydrogen atom), 3', 5'-protected 6- 1-deaza, which is characterized by converting the 2'-hydroxyl group of chloro-1-deazapurine riboside into a triflate, then inverting the coordination using a suitable nucleophile, and then aminating the triflate. Method for producing adenine nucleoside compounds. (4) In producing the general formula (■) (wherein, X is an amine group, R is a hydroxyl group, and Y and Z are hydrogen atoms),
Production of a 1-deazaadenine nucleoside compound characterized by phenoxythiocarbonylating the 2'-position hydroxyl group of 3',5'-protected 1-deazaadenosine, followed by reduction with tri-butyltin hydride, and then deprotection. Law. (2) (5) In producing the general formula (■) (wherein, X is an amino group, R is an alkylthio group or an aminoacylthio group, Y is a hydrogen atom, and Z is an α-hydroxyl group), 1. A method for producing a 1-deaza adenine nucleoside compound, which comprises halogenating the 5' position of deaza adenosine, and then reacting with an alkyl mercaptan or an amino acid. j 2. The specification is amended as follows. -line-3LLjL-rev.L and-62R and
R is hydroxyl group, 251 hydrogen hydrogenation, (3)

Claims (1)

[Claims] α) General formula (1) (wherein, when X is a halogen, R and Y are β-hydroxyl groups,
Z represents a hydrogen atom; when X is an amino group, R represents a hydroxyl group, Y represents a β-hydroxyl group or a hydrogen atom, Z represents a hydrogen atom, or R represents an alkylthio group, an aminoacylthio group, YFi hydrogen The atom Z represents an α-hydroxyl group. ) A 1-deazaadenine nucleoside compound represented by: (2) General formula (■) (wherein, X is norogen, R and Y
(1) β-hydroxyl group, Z represents a hydrogen atom. ), the hydroxyl group at the 2' position of ba/,5/-protected 6-chloro-1-deazapurine riboside is triflated, and then the coordination is reversed using an appropriate nucleophile. 1. A method for producing a 1-deazaadenine nucleoside compound, which comprises protecting the 1-deazaadenine nucleoside compound. (8) In producing the general formula (■) (wherein, X is an amino group, R and Y are a β-hydroxyl group, and Z is a hydrogen atom), 8',5'-protected 6-chloro The 2'-hydroxyl group of -1-deazapurine riboside is converted into a triflate, and then an appropriate 1
1. A method for producing a l-deazaadenine nucleoside compound, which comprises inverting its coordination using a nucleophilic reagent and then aminating it. (4) General formula (■) (wherein, X is an amino group, Rtl-1
The hydroxyl group, Y and Z represent hydrogen atoms. ), the hydroxyl group at the 2' position of 98'', 5'-protected@l-deazaadenosine was phenoxythiocarbonylated, then reduced with tri-n-butyltin hydride, and then deprotected. A method for producing a nucleoside compound characterized by l-deazaadenine (2). (5) General formula (I) (wherein, X is an amine group, R is an alkylthio group or an aminoacylthio group, Y is a hydrogen atom, and Z is an α- A method for producing a l-deaza adenine nucleoside compound, which comprises halogenating the 5' position of 91-deaza adenosine, and then reacting with an alkyl mercaptan or an amino acid. .