JPS6178797A - 4-demethoxyadriamycin - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I. USE:A carcinostatic agent. PREPARATION:For example, 14-brome derivative of (+)-4-demethoxydaunomycin shown by the formula II is treated with an acylating agent such as potassium acetate, etc. to give a 14-acyl derivative, which is reacted with trifluoroacetylated amino group-containing saccharide shown by the formula III (R<2> is acyl) to give a (+)-3'-N-trifluoroacetyl-4-demthoxyadriamycin shown by the formula IV(R<1> is acryl). Then, 14-acyl group of this compound is eliminated, the resultant compound is reacted with methyl orthoformate, etc. to give a compound shown by the formula V (R<3> and R<4> are H, alkyl, or alkoxy). Further, this compound is hydrolyzed to remove trifluoroacetyl group, and then acetal group is eliminated, to give a compound shown by the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 4-demethoxyadriamycin represented by the formula:

The 4-demethoxyadriamycin hydrochloride of the present invention is 22
This is a compound that starts to decompose around 01:'' and ends around 230t:''.
The specific optical rotation [α] crystal 0 at 0C is a compound having + 190 =, ゛. Moreover, the mass spectrometry, infrared and I) l-nuclear magnetic resonance spectra of 4-demethoxyatriamayne 7-hydrochloride are as follows.

'1itit analysis spectrum'(SIMS); m/z
5141mMH], 384 (aglycone), infrared shale (KBr); 3400 (OH,
NH).

1725 (CO), 1620 (quinone).

1590 (aromatic ring) inverted-1゜1H-nuclear magnetic resonance spectrum (d,-dimethyls)
'y)') ; J= 1.1q (3H, d.

J-=6Hz, 6'-83), 1.70-2.00(
2H, m, 2'-H2), 2.00-2.30(
2H, m, 8-H2), 3.02 (2H, $
.

10-H,), 3.40-3.68 (2H, m.

3'-)i+4'-H)l 4.21 (1)1. q
t J=6Hz, 5'-H), 4.60 (2H, b
rd.

J=5Hz+ 14-H,l Changed to brd-+S at D20), 4-82 (IH,d, J=5Hz+
4'-0HI Disappeared at D20).

5.01 (IH+ br s, u+/z=8HL
7-HL 5.34 (IK br So II, /2
=6Hz+ 1'-H)+5.47 (IH+
3.9-0) L Disappeared at D20), 7.90-8.1
0(2H, m, ArH), 8.22~. 8.
42 (2H, m, ArH) 4-demethoxyadriamycin represented by the general formula LI) of the present invention is a compound having anticancer activity and is useful as an anticancer agent (see test side below).

It has already been reported that 4-demethoxyadriamycin has been produced (Brit, Pat. 1511).
680; Special Publication No. 57-36919; A, DiMa
rc.

at aL Cancer Treat, kp-+
62+ 375 (1978)), and according to additional tests by the present inventors, refer to Manufacture 1).

The present inventors conducted an investigation to find a compound that has significant anticancer activity, and as a result, it was found that the 4-demethoxyadriamycin of the present invention has extremely excellent anticancer activity.
The invention has been completed.

4-demethoxyadriamycin represented by the formula (D) of the present invention can be produced using the following reaction formula.

q■nU (JH II (In the formula, 1 and 2 are an acyl group, R'', 1 (+4 is an alkyl group, an ♂-oxy group, or a hydrogen atom.) [First step] This step The method is to acylate the 14-bromo compound represented by the above formula (2) to produce the 14-acyl compound represented by the above general formula (2).

The 14-bromo compound required as a raw material is a compound that can be easily produced according to known methods (N・'l'ano et a
l-+Chem, Pharm, Bull, 31
．． 821 (1983)).

In the acylation of this step, acylating agents such as potassium acetate, sodium acetate, tetrabutylammonium acetate, potassium formate, sodium chloride, tetrabuterammonium forte, sodium trifluoroacetate, etc. can be used. Ether solvents such as dioxane, alcohol solvents such as methanol, ethanol, and isopropyl alcohol, halogen solvents such as chloroform, dichloroethane, and carbon tetrachloride, and ketone solvents such as acetone and methyl ethyl ketone may be used alone or in combination. can.

In addition, when using an alkali metal salt as an acylating agent, quaternary ammonium salts such as tetrabutylammonium bromide, dibutylammonium hydrogen sulfate, benzyltriethylammonium chloride, tributyloctylphosphonium bromide, tributyldecylphosphonium Quaternary phosphonium salts such as chloride and crown ethers such as 18-crown-6 and dibenzo-18-crown-26 can be used as catalysts for promoting the reaction.

The reaction proceeds smoothly at a temperature of OC to 100C.

[Second Step] This step is performed using the general formula % (in the formula, H1+, 几6 and 几7 are alkyl groups, and % represents an alkyl group, an aryl group, a polyfluoroalkyl group, or a hydrogen atom). By reacting the 14-acyl body represented by the general formula - with the sugar represented by the general formula ω in the presence of the silyl sulfonic acid derivative, the α- Anomeric glycoside t- is produced.

This step must be carried out in the presence of the silylsulfonic acid derivative represented by the general formula -.

Examples of trimethylsilyltrifluoromethanesulfonate, trimethylsilylnofluoromethanesulfonate, trimethylsilylchlorofluoromethanesulfonate, trimethylsilylchlorofluoromethanesulfonate, trimethylsilyltrifluoromethanesulfonate, and trimethylsilylchlorofluoromethanesulfonate.
1,1,2,2-tetrafluoroethanesulfonate,
Triethylsilyltrifluoromethanesulfonate, dimethylimprovildilyltrifluoromethanesulfonate, t-butyldimethylsilyltrialolomethanesulfonate, trimethylsilylperfluoro7'thanesulfonate, trimethylsilylperfluorooctanesulfonate, trimethylsilylmethanesulfonate, trimethylsilylethanesulfonate, trimethylsilylbenzenesulfonate, trimethylsilyl p -bromobenzenesulfonate, trimethyl7lyl I)-)luenesulfonate, etc. can be used. The amount of the silylsulfonic acid derivative to be used is determined by the above general formula [phase].
It is used in an amount of 0.1 to 4 with respect to the 4-acyl body.

It is desirable to carry out this step in a solvent, for example, a halogenated solvent such as methylene chloride, 1,2-chloroethane, etc., dioxane, diethyl ether, dimethoxyethane, etc. It is possible to use a mixed solvent with an ether solvent such as.

The reaction normally proceeds smoothly at -20 to 20C.

[Third Step] In this step, the α-anomer glycoside represented by the general formula (to) obtained in the second step is deprotected to form the formula (
to)).

Deprotection in this step can be carried out under dilute alkaline conditions using sodium carbonate, potassium carbonate, sodium aqueous dispersion, potassium aqueous dispersion, etc. in a solution such as methanol or N; .

[Fourth step] In this step, the compound represented by the formula (b) obtained in the third step is protected in the presence of a t-acid to produce a compound represented by the general formula (4). be. As the reagent, ethyl orthoformate, ethyl orthoformate, acetone methyl acetal, benzaldehyde dimethyl acetal, etc. are used. Examples of acids that can be used in this step include WW) luenesulfonic acid, camphorsulfonic acid, and hydrochloric acid. Organic solvents such as ester, benzene, and toluene are used alone or in combination. The reaction proceeds smoothly at a temperature of OC to 100C.

[Fifth Step] In this step, the compound represented by the general formula (4) formed in the fourth pillar is treated under alkaline water bath conditions to remove the trifluoroacetyl group, and then the acetal etc. introduced in the fourth step are treated. By removing the protective group of 4-demethoxy/adriamycin represented by the formula (2), a product in which y=4-demethoxy/adriamycin is obtained. As the alkali used to remove the trifluoroacetyl group in this step, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, etc. are used. This step can be carried out in a solvent or in a hot bath medium, but it can be carried out when all the solvent is used. The reaction proceeds smoothly at 0C-=temperature.

Further, the removal of the protective group such as acetal in the fourth step can be carried out in good yield by a conventional method such as treatment with dilute hydrochloric acid in methanol.

The present invention will be described in detail below with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Reference example 1 (+)-4-demethoxydownoy”p 30.OIQ
(0,082 mmol) fDissolved in anhydrous THF3d
! Add 4 sibilinium hydrofluoride perfluoride 30.0 + 19 (0,098 mrnol) and stir at 23 G.

Tetrabutylammonium formate 146 'l' (0.51 mmol) O anhydrous THF @ solution (4d) prepared from a methanol solution of tetrabutylammonium hydroxide and formic acid was added to the reaction solution, and after stirring for 10 minutes, the reaction solution was diluted with 50 rnl. After diluting with dichloromethane and washing three times with saturated brine, the dry bag solvent was distilled off using anhydrous magnesium sulfate. Pass through a Noriyoku gel short column (developing solution: ethyl acetate/benzene = 1/4) to 31.1 rg (92%).
) of (+)-14-formyloxy-4-demethoxydaunomycinone was obtained. Chloroform-methanol-
An analytical sample was obtained by recrystallization with ether.

mp 183-185C.

[αRoku'+153° (C=0.11. dioxane)
.

It((KBr): 1735 (C=O), 1720
(C=0).

1625 (Kino7) + 1590crn-' (aromatic ring)・1)i NMI-L (CDC凰, ): 62.
14 (1 le ddd, J=15n 5s and
2Hz+ 8-ax -HL2.53 (l)Ld
t, J=15and2Hz8-eq-H), 3.0
2 (lHld, J=19Hz, 1O-ax-H)
(3,34(IH.

br S, 7-0H), 3.38 (1) L dd
.

J=19 an d 2H410-eq -H) +
4.69 (1 le s, 9-0H), 5.26 (1 le d
, J=18Hz, 14-H), 5.39 (IH
,br s, ? -H), 5.53 (IH, d.

J=18Hz, 14-H), 7.78~7.98(
2H, m, Ar)+ 8.24 (IH+ 31CH
O) + 8.3(1-8,52(2H+ ml Ar
)+13.30 (1) L S, Ar0H), 13.
63 (IH+S, Ar0H).

Elemental analysis: C2,)i,,O,-0,75H20,!
-1, calculated value 20.59.23;) [, 4,14 (chi).

Analysis value: C, 59,24; 14.3.87 (%).

Bird resolution mass spectrum: C□H,,o, total 14
．． Value: m/e412.0792° Analysis value: m/e41
2.0764・ Example 2 2.3.6-1-lysooxy-1,4-di0-p-nitropenzoyl-3-trifluoroacetamide-α-
L-liquinhequinpyranose 133'9 (0,25mm
o I), Moleckier Sieg 4A750~ is suspended in a mixed solvent of anhydrous nochloromethane 8J and ether 6-,
At -40C, 0.1051 t of trimethylsilyltrifluoromethanesulfonate was added, and the mixture was stirred at -3C for 1 hour, and then cooled to -15C again. (→-14-formyloxy-4-demethoxydaunomy7non 77.9 ”F
25aj of a THF solution of (0.189mm01) was added and reacted for 7 hours. After pouring the reaction solution into a mixture of gold saturated sodium hydrogen oxide solution (150t) and ethyl acetate (80IILt), the organic layer was separated and saturated brine (ZO
After washing twice with omO, it was dried with anhydrous magnesium sulfate/ram. The solvent was distilled off to obtain the crude glycolide (1=cHO
, LE”=P −NO, C.

1 (, C0) 150η (quantitative yield) t- was obtained. Since this product was unstable, it was subjected to the deprotection reaction in Reference Example 3 without being purified.

Reference Example 3 (V) obtained in Reference Example 2 (几1=c)10. R"=p-
NO□C1) (4Co) (150aF, 0.189
mmol) t-in water bath'r) IFiy and methanol 13
Dissolve 0 mlK, 0. I M NaC)H aqueous solution 1
．． 5+1jt- was added and deprotection reaction was performed for 20 minutes (
The reaction solution had a pH of 8). After neutralizing with 1 drop of acetic acid, 100aj of saturated brine and 100d of ethyl acetate were added for liquid separation and extraction.
The extract was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was filtered through a silica gel 1-column (developing solution: chloroform/a7ton = 9/1) to obtain 84.1 to (73%) of (→-3'-N- ) Refluor obtained acetel-4-demethoxyadriamycin (b) gold.

mp 143-148tl: [α]8°+170' (c=0.11. dioxane).

IR(KBr): 3450 (NH,U)i), 17
25 (C=(J).

1630 (quinone) + 1590 cm-' (aromatic ring).

IHNMR (CDCI, ): (11,32(3rdrJ=7H!.

6'-H3), 1.80-2.38 (4H, m.

8-82+2'-82)+2.97 (IH, t.

J = 6 Hz, 14-0H), 3.08(l
Hld, J=19Hz, 1O-ax-H).

3.40 (IH, dd, J=19andlHz.

10-eq-H), 3.62-3.78 (IH.

m, 4'-mountain, 4.10-4.30 (2H, m.

3'-H+5'-)1), 4.38 (1)L
S, 9-0H), 4.79 (21-L, d, J=
6Hz.

14-H, 5.33 (IH, dd, J
=4and2H2,7-H), 5.55 (IH, d.

J = 4)iz, 1/-H), 6.66 (LH
.

br d, J=IQHz, NH), 7.81-7.96
(21(,m,Ar), 8.36-8.48(2H,
my Ar) + 13.34 (1H, S!Ar0H
), 13.65 (1 l Ar0H).

Elemental analysis: Calculated value as C2sHuFsNOIt-HzO: C,53,59;)L4.50;N,2
．． 23 (ch).

Analysis value: <:, 53.83; 4.80; average 2.
21 (%) Example 1 (-+1-3'-N-trifluoroacetyl-4-demethoxynadriamy/n 12.0IP (0,0''
2 Qmmol) was dissolved in anhydrous THF31- to give methyl orthoformate l#+7! and a catalytic amount of camphorsulfone CNT were added, and the mixture was stirred at room temperature for 2 hours. After adding 50 ILtt of an aqueous solution of sodium hydrogen carbonate to the reaction solution,
Extracted with ethyl acetate (2 x 50 g). The extract was diluted with 5L of sodium bicarbonate water R4fL (30111J), M
Compatible sodium aqueous solution (301d), water (30trL
After sequentially washing with t), it was dried with anhydrous sulfuric acid and IJum. The solvent was distilled off under reduced pressure to obtain an acetal product of 13.5η (constant yield). This was immediately subjected to the next hydrolysis reaction. That is, 0.1M aqueous sodium hydroxide (m*3m12) was added to the acetal product from 13.5 and stirred at room temperature in an argon atmosphere for 45 minutes. The reaction solution was adjusted to 5MH
After adjusting the pH to 8 with Cl, extraction with chloroform (5
X30 milkt). The extract was washed with water (2X 50M) and dried over anhydrous sodium 4A acid.

After removing the solvent under reduced pressure, the residue was mixed with 3M methanol and 0.2
1 d of 5M HCl aqueous solution was added and stirred overnight. After the reaction mixture was evaporated to dryness in vacuo for 1tk, 1sa(v) of methanol was added to separate the insoluble matter.The obtained methanol solution was concentrated to a small volume, and a sufficient amount of ether was added to cause precipitation.The precipitate was After collection, it was vacuum dried over KOH.

Congratulations 4.3q (40%) m9 226-229U (dec,) [α+190° (C0,042, CH, (river).

M8 (SIMS): m/z514cMH)
384 (aglycone) + IR (KBr): 3400 (OH, NH), 172
5 (CO).

1620 (quinone), 1590 (aromatic ring) cIn-'
.

"HNMI(, (d, -DMS(J): δ 1.1
6 (3H, d, J=6Hz+6'-83)+t
7o~2.00 (2H.

"+ 2'-H2) 2.00~2-30 (zi-t
, m.

8-H2), 3.02 (2H, S, l O-H2)
+3.40-3.68 (21-L' In, 3/-
H+4'-H).

4.21 (LH#Q, J=6Hz, 5'-H)
.

4.60 (21(lbr d, J=5Hz, 14
-H2゜Changes to brd-+3 at D20), 4.82 (1
d+ J=5Hz+ 4/-os, disappears at D 20) + 5.01 (iH+ br S+ I' i
/z=3)12. 7-H), 5.34
(IH, br s.

W +/z=6Hz+1/-H) + -5,47(
lH+ 5r9- (JH, IJ2o-ctg arrow),
7.90-8.10 (2H, m, Ar), 8.
22-8.42 (2H.

m・Ar), (See Diagram 1 of Sugar) For comparison, the NMR spectrum of atriamay 7-nohydrochloride is shown in "am".

Elemental analysis ji: C2@H2gCI NO1o・1.
Calculated as 751-120: C, 53,70; Le 5.46; N, 2
．． 41%・Analysis value: C, 53,32; H, 5,03;
N, 2.35%.

-Nodo1 Example 2 tl(J kiH3・hshi1 (+1-3' -N-trifluoroacetyl-4-demethoxyadriamycin 3.6W (0,0060mm
The mixture was dissolved in 1.5 mJ of ftTHF', 0.4 ml of ethyl orthoformate and a catalytic amount of camphorsulfone were added, and the mixture was stirred at room temperature for 30 minutes. After processing in the same manner as in Example 1 to obtain a product, THFo, 31d and 0.1 M NaO
1 ml of H was added and stirred at room temperature for 30 minutes. Reaction hardness, IM
Adjust the pH to 3 with HCl, stir for 1 hour, and add IMNa again.
(Restore the pH to 3 with Jl (chloroform (5X20M)
Extracted with. The extract was washed with 30 ml of water, dried over anhydrous sodium filtrate, and the bath medium was distilled off. Residue a t Small amount of methanol chloroform <1/9) After K bath decomposition, several drops of 0.25M HCl methanol solution were added, and an orange precipitate was precipitated. After diluting with enough ether, (+)-4-demethoxyadriamycin hydrochloride! 0.
7#V (22%) ml) 226-228t: (
dec) (i-obtained. The NMH spectrum of this product matched the spectrum obtained in Example 1.

Example 3 (→-3'-N-trifluoroacetyl-4-demethoxyadriamycin 25.869 (0,043 mmo
l), acetone dimethyl acetal 2M1 camphor sulfone [1.5 mq] The mixture was stirred at 60C for 2.5 hours. Saturated sodium bicarbonate (30%) and ethyl sulfate (30a) were added to the reaction solution and separated. (Stationary yield) of acetal product was combined with flr:THFltnl and 0
．． 1 r4 NaUH5MK! The mixture was dissolved and reacted for 30 minutes at room temperature. After adjusting the pH to 8 with 5M HCl, the following treatment was carried out in the same manner as in Example 1, and 7.9N9 (33ch) of (t)-
4-Temethoxoadriamyci/hydrochloride m1) 222~
227° (dec) f was obtained. The CINM spectrum of this product matched the spectrum obtained in Example 1.

Comparative Example 1 (dichloromethane bath solution of 4-demethoxydaunorbine hydrochloride 20.0 (1.22 g Br*/IQ+c
j CH2Cl,)U,05,xt and 0.25M 1
-1 ml methanol% solution 0.1 mt was added at 10C, and the mixture was stirred at -2 temperature for 1 hour. After adding 2M hexane and 4d of ether to the reaction solution to precipitate a sediment, the soil was removed and the mixture was subjected to vacuum transfer. 3M of anhydrous nooxane and 0.25M HBr water bath solution 34 were added to the obtained orange powder solid, and after stirring for 22 hours, e, which was prepared by dissolving 220 of sodium formate in 2.24 of water, was added, and the mixture was stirred at room temperature for 24 hours. Stir for hours. 5% Na11C (J3 aqueous solution [50, m
In addition to l, methanol/chloroform = x/2 bow Q50
a), then extracted four times with 30 d of chloroform, and the resulting M grain layers were combined, washed with 50 M water, and then dried over anhydrous sodium sulfate. # After removing the veins and dissolving the remaining residue in methanol/chloroform = 1/9' 2 dt, it was dispersed with several 0.25M HCI methanol solutions to precipitate an orange precipitate. After adding 15 di of anhydrous ether, the precipitation was completed and the result was 6.01.
+1 il (30%) of orange crystals leaked out.

mp 186-189C (dec) [α),:' +1850 (C0,0401C)l, (
JH) MS (8IMS) 2 m/z 542
CMH)” (No peak was observed at m/z514.) El (KBr): 3400, 1725, 1620, 1
590eM-'.

1) I NMR (d, -DMSO): δ1.18 (3
H, d, J=6Hz, 6'-H,) 1.69~
2.00 (2H, m.

2'-H,), 2.02-2.32 (2H, m.

8-1-1. ), 2.92 (11-L d, J=
19Hchi1O-ax-H), 3.20 (IH,d,
J=19Hz, 1O-eq-H), 3.44-3.6
9 (2H, m, 3/H+4'H) + 4.
10-4.40 (lm, s/-HL 5.01 (
IH+ brS, ν, 72=8Hz, 7-H),
5.34 (3H, br S+ 14-82+1'
-H), 5.46 (IH, d, J=6Hz, 4'
-IJH, disappeared with D2U), 5.74 (1le S,
90) Disappeared in LD2U), 7.88 (3ru b
rs.

N1 (;, disappeared with D, Q), 7.96-8.12 (2H
, m, Ar), 8.24-8.46 (2H, m, Ar
), 8.40 (IH, S, CHU).

13.36 (IH,br s, A,rOH,D2(
J) l 13.56 (1'H1br s+
4-demethoxyadriamycin obtained in Test Examples 1 to 3 showed excellent results in a cell proliferation test using murine lymphoid leukemia cells (p388). Compared to Adriamycin, which is known as an anti-cancer drug, it exhibited 10 to 20 times higher r-attenuation in terms of 50% growth inhibition rate. That is, 5 g of cultured cells were added to RPMI-1640 medium containing mouse glue/parabolic leukemia cells (p388)'rl O% calf fat.
A 2mM methanol solution of X 10' cells/dKila[shik+]-4-demethoxyatriamymine 7-hydrochloride was sequentially diluted with a culture solution, and the mixture was cultured at 37C for 2 days. measurement

[Brief explanation of the drawing]

The target was lHNM of (+)-4-demethoxyadriamycin hydrochloride obtained in Example 1 in d,-DMSO.
(100MHzFT)Xpel)k'1? hb. The listed country is the commercially available product CS I GMA) (published by Adriamycin Hydrochloride d, -1) 1) 1 NMR in M2O
(10 (IMH-FT) spectrum. Figure 3 shows the (→-14-formyloki7-1) spectrum obtained in a comparative example.
7゛unorbi/4-demethoxy; = reed # = 4-sin hydrochloride as the main component in d-0M80' HNMR (100MH; FT
) is a spectrum. Width is 4-demethoxyadriamycin and mouse lymphocytic leukemia microFFD using adriamycin (p388
) cell proliferation test results. The vertical axis is p388 growth inhibition1i114 (%),
The horizontal axis is once (rrnM).

Claims (4)

[Claims] (1) Formulas ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ 4-demethoxyadriamycin represented by (2) The compound according to claim (1), wherein the hydrochloride has a melting point in the decomposition range of 220°C to 230°C. (3) Hydrochloride is [α]^2^0_D+190°(CH_
Claim (1) or (2) having
). (4) The compound according to claim (1), (2) or (3), whose hydrochloride has the spectrum shown below. Mass spectrometry spectrum (SIMS); m/z 514 [MH]^+, 384 [aglycon]^+ Infrared absorption spectrum (KBr); 3400 (OH, NH), 1725 (CO), 1620
(quinone), 1590 (aromatic ring) cm^-^1^1H- Nuclear magnetic resonance spectrum (d_6-dimethylsulfoxide); δ=1.16 (3H, d, J=6Hz, 6'-H_3)
, 1.70-2.00 (2H, m, 2'-H_2), 2
．． 00-2.30 (2H, m, 8-H_2), 3.02
(2H, s, 10-H_2), 3.40-3.68 (2
H, m, 3'-H + 4'-H), 4.21 (1H, q,
J = 6Hz, 5'-H), 4.60 (2H, brd, J
=5Hz, 14-H_2, D_2O changes from brd to s), 4.82 (1H, d, J = 5Hz, 4'-OH, D
_2O), 5.01 (1H, brs, ν1/2=
8HZ, 7-H), 5.34 (1H, brs, ν1/2
=6Hz, 1′-H), 5.47(1H, s, 9-OH
, D_2O), 7.90-8.10 (2H, m,
ArH), 8.22-8.42 (2H, m, ArH)