JPS63170328A - Dehydroabietic acid derivative and antiulcer agent comprising said derivative as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula (R1 is H, carboxymethyl, 1-substituted-4-piperazinylcarbonyl, 1-piperazinylcarbonylmethyl, 1-substituted-4- piperazinylethyl, etc.; R2 is H, methyl, carboxyl, mehoxycarbonyl, 1-substituted-4- piperazinylcarbonyl, etc.). EXAMPLE:12-Carboxymethyl-dehydroabietic acid methyl ester. USE:An antiulcer agent. A preventive and remedy for gastritis. PREPARATION:A dehydroabietic acid is reacted with acetyl chloride in the presence of Lewis acid to give a 12-acetyl derivative, which is subjected to oxidative rearrangement reaction with thallium secondary nitrate in methanol in the presence of an acid catalyst such as perchloric acid, etc., at normal temperature to give a 12-methoxycarboxylmethyl derivative, which is hydrolyzed with an alkali at room temperature to give a 12-carboxymethyl derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel dehydroabietic acid derivative and an anti-ulcer agent containing the same as an active ingredient.

[Conventional technology]

It is known that sulfodehydroabietic acid derivatives, dehydroabiethyl alcohol visiting compounds, dehydroabiethylamine derivatives, etc. have a cleaning effect. (Unexamined Japanese Patent Publication No. 3g-77gIII, Chemical Pharmaceutical Brennan Vol. 33, /4L7co-lHiroj7 (/
[Problems to be Solved by the Invention] The present inventors investigated the medicinal activity of dehydroabietic acid derivatives, and as a result, they arrived at the present invention.

[Means to solve the problem]

The present invention relates to a cleaning agent containing a novel dehydroabietic acid derivative as an active ingredient.

That is, one of the present invention is (where & is a hydrogen atom, a carboxymethyl group (-OHyoC!O,H), /-substituted-derpiperazinylcarupiverazinylcarbonylmethyl group (-aa, cOC> H
) or its salt, /-substituted-cubiperazinylmethyl group (-0H*O05N-A) or its salt, or /-substituted-piperazinylethyl group (
-0H,0HIO-A) or its salt,
R is a hydrogen atom, a methyl group, a carboxyl group, a methoxycarbonyl group, or a substituted-cubiverazinyl carbonyl (-00<)-A) group or a salt thereof. Moreover, the above-mentioned -A is an 01-C8 alkyl group, a phenyl group, or a hydroxyethyl group. However, when R1 is a hydrogen atom, 'R4 is a /-fm-I-piperazinylcarbonyl group or a salt thereof. The present invention relates to dehydroabietic acid derivatives represented by the following formulas, and anti-ulcer agents containing them as active ingredients.

the /-substituted biverazinyl carbonyl group, /-
hiberazinyl carbonylmethyl group, i-[substituted-a-
Hihe9 Cynylcarbonylmethyl it, /-fm conversion-4
Examples of the substituent represented by A in the '-piperazinylethyl group include a methyl group, an ethyl group, a propyl group, a phenyl group, and a euhydroxyethyl group.

Further, in the present invention, the term "salt" refers to pharmaceutically acceptable salts such as hydrochloride, sodium salt, potassium salt, ammonium salt, and amines.

Specifically, the dehydroabietic acid derivatives used in the present invention are l cocarboxymethyl-dehydroabietic acid methyl (R,=-OR,00,H,R,=-00,OH,),
Cocarpoquinmethyl-dehydroabieti/acid (R1
=-OH, Co, H, R, =-Co, H), /cocarboxymethyl-abietatriene (R, =-0 bird Co,
H, R, =-OH,), /Co(/-methyluda-piperazinylcarbonyl) methyl dehydroabietate (R, =-aoQaa3. R, =-Co□OH,),
lλ-(/-piperazinylcarbonylmethyl)R,=-
Go, C3H5), /J, -(/-71tiluda-piperazinylcarbonylmethyl)dehydroabietate methyl (R, = -OH
sOOυCHa, R1nie Oo, aH,), lcor(/-ethyl-ni-piperazinylcarbonylmethyl) methyl dehydroabietate (Rr = -OHao 00
0t& + Ra ==-co, aH,) -/λ-(
/-7'robinylmethylpolydehydroabietate (Rr = -OHaOO(
JOxm*Ra=-00*CHs),/2-(
/-phenylterhyperacinyl methyl dehydroabietate (R,=-OHtOOOO○@
k1m tooth=-00,CH,), l-1(i-<colhydroxyethyl)-p-piperazinylcarbonylmethyl)
Methyl dehydroabietate (R1=-OHaCOυC
Crystal OH, R*=-00, Leakage/2-(/-Methyl-Hiro-
piperazinylcarbonylmethyl)-/lnorabiaetriene(n=-cC>oR,=-H),/-(/
J-(/-methyluda-piperazinylcarbonylmethyl)dehydroabietoyl)-tomethylpiperazine (Rr
=-OHa OO0OHa + Bonnie aoQc piece, /Col (/-Methyl-Hiroshi-piperazinylethyl) methyl dehydroabietate (x, =-am* 0HIQO
H□B = -00, OHj).

/-dehydroapietoirudermethylpiverazine (R
, = H, = -coQoH, ), /-tehydroabietylderethylpiverazine (R, - = H, R1 = -c
oOcmHs) Equal force 4 is given.

The dehydroabietic acid derivatives of the present invention are generally produced by the following method.

The raw materials for the dehydroabietic acid derivatives of the present invention include dehydroabietic acid, methyl dehydroabietic acid, apietatriene obtained by reducing the carboxylic acid of dehydroabietic acid to a methyl group, or dehydroabietic acid deoxidized with lead tetraacetate. After carbonation, t-norabietatriene obtained by catalytic reduction is obtained (hereinafter referred to as methyl dehydroabietate, abietatriene,
/Norabietatriene is called dehydroabietic acids. ).

In order to introduce a carboxymethyl group into the 72nd position of dehydroabietic acids, the following operation is performed. That is, dehydroabietic acids are combined with aluminum chloride, stannic chloride,
The mixture is reacted with acetyl chloride in the presence of a Lewis acid such as boron tsulfide to obtain /λ-acetyl-dehydroabietic acids. Next, 2-acetyl-dehydroabietic acids are subjected to an oxidative rearrangement reaction in methanol with an acid catalyst such as perchloric acid and dibasic thallium nitrate at room temperature.
Comethoxycarboxymethyl-dehydroabietic acids are obtained. Further, alkaline hydrolysis is carried out at room temperature to obtain colcarboxymethyl-dehydroabietic acids. In addition, 12-methoxycarboxymethyl-dehydroabietic acid methyl force C:, / When obtaining 2-carboxymethyl-dehydroabietic acid, reflux may be performed using a solvent such as ethylene glycol or diethylene glycol during alkaline hydrolysis. .

The following method is used to introduce the /-substituted-p-piperazinylcarbonyl group into the 71st position of dehydroabietic acids.

That is, dehydroabietic acids are converted into silicoacetyl-dehydroapiedenoic acids by the method described above, and then converted into /2-carboxy-dehydroabietic acids by the noroform reaction. Then, by reacting with thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, etc. as cochloroluponyl-dehydroabietic acids, and then reacting with /-substituted piperazine, carbonyl) dehydroabietic acids are obtained.

Similarly, replacing /- to the lj position of dehydroabietic acid
The u-piperazinyl carbonyl group is introduced after converting dehydroabietic acid to dehydroabietyl chloride.
By reacting with a -substituted piperazine, a pt-dehydroabietyl-substituted piperazine is obtained.

In addition, a syn-substituted biverazinylcarbonylmethyl group is introduced into the 72nd position of the dehydroabietic acids by a similar operation. Sunawa? :+,/- After converting 2-carboxymethyl-dehydroabietic acids to /cochlorocarboxymethyl-dehydroabietic acids, /-
By reacting with substituted piperazine,
fffim-4=-piperazinylcarbonylmethyl)dehydroabietic acids are obtained.

In order to introduce the /-substituted-+-piperazinylethyl group into the 72nd position of dehydroabietic acids, the following operation is performed. That is, by reducing l-cochlorocarboxymethyl-dehydroabietic acids with sodium borohydride etc., /-
Reacting mono(-1hydroxyethyl)dehydroabietic acid and Lp-)luenesulfonyl chloride, /
, 2-(2-(p-)luenesulfonoxy)ethyl)dehydroabietic acids are obtained. Subsequently, by reacting with /-substituted piperazine, 1)/2-(/-substituted-terpiperazinylethyl)dehydroabietic acids are obtained.

In addition, the following operation is performed to introduce the /-piperazinylgalbonylmethyl group into the 72nd position of the dehydroabietic acids. That is, by reacting /,2-chlorocarboxymethyl-dehydroabietic acids with /-formylpiperazine and then removing the formyl group under acidic conditions, /λ-(/-hiheracinylcarbonylmethyl-dehydroabietin) Acids are obtained.In addition, /-piperazinylcarbonyl M, /-piperazinylcarbonylmethyl!, /-f-conversion-4' and especially salts corresponding to each are obtained. Can be done.

The /-substituted piperazine mentioned above includes /-methylbiperazine, /-ethylpiperazine, /-propylpiperazine, l
-phenylpiperazine, /-(,2-hydroxyethyl)piperazine, etc. can be effectively used.

When the dehydroabietic acid derivative of the present invention is used as a wiping agent, it can be administered either orally or parenterally, but oral administration is particularly preferred. Forms for oral administration include tablets, capsules,
It may be a solid preparation such as a softener or a granule, or a liquid preparation such as a solution or suspension. Formulations suitable for oral administration may also include a pharmaceutical carrier or adjuvant. Carriers or adjuvants used for solid preparations such as tablets and capsules include, for example, binders (e.g. acacia, gelatin, dextrin, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone), diluents (e.g. lactose, sucrose, etc.). , mannitol, corn starch flour, potato starch flour, calcium phosphate, calcium citrate, microcrystalline cellulose), lubricants (e.g. magnesium stearate, calcium stearate, stearic acid, Merck, silicic anhydride), disintegrants (e.g. corn starch), powder, potato starch, carboxymethyl cellulose, carboxymethyl cellulose/calcium, algin (m), wet MJ (eg, sodium lauryl sulfate), and the like. In addition, carriers or adjuvants used for liquid preparations such as solutions and suspensions include, for example, aqueous media (e.g., water), suspending agents (e.g.,
Sodium salt of acacia, gelatin, methylcellulose, carboxymethylcellulose.

Hydroxymethyl cellulose, aluminum stearate gel), surfactants (e.g. lecithin, sorbitan monooleate, glycerine monostearate), non-aqueous media (e.g. glycerin, globylene glycol,
vegetable oil], etc. In addition, liquid preparations contain preservatives (
Examples Eva, p-hydroxybenzoic acid methyl ester.

p-hydroxybenzoic acid propyl ester), flavoring agents and/or coloring agents.

Although the dosage varies depending on the method of administration, the patient's age, weight, condition, and medical treatment, the preferred dosage per 7 days is usually about / ~ / 00 mfkg, especially ~50 mfkg.
~/It is boiled.

〔Effect of the invention〕

The dehydroabietin derivatives or salts thereof of the present invention have an excellent anti-ulcer effect and are therefore useful as therapeutic and preventive agents for gastritis, peptic ulcer diseases such as ulcers, duodenal ulcers, etc. The present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these in any way.

Example/l cocarpoxymethyl-dehydroabietate methyl aluminum chloride (0,,) 9 mol)
Methyl dehydroabietate lI7. / J (0, / jm
ol ) and acetyl chloride j j ; J , li' (
Carbon disulfide (!;001
11)-m solution was added at 0°C. The solution was added and refluxed for 41 hours. After distilling off the carbon disulfide, pour it into hydrochloric acid, perform ether extraction, wash Kosho Chirno with water, dry it, and then
Extract the ether! ;Q, 711 72-acetyl-
Methyl dehydroabietate was obtained. Furthermore, recrystallization was performed using methanol to obtain free crystals of ffF.

Melting point 12g-/, 30℃ RvKBr/72! ;, / l, r OCm
-'ax NMRδ- (CDO 舅 こ, j こ (jH9th), 3.4
4 (JH, θ), 7.03 (jH1θ), 7.3
g (jH,B)/--acetyl-dehydroabietic acid methi #3! ;、A、! i' (0.7 mol
) in methanol/l, dibasic thallium nitrate, 3
Hydrate 4cA, 71i (0,//mol) and 70% perchloric acid 50M were added and stirred at room temperature for 14 hours.

The reaction solution was concentrated, extracted with chloroform, washed with water, and dried over sulfur. Remove chloroform and crystallize methyl J-methoxycarbonylmethyl-dehydroabietate, ? 9.3? , lil got it. Furthermore, recrystallization is performed using methanol, and 33. Colorless crystals of g01/ were obtained.

Melting point / da 7 - / da g °C IRv point / 723 cm -' NMR δ (CDOIm) , 7.63 (ffH, 8)
, A, ri0(jH,B)7, riO(jH,5) 12-methoxycarbonylmethyl-dehydroabietate methyl 3J, gg in tetrahydrofuran (co!rO
m! ) and methanol (130ml), and then dissolve it in a mixed solution of N-NaOH/! 0/nt was added and stirred at room temperature for 76 hours. After the reaction mixture was made acidic with -N-HOI, it was extracted with chloroform and treated in a conventional manner to obtain methyl cocarboxymethyl-dehydroabietate as crystals. Furthermore, recrystallization was performed using methanol to obtain 26.9 g of colorless crystals.

Melting point llr&-/It"(:.

Engineering R, KBr 3. , O-coQ 00 (broad)
, /78, /700cm ax NMRδ (CD01g), 7. A,? (jH, θ
), 4. ? ! ; (jH,8)7.0j(jH,s
), 10JrO (disappeared with jH, broad, D, O) Example Co 3.7 g (ffmmol
) was suspended in diethylene glycol, NaOHO, 9AjJ was added thereto, and the mixture was heated at 750°C for an hour. After cooling, dilute hydrochloric acid was added and extracted with ethyl acetate. Next, wash with water, and after drying, ethyl acetate is distilled off.
J, P f7) crystals were obtained.

Furthermore, recrystallization was performed using methanol to obtain colorless crystals of Hedesal.

Melting point 257-260℃ ,? 00-2! r00 (bro
ad), /rioocm-KuLX NMRδ (DMBO-da) JJ (7(-2H+
s), AJko(jH,s)6,? da(jH,s), /-, ko(Jkl, broad, disappears with DIO) Example 3 /cocarpoxymethyl-abietatriene Dehydroapietate methyl was replaced with abietatriene, but the same procedure as in Example 1 The following compound was obtained.

/, 2-acetyl-abietatriene melting point 10! -104℃ RνKBr/6zaocm-' ax NMRδ(ODO-θ O, de lI (xa, 2,
Δ/ 7 (,74θ] to 8/ (AH, d, J
=7Hz), J,jJ (jH,8), ? , oJ (jH,8
)7.3 g (jJ(, θn/, 2-methoxycarponylmethyl-abietatriene R-CC'/73!, /, 2≧so, //j!
cm-Tsuta m&x NMRδ (ODO 舅 0.93 (AH, θ), /, /za (JH, s)/, λ/ (AH, d, J=7klZ)
, jjA(jH,s), 6.9'l(jH,B)7.
0j(jH,s) /λ-carpoxymethyl-abietatriene melting point /
/! ;-//7℃ I RW installation 3300-2300. / 70! rcm-
'NMRδ (CDOIs) 0-de,? (AH,B
), /, / j (JH,B)/, J O(AH,
d, J=712), 3.6 (koH, s), 6. 9 (jH,s) 6.9g (/L θ), 9J Methyl edenoate! ,00
,? (/emmol) was dissolved in 10ml of pyridine, and iodine 3.54N (/emmol) was dissolved in 10ml of pyridine.
) was added and heated to ioOoC for 5 hours. After the reaction, the solvent was distilled off under reduced pressure, and then 50Rt of ethanol, N
AOH17 and Mizuhiro were added and the mixture was refluxed for 1 hour.

Water was added and extracted with ether, and the aqueous layer was separated. Activated carbon tit in the water layer? Add and filtrate to e-liquid/N-HC! A precipitate formed when 1 was added. Filter the precipitate and add ethanol)
Recrystallization was performed to obtain Hiroshi 61/U-hydroxydehydroabietic acid as a powder.

EngineeringRν"'l'3.300-2300./A
, 7 (j
H,s), ri,Oko (jH,a,)/ko,! ;
(disappeared with 2H, broad, Dlo) 12-carboxy-dehydroabietic acid co-ru 011 (7mmo
By dissolving 1) in ether and distilling off the ether solution of diazomethane, methyl methoxylponyldehydroabietate was obtained.

Melting point // dar/15℃ Engineering RshiC Showarasu/7-Ogoyax NMRδ (ODOIJ 3.4t (AH,s),
7.0.2(jH,B)7.1. t(jH,B) methylcomethoxycarbonyl-dehydroabietate, /b I (6 mmol) /N-NaOH
It was dissolved in an ethanolic solution and refluxed for 75 minutes.

When diluted with water and added with NH[l, crystals were precipitated. Separate the crystals and recrystallize with methanol to obtain 7.1
．． 91/- of methyl hydroxydehydroabietate was obtained.

One point /ri0-/ri7℃ OHO & Engineering Rν J300-1! 00. /7J(1),
/ A 90cm-'ax NMRδ (CD01m),? , 70 (3H, 8),
7.014 (jH, B) 7.74 (jH, 8), ? , J A (/H, broad, disappeared with DmO)
/to methyl 2-carboxy-dehydroabietate
lIg (+, jmmO1) in anhydrous benzene -0at<
Dissolved thionyl chloride 0.361 (e, 7 mmol)
was added/g hour and stirred at room temperature. After the reaction, the solvent was distilled off under pressure to obtain 7tI of methyl /J-chlorocarbonyl-dehydroabietate as a resinous product.

0HOA’.

Engineering RI/max /7AO117occm-'/2-
Methyl chlorocarbonyl-dehydroabietate 2to
ml of anhydrous ether/-methylbiperazine o,
Ether solution of e 3g (Q,, 7mmol)! r
rrLt was added dropwise. After stirring at room temperature for 7 hours, /N-N
After adding aOH and separating 1 ml of ether, washing with water and drying, the ether was distilled off to obtain 8 gip of methyl/2-(/-methyluda-piperazinylcarbonyl)dehydroabietate.

Further, recrystallization with ether was performed to obtain colorless crystals of 82/l/l.

Melting point /A/-143℃ IRvCHC&/ 720. / 610cm-'ax NMRδ (ODC) J), JJ (JH, s,), J,
l, 7 (,?H,8)6.97(-H,a) Example to Example /Methyl 2-carboxymethyl-dehydroabietatej 2. ! ,9 (0,017m
Thionyl chloride 5op (0.91m01) was added to 01) and stirred at room temperature for 76 hours. After the reaction, excess thionyl chloride was distilled off under reduced pressure to form yellow crystals.
Methyl i/J-chlorocarbonylmethyl-dehydroabietate was obtained.

Melting point //! r-//A℃ EngRshidafuku/7dej,/7ηhear-EaX NMRδ(ODC]J) J, A/(Jkl, s
), sail/da (ko H18] 4.9.7 (/H,s)
, 6.97 (/H, θ]/cochlorocarbonylmethyl-dehydroabietate methylco, 73 da 11 (
7 mmol) was dissolved in 20 ml of anhydrous ether/-
Formylpiperazine 0. g/, 9 (7mmO1)
and pyridine/ml ether solution were added dropwise. After stirring at room temperature for 1 hour, water was added, the ether layer was separated, washed with water, dried, and the ether was distilled off to obtain a resin-like product. ast
i/, 2-(/-formiluderpiperazinylcarbonylmethyl 9-methyl dehydroabietate was obtained.

EngineeringRνCo/is, 730%/1,1! , /4!
Hachi-1iLX NMRδ (ODOIJ 3.4? (gH,s),
7.96(2H,B), OA (/H,B) The obtained /2-(/-formiluderbeverazinylcarbonylmethyl]tehydroabietate methyl/N-H
0I methanol solution! It was dissolved in rOrnt and stirred at room temperature for 76 hours. Remove methanol and recrystallize with ethanol/ether...? 01/,2-(/-piperazinylcarbonylmethyl)dehydroabietate methyl hydrochloride was obtained.

Melting point 2.23-22g℃ (decomposition) IRvKB"
2g0O-2700,260! r, 2'A70. /7
Add 2N-NaOH to 20°[/64LOcWL-'/J-(/-piperazinylcarbonylmethyl)dehydroabietate methyl hydrochloride,
The mixture was made alkaline and extracted with ether. After washing the ether layer with water and drying, the ether was distilled off to obtain methyl/co(/-piperazinylcarbonylmethyl)dehydroabietate as a resinous product.

EngineeringRνca1m l? -yo, 16yo5 儂-1ax NMRδ(ODO shame ko, t, 2 (*H, m), J
, ls O(4cH,m)3.6! (!rH, e), 6
．． 9! r(,2H,a) Example 6 Methyl carbonylmethyl-dehydroabietate obtained in Example j 9.761 (mmol)
'jz bath dissolved in 100ml of anhydrous ether/-methylbiperazinco,! An ether solution of 11 (JjmmOl) was added dropwise. After stirring at room temperature for 7 hours, NaOH was added, the ether layer was separated, washed with water, dried, and the ether was distilled off to give 12-(l-methyl-terhiverazinyl). Methyl dehydroabietate! )is.

Furthermore, 4. recrystallization was performed using hexane. ．． 11 g of colorless crystals were obtained.

Melting point qg-10oc X R'san2790- / 72 j, / AQ!
cIIL-'NMRδ(ODCla) 2.24 (
,? H, s), J, 3g (Hiro H, broad), 3
．． A A (jH,a), A,g 7 (2H,s
) The obtained methyl /2-(/-methyluda-piperazinylcarbonylmethyl)dehydroabietate was bathed in methanol, and a methanol solution of /N-H0I was added to make it acidic. Methanol was distilled off, and the residue was recrystallized from dichloromethane to obtain methyl/2-(/-methyl-goopiperazinylcarbonylmethyl)dehydroabietate hydrochloride.

Melting point: 79°C / 6°C (decomposition) KBr, 24°C: 0.21.00% / 730% / A AOcm-'ax Example 7: Hydrochloride / - In place of methylpiperazine The following compound was obtained by carrying out the same operation as in Example 6 except that /-ethylpiperazine was used.

/co(/-ethyl-hiro-piperazinylcarbonylmethyl)dehydroabietate methyl ester/7%/6
Light cn1-1 NMRδ (ODOlm) 0.97 (jH, d, J
=7Hz)1. ? ,1(If(,m)Jj !r(j
H,s), 6.9k(λH98)l-(/-ethyl-Hiro-piperazinylcarbonylmethyl)dehydroabietate methyl hydrochloride Melting point CoO Darko 07°C (decomposition) Engineering RνK”r2
470%2/sOj, /720. /A'l! rcrr
t-'ax Example t The following compound was prepared in the same manner as in Example 6, except that /-propylpiperazine was used instead of /-methylpiperazine.

/, 2-(/-Flobi-Hiro-piperacinylcarbonylmethyl)dehydroabietate methyl Rv:'! ,
/ 72! r, / 4 /I Gong-'NMRδ(O
DOIJ OJri (3H, t, J=7Hz), 3, J
ri (4H, m), j, G? (jLs) A, gza (ko H9
8) Methyl /co(/-propyl-9-piperazinylcarbonylmethyl)dehydroabietate hydrochloride Melting point 76g-/7/'C (decomposition) IRvKB" 2AA!r, 2!9!, Kotata 5, /7
aO5/ b j 5x-'ax Example D The following compound vl was prepared by carrying out the same operation as in Example 6 except that /-phenylpiperazine was used instead of /-methylbiperazine.
I got J.

/co(/-phenyl-Hiro-piperazinylcarbonylmethyl)methyl dehydroabietate XRv"" / 7
．． 10. / 43! , 1400cm-'NMRδ(
ODOlm) 3.4 j (,3H,s), 3.
7-tei (-H,e)A, r-7,5(7H,m) Example 10 The same procedure as in Example 6 except that /-(-monohydroxyethyl)piperazine was used instead of /-methylbiperazine. The following compound was obtained.

/co(/-(cohydroxyethyl)-derpiverazinyl methyl)dehydroabietateXRνcH”l!5J4t00./7JO,/430
,/2.1S-OJ-'ax NMRδ (ODO 舅J, lco(+H, broad).

,? J co(-H, t, J=7Hz).

J, AA; (JH, B), J, 70 (, 3 H, 5) A
Jj(,2H,a) Example // ζ nyl l - g - l vinyl 1-endehydroabiedic acid 3o! /(o, imol) anhydrous benzene/5
Lead 1 acetate 5017 (0,IO
l) was added in several portions.

After stirring at room temperature for 7 hours, the mixture was refluxed for 3 hours. Pass the precipitation once,
After washing the P solution with dilute hydrochloric acid and water and drying, the benzene was distilled off.
! , 4tli of oil was obtained @this was mixed with methanol/rO
ml of 5% palladium on carbon was added thereto, and catalytic reduction was carried out under hydrogen at -atmosphere and 20°C. After a period of time, palladium on carbon was filtered, and methanol was distilled off to obtain an oily substance. This was refined using silica gel column chromatography (hexane).

/7.7j9 7g-norabietatriene was obtained as an oil.

NMRδ(ODOIJ/,0/(,3H,d,
,TnearH2),/,l2(3kl,13),/,23
(AH, d, n7H2), t,,? ~7. ．． ? (jH
, m) The following compound was obtained by carrying out the same operation as in Example, except that methyl dehydroabietate was replaced with mononorabietatriene.

/ Coopcetyl-1j-norabietatriene X RWCC14/ A g jcIn-'Anus3. X NMRδ(ODOlJ)2.3 + (3H,a),
6.19 (jH,ts)7, daλ(jH,5) 12-(/-methoxycarboxymethyl)-/ mononorabietatriene R,004t2! rcrlL-'ax NMRδ(ODOla)J,A j (!rH,s)
,6. Day (jH, a) 7.0! (jH,B) /cocarboxymethyl-/g-norapietatriene melting point //I-/λ10C Engineering R! /” 3300-1300./risova-
'ax NMRδ(ODOLJ),? , A I (ko H18
), 6.9 da (jH, 8) 7, OA (jH, B), /
0.2 (jH,'broad) The same operation as in Example 6 was carried out, except that /cocarpoxymethyl-/g-norabietatriene was used instead of l-monocarboxymethyl-dehydroa and methyl ethinate. The compound was obtained.

l2-chlorocarboxymethyl-1g-norabietatrieneIRνR"O""'/2-(/-methyl-tei-piperazinylcarbonylmethyl)-/monorabietatrieneRν00/Arijcm-' ax NMRδ((,!D(31,), 2.λde(jH,
s ), Ko, qo < ya, m) 3, Gu (4 < H, m)
, 3.7 co(2kl, a) A,9A(-H,s) lco(/-methyluda-piperazinylcarbonylmethyl)-7g-norabietatriene hydrochloride melting point /g! ;-/Zade℃(decomposition XRvKBr2
7!0-2QOO1/4! Ocm-'ax Example 1 co/-/2-/-methyl-hiro-piperazylcarbonylmethyl dehydroabietyl-g-methylbiperazine and its hydrochloride Example-1 cocarboxymethyl-dehydroabietin obtained Acid, jo, 9 (7 mmol) K thionyl chloride (2 mmol) were added, and the mixture was stirred at room temperature for 76 hours. After the reaction, excess thionyl chloride was distilled off under reduced pressure to obtain lλ-chlorocarbonylmethyl-dehydroabietyl chloride.

Dissolve K 077 (it mmol) in anhydrous ether layer 0rtl/-methylbiperazine muda, 51 (/hirommol button) Ether solution of yfr'#
I got a J. After stirring at room temperature for 7 hours, -N NaOH was added, the ether layer was separated, washed with water, dried, and the ether was distilled off to form a resinous product.
/-Methyl-Hiro-piperazinylcarbonylmethyl]dehydroabietoyl]-gumethylbiperazine was obtained.

EngineeringRν[,27de5.16hirn-' NMRδ(CDC1,)ko,,19(AH,a),u,
, 79 (ffH,m)3.4l-2(4tH,rn)
, J, Riichi (AH, m) 6, Tada (2H, s) Furthermore, /N-H0I methanol solution was added.

Methanol was removed and the mixture was recrystallized from acetone to obtain the monohydrochloride as a powder.

IRJ/KBr2690.24/j, 24t 70.
/ A'IO, -'mGood
lil (yOmmol) f was added dropwise to a 0ml suspension of tetrahydrofuran solution. After stirring at room temperature for an hour, add N-H01'i and extract with ether.
- is separated, washed with water, dried, and the ether is distilled off.3. s
gi/2-(2-hydroxyethyl)dehydroabietate methyl was obtained.

Engineering Ryoi 3630. /12! ;cm-'NMRδ(c
DOlJ) ko, 9θ (-H, t, I=7Hz), J, t
g(3H,a)3.79(koH,t, J=7)1z
) , l, , 97 (JH, e) ri, θ months (JH, 8
) /u-(J-hydroxyethyl) methyl dehydroabietate 3.5,! Dissolve L, p-toluenesulfonyl chloride λ,92, Si' (/3 mmol) in Viridine Oat and heat to
It was spread for 76 hours. -N 801 was added, the ether layer was separated, washed with water, dried, and the ether was distilled off to obtain 5.0-I of methyl co(co(p-1 lyenesulfonoxy)ethyl)dehydroabietate. .

EngineeringRvKBr /riJO, /400. /Koku5, //9
0. //Zaova-'■NMRδ(ODOlJ) for SOL 2. Q j (,?H,s
), Ko, Dej (,2H,t, J=7Hz)J,A
j (JH, B), Q, / ,? (2H,t, :I
=7klZ)6, za ta (,2H,8),2kot (
λH, d, , T = de Fiz) 7.73 (JH, d,
J=9Hz), dissolved in xylene, 30rnl,
/-Methylpiverazinco, oi (Ommol) was added, and the mixture was refluxed for 3 hours. After cooling, JN NaOH was added, xylene was separated, washed with water, and after drying, the ether was distilled off and a resin-like product was obtained.
Methyl (hyherazinylethyl)dehydroabietate was obtained.

Engineering R point/7J,! ;cm″″I NMRδ(ODOlJ)Y3λ(jH,s),λ41(
ffH, θ] J, &! (JH, e), 4.92 (/H9
/N-H0I methanol solution was added to θ97.0/(JH, θ), methanol was removed, and the mixture was recrystallized with ethanol to obtain a hydrochloride.

Melting point /? ,? -/9! °C (decomposition) Engineering RνKB” 2410-.2300. /7.211
;l Tang-1ax Example/Tei/2-Chlorocarbonylmethyl-The same operation as in Example was carried out except that dehydroabietyl chloride was used in place of methyl dehydroabietate.

l-Dehydroabiethyl-q-methylpiperazine RνCC6 100. /AJ! ;cm-'ax NMRδ(ODOIJ x, cof(,7H,s)1.7
．． ．． 7 g (koH, t, J=7Hz), 7j g
(JH, t, J=7Hz),! , f ~? ,,7(J.H.
, m) /-dehydroabietoyl-ni-methylpiperazine hydrochloride Melting point /13-1 g °C (decomposition IRW"rJ 700-JQ !10. / A 'I
Ocm-'ax Example/j/Cochlorocarbonylmethyl-The same operation as in Example was carried out except that dehydroabietyl chloride was used in place of methyl dehydroabietate.

/-Tehydroabietyl router ethylpiverazine Rν,=”””' NMRδ(ODOla) /,07 (,:lH,t
, :J=7Hz)2.3-co,A(TeiH,m) ,? , '7/(Hiro H, t, J=7Hz) 6, Day 7. ．．
7(jH,m) /-tehydroapietroyl-ethylbiperazine hydrochloride melting point //, 0-143°C (decomposition)
, too%-rij5, /6 Hirogogo 1 Example/6 Stress ulcer suppressive effect A distilled aqueous solution of the indicated test compound (Example j, A, 7
, //, /3, /da and 15) or gum arabic suspension (Examples /, 3, ff, 9 and 10)
The compound synthesized in ) was orally administered at a dose of 100 m97 (o, -ml/1001 body weight). Thirty minutes after administration of the test compound, the rats were placed in a stress cage and fixed, and =λ
The mice were immersed up to the chest in a water bath at ±/°C for 76 hours. Next, after killing the victim, remove the helmet and inject thiformin solution into the stomach.
2! nl was injected and fixed for about 70 minutes. An incision was made along the greater curvature of the helmet, and the long axis (mx
) was measured under a stereomicroscope, and the sum of the long diameters per animal was taken as the ulcer coefficient. The ulcer suppression effect was calculated using the following formula.

The results are shown in Table/.

Table / *: Hydrochloride Example 7 Stress ulcer inhibitory effect In Example 6, the test compounds shown in Table 1 were orally administered to rats at the doses shown in Table 1, but the stress ulcer inhibitory effect was determined in the same manner as in Example 6. It was measured. The results are shown in Table 1.

Example 7g Hydrochloric Acid/Ethanol Ulcer Inhibition Effect DOnr7u male rats (6 to 7 weeks old) were fasted for 1.20 hours, and then a distilled aqueous solution of the test compound shown in Table 1 was prepared. : Administered orally at a rate of 002 ml/10017 body weight. One hour after administration, a mixture of hydrochloric acid and ethanol (/:jO)/i was administered intragastrically. After a rat rough period, the rats were killed by buffeting, and the male rats were removed and fixed by injecting /% formalin-soluble wLlλat. Hereinafter, the ulcer suppressing effect was determined in the same manner as in Example 16. Table λ
Shown below.

Example 9 After fasting male Donr7u rats (6 to 7 weeks old) for 2 hours, the pylorus was ligated under ether anesthesia. Immediately after ligation, a distilled aqueous solution of the sample compound shown in the table was added to a
It was administered intraduodenally at a rate of 0 g of ShiO9-. At hour S after administration of the test compound, the abdomen was opened again under ether anesthesia and the stomach was removed. Centrifugation of stomach contents (J 000
rpm.

The supernatant was diluted with 0.0/N sodium hydroxide and titrated with O1 to determine the acidity, which was then multiplied by the liquid volume to determine the gastric acid secretion t.

The inhibitory effect on gastric acid secretion was calculated using the following formula.

The results are shown in Table.

Table - *: Hydrochloride Example, 20 Acute toxicity test A distilled aqueous solution of the test compound shown in Table 3 (the compound synthesized in Example 15 or gum arabic) was administered to ddy male mice (4L-j weeks old). A suspension (a compound synthesized by the experimental group) was orally administered at a rate of 100 i/ml of body weight. After administration, the mice were allowed to freely take in water and copper, and death was observed for up to 7 days. 5oqb lethal dose (LDm
s) was calculated. The results are shown in Table 3.

Table 3 *: Hydrochloride Applicant 2 - Arakawa Chemical Industry Co., Ltd. Mitsuru Kago Kogyo Type A Company Representative Patent Attorney Hase side - (7 others)

Claims (3)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 is a hydrogen atom, a carboxymethyl group (-C
H_2CH_■H), 1-substituted-4-piperazinylcarbonyl group (▲numerical formula, chemical formula, table, etc. available▼) or its salt. 1-piperazinylcarbonylmethyl group (▲Mathematical formula, chemical formula, table, etc. available▼) or its salt, 1-substituted-4-piperazinylcarbonylmethyl group (▲Mathematical formula, chemical formula, table, etc. available▼) or its salt Salt or 1-substituted-4-piperazinylethyl group (▲There are mathematical formulas, chemical formulas, tables, etc.▼) or its salt, and R_■ is a hydrogen atom, a methyl group, a carboxyl group, a methoxycarbonyl group, or a 1-substituted -4-Piperazinylcarbonyl (▲Mathematical formula, chemical formula, table, etc. available▼) group or its salt. Moreover, the above-mentioned -A is an alkyl group of C_1 to C_■, a phenyl group, or a hydroxyethyl group. However, when R_1 is a hydrogen atom, R_■ is 1-substituted-4
-piperazinylcarbonyl group or a salt thereof. )
A dehydroabietic acid derivative represented by (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 is a hydrogen atom, a carboxymethyl group (-C
H_2CO_■H), 1-substituted-4-piperazinylcarbonyl group (▲Mathematical formula, chemical formula, table, etc. available▼) or its salt, 1-piperazinylcarbonylmethyl group (▲Mathematical formula, chemical formula, table, etc. available) ▼) or its salt, 1-substituted-4-piperazinylcarbonylmethyl group (▲Mathematical formula, chemical formula, table, etc. are available▼) or its salt, or 1-substituted-4-piperazinylethyl group (▲Mathematical formula, chemical formula, etc.) , tables, etc.▼) or their salts, and R_■ is a hydrogen atom, methyl group, carboxyl group, methoxycarbonyl group, or 1-substituted-4-piperazinylcarbonyl (▲Mathematical formulas, chemical formulas, tables, etc. are available▼ ) group or its salt. In addition, -A is a C_1 to C_3 alkyl group,
They are phenyl group and hydroxyethyl group. However, when R_1 is a hydrogen atom, R_■ is 1-substituted-4
-piperazinylcarbonyl group or a salt thereof. )
An anti-ulcer agent containing a dehydroabietic acid derivative represented by the following as an active ingredient. (3) The anti-ulcer agent according to claim 2, which is a preventive or therapeutic drug for peptic ulcer disease or gastritis.