PH27126A - Novel benzimidazole derivatives - Google Patents

Description

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NOVEL BENZIMIDAZOLE DERIVATIVES

The present application is a divisional appli- cation of S.N. 34408 filed October 24, 1986.

DESCRIPTION Field of the invention

The object of the present invention is to provide novel compounds, and therapeutically acceptable salts thereof, which inhibit exogenously or endo- genously stimulated gastric acid secretion and thus can be used in the prevention and treatment of peptic ulcer.

The present invention relates to the use of the compounds of the invention or therapeutically accep- table salts thereof, for inhibiting gastric acid secretion in mammals and man. In a more general sense, the compounds of the invention may be used for pre- vention and treatment of gastrointestinal inflamma- tory diseases in mammals and man, including e.g. gastritis, gastric ulcer, and duodenal ulcer. Further- more, the compounds may be used for prevention and

=. = treatment of other gastrointestinal disorders where gastric antisecretory effect is desirable e.g. in patients with gastrinomas, in patients with acute upper gastrointestinal bleeding, and in patients with a history of chronic and excessive ethanol consumption. The invention also relates to pharmaceutical compositions containing at least one compound of the invention, or a therepeutically acceptable salt thereof, as active ingredient.

In a further aspect, the invention relates to processes for preparation of such new compounds, to novel intermediates in the preparation of the com- pounds of the invention, and to the use of the active compounds for the preparation of pharmaceutical compo- sitions for the medical use indicated above.

Prior art :

Benzimidazole derivatives intended for inhibiting gasirig acid secretion are disclosed in the British patent specifications 1 500 043 and | 525 958, in the

US patent 4 182 766, in the European patent specification 0 005 129, and in the Belgian patent specification 890 024. Benzimidazole derivatives proposed for use in the treatment or prevention of special gastrointestinal inflammatory diseases are disclosed in the European patent application with publication no. 0 045 200.

The invention

It has been found that the compounds of the formula 1 are effective as inhibitors of gastric acid secretion in mammals and man: ! . Rr’ R ) 6 ~ R 8 JN _R N oo 4%

RO 5 5 4 3 |3 5 ) cH g —ereh2 12 “3 = _. C me = 2 | \ I 9 R

HC-R 0-c-r° 0 and physiologically acceptable salts thereof, wherein £ is -8- or -S50-3 ] 2 3 4 , .

R', Ry R* and R , which are the same or different

3 Cs are (a) H (b) alkyl containing 1-6 carbon atoms (c) cycloalkyl containing 3-7 carbon atoms (d) alkoxy caontaining 1-6 carbon atoms (e) alkoxyalkyl containing 1-3 carbon atoms in each alkyl part (f) alkoxyalkoxy containing 1-3 carbon atoms, in each alkyl part (g) halogen (h) -CN (i) ocr, (i) -nNo, (x) -cor'® (1) alkylthio containing 1-6 carbon atoms in the alkyl part (m) alkylsulfinyl containing 1-7 carbon atoms in the alkyl part (n) aryl (0) arylalkyl containing |-6 carbon atoms in the alkyl part (np) aryloxy (q) haloalkoxy containing 1-5 carbon atoms and 1-6 halogen atoms (r) arylalkoxy containing 1-6 carbon atoms in the alkyl part

Ps (s) R! and RZ, r? and r3 orR> and RY together with the adjacent carbon atoms in the benzi- midazole ring form one or more 5-, 6~- or

J-membered rings, which each may be saturated or unsaturated and may contain 0-3 hetero atoms selected from N, 5S and 0, and whereby each ring may be optionally substituted with 1-10, suitably 1-6, or 1-4 substituents selected

SOR from alkyl groups with-1-3 .carbon atoms and halogen, or two or four of the mentioned subs- tituents together form one or two 0X0 0 : I l 2 2 groups (-C-), whereby if R and R”, R and

R3 and R* together with the adjacent carbon atoms in the benzimidazole ring form two rings the rings may be condensed with each other; : R> is (a) alkyl containing }-6 carbon atoms (b) mono~ or dihydroxy-substituted alkyl containing 1-6 carbon atoms (¢) amino-, monoalkyl (1-3 carbon atoms)-amino-, and dialkyl) (1-3 carbon atoms in each alkyl part)-amino-substituted alkyl containing 1-6 carbon atoms, optionally in the form of a salt such as the bydro- chloride i + (d) carboxy-substituted alkyl containing 1-7 carbon atoms, optionally in the form of a salt such as the sodium or potassium salt (e) cycloalkyl containing 3-7 carbon atoms (f) alkoxy containing 1-6 carbon atoms (g) mono- or dihydroxyrubstituted alkoxy containing 1-6 carbon atoms (h) amino-, monoalkyl (1-3 carbon atoms)-amino-, - and dialkyl (1-3 carbon ‘atoms in each alkyl part)~amino-substituted alkoxy containing 1-6 carbon atoms, optionally in the form of eo salt such as the hydrochloride (i) carboxy-substituted alkoxy containing 1-7 carbon atoms, optionally in the form of a galt such as the sodium or potassium salt (j) alkoxyalkoxy containing 1-3 carbon atoms in each alkyl part . (k) alkylamino containing l-6 carbon atoms (1) dialkylamino containing 1-4 carbon atoms in each alkyl part (m) mono- or dicarboxy-substituted alkylemino containing 1-4 carbon atoms in the alkyl part, optinnally in the form of a salt, and optionally in esterified form, especially in the form of a mono- or dislkvl ester containing 1-4 carbon b atoms in the alkyl part or in the form of a mono- or dibenzyl ester. (n) aryl, optionally substituted with alkyl containing 1-4 carbon atoms, alkoxy containing 1-4 carbon atoms, halogen,

CFg, alkanoyl containing 2-5 carbon atoms, alkoxycarbonyl containing 2-5 carbon atoms, or carboxy. whereby the carboxy group optionally may be in the form of a salt auch as the Na salt (0) aryloxy, optionally substituted with alkvl containing 1-4 carbon atoms, alkoxy containing 1-4 carbon atoms, halogen,

CFq, alkanoyl containing 2-5 carbon atoms, alkoxvearbonyl containing 2-6 carbon atome or carboxy, whereby the carboxy group optionally may be in the form of a salt much as the Na salt (p) arylalkoxy containing 1-6 carbon atoms in the alkoxy part, wherein the aryl part optionally 1s eubetituted with alkyl containing 1-8 carbon atoms and/or alkoxy containing 1-6 carbon atoms. or carboxy whereby the carboxy group optionally may be in the form of a salt such ss the Na anlt i r® and &® are the game or different and eelécted from (a) H “(by alkyl conteinineg 1-6 carbon atoms

RY in (a) H

Cv) alkyl containing 1-7 carbon atoms

Cte) alkoxy containing 1-7 carbon atome 16 (4) aryl (ee) arylalkyl containing 1-7 carbon atoms 5 in the alkyl part

SE) aryloxy . (g) arvlialkoxy containing 1-7 carbon atoms in the alkoxy part ~~ (h) alkenyloxy containing 1-7 carbon atoms in the alkenyl] part : _ a -

— uv ide ATR 2 —_— ERR a iB xB LE :

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IEA R I L 0 ¢ RR AR A Tone REE os Coy ish gh | oO : he E : i 4 '

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Wi Het Lo SE HE Es & Ha Re Sib PRE containing wh £3 is er Gof BY. 3 ki . ill thE A 4 J po wi, “RA SE ge r ae 1 5 no: : SEE 5 so Bl SE + I= 5 args ry fae ud 7 Vig Hg a (mY. dial x dy, le x in’'each# i. Boo BERS. GE 5 ioe gn

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LA = ASR ge. gh “gk: 3 ow Din : — iE e F 4

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Lat as Be Tor 6-me . oxygen, Fie ws ob ou :

SR ai Fal : tain an Fo Fe ES PE . is yer Toa UT fa conta Co wo BW ER ; pA Pai oh 5 Ca py may optionally bh & pe Eo) 10

Hae gc Soi i. Whic it po el ED 300 3 SIT Heres hoe ving. | alkylated ni rn Xd 3% ¥ a I ey ie Cal A optionally WIT i sp TE

Cage phir or an og EN ah :

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LE Fe A IR che + PR fk Ei CLS . Fs Td i Fa i WE A ’ Fo ae A BE vk hss ¢ i Ji . SE Ce + jd aR NE AW pg Lo ¥

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CLE ey oR fo i A - ot B El i Ma : ‘ ?

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CET LTE a cob af gh 3 :

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Cad aE YL PEE, CR ; i CT : x nahi 1: COE La 14 3 he hi beige ss eat a . DRIGINAL ee eo wg ¥ iy SE TR EE CL BAD Fang Ak i Fe iE ZB 24 dh bs RIE oo COIN LE Ai ad Be sical of i

HE 3 at A AEs oe SER dow, ell : lk foe oo ETT 2N 19 hl] i A 8 J rai wT A Papel lp iar 9 We Lu FINI vy lee Hr etn AE. ENG 1 ¥: au LARAE NB AL (Ee donnie pi Es x

E- re id yi $8 yok, oR IL ds rd RY dy MEE FRR... EA LOE i ie CB ded : HR SIRI JS CI nT FY ig La io) pe ; nf

Ee £1 ! 5 KX J ES ) A f 424 HL Ric i ah ) - . a pt: 2% Ad: od RN Sg ta » : % Jnl | y 3h

HE A } p Pua ) NES oo! ES ok AE ERE LI A¥ IRON La Eg a A 4 a 7 FY offer 3d. } Has R . [ = SRE TEL SA: CR IE .. SEER VANE: TARY 4 ey ard ASH Ea he Es Ta FE FEE i [E0e a . ER AN ei G0 : 5 5 ER : w 3 | : BSA § PR dN hag Linu il RAE ald N } SR ea REN WR 3 lh

(b) Alkyl containing 1-4 arhon rtome; kRIZ 1s (a) alkyl containing 1-8 carboy atoms (h) Alar cembaining 1-6 carbon atomr: with the provisos that (a) & ig hvdvngen, alk-l, arvl ar arylalkyl when the follawine condibttone (al): (a3) are fulrilled aimaltans nel: (al) Rl syed wi tye both hides sys 19 (az) FY and #7 sre eelectad from the groupe hydrogen, plhyl mlkews, ORG op norl? and } Bb (a3) RY ig alkel. ~arboxyernbhastitated slkyl in its acid form, aminc-subgtituted alkyl. or 156 RY ig aryl smbstituted hy alike], alkoxy, halogen ov Cb.. (bh ro 12 nat Zopethuylpropoy ghan Rr, g%2, v7. rRYRS. RT, EYL and RY are hydrogen and

X ie 5.

In additicn. the inventicn includes the tun compounds acnhording to examples 4 and 3 below, for the mame inventive arpects as the ~empouande } AD ORIGINAL d

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FRR IRS SGC RRA SEER Cg oy WOH : Co + CREE ov. ELEY

PAR CHR CR I 7 <I fu . ; 39% i SNE EO

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CL iY DE ERY ingterecmeric = forms possible gi Tpure’’ 3 yg ok

Si Yew i ERS cE a cE : B48 YRS dR kL co IT Aes . 36 amnpant lomers ld Cou fg ge Ble alle” Mid A BE

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CAT TER TE NER a - : . : Tg dof FOR Re EEG rn

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Caeand fff compounds of the invontion thal fergl. BE ed

CUMERIRE CC Viiti0es (XeB) Ray be any vhion thal sperm. Ln WY of

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Chula don asymsotrio carbon atoms, as ddpeidbed: ii WE EF L 3 eS en EE La ; Lo y : AQ Redd bad oo & ahr eT Al NEE Ss . ¥%e . a t . CE Sa SUF 3 BY gy ? .

Nariel 207 above oat UT TRIE aah Alu > Eh LS ERIE «YT. different diastereomeric :’ rm TOE LE

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Ed (0 or a + P Ppl bs! ! J cd Ca 2 Po * or & & - rest . = i

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Te AT Val poe oy ud te PE . bby EN - EB + i Te, SNL AEC ww od LL AAA re LL Shite Cove Ry SE CREE LE PE fy 8 OR ek A gi Sy Se Eo SU ew Ho Sho gay Mer XO > en AAG PN EE oN IR ERAS 4 Ca i XK B. " . . Zeg o J Th AR ro

Fi 7X Frag he ¥ fi: She dat ey oo TR ca Cree TRE ERT TTT AE pat 2X HF

Hey | I TR oly AF BEET Joon x \ “ay : Cot i Ch We 2PREe ar

AE ii IY SR, ¥en Yoon we . tL R10 SR 3 tr. HEAR Wy

SE g er 5 aS th ey! oR 4 Bi Sa Pad 4 on wr i; BARD (AH (FNAL 0 ¥ | Lat ¥ 5

Cited WM A Mcp So ey dl pee 7 et ty ca :, NERA IE * VC " anys SE CoE

Fal RR Rc: A Gla ade de fob Bi Co J La na A en ky. BN w tut RSS WII ie A 8 1 fs UE he The a2 0% J Soils BLT § ra A CEA oy 3 es RY shld pa ri Tu Phan Tere ag TR TERE Che SBE Cf” ox i

Ber ie I 2k 4 PATSEISRY i da aa, oN i, ay TAINAN en oe on Aen id p% tide argo FR #1 Rf 7

Rah AE LAAT IE ps Rl Sdd i by ROLE LS > ig Cr ERE YER i gee Sa < , ‘al RY [a BE Cle XN Ay WC Gas 0 ae LTT OER 5 Pov re Beg IST Lc ar ll SR

USNC (SARI 0 AA Td 0 Te vi SAREE RR EY ; : PD ; x ga - ¢ or Xe Vie f A & J

XY 4 RT Th Ra CE AE Rik: a vo! ' Sh . wi Cl ol Gt . I 3 CLA ! BS 15 LY 5 A i dich BAA “RE URLS FR. TY pe Hg. ®t 4 ry FR Gof, Hv A FSR ee ———— CL ——————————— possible ap well ag the pure enantiomers and racemic mixtures are within the scope of the invention. :

Preterrad groups of compounde of the formala are: 1. Cempannde wherein Xd Ho 2. Cemponnds wherein X oie -d- 3. Compenmdg wherein pl . gr h' and k Care the game or Jdjffarent and fe dected from (a) H . (by =wlkvl baving 1-6 carbon alome (or) Aikery having 1-0 carbo atoms In the alkyl part, oF

Lay 7D and KY bogelher ibe adjacent racrhan atawe in the benzimldanole ring form a paturated or pnsainy atad bor fo omepbared ring containing carbon atom only

Cote) pt ancl gH tawathoay with act jacent . ~arhon atoms an Lhe Lennimidezsole ring . form a saturated or wneatvrated b- ov .

R-memhered ring containing carbon and 13-0 "” ORIGINAL A rr oe 2 2 & 2 ia by ny i bY 3% = x

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EA I yg $0 4 BR Ee xii I cp Hat EH] ’ Hay lee Li on 3 aE a a, RT I 5 4 H

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TER SEN SH af fon arbon ati, Mt i's Cw bstitited hE EE ex 4

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Sn Rey is Cyne Edy Rs L oofd IPR, alkyl co ii. al gi Li oy

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TR 27 5 1 i ] 3 i Fah, %

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AS PARTE ry AE FURIE ©

SEE BRIE 5 Ni A aw 3 £2 Ll ! Lt EN El SER fr -

RH Wee mb

Vigoss be in the form of A gall: mono- or dienrboxyenbetituted alkvilnamine containing 1-4 carbon atome in the silky) part: amino, wonoslkyl (1-3 2arbon mlome) amino-, and dialkyl 91-3) aarhbon stome in esch Blkyl part)-amino-enbatitnted 8lkyl containing 1- 6 carben atoms, optionally in the form of a galt «uch ae the hydrochloride: and Amina, monoalkyl (1-3 earbes atoms mmins-, are 19 dialkyl (1-3 aarbon atoms In “ach mlkyl part)-amino-gubst i tuted alkoxy nontaining 1-6 aarbon atoms. optionally in the form of a enslt ench ar the hydroohloride, 7. Compounde wherein R? ig carboxyv-pguhetituted phenyl, preferably with the carboxy groan in position 4 of the thenyl ring.

8. Compounds: wherein RY ie dislkyl (1-3 carbon atome)-aminc-eubestituted alkv] 21-6 carbon atome} in the form of o padi.

29 9. Compounds whereln RV ie dialkyl (1-3 carbon stome)-aminc-substitnted alkoxy containing 1-8

15 - BN Ta \ pet E po Orta —

. carbon atoms in the form of a salt. ‘ 1) rr A oA 19. Cowpousles wheveldlo V0 7, BD snd £77 all ave

H. 11. Compounds wherein RU snd RY are slky! . : Po containing 1-8 oorbon mboms vhen RT and nd Ea

H. ' . A . ‘ Co 12. Compounds wherein rt, J snd RY ave Ho and 2? . ao: . .

R® ie OUCH, or chp and KY sre Boag RY ge

OCHg . 19 13. Compounde whereln RY ig H. silky] containing 1-6 aaprhon stom ay alkoxy containing 1-A oarbon atoms, 14. Compounds sharein FB is wikyl covtaining 1-6 carbon atoms or alkoxy conbaining 1-w carbon atoms. : 15. Compas whepe in RY feo wdrowy ant aining ¢ 1-6 onrbea atoms, [2 In ~ 1h" 7 J ’ 16 BAD ORIGINAL [

C

16. Compounds wherein r? is H or

CHy, especially H. 17. Freferrvesi pobaltitnted dp peettion 1 of the benzimidazole nu l=ur are; ‘BAD (ritenant Yj ,

-CH{CH3)0C00C,H, -CH,0C00C,H, ~CH,0C00CH, CH(CH,) , ~CH,0C00CH, CH(OH)CH, OH . - + -CH,0COCH, CH, CH, CH, C00 Na choco! cova’ : ogo —4~(00"Na" -CH,0COCH,N(CH,) ~CH,0C0CH,N(CoH, ) ~CH,0COCH, CH, N(CH,), =CH,0COCH, CH, N(CH, ) ~CH,0COCH, CH, CH N(CH, ), ~CH,0CO0CH, CH, (CH, ), -CH,0CO0CH,N(CH,), ~CH, 0CONHCH, COOH 20 . ~ CH; OCONHCHCOOH

CH, CH, COOH "whereby the amino-containing groups optionally are in the form of a salt and the carboxy groups optionally are in the fora of a salt or an ester, 18. Preferred benzimidazole structures are: ;

CH

CH, 3

N N .

N CH N

Cl 3 | \

CH, 0

N

N N

OL JIC LO

: N

N 0 - 18 ~ ! § . ‘ bk

In

Jos

COCH, N SN N

N—

I AAs p

N C-OCH N . il 3 | - 0

Additional preferred compounds are obtained by combining the indicated preferred meanings for some or all of the radicals X and R'-R'O as indicated in the yroups 1-17 above. Examples of especially preferred combinations are 19. Combination of 1, 3, 6, 14 and 18. oo 5 20. preferred of the pyridine fragments are: - OCH OCH, C He OCH, i. AO) 0 O O O O : N N N N

OCH, CH 2 CH 3 ©! CO ; OL ; TOL

N N N N

CH, CH, or” “or”

N N

- 19 ~ ! 3 a

21. Preferred of the pyridine fragments is )

OCH4

CH, Vz CH, 22. Preferred of the pyridinylmethylsulfinyl benzimidazole moieties are

OCH,

CH CH

3 - 3 z | . >

XN CH,,S0 | Ji pr 2 N =

S OCH,

CH OCH

CH, pz | 3 P 3 : N

Ny H oI i C 2 I

OCH,

CH CH

3 3 :

NS | ;

N CaSO 0CH4 23. Preferred groups of the radicals RS and R8 are H, CH and CoH - 20 - - ip to BETES Bug Cl ae alent beni me ae Lo TORRE Ry ee) TT TT

ER AE LNIRR OPAC 1 Wg 0 pe THER al Ta MAT ld con, RR EL 6 ogame ag wR

SE IPR id TERS el asi Tr RRR a: Nr Foe : By Bei ve ®

PRE ith , nun gl bia or ad Sav, ee E LANE ATR ent AR po RN rw RTS ye MN TERR RIES le SE Ee Ef

DER RE ERNE TE GRE A SY 4 iad SI . : IE Tg EI i= BR fg BoB 2

SERRE CORY Logbae E EER

SONA i RRR BRRRG np Loe ’ ha § GE be NE EEL NL

FeAl ns 0 LTT Re Tr Cr ERO gt CIRCEROE

A ARR TA EY SST pS ro PE when \ ] ORR EL ryt i Ee ar. 4 :

AON REE JRL BR 1 TREE WY as ae hk . ; ir fk TE Py E0 Rss ¢ %

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ACE RPRSEEL RRR: hfe Ey EL pam Tn PI Lo Ee a GT RAL EER 1

So AS OMENS: ARIE: dy Cg gh ed Lome EE EY CL FL OE a J

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RRR Ey aa Le LER Rear ETE LF

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Sted gE SRTE SER AO ray BT TB ear Te Bethe CG ay oa RT SEER RR Eas

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CHR Re Rg lower alky bl Yipa, sapeg) plly preferred {lz4 [ £0 ghicy of

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SR EARR, GSE parbon atORE CID RLY YR gsibvl, noproRyls fn Baal R ak sO RRR TA rd SEE Uf na pe Fant: RE TEC IE A SA | Sa oN Ed od

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SET ATEN DLN SEE. «+ thie’, TRL gy PL Fo OXY 8 5 = “Site ltl A SR GO

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GEENA E RR 1 ISR RAC RMT RT Ti TE al gE Lp . ne pt Uo cpl SERENE Yo 3

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CRT aden i STERIL Yintane aérimisiaheior ‘RE. BZ, BRAWRYERC URIBE §-

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Le Vian hab Lyi Preferably a lower alkyl having aespegia dy Ve Bln gr * Gd fh ee © RE Pa Ec we, AREY Pe @ Cod

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Ho ps = Lows EE .. x ) n lh Food ay kG EAL AR,

SE ED :, Nr HERI

Saas ETE Ni ak coon WEE po CE _—

RY; TEN aoyelopentyl, ovelohexvl and methyleyelopentyl. rl, rR, RY, RY and KY representing an alkoxynikvl a alkorvatboxvy aronn hare preferably 1-6 carbon stome in the alkoxy group b or groups snd alkvl group, reppectively. agpecinlly praferved 1-3 carbon atoms in the : alkoxy dareup or groups avd the alkyl group, i regpectively. =.g. methoxyesthyl, mathoxypropyl, ethoxyethvl, propoxyethyl methaxvethoxy, 12 methoxvoropoxy, ebhoryelhoxy and propoxvethoxy.

Rr’ repragsentlng an alkenyloxy or alkynyvloxy aroup hae preferably 2-7 carhon atoms, eapecially preferred 3-4 oarbon abeme, eg. Co allvlcyy, propergvloxy, Z2-botenvioxv and 2- . 15 nutynyloxy.

Illustrative examples of ring structure formed by Rl and 8“. R® and KR? and BR? and pg! are -

CH,CHo Ho, -CHCHaCHACH, -. CHACON) 5 Hg =. (CHyp)g~. CH=CH-CR=CH-, -CHaiCHy-, OCRRP~, ~

PCH, CH, O- . - OCHy CH, CHpO~ , ~OCHLCH, - , -

CHuOH NI-. -CH=CH-CH=N-. -COCHpCO0-. -~5CHpCHg-, - 23 - pooRemA o) “i oo : of

TM

-8CHa8~. -BUHL,OHLS-. and ~C{CHAY a= C0-C{OHgY, - r® and k', er RY snd BY representing a LH to 6- membered saturated or unsaturated ring ie preferably =» paturated carboovelio vine or a aaturated ring containing an oxygen wtom in the j-porition in the pyridine ring, a. g. -

CHoCHoUllg PE CH OHG UH Ho ~ . =i -CHLEH, , or ~~

CHoOHAU He -

H i 7 :

R and RB’ when represent: sn nlkylamine or 192 dialkvlemince growp is preferably NHCRg,

NHC oH, . ~H(CHq) on N(CH Yea ar -HHCH(CH) 5 .

RY when iepresenting an amino-. monpoalkviamino- and dialkylamtnn Euhe td tated Ally! aroup hae preferably 1-434 eoarbon atame in the alkyl gubstituent or 2ubstituente on the amine group.

The samwioo-. wonealkvlamine- or djslkylemino gubatltuapnt lg preferably atteched to an 3lkvid group ocombainine 1-3 carbon atoms. ”

RY when representing an amino- mevoslkylamino- 2

BAD ORIGINAL 774 and dialkvlsmino substituted alkoxy gronp hae preferably 1-3 asvbon stome tn the alkyl subetitusnt or subastitnente on the amino group,

The amino-. monoslkytaminoe- or dialkylanino pubatituent ie preferably attached to ap alkoxy ” gronp containing 1-3 aarbon ston.

For the compounde with the general foryala 1 containing me vnevmmety ie centre, olh the pure ensntiomere snd the racemic miytnrer aye within 12 the peope nf ihe present invention.

Further 1l1netrativer axamples of the radicals in the fornnls I are given in the axamplas and

Liste of apscific cowpounde given elrewhere in this spenificabion. [llustrabive examples of compeunde included in the Bgcope of the invention sre given in the following Table 1. \ A)

BAD ORIGINAL £j ee

! L

Ce — on, : xT x rr x x x x x = © ™ = oo ™ ™ 0 x FON Cony = bo = xT x rr = - - - [=] o oO O oO © [&5) [&) ; 1 1

[20] = ™ ™ mm ~ x x T r = = ox PSN “ ~ Oo Oo oO OL

T xT oo o oO oO o Cc

Q [=] . oo oO oO

Ve) ™ = oo) ™ Mm _™ x x x XI = ox o> [ae] oo - + - © © © © oO o Oo < ™ xT

QJ) ® ~ ’ ! ! oN 0 S = . x T | oJ oy od oJ [a IY] xx x x x x . ™ © © oO QO - 7 1 i ™ Nod

O o~ oN o~N T x = : x = x Q Q Oo [=] [= [) o oO < t ' I ' 1 ' - . ox p= x at = Tr x XI x = ~ ox - x x x x T - x x

JR— | . { o~ = T T T ba us x In ut x x -

Tex xT ad J

T T x x x < Q Q o o o oo oo cc = wv vn I bt a > a no — - 26 - i : f i iil

WB

EEE —— a ———— EE — on | ) a J - - - x T x x x x ! . . ! “ mm Mm oo o oo m 0 =>

J 2 £2 x x xT = x x x x x { =|{8ss8esc °F 2 ! \ wm em em eo ™ ™ m ™ ™ bx xz x = TF TL = 5 5 5 - 5 5 5 5 8 9 oO Oo Oo o oO x | © © © © © oS o oS So S oS ’ ‘ ™ ™ on ™ o> oo ™ o o o N wo | =z 5 5 5 = 5 5 5 5 S x | © © © « © © © © © < © \ . = 0 ™ ™ = 5 x < 3

Q «2 9 =” _ | nO on [a V] S un ! lag xT ~T = 8 x | = o = 9

Oo mm OO [8] ~N OO

Ww XT NNT o™ = . b- 8 = 5 8 & \ S

NO © © = “ < = NN NNN WN oy o™ oN = = = xT xT xT =X x 5 S S S °c 35 3 & © © oO oo Q oO oO

S Ss S oS o oS oO oOo oO } 1 <r } } = ~ —— x T= TT T x T x * = ee ——————————— ; “a, | ~~ xx x =T xT xT x x + = = ~ . ee oc ~~ xx TT x x xT T * = = = ——— —_ p = _- - - - - T pu ot T I x oo cc © © oo © o o © o o 5 3S 2 S A a Nn w) wv wm wv Ww on mo - ox x x x bo ot x x rr TT xT T= © oO x o® | o™ on ™ on ™ oo ™ on oo ™ . = T x x T I X* TT xT =x x o o o o 00 OU OO = o ™ oo o™ ™ oy ™ ™ ™ oO ~ = T = - r = xT = mT ~ oO © OQ oO Cow WOO x O oO So So o oO © © © xT oO c ™ od [ag] od ™M on oT ™ MM [20] ™ 0 = x x x x x x x x x x o i oO = [= o =) Q =) oO © © o or o ™ x x © [SS] oo oJ wn —

RN a \ _™ ™ om fn od be ot x = oN oy NO oJ oN o oO ~~ (ae! . I x pu a x oo ON ~~ ~™ oo —

I) o =) w rr xT x =x x ™ oJ oN oN oJ [8] oO [5] [88] oo x i Io x x x. I I I mM NO o o oO oO Zz = ZZ Zz TT =X ~ ? © <Q < ' ' ' ro OS © 1 -——————— <r = ™ x x T x rr TT x =x xr = x ! oO ™ ™ - \ ox T x x x rr TT xT xT =x ~ | od a = / x x x b= od I TT TT TT TT OO ~ ™ a = bu of = x = ad rr TT xT x OO =x x 2 ot o © Cc © oo oo o >< wv wv wv wv vw wn wn) wv wn 3 a i - 20 w 1 i . - i . . of tee SE — ee ———

CL . 1 .

IY

J mere - Tm ™ aa) [a] oo a2) ™ nM on x x x x x x x = . [4 o © =f o Je od [5] x o [8] pe © oO x -— ™ = x

Io ot Q ™ ™ on ~ ™ ~ ™ Oo ™ oo © x xT I xT x x x oJ xT c [oH | © o x © o ow =) won x on x

OQ

™ ™ ™M on (30) oo MO oo ™ x xT x x x x x ox ~ j=ut [&} o [&] © O [8] © x [5 © © x x o © eS Oo o oS co, © xT . ! x

OQ

=] ! ~ ™ oo oy ™ ~ ™ lo n= x I > o of = x

De | [8] o x wo © [=] o x x x x x [= . t ! { ! ~ - x ~ QO . . oO x 0 O oy i | = = ™ ~ oO x - Ql & = 8 . . x x

I ~. (8) w ™ oN od

J oO oJ mo oJ x Nx x . = x Io od x oot OOO oO o [=] o = [= < < o T ” 1 \

I

< x x hu of x x x x T x x a x x x ! ) ! Mm mm 0 ™ ™ } o ™ ™ x [J o x Fa oy —_ 5 x = rr xT = © ex o o x [) 0 ' [= o oo © © o 1 [=] o = oJ 1 o ~N [554 , T ou 7 x ~ © x - <Q . oo oO , 1 1 mm ™ ™ oy ™ ™ ™ ™

Ne o I I x — 5S < TT xT I XI x x oO © &) [& 1 [&) oO © © [&] [=] 1 1 | oo o - O —_ ox bo ot x Io of x x xT x x T = be at x xT c o o o o oo oo © © oo Oo Oo oO > | wn wv w wu wv wn wv wv wv wv wv w) wv =< — - 29 = ! 4 !

Lwtih eo

- bo ‘ : LE] ’ CL

Pon . i i 24 ¢ - ht Lo ———————— ee ———————————————————————_——— i ™ ™ ™ on = = = ™ = =r £ 2” x [+4 o oT S - 5 x bo x © oO oO TT O ) ~™ ™ Mm mM ™ EE © = T x rr =x T rT x = oc = x oof T° - O |] |] [85 oo |] [&) oo Q ~ ™ ™ © ™ ™ mm ™ oo ™ m mm x T x = - rr xr =< ~ x 5 5S J o Oo oo o © oO O x T o S ee S < o oo Oo © S © & x ow o — reed ~ ~™ ~ ™ ™ ‘™ o. o

I © = = - = = =x x rr © =x i [4 Tr ba - S - S o o w O oo oo o . [1 ! on . ! x oO o wn oy . « _f oJ oo ; Te oT (a2) ™ fae)

NN A < x x - xX I x (8) ~ ~™ oo on Q [&]

TJ g & NT ™ ne © =x I mo c z= =, 85 9 3 oO [ Z oO © Z x = . . V 1 Tl S = = o | o 1 1 o o . ' V . < - _ x rr =x - - I T = = =x x xT Oo =—T _ ! ~ . i ' . . - eo“; | x oo [a] ™ ™ . — ” « I = x x - rr = x rr TT Oo : p | x fl OO o ST = -

S

Io ot 3 o ~N h = =" = ™ —_ a = x x = TT TT © = oO oO O +~ x xT x oO ! — os — x a x rr - - I - x rr x x Tz Oo o oo oo o o o Cc o o o o © Oo © = ve) a A A A A ~ a) ao a A A hn

SS re ee eee ee eee eer : i - 30 ~- |. ig.

; Co Tew i . R . ~ She el, coe id 4 deer, BR 3 * PS : : . , . i SNORE eee fro BE aed Lo :

Ce wie ew . . Cog Toon ul ER Rd al oman ETe YOMEL SE A : Es 0 : : RE REN co > Apel Fa ply ol NEE EB 3 i FN TEE : See EE a eRe eR CE : GR : To . . 19 Foo] CANCER Eo i ie | 0 v4 ! 0 CELA Gen OY em STRAT A

Po CoD ERG TERE Ae pee

A Loe Seno OR . TE FRR LE } . SE ie lk ow, ar ue 5 . . pole so The ey CE . Lo SLE en Lay Co « Ly . - } N i | si . . o : . Tem ww : ™ x x x x ‘ . Lt : on food bn = o oo bn ot Oo x = rr TT xT =x xT

Ka oe [85] xI : ' ) . | tm rent etter eet ele — eters EArt. - a me — ™ ™ ™ ™ Mo a) Mm em om Mm Mm Mm mm © x x xT = xr x x II xT XT XI xT =x =< x o@ o o © o ow = RE LOO ‘ ee reese ete feet eee ert eee eee ee tee ee ete oe ee ea eee mtg on ™ om ™ Mmm om Mm Mm mm ™ ~™ = x rr =x x rr x = rr XT x xT =x : : x = of OQ oO © OO oO LY OL Ww OY {I~ oO I) o © © oOo oO © © cS © © oo oOo ¢ . ox o S ~ . ee mM ™ mm ™ me em Mm Mm em mm oe - == x xr = T TT xT = Xr TT T..T x=

Si - - - © o oO o Oo oO © wo wo © . CE ye oO . . . hoe . { . A Cal = bo, — } : - i bo N : Ie i ~~ © !

SEE hp . = oO oN : pe

CoE : + Jf NF Toe # x . . ! [i] hn — ™M © ~N . i is =z / = wx =z, —~ . oT Nz WZ SF 4 Th fo, 5 . ™ © = N.— © ‘mx

Vo wn x pis 0 OO VU. XT Oo ZT

Jo] = Co w iQ = = += OO i = . po o iN x NN NN oOo xT : Se ™ LO +Z XT XI © +Z a : _ ™ CO ~~ NO OQ o | ™. = NXT Xe. NN Nox = | x TN o | mM I Ou VET xT ET oO o ™ oy oN rz oO NNO Oo ON : | ~~ ~ x x pd [] oN x x ON NN I

Co © OQ © I TT © OQ XT TT TIT © _—— = —- co Tr To o x rr = x xr x= = ET XT TT. xT. xT i L SL ; deeb, tet Sllio Tw <n - :. ISL Te

Li : 5 . ne Co tole ~~ y= . | Tg Ee : wot x “wo =x = T Tr = x TT xT x 4X Xx TTT i oa

Co ~ Aeon Cl ; re i laa} om on ™ Cs ™ Le 5 oJ ' IE x x = x x [SE XI oe. xr . x = O QO Q oO SL OQ oo iE © ox x. OS oc oS o © TT x ,¥r xT O!xX © ) 3 Lo s SpE Sel BR

Lo ve — — ws Coe v Tz oo o x xr =< x rr TT x "THT XT .T =x

Lo. = — M : — : i “ . o o oc © o Oo oOo © co oo oo © of : >< 3 3 wn wn on 7 von nv Bi. 1 KB» . - 31 RA ert } i , - : Ly il i ! . i}

EC : - Soke LihoaRn AT

Or . EEE §: So eR i + . Ape, , . . CE A . : ce LL" ¥ i a 5 : : i oy ve } CA ! To a pe] v cL : isd ¥ (e He Sn ¥ oH oo - cu . SL . eT ER 5 Saad so =a EA LM LE " San & Patt on . oo oe FL ) oF SE

Co nl i - . ! . . : = Ce : " Co EL ier FART } . . R LH og o LT p tht SL oo The: invention takes into consideration “that Cy

SE go Ro BE compounds of formula TIT may be metabolised oo fond before exerting their effect. Such metebglism ne may. occur in Lhe N-gnbghtituent in position 1 in

AT CL ’ b the benzimidazole nucleus. Moreover. compounds : of the invention wherein X ie S are believed: to to exert their sntleescretory netivity after : metabolism to compounds wherein x is SO. these oo cofilderations nre also un further aspect of ‘the g | gi! Ea -

Yo Cee 10 todition he

Toa Me LL gl tll She : od EEE BS

Coe Lali HR i.

Chm E RE oo vo. La TUE it Is believed that all compounds of vo EINER hn en " a - : : CE Ch 5 i 7g ie ; BE formula T wher=in x 1g 80 after administration

Ce . Fath LT

AE Cd co : 2 . toh living arganism, exert thelr antiaccretdry

Co 2 i: © SE effgats After metabolic or pure chemical nC So RAR

Ag CT oo 156 trafdformation to another. reactive especies. ; fa ee ’ : Acagrdingly. tha game 1g true aleo for. ithe

He : . ENE

L- compounda of formule J wherein X ie £, but “via

Sy ' : vor initial treneformaticn to the correspondings as

Co well as puch reactive specles per ae. are LE oH

CE oa Ci Ld ; 20 inaluded within the eoope of the prasent ol ¢

N invention. gy) REY 1

PASI ek CEE 3 Ce Td

EE Ed , . re - i - ETP a RE Ta To ne

Coa BD ted

LC FR Co 3 wo : . es

EE GE | ane Seen

Lo fH rah Con

SE ga IE Co

Hee | ld Co oo Sl fn io GATE Te Ey . . :

Ch ERY : : Bo “yo - . co, : Ske pi : . IRN a A i

Cl ah . ER Co co : En aA :

Ce ZiR0das - 32 - hog

Co Bsa | ae So . SIRE ART : oo AE BAD ORIGINAL SLE oo AIRE \ wrEaE Co ; : Po SEN : ER : BL adr : : ty EL nti !

AA SRE Co

Co SR . SRI Co .

SEL Al | . i

EE ew ' COR ARNE ’

" Preparation

The compounds of the formula 1 may be prepared by

A. Reasnting = compound of the formals TI 7 r! r® r8 ) / R

O | O I

CH, -X._ ud

H,, ~X o 3

N BR

M rt wherein r!, RY, r3, r4, rE, rT, RB and x are as defined under formula 1 and H ig either a metal cation such as Nat, R* and 11? or a quaternary amponium ion. ench as tetrabutylammonium with a compound of the formnla 111

Q

RC -¢ - 0 - cHRY - ¥ 111 wherein RY and Rr? are as defined under formula - - 33 - 2

BAD ORIGINAL GJ)

Lo.

I Zand Y 1s halogen sueh ag 2, or 1. or a funotionally equivalent group,

The resction of a compound of formula IT with a compound of formmia IIT 18 enltably carried out b nnder protective ges In absence of water.

Suitable solvents are hvdrocarbong such as toluene avd banana and halnuanated hydrocarbone such ng methylene chloride and chloroform.

Tha reaction of the componndg of formala I1 and

III may be carried out at a {temperature between the aml ant temperature and the Loiling temperature of the reaction mixture.

B. Oxjidizing a comppound of the formula 1.

Rl : 8 6 r!

R ~ R 2

Rn

N J

1 / f

CH, - X I

Lew pe pn ~. ” We ~~ 9

Hp-R at al - 34 - BAD CruilinAL 1 4 - = wherein ¥ is 5, Rr. p%. pr? rl wv" RS. RT. RP and r9 have the meanings given. to glve =a compound of the rame formula Y wherein X is 850.

Thier oxidation may he carried out by nasing an oxidizing agent pelacoted from the group conglirting of nitric acid. hvdrogen peroxide, peracid, pereelars, ozone, dinitrogentetranxide, fodoesohanzepe, K- halosuccinimide, 1-chlorobenzotriazole, t- 1 butylhypochloride, diazabioyelo-12,2,.21-o0ctane bromine complex, sodium metaperiodate, fe Len ium dioxide, manganaasa dioxide, chromic acid, cericammonlium nitrate. bromine, ohlorine, and enlfury! chloride. The oxidation nsually takes place in a solvent wherein Lhe oxidizing agent ie present in some excegs in relstion to the rroduct to be oxidized.

The oxidation may alec be carried out enzymatically by using an oxidsting enzyme or 29 microblotically ty nring a guitable microorganism.

I. ORIGINAL 7) be

C. For the prepavation of aompounds of the formula I wherein r? § H, reno bd ng n sompound af the formls JV 1 n! R 2 8 n® | R

R EIEN

ING | | | v

PaaS Pp ~~. 3, : j -

Fou, X x i R at

CH, 08 wherein rb. p? mY. pd gS RT ana RY and X are

AG defined uncer formala 1. with @ Aamponnd oF the foremla VU rAcony v or ap motivated derivative thereof, whevein Rr ig ne defived ondey forwnin 1 Rp

The resction of a compound of formals IV with a . - 36 - | - /

BAD ORIGIN. A compound of formula V is guitably carried ont either directly in the Presenne of dieyclohexy loarbodi imide and if desired also in the Presence of N,N-dimethylaminopyridine (DMASP) or with an sctlvated form of compound

V, such sg sn acid halide or & mixed anhydride or a carbonate.

Suitable solvente are hydrocarbons euch as toluene and henzene or halogenated hydrocarbons 19 such as methvlene chloride and chloroform or polar rolvente puch as acetone, dimethyl formamide (DMF), tetrahydrofuran (THF) and pyridine.

The reaction of the compounds of formula IV and 16 V may be carried out at a temperature between - 16°C and the boiling temperature of the reaction mixture. * .

D. For preparing compounds of the formula I wherein R? ie H and which contain an amino, monoalkylamino or dialkyvlamino substituent in the radical RY, reacting a compound of the formula VI 1 rl R

R® r® | R ~._ 1 :

Pe

TS oHX ‘ a

CH,,0CCH,, : ’ 0 wherein pl, RE jg, pt rE E7 RY and X are as b defined under formula I, and 2 ie halogen such : ag C1. ov on functionally equivalent eroup, with a compound of fhe formals

Pas

HN “

Ale wherein gr! and rl? are the fama D1 Al ffereat H 1@ or alkvl contalning 1-6 carbon atome. : aap oriGmAL* 63) - 38 - be

The reaction is carried ont in =» suitable solvent ench ag acetone or scetonitrile at a temperature between the ambient temperature snd the boiling temperature of the reaction b mixture.

E. For the preparation of compounds of the formula 1] wherein r? is H and rd ise monoalkylaminoe containing 1-6 carbon atome, reacting a compound of the formula 1 al n ® 6 2 “0 ~ Iv

TS cE, X i 3 rd

CH, 0H wherein rt. RZ, rR, re, RS, RY, r8 and X are as defined under formula I, with a compound of the formula @ = ¢ = N - RS VII —- 39 - 2 sD ord AL £ . \ -

: wherein R'? 1g alkyl containing 1-6 carbon atome. :

The reaction of a compound of formula VII with a compound of formulas IV is carried out elther oo directly or if desired in the presence of a suitable bsse such as pyridine or N,N- dimethylaminopyridine, Buitable solvents are hydrocarbons such as toluene and benzene or halogenated hydrocarbons such as 19 methylenechloride and chloroform. The reaction of the compounds of formulas IV and VII may be carried out at a temperature between the ambient temperature and the boiling temperature of the reaction mixture,

F. Deblockatlion of a protecting group in the

Rr gubatituent in a compound of the formula I:

Thie may be done in different waye well known by a person skilled in the art. Thus, for instance, monohydroxyalkyl may be protected ae an egter group. which mav be deblocked by hydrolysis, geminal dihydroxy-alkyl or geminal - 40 - | ap ORIGINAL E51

Lo.

dihydroxy-slkoxy groups may be protected ae acetonides, which may be deblocked by acid hydrolysis. Amino- and monoalkylamino-alkyl or amino- and wmonoalkylamino-alkoxy sae Rr? may be protected by a tert-butyloxycsrbonyl (%-Boc) — which ean be deblockerd by acid treatment, and a carhoxyalkyl or carboxy-alkoxy group ag RS may be protected as an ester, which may be deblocked by hydrolyeis.

Depending on the procere conditione and the starting materials, the end producte of the ’ formula I are obtained either as the free base or ag a salt. Both the free base and the salte of thepe end products are included within the scope of the invention. Thus, salts may be obtained ae well as hemi, mono, gesqul or polyhydrates. Acid addition ealts of the new compounde way in a manner known per _ge be . transformed into free base using basic agents such ae alkali or by ion exchange. The free bases cbtained may also form salts with organic or inorganic acide. In the preparation of acid addition enlte preferably such acide are used which form enitable therapeutically acceptable galts.

Examples of such acide are hyvdrohalogen acids, sulfonic acid. phosphoric acid, nitric acid, and perchloric acid; aliphatic, aiicyelie, aromatic or heterocvelic carboxyl or sulfonic acids, such as formic acid, acetic acid, propionic acid. succinic acid, glvecolic acid, lactic anid, malice acld, tartaric acid, citric : acid, agcorbic acid, maleic acid, hydroxymalelc acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzolc acid, p-hydroxybenzolc acid, salicyclic acid or p-aminosalicylic acid. embonic acid, methanasulfonic acid, ethaneesulfonic acid, hydroxvethanesulfonic acid, ethylenesulfonic acid, halogenbenzenesulfonic acid, toluenesulfonic acid, napthylsulfonic acid or sulfanilic acids, methionine, tryptophane, lysine or arginine.

These or other salte of the new sulfide yp io wh I oA Car ET Gp a Ke 4 . . eo “ dv L a | 5h , } CO 15 3 ot rg pi * Hy vo Yen nd BEE TT CAE SE § Lo Cw a Pe Fo RRS CE ah : EI Ca CRA Cem LT : 3 t CoE : SET ap ene i RH . CT . i Eo ERE nL Ea 2 t : sgomponnds, as e.g. plorates, may serve nas Soak : Co purifying agents of the free basea obtainad. Lo fe WE oY oo - : " Balte of the bases may be formed, separated Loe

Ll . ol HN cl " KA ! J . Co from solution, and then the free bare can be 4 . : An - : 3 oo LEE co : a 5. Yecovered in higher purify from a new -ealt Co - ‘solution. WL - PE TE - Sd . . A .

Co SRI ) oF CAR

Hacenatos obtained can Le separated acdording i : Co 3 na : . to known wethods, a.g, raocrvetalllization’ from

Ce El Sn 40 ah optically active solvent, use, . of § : . Be Lo to a ot a \ ’ RY EL |e, . i Qroorganisme, reactlons with opticallyiactive ro HR Sg TE

Lo ad CE forming diastereomeric salts which can be }

Lhe Toad oy 1 a ae

Poe ud geaprated, (e.g. reparation based on different : i Ca i Wy ; wo gplubllitics of the diastereomers), acylation of a nitrogen or oxygen atom in a eubstituent : : 16 ban optically active activated carboxylic ol : Cn EE ay i : oe adid. (e.g. acid chloride), followad: : by CT . A Co ’ . EH oa oo 3 ; wy Ce chfomatoarahts separation and deacylation,’: — Sh ar . a . AR ml - .

Gif table optically active acids for i’ salt : i I formation are the L- and D-forms of tartario agid, di-o-tolyl-tartaric acid, malic and Ee

BE td } IE Ear - ' BEER no no Ee oR Come Ln ALT nafAdTLo acid, camphorsulfonic acid or Who con = CEE : EE Tad , NENA . . teh BERRA Cr

Cy Ci SE

CE Co ddan agin CL

CEN ier RE . E Eyer . BA . Se it

Ra A HS . CESARE : gs i : ABE . Co nag - poate = IRE : Cdr hye

Co RAE - 43 - CURA Co A : . eo TRE RI RRA ay. AN : thE Le D ORIGINAL of Fo

CY CEE LAR

: g : cs vast ney : ERE Co : Eos: - CR eu : . MAREE NSA AT . = Et A re 0G : TT : Eo th RHE Loa

Se EER aa Cab : CTE HEA SBE LE i no aw © ray REY wl CCI: EERE : . So “Ree bo . a

. SE SUE 9 fi ’ Co CL Ee ald a ge i Sey 3 + oo CL uke RT ; . : VOT ’ Co TEE SnAg «4, . . w . a “iw . . . a o { fo aie, i Lo ; “) pd te ra 4 SR rr Coe al EE PE [A i Wh . ! nie EA : yr 5 AE Co : a J TET SE y : EEE CET oe : - CER SEIT ro

Ce Ba, and for acylation O-metbylmandelic) acid. EER - Breferably the more active part of the two a fd Wr Ap A cL . : antipoder 1s 1solated. a nn Ne

In the cage of diastereomeric mixtures oo vo 6 (racemate wixinres) these may be separated i ERO ee etereoniromer io (diaetereomeric) oure racenns tern by mesne of chromatography ~ or fractional crysitsllization. a

Lo Loe a | Co

DoE i fe _

LE ag ~The starting naterinle utilized in the methods : : fy 10 ALE. are In eowe cases novel, Thess novel - Cre UN i : 2 we Co HY | . 1 - gtarting materiale may, however, be obtained ea : ST : ageording to processes kuoun par_gea. Se - pL ote en wi

At Ll § . Loi materiale of the formals II1, IV, V, . co Sr AC oh

So YL. ana VIT may be obtained by knowa wéathods. 7 oo w 0 16 This, starting materiale of the formula ILL may oe be obtatned from an acid chlorids RYCOUL- by oo pda . Seyret ,

NE LO

: Lo : treatment with s keho-contuining compound? RICHO wre A . : Re ey : far Er - in: the presence of ZnCl, ap ie exemplifled

Bh ’ Sh so below. Starting materisle of the forngiag VI EB ~ * to : RAL Bait, . Saxe Le v

So Hr Ey Calm : SL, 20 May. be prepared by reacting a compound ef ythe CL . ; H 8 x Vet . y -\, . et ’ N ay - . ™ hat : Fa . a.

EL bi TL

LET a he : Ca

HEE | gy Foi iA

SEERA 28 | Chak or o FRY J ona Clea

IP SEs Au x CR g gn I Ee coe SYA cL caddies JE : HRA : - 44- ae EE CE LC . CC Ie hE KE nL a .

Lo OER SRE ARIGINAL N £

Zo Eten asl Y' BAD ORIGH F ] Ri . RELA SAH TA "oo SN 5 Pia . . SEE - . ~- gt Ah . : : ELE AMEN co . . EY LAR Soil wl Teor .

AA CTE ’ Sar CT ;

To Ce co BR Poe

"oo ' he : oti; . ’ 2 ' ay iT ‘ rgb o ¥ - 2 CB 40 Bh Ty STE . CT Tan It Cr nea A i. ; i . aE - BE CL Tat Co EERE eo Eh dedi ay CAN: Es § 0 T An Lo Sore REE Te ale Rd .

To se T : iE ' re FEE Lo RES REE ct Te Tl 4 : SA : Co Coda CLE rR TE

Fon oo RE Chan EET pa Ne ae wo : E Cire Coo eu RY . 2 Sr : ales . r . .

RE 5 Tarte ‘ :

LE JE : Cah : Co 5 IE Farlis ot

E a Hans SE ; dr Co SREY SE

Cr a Gp { . , . . ay 4 oo. . : Hornula IV with a -halogenated carboxylic. - acid Co gl is. pe halide. Starting materinie of the formula IV Co may he prepared a8 exenplified ,. under REE : ’ GE ’ o to . .

Mpreparstlon of lutermedistes” below. Ta ’ C45 3 b The: compounds of the formulas ITI, IV, EV VI

LY CRN : and VIL sve in some capes novel snd constitute - pi Ee. oo fae evch part of the lovenfion. This applies in wo Cogn ee : : its So gRartion lay ro componnds nt the formula. Iv,

Sv FA a vo HEN ie i iB > Sod Ghich thane represent one nepect of the ‘present : ts Fo yo a 23h. SO oo } - .

CL ET i co CE FA 1a nvent ion eh :

RK . pi Cid . E dL ir nr

CEE Ce oe .

Co HO i grating wnteriatle having %=5, utilized In . ’ EE BE iY . : glpthed I msy be obtained according to Mathod A. . = AA Sd 1, i di Fe ee 4 : Sa - Sa ] . A . . o LN . yf Cr .

Bhbr ~1int-al) nae the compounds of the invention . AT PCL . Ee Aen : .

Cy fire formulated into pharmacegu tical formglations fe Ei, Co

Co . 1b tor eral, rectal. parenteral ov nther ‘mode of a — Sh JOO , :

A Fil : Lond

Ke ba ‘ ne LE po aduintatration the pharmacentical formulation Ee

Lag Len . oe ' < ey . . wd it . . : . al . SRN . EI : : Hoaont a2 inR a compound. of the invengion in : p : . an i : JL 4

Rohe . ae :

Eogomb ination with a pharmaceutically agteptable ; rd SOEs wl Hes : any EE no : preter ~The carrier may be in the Laut of 8.4 Cb oo CL CY Ae : : . NER . CART AL SY : PEE LTA : eon 20 re id. remi-&olid or liquid diluen shor a. hoootnb ; CoN oo Le Ay cE RE . Co La : 0 ah egal me . A Av, x waRE Lt es Ca ae TY - wn SR 3 Hh : A :

De Rn Trick So , . : a ’ al , Loe ee tS Lo ale cures a Ch

ST CRE Ce 5. a - . o> A 5 on a dE cl Loe $ CE - 4p - Ril Loal ig i 35 BAD ORIGINAL, 2) . CL Rd NS . PRL SES Lilac NT Pe Se A SL . EH agli : Sh Ep? . . CWE SSH TEI Lasasn sa : ; ; - . hie RIE bene L co ) a) 75 on we ae } Co Ev . w aI% A Co : , | . IR w= : ts hy jd ! ’ : = oo : 1 i : a OY J c\ EL pe et 1 ’ . nao <1 So FREE So gag ke Ek wal capsule. These pharmaceutical preparations are a further object of the invention. Usually the amount of active compounds 1s between @.1-95% by weight of the preparation, between 2. 2-20 by weight in preparations for parenteral uee and hetween 1 and 6% by welght in preparations for orsl administration.

In the preparation of pharmaceutical formulations containing » compound of the present invention in the form of dosage unite for oral administration the compound selected may be mixed with a solid, powdered carrier, such ae lactose, eaccharose, rorbitel, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or snother guitable carrier, as well as with lubricating agents such as magnesium stearate, ~alnoium stearate, sodium stery fumarate and polyethylene glycol waxes. The mixture ie then processed info granules or preseed into tablets. Granules and tablets containing sulfoxides may be coated with an enteric coating which protects the

B - 46 - \ a0 ORIGINA- 5]

active compound from acid degradation as long ag the dosage form remains in the stomech. The enteric nonting ie chosen among pharmanent ically soneptable aenterjic-coating

H matarisle e.g beeswax, s6hellac or anionic film-forming polymere ench ar azllunlaose acetate phthalate, hydroxveropylmethvlcel lulose phthalate, partly methyl astorifisd methacrylio } acid polymers and the like, if preferred in combination with s suitable plasticizer. To this coating various dyes may be added in order to distinguish among tablets or granmlea with different ncotive compounds or with different . amounte of the active compound prefant.

Soft gelatine cspaunles may be prepared with cappulen accantaining a mixbtare of the active comping ar compounds of the invention, vagetahls oil. fat, or other suitable vehicle for anaft gelatine oapeules. Soft gelatine capsilag mney also be enterin anated BR degeribed above. Hard gelatine caprRules may aontain gramles or enterie-conted granules of - 47- =

BAD ORIGINAL | 4 \.. | =

: the active compoind Hard gelatine capanles nay ale oombain the active componand in nomhination vith a solid poudsred asarvier enoh a8 lactose, eawscoharese., gorbitol, mesnnitol, potata pharch, ny lopaciin, cellulose derivatives or gelatine The hoard gelatine capgulern may he epteric ocsted ne degoribad ahove

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different unit, dos= amponler or viele.

Solutions for parenteral administration wav aleo ne prepared ss a dry preparation to he reconatitutad with A gnitahle golvent, b extemporanecuely hafore ape. : The typirnsl daily does of the active rubstapoe varies within a vide rapge apd wild depend on various frotore enrch an for example the individuy]l reguirement of each ratient, the 19 route of adninictration and the digasge. In general), orsl and parenteral domsge will be in the range of & to BPA mg por day of antive anbetanae

The invention is 11lustrated by the following examples. .

Example 1. Freparation of acetic acid, [2- [13,0-dimethvli-d-methoxy- 2- pyridine methyl lanl £inyl]- 1H : benzimidazol-1-v1 methyl ester | podium galt. (Method A) - - hr - a0 ORIGINAL J

To NsOH (¥.48 g. #.212 mol) dissolved in HoO (20 ml) wae sdded under stirring 2-[[(3,56- dimethyl-4-mebhoxy-2- pyridinyl)methyllsulfinyll-1Hbenzimidazcle (1.89 a 3.006 mol) and tetrabutylammoniumhvdrogen enlfate (2.44 g 0.208 mol). the mixture use stirred for about 5 min at ambient temperature and then extracted 3 timee with CH.Cl, (33 ml). After reparation the combined CHBoCle phages were dried over

Na,60,, filtratedand the solvent evaporated off : giving an oll. The reeidual oil was dissolved intoluene (42 ml) and heated to +60°C.

Chloromethy] acetate (A 70 g @.9066 mol) : 16 dissolved In dry tolvene (180 ml) wag added under a protechbive gag and ander etirring. The solution was xllowed to stand aver uight at +60°C. The toluene wae evaporated off and the residual oll was chromatographed on = silica column neing CHaNHR-CH, C1, (5:95) ag eluent and then the product war recryetalliged from isopropylether giving the product (&.39 g 17%).

The identity nf the title product obtained was

BAD ORG gy me confirmed with NMR

Examples 4-6 ~The compounds listed under Examples 2-6 below were prepared using the method axemplified in

Example 1.

Example. 7 Prepsarstion of adipic acid, (2- ([(3.5-dimethyl-4-methoxy-2- pyridinyl)methyllasulfinyl}-1H- . benzimidaznl-1-y1lmethyl moncester 19 ecdiaom salt

Adipie anid, [(2-1(3,5-dimethyl-4- methoxy-2- pyridinylimethyvlisuifinyi]-14-benzimidszol~1- ylimethv] chloromethyl ester (@.61 ag. 0.9011 } mol) (eyntheslized according to method A) wee digeolved In 5#% agneons acetonitrile (48 ml) and three equivalents of agueons NaOH was added slowly under continuous stirring. The acetonitrile wae evaporsted off, the residue was warched with CH,C12, and the residual. water oo - B22 - 3 ~ 'BAD ORIGINAL A \

wae evaparated glving rn oily regldne,

Chromatography on 510, with ethvl acetate- ethanol as eluent gave the desgirad compound (B.22 4g). The identity of the product was confirmed with MMR,

Example 8, Preparation of terephta:ic acid, [2-114-wethoxyy-3.6-Adimethy 1-2 pyridinvlimethylisulfinvl]-1H- benzimidazol-7T-vil-methyl monoester 19 rodium malt. (Method (1)

To terephthalic acid (166 g @. 01 mol) in THF (62 ml) nae added dilscpropylethyl amin (2.6 g @.92 mol) and the mixture was cooled to -108°0,

Isobutyvichloroformate (1.38 2 P.21mol) digrolved in THF (29 ml) wae ° added dropuiee under shivring. After the addition, the temperntnrve of the mixture wae raised to +15° and [2-TT(4~-methoxy-3,.5-dimethyl-2~ pyridinvl)methyilenlfinvil-1H-hensimtidazol-1- vllmethanol dierolved iu THF (200 ml) wae added dropwise. Tha mivtore use ertirred 2h st room - RY -

GINAL »

BAD ORIGINA &J

= ee eee temperature THF wae evaporated and the residue wag dlesolved in CBpCloand washed with water, After sepnration tha CHoCl 4 rhage wasn evaporated. The reeidusl oi] wae diseolved b An mebhylacetate, HoO was added snd the pH wap adjusted to 2.Fb with NaOH (1M). After

Beaparation the athylacetatn Phare was evaporated and the regidie War desulved in

CHpCl., Arie reves Nan,80,, filtered and the 19 solvent wae evaporated, giving the desired compound *¥yield @. a g. 16%). The identity of ’ the title compound obtained wag confirmed with

NMR,

Example @, Preparation of N.H-dimethyl-B- rlenine, [2-04 methoxy-3,5- dimethyl-2- } : pyridiinglmethylleul finy1|-15- benzimidazol-1-y1 methyl eeter.

Method 0)

N.N-dimathy1-n- slanine (@.76 g © por mol) and

N-methvl morpholine (P.99 ¢ @.01 mol) was added \oap ORIGINAL 9 hrm to CHo ly (15 mi) The malation yap ooaled ta 12% and Asabutylehlaraformate, (9 68 7.005 mal) dliasalved In CHeCly (15 ml), was added wndar Inert atmosphere. The eaalntlon wan f ‘stirred for abool, 20 min at -10°C. t2-1104- methoxy -3 S-dime lhe -7-pyridive Limethyl 1- enlfinvil-1H-Lenzimldanal-1-v] Imathano dissolved {yj Hala (15 wb) wae ndded dropwise to the mixed wnbed 1de ab 1070 Phe pollution 1a wag stirred 2h ost 107, and the temperature wae _ theres f ie rajaad to yeom temrervatore NaOH solution (OH ml © 54) vas added vader stirring and the mistorg yaa tipped for about 5 min.

After aoparallon Lhe Hetil, phones gre dried over HAR, filtered sad the egolntion was evaporsted oft, elving the doagir~d compound (yteld 2.7% p20 3.0%. The NERRIE af the title compound wun cont trmed with HUE

Melting point: 230%

Examples 19 and 12.

The compound listed Examples WW and 12 in

Tahle 2 wae prepared by Method (0. ao ORIGINAL 2)

EE 4 a —i————————————————————————— er —________.

Example 11. NH .N-diethylipiyeines, f2rcca. methoxy -3. fi-dimethy-9.

FYPIAiny me thy) Tent f3nvl J-1f- haynmd Padn=at-1-v] fmel hv aster | (Hethad 0

A mixture of E200 (4-mebhoxy-3, 6-dimethy]-2-

Pyridiny lime thy l jaul finy 1 1-1H-benzimidaso]-1 - vllmethano) (3.8 @ Ad.M3 mal). N.N- dileyelohaxylesrbodiimidae (2.1 ga 2.79 mal). 19 NR, H-disthylgivoine hydrochloride (1.7 g 2.010 } mol) aud 4-Jdimethylaminopyridine (1.3 ¢ 2.9011 mol) in pyridine C16 ml) wae etirred nt rem Lo temperature far 35 hy. N.W-dievelabaxy] ures which hoadd precipitated . uae Yeme ved by 16 filtration. The flitrate wae evaporated, the residue nan dipsalved In dlohloremethane. The dichloromzthanesolnt ion wae Wasshod with NaOH 3.2800 oo (P.W2p wel), disrolved in water (26 ml) and then once with water (z6H ml). The organic phase wae dried (Hanh, , filtered and the eolvent wae evaporated off, giving the desired product. The identity of the product was confirmed with NHR. "6 - ‘aes ORIGINAL on

L..

TT eee iniiiiiniim———— _______ 32 oOo o - >

Y= + cm _ _

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' {dentifying data for the compounds according to examples 1-12 are given in Table 3 below. .

Table 3 Identifying data for compounds of the invention :

A

Ex. Solvent

NMR data <ppm (500 MHz) y 1.15 (s, 9H), 2.3 (s, 3H), 2.35 (s, 3H}, 2.4 (s, 3H), 1. CDC 4 2.45 (s, 3H), 4.9-5.0 (q, 2H), 6.35-6.40 (gq, 2H), 7.3 (s, 1H), 7.35 (s, TH}, 7.55 (s, 1H), 8.2 (s, 1H) 1c 2.5 (s, 3H), 2.6 (s, 3H), 2.7 (s, 3H), 4.15 (s, 3H), 2. CoC, 5.35 (s, 2H), 6.85-6.95 (q, 2H), 7.75-7.9 (m, 2H), 8.5 (d, 1H), 8.25 (d, 1H), 8.55 (s, 1H) : : , 2.2 (s, 3H), 2.25 (s, 3H), 3.7 (s, 3H), 4.95-5.1 (q, 2H), 3. CoC 4 6.7-6.8 (q, 2H), 7.3-7.5 (m, 4H), 7.55 (t, 1H), 7.75 (d, 1H), 7.85 (d, 1H), 8.05 (d, 2H), 8.15 (s, 1H) / A — 1.3 (t, 3H), 2.0 (d, 3H}, 2.3 (s, 6H), 3.8 (s, 3H), 4.2- 4. D400 4.35 (m, 4H), 5.0 {d, 1H), 5.2 (d, 1H), 7.4-7.6 (m, 2H), 7.8 (d, 1H), 7.9 (d, WH), 9.2 (s, 1H) 1.25 (t, 3H), 2.15 (s, 3H), 2.25 (s, 3H), 3.7 (s, 3H), ) 5. CDC, 4.05-4.4 (q, 2H), 5.0 (s, 2H), 6.35-6.75 (gq, 2H), 7.35- 8.0 (m, 4H), 8.2 (s, 1H) 9 —-— 6. (90 MHz) 2.15 (s, 3H), 2.20 (s, 3H), 3.55-5.05 (m, 12H),

CDCl 6.55 (dd, 2H), 7.3-7.95 (m, 4H), 8.2 (s, 1H) 7. (500 MHz) 1.55-1.7% (m, 4H), 2.25 (s, 3H), 2.3 (s, 3H), 2.25 (t, 3H),

CD00 2.45 (t, 2H), 3.8 (s, 3H), 5.05 (dd, 2H), 6.5 (dd, 2H), 7.45 (dd, 1H), 7.5 (dd, 1H), 7.55-7.65 (m, 2H), 8,10 (s, 1H) ee -

Table 3 cont.

Ex. Solvent

NMR data &§ ppm (500 MHz) : 2.1 (s, 3H), 2.15 (s, 3H), 3.65 (s, 3H), 4.8-5.05 (q, 2H) 8. DMSC 6.7 (d, 2H), 7.35 (t, TH), 7.45 (t, 1H), 7.75 (d, TH), 7.8-8 (m, 4H), 8.05 (s, 1H) 2.15 (s, 6H), 2.2 (s, 3H), 2.25 (s, 3H), 2.26 (t, 2H), 9. CDCl; 3.75 (s, 3H), 4.95 (s, 2H), 6.4-6.55 (q, 2H), 7.25-7.5 (m, 2H), 7.6 (d, TH), 7.8 (d, WH), 8.1 (s, TH) 2.25 (s, 3H), 2.4 (s, 3H), 3.8 (s, 3H), 4.85 (s, 2H), 5.4 - 10. CDCl; (s, 2H), 6.4 (s, 2H), 7.3 (d, TH), 7.35-7.5 (m, 2H), 7.65 : 20 (d, TH), 8.05-8.15 (q, 4H), 8.25 (s, 1H) , - 0.85-1.0 (t, 6H), 2.15 (s, 3H), 2.25 (s, 3H), 2.45-2.7 11. (90 MHz) (gq, 4H), 3.4 (s, 2H), 3.7 (s, 3H), 5.0 (s, 2H), 6.55 (s, 2H), 7.3-7.95 (m, 4H), 8.2 (s, TH) 0.9 (d, 6H), 1.95 (m, WH), 2.2 (s, 3H), 2.3 (s, 3H), 3.95 12. CDCl; (d, 2H), 4.95-5.05 (q, 2H), 6.45-6.65 (q, 2H), 7.4-7.55 (m, 2H), 7.7 (d, TH), 7.85 (d, JH), 8.2 (s, TH) - 59 = i

Preparation of intermedistes

Erepavation of chlorvomethylbensoste:

Benayl chloride (2h g, A. 25 mal) and foged mel, (1.2 g, A.0073 ml) were heated in the presence of dry parafovna]dehyde (7.6 gg, @.756 mol) for Zh giving an oll, which wap dietiled in vacuo giving the desired compound (175 g. 41%) . The identity of the product Has confirmed with NMR: (6h@Q@ MH=: CDCIq) 6.0 (m. s 19 2B), 7.5(dd., ZHY, T.65 (t, 1H), B,1 (aA, 2H).

Erevaratlon of [2-104 -Mebhoxy-3.5-dimethyl-2~ pyridinvilimethyl)-pulfinvl]l-IH-benzimidazol~1- yllimethanol 2-11 (4 Mathoxy-3,6-dimathyl-2- pyridinviimethvilrulfinyl-1H{-benzimidazole (3.15 [- 10 mmoles) and N,N- dimethyvlamincoyridine (120 mg, 1 mmol) was dlegolved in methylene chloride (60 ml). A golution of formaldehyde (58 M, 10 ml, £3 mmol) ’ 217 wag added and the mixture wae stirred violently co lao ORIGINA- J}

for 2 minutes. The phases were geparated and the methylene chloride solution was dried (sodium sulphate), filtered and evaporated to dryness. The slightly red residue was the b title ~omponnd as an essentially pure oil.

NMR: 53% WHz, CDC, 2.16, 2.27. 3.74, 4.89, 5.89. 7.33, 7.63. 7.96, - Pharmacent ical preparations conteining - A compourid of the invention ns antive ingredient are illustrated in the following formalations.

Syrup . A syrup containing 1% (weight per volume) of active gubstance wae prepared from the following Ingredients:

Compound according to Example 7 1.0 8

Sugar, powder 30.0 8g

Saccharine 0.6 g

Glycerol 5.90 & ~Flavouring agevet 0.06 g 3 i - 61 = ap ORIGINAL M

Lo

Ethanol 96% 59 g

Dietilled water q.s. to 3 finsl volume of 100 ml ’ sugar amd saccharine were dissolved in 60 g of b warm water. After cooling the active compound wag added to the sugar solutlon and glycarol and a e&olution nf flavouring agents dleeolvad in ethanol were added The mixture was dlluted with water to » final volume of 10@ ml.

Enterjc-coated tablets

An enterio- coated tablet containing 20 mg of active compound was prepared from the following ingradients: 1 Compound according to Example b 200 g 16 Lantoneae TA0 g

Methvl cellnlora 6 8

Polyvinylpyrrolidone croee-linked be g

Magnesium stearate 15 &® . Sodium carbonate 6 g 20 . Distilled water q.6. \ - 62 - | el 5 i

II Cellulose acetate phthalate 200 g ~ Cetyl alcohol 16 g " Isopropanol 2000 g

Methylene chloride 2000 ag b I Compound according to example 5, powder, was mixed with lactose and granulated with a water golutien of methyl cellulose and sodium carbonate. The wet mass war foraed through a sleve and the granulate dried Jn an oven. 12 After drying the granulate wap mixed with ’ - polyvinylpyrrolidone snd megneeium stearate. : © The dry mixture was presaed into tablet cores (10 #29 tablets), each tablet containing 20 mg of active substance, in a tableting machine 16 using 6 mm diameter punches. 11 A solution of cellulose acetste phthalate and cetyl alcchol in siopropancl/methylene chloride was sprayed onto the tablets I in an

Acoela Cots®, Maneety coating equipment, A final tablet weight of 110 mg wae obtained. - 60 -

BAD ORIGINAL i

Solution for intravenous administration :

A parental formal ation for Intravennnug nee, containing 4 me of aotive compound per ml, was vrreparvad fram the following Ingradiante. } 5 Compound Aocarding pe Kxnmple § 4 gq

Polyethylene Hive l a8 Poy injection 490 g

Diecdinm hyvbyvgen thosphe ta a.m.

Btevide wut. teem Final lume of 1298 m)

The Aantiun Compo d BET diegnlvad in ’ 19 Polyvathylena glveol 490 and 560 ml of watap AR added. pH of the solution wae bronght tea rH 7.4 by addine a» water frolntion of digodinm Lydrogen phoephate ane Water wae added te a final volume of 1900 wn). The golubing war Filteraod through 20.22 um filter ang tmediately dippenged into 18 ml sterile Appel ep The ampon dar ware sealed, } : ) . 64 - ! SNA A

BAD ORIGIN & . \

oo \

Biclogical Tests

Cy

Inhibiting effect in vive on gastric acid : gegretion in conscious dog

Test method b Chronic gastric fistula dog were need, These “ dogs have heen surgleally provided with a gastric cannula in the stomach and a duodenol fistula, used for direct intraduodenal administration of test compounds. Following a - | 10 4 weeks recovery period after eurgery, teats were performed once a week on each dog. Food and water were withdrawn 18 hours before each test.

The test compound suspended in @.5% Methocel ® 16 (99 HG 15099, Dow Chem Corp) wae administered either orally by uslng » stomach tube or intraduodenally via a catheter *%hrough the duodenal fistula. After 1 hour gastric acid secretion was induced by continuous infusion of histamine at individual doses (402-6290 umol/Kg, h), resulting in approx 99% of maximal - 65 - oo a eee

J RT wd . .

Li file ew Cn Chuo . “he, » . ; 3 n fees en = . wi & : } Ao Es : FI FE

Eo SIC wl $A okegn oy od be i . %. . > bly x , . 1B RY . ae SR Fo & .

B® . : Mia : SE SRE ¥ . . oe oo der } ae [Dr i a ts Pa go yy yn wo , x } iH ; sie ; . a ! -, AE . LR fo Cie be no a i Sa = ros Lm Te SE a Co rg

FE SoA Pre * J, ae Sow NT roe Se . “rt oy % eo" a . gecretion of gastric acid. The gastric -julce hE : . : Ls v te hie a was collected vy Tree flow from the géstric Ln

Ce Moen . ] Ca ” st i

J . cannula in consecutive 30 min samples: for 2 ) Re i A ‘ Coan EE i r a N : _ . So nL ! Hh g ~ hours. The samples were tilrated to pH 7.0

Ky : foe , 0 : ; : Ll Sa $ 34 8 with @.1 M NaH using a Radiometer autdmatic ’ . ¥ Fn iN : titrator sand the acid catput was calculated. . The pe cent dnhidbd tion of scid secrati GN Wan i

SN Ce Falenlated by compen hg tn each dog thet! ‘ac id :

NA me Se Co \ : WG = -E FAG oy Co ¢ ta QUtpul in cuonblial rests when oonly the vehicle ~ Fane ee Bal ao ih ; sha EE § Cr Ey . SAA

Bg aE at i is Tyoidgt ul . . . . - I oa “ae cid [410 vei. The peak inhibitory effect foreach x CER Cp a ! wx, yoo a SAE Ah. SA “4 i © Pegg & pound was derormined, LE ] me LORE ni So ef

Ji ' : Ae ple CL wo RE : Le he :

I CE SI Ti

FE So J The: test rend cae given in Table 4 bela, : . . ay Sx : < : Hed Ey : oo . Aras Yo ih E oy 5 Ce wr : | . fable A. Lastyic acid dnbibitionn in the deg pf hE i : , i Leper em ee wnt em a man a ea JU, ep ——— f

Coal Ee : : 2

Co : Test compound Administered amount Inhibition }

SL Are : : SE of test compen nf gastric } ne (ral admlnistra- adic X07 : a:

Wet , NSA < nse” : tion, tunel ae: re tion 2

Hn EL to ! yo HE i eo en =e emi ms oreo i train preemies a crm mem ni 4 ; : nn ST L'E " Example 2 Fl TRL

Se © Example * 2 Phe ee TR gr | Cog Cal

FRR Ea CEE

BE SAN tor cr me i CoA THT : a REG SARE . Seo Tet a i ; Sut BNE is Toefl . oo gs LE \ : Coa

Soh Sols Li ed ' i EOL Isl

Es AE (ahd Fo Re ; Srpete AAU BET oR : SYS En Re ow Lo ld * # ET Ey ST RR} a : EE Te Co

ATRL Pr Lode . i i ) Cy i . x2 1 Ce ead : i “ mgt alt oy : Cae i : Tika CAL i : : Ln a ons — dT GE Co TE - Semi - 6 - CER AY wre : sly BAD ORIGINAL SHA - wo “gel fd a Se v } CE Fal oo

Lo NAT ah Ce

EI wed ee oo heeled : Hoh Ape Lee kgm : eR Caps ER i

Hg ee vie pi : SEA afin co CR he : Lo Lin da : " Sat “ ad, : IS SE ~ oF SAE ry

Claims (3)

1. x . A a 7 i JE La itd oo hid TERE i: re IIE, DRL ns a ge Zi Digan, da Zhe ota od M4 , } © i HF EN SE £IE ALE AL LG A i Rd 5 EE RRR IRIAT 7 TORE LY ht A EN EI SE EEE {EATER TDR pI Fs BNE a SER 1 ET PITRE 0 YORE rt 3. GLB Lr dX, NR UE SEU DAE ! fo py IE OE a, RU LE EAE A RRR aS ie J ERR NEE 3 HS RENE SIR Lat RY BAPE a ob Ea ely ARERR al FC ET it i [AT ' y ’ {ARPT 0 ATR " EE 47" 2) GN TA EY a A fii a J Pa UREN . PIER SET TH ell AE CER RRR TaN TN Ca J oP LR TF 00 ob TE SR A OE CUE 1% RE i rfl pe: 4 ET x Ba a nd AE das id A wo i 8 ed I nh IE REN BCS I A vy SI R - y 13 Ae rg 2 s X T Bi 3 Rh gi + poy Eo ak St 3 EE pei es | fae Te NTC WE CIR ass oh LF pe UR Le ES R Tem Lima Ry hay TE i CONE NR ON REX hi r dl Lgl a Woy } Pow We fr dnl EER 254 0 Rips Ce » ray TE TT SE iY RTE av iT CS EE TLE SCRE prpdial i Sa vA EA Lo a 1 | “ A dy EP AA oe EAST i = i Bd 3 on LE ro, ; ! a 7 [a o Tat ar ro ie oe yi ER $v aE | Cd mniev Tg : BH Eo) <a Re SE , r sl : uy E oh - -. Him A Talet I SA 2 Cee CL “e : . : : A Le Pras gn Me E + © ie Wo “ ~ Tog me Bh Lo "ie h + I Er : . iy Cok “ Cf Ard . ' PL a = i 1 2 Cg. . CT ti oi . Eg ra Lo . " A TL TS Co : ne Lot Ae 2 ale TY : Co : { Cotes . . : Coe eR 3 ae Claimst Loe o TS oe de LA : LE ks 2 boo TE my Iw SH CL ly . w PE i" x ’ ‘ : : SE 21% 8 rvompound of the formula cog oer ET SE Lo ST - Lo 5 iE alo Teo 7 4 Lo dm * CO EYE ENTS ge 5 R . Rr ’ oo Lapa, tue be . 1 aE Ho é : 2 CO a3 By eT ; BR | R ! . -y se . : 4 A. : pod . be u An Lo Cr iee Co Tey yw i R Goo Te TU on ! . v ers oa y Craned NE Se ~ . LORE 3 Vv " . . - iy ¥ LI ob Sh . PA : Lop EE NL : LL 4 ih ph FORE cL a ERE : + . . ' a“ Bl ! 8% Ae TE | Yona o,- x 4 * iS SI bet 1 KA ER hen . ¥ samo : . La ¥ ' & ’ ’ pi \ YE ig N " ’ Yi : 2 3 5 iol tly ak $0 Ot ’ SA v . 4 i A a 43 Coe 4 CT ‘ . , Cn i. a iol Bo hu he Coos go Cub Tm Tae E- TAR lh ve yen , , Coa i vy Pn te = 0 pi CX da : : CEE Te ae ne a Ra ne ee - roe oT sad ee Cee aia a gL 3 Wm TRG of wa Co a he : © ges hh Fa Coe Ege FT Cah been TRE a "GM fora i "oa : . . . Th Wn road ge Et Sek Ln ona CoE ie EE hatont i 4 ota VRE TE wii nm; apd. physiologically acceptable salts theteot,. Coan ai MYR ae CE ke Crate Co : 1 a th Sg FER HEL 2 EF - ot iy ros , En Cn he VIE She hg bp ui E Lt 3 ol “y 4 ), s hE . of ein xX {ia -80~ ) . - Slee La Yor LB - x oo vd J i Vhs x = i 1 ala oo wherein X be Coa Lend PU ER he TE RENE CH * 47 L LE vo gd hee ro CE Me bg fA THE ab ARE Rotor ps a hes ihe FhpRE bmw ARR WON EEE Ry “RE, "R and RY, which are 5 She. i 3 i SR 55 aR EE Fay Cl STE Sea A Te spb LAL ’ ¥ 2 1 7 iy SA R pe Tr ly Nol pe eo cond ade a? FR DTU ENE : AREER NE Rl ER Tay Xe TE Ee Cr : Ki Lo a . wl t Day Rae . 4 er, Kg b hE LE i Lay Le pn oREEae 4 o ent, ard weld ves RE 8 Dah id ONELNELE 54 » ong oe SO CRE Seay i . Co wh CN Cal baie Swapp kV TRG Ct § A Ft. | gE Fe WY Re y Sat LE oR ara ah of BR id w iE £1 ing eit EE Ce aR be a WR Grn TS ee FA i; Ha By Sr BE . 1 ) GL ) AF ‘ © J " L TL I eo “i W CE LER a RL x 2 i: vi <2 EE bE i yond ARERR Coa 8 RETREAT ER oe CER FON AREA UTR EGF { aon Lip gE Sie Hh EN 3 Dias 0 LiNTRRE (ERR ou AR he okt yit alkyl ‘containing 1%6 cation ite & 52 SEAN RRL Ge CN FoalER aE SEER Bad : oo pg fl Whe LTE ¥ AEE ea Lak § of ERIE culo omiRE » Bg bet fT GE a BOR of IS . J Kg i. = vf . lr . Led fh Pde. Vig Li, ale id nL BRYN a Eh CE ie PLE) 3 alkoxy containing Anh cart atoms 5 a liged Cs i, Sey BA } al ol IA AE Cd 5s ka ite . n Ra .
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3. 3 SUR J JM Tah ' . ‘ " reg ORLEL Nn i" § ee Lo vil ST GR & ¥ 4 aE EEE ow, DERE Cary ME SRR SR

   . " 27126 . (=) H (b) alkyl containing 1-7 carbon atoms (2) alkoxy containing 1-7 carbon atoms with the provieas thal (a) pr? ir hydrogen. alkyl or phenvl whenn the following condibions (al)-(ald) are fulfileed simul tansaously: (al) Rr! anid pA are hath hyvdrogene, (nn?) RY and RA ara aalected from the gronps . 19 hydrcea=n, alkyl, or alkoxy, (ad) Rr" in alkvl., carbaoxvenhstituted alkvl in ; ite acid form, swino-sabstituted slkvli, or Rr" ie phenyl substituted by alkyl or slkoxy. (hb) RY ie nol, Z-methylpropoxy when rh, RY 1h R3, rt, RY, KT. B® ana B? are hvidrogen and x ie

   £. - 68 - ‘oro ORIGINAL d Lo