AP309A - Novel pyrrolopyridines, pharmaceutical compositions containing them and their preparations. - Google Patents

Description

The present invention also relates to the use of the compounds of the invention for inhibiting gastric acid secretion in mammals including man. In a more general sense, the compounds of the invention may be used for prevention and treatment of gastrointestinal inflammatory diseases, and gastric acid-related diseases in mammals including man, such as gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis and Zollinger-Ellison syndrom. Furthermore, the compounds may be used for treatment of other gastrointestinal disorders where gastric a.ntisecretory effect is desirable e.g. in patients with gastrinomas, and in patients with acute upper gastrointestinal bleeding. They may also be used in patients in intensive care situations, and pre- and postoperatively to prevent acid aspiration and stress ulceration. The invention also relates to pharmaceutical compositions containing at least one compound of the invention, cr a therapeutically acceptable salt thereof, as active ingredient. In a further aspect, the invention relates to processes for preparation of such new compounds, and co the use cf che active compounds for the preparation of pharmaceutical compositions for the medical use indicated above.

bad original &

-2—

Pricr art

Certain pyrrclo[2,3-b]pyridines have been disclosed in

Saify Pak.J. Pharmacol. 86 Vol 2(2) pp 43-36 (1985), Saify,

J. Fharm. Univ. Kar. 2(2):99-103 (1984),

Cimpe et al . J. Prakt. Chem. 80 Vol 322G) pp 517-21 (1980)

Cgali et al., Indian Journal of Chemistry Vol. 27B, 656-651

8 6 :

Che invention

It has been found that compounds of the following formula I are effective as inhibitors of gastric acid secretion. The compounds of the formula I exert this effect by inhibiting the gastrointestinal H~K⁺-ATPase enzyme.

Che compounds of the invention are of the following formula

CH.

R‘

R'

J P a pharmaceutically acceptable salt thereof, wherein

O-R⁶ N-O-R⁶

II I II

X represents -C-, -CH-, -C-, or -CH--;

H

R-¹- represents H, lower alkyl, O^-v-R', halogen, phenyl or phenyl substituted with (l-6c) alkyl, (l-6c) alkoxy, (l-6ci acyl, halogen, CF-., CN, NH_?, NC^ or (I-6c) aikcxycarbcnyl;

AP Ο Ο Ο 3 Ο 9

-3ο

-> II

R“ represents Η, lower alkyl, CH^CN, CHjC-Nl·^, halogen, / O-R , CH₂-N , S-CN, CH₂OH, CH₂CsCH, CF₃,CH₂NC or NH₂;

Q

R. represents H, lower alkyl, CF^, O-R , NH2, lower 0

II 10 in alkylamino, di-lower alkylamino, halogen, CN, S-R ,. S-R* 10 cr NHCCR ;

5

R and R , whicn are the same or different, represent H, lower alkyl, CN, halogen, O-R¹¹, NO-, NH-, lower

13 14 alkylamino, di-lcwer alkylamino, S-R‘“, NHCCR , NHCCR* ,

0

II 15

C?₃ or C-R ;

δ ^a 9^1 13

R , R , R ,R , and R which are the same or different, represent H or lower alkyl;

R represents lower alkyl or phenyl lower alkyl;

¹4

R and R , which are the same or different, represent lower alkyl;

R¹^ represents H, lower alkyl, CH or lower alkoxy; provided that R¹ and R² are not simultaneously H.

As used herein, the term ’lower· when applied to hydrocarbon groups, alkoxy—, alkylamino-, dialkylamino-, alkylthio, alkylsulfinyl-, phenylalkylthio-, phe.nylalkylsul f inyl, acylamino- or aikcxycarbonyl groups includes- straight and branched chain hydrocarbon group having up to 6 carbon atoms.

:ο

The term halogen includes fluoro, chloro bromo and iodo.

Both the pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers are within the scope of the present invention. It should be understood that all the diastereomeric forms possible (pure enantiomers or racemic mixtures) are within the scope of the invention. Also

bad original · . AA

-4included in the invention are derivatives of the compounds of the formula I which have the biological function of the compounds of the formula I.

depending on the process conditions and the starting materials, the end products of the formula I are obtained either in neutral or salt form. Both the free base or acid and the salts cf these end products are within the scope of the invention.

Acid addition salts of the r.ew compounds may in a manner known per se be transformed into free base using basic agents such as alkali or by ion exchange. The free base obtained may also form salts with organic cr inorganic acids. In the preparation cf acid addition salts, preferably such acids are used which form suitably t ne r ap eu 11 c a 1-y acceptance sa^ts.

Examples of such acids are hydrohalogen acids, sulfonic acids, phosphoric acid, nitric acid, aliphatic, alicyclic, arcmatic or heterocyclic carboxyl or sulfonic acids, such as formic acid, acetic acid, propicnic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydrcxymaleic acid, pyruvic acid, p-hydroxybensoic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydrcxyethanesulfonic acid, ethyle.nesulf onic acid, nalogenbensenesulf;nic acid, t cluenesul f onic acid cr n a ρ n t y . s u _ c c η i c acid.

These cr ether salts of the new pyrrole[2,3-b]pyridine, as e.g. picrates, may serve as purifying agents cf the free cases obtained. Saits of the bases may be formed, separated from solution, and then the free base can be recovered in higher purity from a new salt solution.

AP Ο 0 0 3 0 9 _ς_

Base addition salts of the new compounds may be transformed into the acid form using inorganic or organic acids, and then reconverted to a therapeutically suitable salt such as sodium and potassium salts by addition of NaOH and KCH, respectively.

Preferred groups of compounds of the formula I are:

0-R⁶

II I 5

1. Compounds wherein X is -C-, -CH- or and R is as defined above

2. Compounds wherein R is lower alkyl, optionally 7 7 substituted phenyl, CH„OR or halogen and R is as defined above.

i. Compounds wnerein R is H, lower alkyl, CH₂C=CH, CH₂CH, n

CH₂CN, CH₂CNH₂, CH₂NC, NH₂, CH₂N CF, .

N, SCN, halogen or

9

4. Compounds wherein R is H, lower alkyl, O-R , NH₂, lower alkylamino, di-lower alkylamino, CsN, S-R^, S-R¹⁰, halogen, CF-, cr NHCCR*⁰ and R^ and R¹⁰ are as defined above.

. Compounds wherein ?. and R are the same cr different and selected trom H, lower alkyl, CbN, halogen, O-R*, NO-,, . 12 NH, , iower a_.<y_amino, di-lower alkylamino, S-R ,

II

NHCCR*³, CF₃ or C-R^x3 and R^1X, R^x“, R^±J and R¹⁰ are as defined above.

„12 „13 ,15

More preferred groups of compounds cf the formula I are:

-615

OH OCH, C-C,H_c . 11 ¹ ι ³ I 2 5

j.. Compounds wherein X is -C-, -CH-, -CH-, -CH-, or -CH, 2. Compounds wherein R¹ is CH-j, C₂H₅, CH(CH₃)₂, CH₂CH₂CH,, Cl, 3r or phenyl

C ·»

3. Compounds wherein R is H, CH-j, C^, CH₂CN, CH₂CNH₂, F,

Cl, cr, SON, CH,CK, CH.CsCH, CF, or CH,NC 4» £ «3 z»

4. Crmpcunds wherein R³ is H, C«₃, C,H₅, CH CH₇)₂,

CH,CH,, CF-, CH, CCH,, OC,H₌, CCH CK,),, NH,, NHCK,, .ΊΓ

C,H,, N;CH₃j,, N(C,H₅),, ., cc ^g> _o; shcoch3 . r, S-CH₃, S-C,.^, S4 5 lomcounds wherein R and R are the same cr different and selected from H, CH,, C,H_,

J 4-3 ^H,),, F, Ci, 3r, OH,

CCH,, CC,?’ , CCH CH,), , NO,, NH, , NHCH,, NHC,H_, N(CH,), /λ ,-4- iZ Λ* 3 m3 -J

S-CH₃ or CF₃.

The radical R^J is in position 4, 5 cr 6, preferably in cosioion 5 or ό in the comcound of Formula I.

5

The radicals R and R are m positions 2, 3, 4, 5 or 6 cf the phenyl nucleus.

AP Ο Ο Ο 3 Ο 9

/· ,· Τ t

F

ch₂cn

CHg

F

AP Ο Ο Ο 3 Ο 9

Ι!

Ο λ»

ΟPreparation

The present invention also provides processes for the manufacture cf the compounds with the general formula I. The compounds may be prepared in the following way.

A. A compound of the general formula II

3 wherein R , R and R are as defined above is reacted with a compound of the general formula III

^c· wherein X, R and R are as defined above and Y is a leaving group, such as a halide, tosyloxy or mesyloxy whereby a compound of the general· formula I, wherein X, R*, > 3 4

R**, R , R and R' are as defined above, is obtained. It is convenient tc conduct this reaction in a solvent. The solvent usee ior the reaction is preferably a polar solvent such as acetcnitril cr dimethyl fcmamide or an alcohol, e.g. ethanol or isccropanol.

The reaction temperature ranges usually from about 20°C to about the boiling point of the solvent used, more preferably from about 20°C to about S0³C. The reaction time ranges from about 0.1 to about 96 hours.

AP 0 0 0 3 0 9 — 11 —

3. Compounds of the formula 1 wherein X is CHCH and R^₍ R^₍ 2 4 5

R , R and R are as define! above are prepared by reducing 12 3 4 a compound ct formula I wherein X is C=O and R , R , R , R and R³ are as defined above, e.g. by reacting with a reducing agent such as NaEH^, LiAlH^ or by catalytic hydrogenation .

1

C. Compounds of the formula 1 wherein R is CH and X, R ,

4* 5

R , R and ?. are as defined above are prepared by reacting 13*4 5 a compound of formula I wherein X, R , R , R and R are as .efmec aocve ana λ is (l-5C:alkyl with a dealkylation agent such as B(3r)₃ or CCH^SiI

T. Compounds of the formula I wherein X is CHO-R^ and r\

3* 4 5

R , R , R and R are as defined above are prepared by acting a compound of formula I wherein X is CKOH and r\ t j It)

-3 _h4 .-. , λ , R formula IV and R are as defined above with a compound of

IV wherein R is as defined above and 2 is a reactive esterified hydroxy group.

Ξ. Compounds of the formula ΐ wherein R⁴ is 2-CH, R^ is 4 12 3 different from R , and X, R , R and R are as defined above are prepared by reacting a compound of formula I wherein X that R⁵ with a dea ¹ 2 3 -R“, R , R and R are as defined above provided 4 4 s different from R , and R is 2-0 (C,-C.-alkvl) ,

0

Ikylation agent such as 3i3r). or (CH.), J j 3 si:

The invention is further illustrated in the following Examples .

(JACOB'⁶'*¹*'- 2

-12Examples ixamc. e

Preparation of 2-methy	l-7-(2-p	heny
bIpvridine
A solution of 85 mg (0	.6 4 mmo1	) cf
pyridine and 140 mg [0	.”6 mmo1	) cf
1 ml acetonitrile was	refluxed	for
evaporated and the res	idue was	tre;
solid that formed was	isolated	by

2C '62%' of 2-methyl-7- (2-phenylethyl)pyrrolo[2,3-b3pyridinehydrccromide.

^H-NMR, 500 MHz,CEC1,:· 2.78(s,3H), 3.44,t,2H), 5.40 t,2H)

5.44(s,lH·, 5.97!dd,2H;, . 08 (dd, IH. , 7.18(m,3H),

”.31 id,IH; 3.1”{5,IH! .

Example 2

-Chlorc-2 -metb.vl - (2 -phenvlethv1) pyrrolo [2, 3 -b] pyridine hydrobromide

A solution of 28.4 mg '0.17 mmol) of 3-chloro-2-methyl pyrrolo [2,3-bjpyridine and 36 mg (C.2mmoli of (2cromcethyl;bensene in 0.4 ml of dimethylformamid was heated at 80^cC for 20 h. The solvent was evaporated. The solid that formed was treated with ethyl acetate and isolated by filtration to give 30 mg .'50%; cf

3-chlorc-2-methyl-~- - 2-phenylethyl'pyrrolo(2,3-b j pyridine hvdrobromide.

f. H-NMP., 500 MHo,CDCl-; 2.77is,3H), 3.45it,2H), 5.40<’t,2H), 6.95(dd,2H), 7.14(dd,lH), 7.2(m,3H), 7.28(d,lH),

8.24(d,IH).

AP Ο Ο Ο 3 Ο 9

-13Examp1 e 3

3-Cyancmethyl-2-methyl-7 -{2-phenylethyl)pyrrolo[2,3b]pyridine

A solution of 130 mg (0.76 mmol) of 3-cyanomethyl-2-methyipyrrolo [2,3-bj pyridine and 150 mg (0.81 mmol) of 2bromoethyl-benzene in 2 mi of acetonitrile was refluxed for 40 h. The solvent was evaporated and the crude product .was chromatographed on silica gel with ethyl acetate: methanol:

water 100:12:4. Recrystaliization from a small amount of ether: petrcleumether 1:1 save 53 mg (25%) of 3cyanomethyi-2-methyl-7 - (2-phenylethyl)pyrrolo[2,3-b]pyridine.

3-Methyl-7-(2-phenylethyl)pyrrolo[2,3-b]pyridine hydrobromide.

A solution of 0.3 g (2.3 mmol; 3-methyipyrroloΓ2,3b]pyridine and 0.5 g '2.7 mmol) (2-brcmcethyi) benzene in 10 mi acetonitril was refluxed fcr 72 h. The solvent was evaporated and the solid that formed was treated with ether. Recrvstalization from ethyl acetate gave 0.2 g <2V%) of the title compound as a white solid.

BAD oW^elNAL

-14* Λ 'J

Example 5

-Hydroxymethyl-3-methyl-7 - (2 -phenylethyl) pyrrolo [2,3b’;yflline hydrobromide

A solution of G.ll g (0.68 mmol) 2-hydroxymethyl-3methylpyrrolo [2,3-b]pyridine and 0.13 g (7 mmol)

2-brcmcethyl) benzene in 5 ml acetonitril was refluxed for 24 h. The solvent was evaporated. Chromatography on silica gel eluting with methylene chloride and methanol (10:1) gave the desired product.

0.03 σ 13%) ( *(-( -NMR, 5 C 0 MHz , CDC 1₃ ) , 2 5.1 t,2H), δ .95-7.0'm,2H) 7.35 -.dd, IH) , 8.15 (dd, 2H) .

s,3H), 3.4't,2H) 05(t,IH), 7.2-7.

, 4.9 5 ( s , 2 H) 25 fm,3H),

2-Chlcro-3-methyl-7- (2-phenylethvl)oyrrolo[2,3-bipyridine

A solution of 0.1 g (0.6 mmol) 2-chloro-3-methylpyrrolo(2,3-b)pyridine and 0.14 g (0.78 mmol) (2-bromoethyl) benzene in 10 ml acetonitril was refluxed 72 h. The solvent was evaporated. The solid that formed was treated with ether and ethyl acetate and isolated by filtration.

Chromatography on silica gel eluting with methylene chloride and methane! (10:1; gave the desired product.

:1.:3 g 13% .

2.3 (s,3H- , 3.35(t,2H) , 4.8-.t,2H) , H , 7.05'dd,IH), 7.2-7.25 urn,3H> , . 3'dd,IH,

J» «*

AP Ο Ο Ο 3 Ο 9

-15Example 7

6-Amino-2,3-dimethyl-7- (2-pheny 1 ethyl) -pyrrolo[2, 3b]pyridine hydrobrcmide

A solution of 6-amino-2,3-dimethyl-pyrrolo[2,3-b]pyridine (l.Cg, 6,2mmcl) and phenethyl bromide (l,7g, 9,3mmol) in. 20 ml CH^CN was refluxed for 48 h. The mixture was allowed to cool and the precipitate was filtered off. Chromatography cn silica gel eluting with methylene chloride and methanol (9:1; gave the desired product (O.lg, 6%).

500MHz, CDC1₃+CD₃OD) 2,I0(s,3H), 2,25(s,3H), 3,20(t,2H), 4,70ic,2H), 6,60(d,lH), 7,10(dd,2H), 7,157,20(m,3H), 7,75(d,lH).

Example 8 , 3 -Tlmethvl-7-phenacylpyrrolo [ 2 , 3 -bi pyridine.

A solution of 2,3-dimethylpyrrolo (2,3-b] pyridine (146 mg, 1 2 0 mmol) and phenacyl chloride (17 0 mg, 1.1 mmol) in 3 ml

CH3CN was refluxed for 4.5 h. The mixture was allowed to cool and the precipitated product filtered off and washed with a small volume of ice cold CCl^ affording 207 mg (69%) pure tide compound as the hydrochloride salt.

Jh-NMR, 300 MHz, DMSO-dg), 2.29(s,3H), 2.42(s,3H), 6.66's,2H), 7.65m,3H), 7.80(t,lH), 3.11id,2H), 8.47(d,lH), 8.52(d,IH' , 12.5 (b,IH) .

0 Example 9

- Chioro-2 -methyl-7-phenacylpyrrcIo f 2 , 3 -b 1 cvridinehydrochloride

A solution of 200 mg (1.2 mmol) of 3-chloro-2-methyl 35 pyrrolo-[2,3-b]pyridine and 204 mg (1,3 mmol) of 2chloroacetophenon in 10 ml of CH^CN was refluxed for 48 h. The reaction mixture was cooled to room temperature and

RA

-16— stirred for one hour. The precipitate was filtered off to give 260 mg (67%) of 3 chlorc-2-methyl-7-phenacylpyrrolo; 2 , 3 - ο j pyr idmehydrochlor ide .

(*H-NMR, 5C0 MHz, DMSO-d,.) 2.50(s,3H), 6.62(s,2H), o

7.68it,2K), 7.78im,2H), 3.11id,2H), 3.62{d,lH), 8.70{d,lH).

Sxample 10 , 3 - Dimethy 1 - 7 - p-brcmcchenacyl)pyrrolo ^r 2, 3-b]pyridine, hv hr?bromide

This oompound was prepared by reacting 2,3-dimethylpyrrolo

2,3-b]pyridine with p-brcmcphenacyl bromide following the procedure in example 8.

Yield: 92%.

•‘H-liMR, 300 MHz, DMSO-d,; 2,29 (s, 3H! , 2,41 (s, 3H) , 6,47 o (s, 2H), 7,63 (dd, IH), 7,92 (m, 2H) , 8,03 (m, 2H) , 8,43 (d, IH), 8,64 (d, IH), 12,3 (b, IH)

Example 11

2,3-Dimethyl -⁷ -(2-chenvl-2-hvdroxyethyl!cyrroio f2, 3bcvridine.

l solution of 2 , 3-dimethy 1-phe.uacyipyrrolo [ 2 , 3 ] pyridine 120 mg, 0.4mmcl) in 3 ml MeCH was treated twice with 20 mg

MaEH, ccrticns and allowed to react fcr 4 * temperature. The solvent was evaporated partitioned between 50 mi ZH-Ti- and 25 * t. z.

Λ	organic layer wa	s separated, washed wit
	dried ever MgSO^	and evaporated leaving
	compound as the	hydrochloride .

2h at room and the residue ml 2.5% NaOH. The ml 2M KOI,

113 mg ( 9 4 %) title ;-H-NMR, 300 MHz, DMSO-d_g 4.31(dd,lH), 4.97(dd,lH),

7.3 7 (m, 3H) , 7 . 53 ί t, IH) , 7 . 2.26(s,3H), 2.48(s, 5.15(dd,lH), 5.91(dd, 6i:d,2H), 8.51(t,2H),

3H) ,

AP Ο Ο Ο 3 Ο 9 —17—

Example 12

-Chloro-2-methyl-7- ( 2-phenyl-2-hydroxyethyl)pyrrole [2,3bpyridine

Tc a solution of 120 mg (0,37mmcl) of 3-chloro-2-metyl-75 phenacylpyrrolo[2,3-b]pyridine hydrochlorid in 2 ml methanol was added 30 mg (0,79mmol) of sodium borohydride. The mixture was stirred fcr 20 h at room temperature. The solvent was evaporated and the residue was partitioned between 2 ml of 0,2 M hydrochloric acid and 2 ml of ethyl acetate. The aquecs layer was basified by addition cf 2M sodium hydroxide and extracted twice with 2 ml of methylene chloride. The combined organic phase was dried over sodium sulfate and the solvent was evaporated. The residue was treated with acetonitrile and the precipitate was filtered off to give 20 mg (19%) 3-chloro-2-methyl-7-(2-phenyl-2hydroxyethyl) pyrrole-[2,3-b]pyridine .

500MHz, CDCl^) 2.55<s,3H), 4.76(dd,lH), 4.91(dd,lH), 5.32<dd,lH), 6.73(dd,lH), 7.20(d,lH),

7.25{m,IH), 7.28(m,4H), 7.38(d,lH).

Example 13

2.3- Dimethyl-7- (2 - (p-cyanophenyl) -2-hydroxyethyl)pyrrolo

12.3- bi pyridine.

The title compound was prepared on a 0.4 mmol scale mainly according to example 11 above yielding 63 mg (61%) pure title compound as a yellow solid.

,*H-NMR, 3 00 MHz, CDCl ). 2.27(s,3H), 2.5I(s,3H),

4.73(dd,1H), 4.91(dd,l£), 5.3c(dd,lH), 6.65(t,lH), ~.03(d,lH), 7.40(d,2H), 7.56 id,2H),7.73(d,1H) .

-18—

Example 14

-Methyl -7 -phenacyl -pvrrolo (2,3-b] pyridine hydrochloride

2-Methyl-pyrrole'2,3-cjpyridine (0.5g, 3.78mmol), phenacyl chloride (0.62g, 4.0mmoi) and acetonitrile (10ml) were refluxed for 12 h. The solid was filtered off and washed with cold carton tetrachlorid (2ml). The crude product was recrvstallized from chloroform'ether, 1:1, to give 0.95g '83%! title ccmpcund.

NMR, 300 MHz, TMSC-dJ; 1.25!s 0

6.0 ' s,1H) , 7.05'm,3H·, 7.30(t,IH), 3.65:d,1H) .

H ’ , 6.6 5 (s, 2 H! , 8.1Q(d,2H), 3.50(d,1H),

Example 15 , 5 -Dimethyl2-tri fiuoromethvlphenacyl . -cyrrclo [2,3b'pvridme hydrccrcmide

The title ccmpcund was made according to the general method from Example 14. 2,3-dimethy1-pyrrole2,3-b]pyridine '433mg, 3mmcl·,, 2-triflucrcmethyiphenacy 1 bromide <798mg, 3mmcl' in acetonitrile (5ml). Yield C.44 g (36%).

<~H-NMR, 300MHz, DMSC-d_g), 2.45(s,3H), 2.50(s,3Hi,

6.55:s,2H) ,7.65Ό,1H), 7.95(t,lH), 8.05im,2H), 8.40'd,2K·, 3 . 6 5 (d, 1K) .

Example -16

- Er cm.o - 2 -methvl - ~ -ohenaev 1 - tvrrolc (2 , 3 - b ’ cvridine hvdrebromide.

The title compur.d was made according to the general method from Example 14. 3-brcmo-2-methyl-pyrrclo[2,3-b]pyridine (250 mg, 1.19 mmol! phenacyl bromide (200 mg, 1.3 mmol) in acetonitrile (50mi). Yield 146 mg (3~%).

AP 0 0 0 3 0 9 —19— (¹H-MMR, 300MHz, DMSO-d_g), 2.5(s,3H), 6.7(s,2H), 7.65(t,lH), 7.75(m,3H), 8.1(d,2H), 8.6(m,2H).

Examcle 17

2-Chloro-3-methyl-7-phenacylpyrrolo-[2,3-bi pyridine.

Hydrochloride .

A solution of 1.2 g (7.2mmol) 2-chloro-3 -methylpyrrolo [ 2-, 3 b’pyridine and 1.3 g (8.7 mmol) phenacyl chloride in 50 ml acetonitrile was refluxed fcr 48 h. The solvent was allowed to cool and the precipitated product was filtered off and dried, affording 1,5 g (65%) pure title compound.

(^H-NMR, 300 MHz, CDCl-j) 2.35(s,3H), 7.0(s,2H), 7.4(dd,lH),

7.55(t,2H), 7.65(t,lH), 7.8(d,lH), 8.2-8.3(m,3H).

Example 18

2-Chloro-3-methyl-7-(2-phenyl-2-hydroxyethyl)pyrrolor(2,3b)I pyridine

A solution of 0,8 g (2,5 mmol) 2-chlcro-3-methyi-7phenacyl[2,3-b]pyridine in 50 ml methanol was cooled tc 0°C. It was then treated with NaBH^-port ions until all starting material had reacted. (The reaction was followed by TLC). The solvent was evaporated and the residue partitioned between methylene chloride and water. The organic layer was separated, dried over and evaporated. The residue was treated with ether and isolated by filtration tc give 0,6 g (84%) of the title compound as white solid.

bad OWD'N*¹-

-20Example 19

1-Methey/-2-methyl-7-phenacyl pyrrolo[2,3-b]pyridine .

A solution of 3,75 g (4,6 mmol) 3-methoxy-2methylpyrrolo[2,3-b] pyridine and 3,75g (4,3mmol) phenacyl chloride in 50 ml acetonitrile was refluxed for 14 n. Working up m the same manner as ex. 17 gave 0,5 g '34%) of the desired product.

\h-NMR, 3 00 MHz, 0DC1-) 7.35(t,iH), 7.5(t,2Hi, 7.6(t,lH 8.35(d,IH).

55(3,3H!

., 3.95(s,3H), 7.3(_S,2H), 7.9!d,lH), 3.25(d,2H),

Examp1e 20

-Methcxymethv1 - 3 - methy 1 - ~ - phenacyl pyrrole j2, 3 -b] pyridine.

'4» .· 4 v -. _r ' * ^r ί

A solution of 0,13 g ¢0,4 mmol) 2-.methcxymethyl-3methylpyrrolo(2,3-b]pyridine and 0,16 g (1,1 mmol) phenacyl chloride in 23 ml acetonitrile was refluxed for 15 h. Working up in the same manner as ex. 17 gave 0,35 g (20%) of the title compound.

‘H-NMR, 3 00 MHz, ODCl.) .05 's,2H;, 7.4 .25 d,OH), 8.3^: .4's “* i *“ .45(s,3H), 4.3(s,2H), 5 5 ’ t, 1H - , 7.3 5 (d, 1H) ,

-Chi orc -3 -methvl' p - f Quorocher.a<m/l) oyrreIc ί 2 , 3 b]cyridinehvdrochloride

A sclution of 1,2 g [2,3-b]pyridine and chloride in 50 mi a mixture was allowed (7,2 mmol) 2-chloro-3-methylpyrrolo 1,5 g (8,7 mmol) p-fluorophenacyl etonitriie was refluxed for 48 h. The/ .t&z and the crecicitatec productdSr to coo.

AP 0 0 0 3 0 9

-21— filtered off. The solid was treated with ethyl acetate and filtered off again affording 1,4 g (57%) of the desired product.

(¹H-MNR, 300MHz, CD^OD) 2.4(s,3H), 6.45(S,2H), 7.4(dd,2H), 7.65(dd,lH), 8.25(dd,2H), 8.45(cl,lH), 8.7(d,lH).

Example 22

2-Chloro-3-methyl-7- (2 -(p-fluorophenyl)-2hydroxyethy1}pyrrolo '2,3-bj pyridine.

A solution of 1,9 g 2,8 mmol) of 2-chloro-3-methyl-7-'pflucropnenacylipyrrole [2 , 3-b]pyridine hydrochloride in 50 mi methanol was treated with Na3H. in the same manner as 4 ex. 18 to give 0,85 g (99%) of the title ccmpound as white solid.

;^LH-NMR, 300 MHz, CD,OD) 2.3(s,3H), 4.5(dd,lH), 4.9(dd,lH), 5.3(dd,lH), 6.95(t,iH), 7.1(t,2H), 7.45-7.55(m,2H),

7.8(d,IH), 8.0(d,IH).

Example 23

2-Chloro-3-evanomethyl-7-phenaoylpyrrolo[2,3-blpyridine

A solution of 0,66 g '3,4 mmol) 2-chloro-3-cyancmethylpyrrolo[2,3-bjpyridine, and 0,65 g (3,8 mmol) phenacyl bromide in 49 mi acetonitrile was refluxed for 20 h. The mixture was allowed ts cool and the precipitated product was fiitred off and recrystaiiized from acetonitrile. Chromatography on silica gel eluting with ethyl acetate gave the desired product (0,094g, 9%).

(^XH-NMR, 300 MHz, CDC1₃) 3.9(s,2H), 6.15(s,2H), 7.05(t,lH),

7.5-7.65(m,2H), 7.7(t,lH), 8.1(d,2H), 8.25(d,lH).

-22— example 24 , 3-Dimethy1-7 -(o-methvlthiophenacyl) pyrrolo[2,3b cyridinehydrobrcmide.

A solution cf 0,2 g (1,4 mmol) 2,3-dimethylpyrrolo[2,3b]pyridine and 0,34 g -1,4 mmol) o-methylthiophenacyl bromide was stirred at rocm temperature for 4 h. The precipitated product was filtred off and dried affording

2,11 g ‘20%; of the title compound.

H-NMR, 300MHz, 22C1- 2.25(s,3H;, 2.45(s,3H), 2.6is,3H)

6.9(s,2H', 7.35-7.45'm,3Η!, ^.6(t,lH), 7.75(d,lK),

-1 .25 ' d, IK) , 3 . 65 (d, IK' .

example 25

-Kvdrcxv-2 -methvl -- -oher.ac /Icyrrclo ; 2,3-b]pyridine

To a solution cf 0,05 g (0,16 mmol) 3-methoxy-2-methyl-7phenacyl pyrrolo[2,3-bjpyridine in 10 ml methylene chloride was added 0,5 ml (0,2 mmol bortribromide in methylene chloride (IM; at FT. The reaction was followed by T.L.C.

Che mixture was stirred 20 h. and was evaporated. The product was solved in 2 ml methylene chloride/methanol 10/1 and a small amount of water and chromatography of this mixture on silica gel eluting with methylene chloride methanol 10'1 gave the product as an oil. The oil was treated with ether tc give the title product as yellow

-K-NMR, 307 .55·’bs , IH) ,

MHz, EMSC-d-), 2.35(S,3H), 6.45(s,2H),

7.7it,2H), 7.8it,lH), 8.15(d,2H), 8.4'd,lH), /

AP Ο Ο Ο 3 Ο 9 —23 —

Example 26

2, 3-Dimethyl-5-trifluoromethyl-7-phenacylpyrrolο[2,3b; cyrodir.e

A solution of 0,1 g (0,47 mmol) 2,3-dimethyl-5tr:fluoromethyl-pyrrolo[2,3-b]pyridine and 0,13g (0,84 *· · mmol) 2-chloroacetophenone in 5 ml acetronitrile was refluxed for 48 h. The solvent was evaporated. χ

Chromatography on silica gel eluting with methylene chloride and methanol (100:5) gave the desired product. (0,023 g 15%) .

(^:H-NMR, 300 MHz, CDC1-) 2.3(s,3H), 2.45(s,3H), 6.15(s,2H), ^.55(t,2H), 7.65(t,l.H), 7.75(s,lH), 7.95(s,lH), 8.05(d,2H).

Example 27 , 3 -Cimethy1-7 - (c-cvancphenacyl)pyrrol? [ 2,3-bi pyridine .

A solution of 2,3-dimethylpyrrolo[2,3-b]pyridine (146 mg, 1 20 mmol) and p-cyancphenacyl bromide (248 mg, 1.1 mmol) in 3 ml CH-jCN was refluxed for 1.5 h. The mixture was allowed to cool and the precipitated product filtered off and washed with a small volume of ice cold CCl^ affording 313 mg (85%) pure title compound as the hydrcbromide salt.

300 MHz, CDC1₃) 2.30(s,3H), 2.50(s,3H),

7.10(_S,2H), 7.40idd,lH), 7.68(d,2Hi, 8.00(d,lH),

S.2?;d,lHI, 8.3?(d,2H), 13.5(b,lH!.

0 Example 2 8

2,3-Dimethyl-7 - (p-f luorooher.acy 1)pyrrolo[2,3-bi pyridine .

The title compound was prepared on a 1 mmol scale from 2,3dimethylpyrrolo[2,3-b]pyridine and p-fluorophenacyl bromide following the procedure in example 27 above yielding 260 mg (64%) pure product as the hydrobromide.

-24(¹H-NMR, 330MHz, CDCi,), 2.28(S,3H), 2.56(s,3H), 6.99(s,2H), 7.13(m,2H), 7.38(dd,lH), 7.83(d,lH), S.24;d,lH), 8.35(m,2H , 13.3(b,lH).

Example 29 , 3 -Cimethyl- - '.p-metcxyphenacvl) pyrrolo[2,3 -bipyridine.

The title compound was prepared from 2,3-dimethyipyrroio ]2,3-b]pyridine (120 mg, 0.82 mmol) and p-methcxyphenacyl bromide 2 3'’ mg, 0.9C mmol) following the procedure in example 2 above furnishing 223 mg (73%( pure hydro'cromide as a light yellow solid.

;“H-NMR, 330 MHz, CCC±₃) 2.27(s,3H) 3.88(s,3H), 6.91''3,2H) , 7.00im,2H), ^.cl(d,iH), 8.22 d,lH), 8.28(m,2H).

2.53(s,3H), 7 . 37 (dd, IH) ,

Ex amp1e 3 0 , 3 - Dimethy 1-7 - (m-methcx’vrher.acyl) cyrrolo f2,3 -b] pyridine .

The title compound was prepared on a 0.9 mmol scale fr 2,3 dimethyIpyrrolo{3,3-b]pyridine and m-rnethoxyphenacyl bromide in the same manner as described in example 27 giving 228 mg (73%) pure product as the hydrobromide.

’H-NMR, 3 3 3 ΜΗ z,

91(5,3H), 5.9, 4 J \ “ , - Π i , > . > z

22d,lH) .

CDCI,) . 2.27 ί3,3H , 2 Η , 7.13 dd, 1H; ,

2.57·s,3H), .31 dd,IH), . 3 9 ( d, 1H) ,

Example 31 , 3 - Dimethyl - 7- (c-methcxyphenacyl. pyrrole [2,3-b] pyridine.

The title compound was prepared on a 1 mmol scale from 2,3dimethyIpyrrolo[2,3-b]pyridine and o-methcxyphenacyl bromide in the same manner as described in example 27

AP 0 0 0 3 0 9 —25— yielding 244 mg (71%) pure hydrobromide as a light yellow solid.

(K-NMR, 300 MKz, CDCl-j). 2.26(s,3H), 2.60(s,3H), 4.20(s,3H), 6.71(s,2H), 7.04(m,lH), 7.11(d,lH), 7.35(dd,iH), 7.5?(m,lH), 7.69(d,lH), 7.95(dd,lH),

8.20(d,lH).

Example 32

2,3-Dimethyl-t-<2,4-difluorophenacvl)pvrrolo(2,3c’pyridine .

The title compound was prepared on a 1 mmol scale from 2,3dimethylpyrrolc[2,3-b]pyridine and o,p-difluorophenacyl bromide following the procedure described in example 27 giving 194 mg (56%) pure hydrochloride as a yellow solid.

(H-MMR, 300MHz, CDC1₃) 2.27(s,3H), 2.53(s,3H),

6.76(d,2H), 6.96 im overlapping signals, 2H), 7.34(dd,lH), 7.33(d,lK), 8.15(m,lH), 8.22(d,lK), 14.9(b,lH).

Example 33

5-Chloro-3-cyancmethy1-2-methyl-7-phenacyIpyrroloί 2,3-b] pyridine

A mixture of 5-chlcre-3-cyanomethyl-2-methy 1-pvrrolo [2,5rb;pyridine (147 mg, 0.7 mmol) and phenacyIbrcmide (142 g, 7 mmcli in-12 ml CH^CN was refluxed for 22h. The reaction., mixture was coded and precipitated title compound was collected and washed with small portions of ice cold diethyl ether. Treatment of the filtrate with diethyl ether afforded a second and third lot of pure title compound. Total yield 257 mg (91%) calculated as the hydrobromide.

i¹H-NMR, 300MHz, DMSO-dg). 2.53(s,3H), 4.24(s,2H),

6.50(s,2H), 7.70(t,2H), 7.83(t,lH), 8.10(d,2H), 3.90(d,lH),

9.042(s,IH).

-26Example 34

2, 3-Dimethyl-7 - (2-ohenyi-2-methoxyethvl)-pyrrole[2,3b]pyridine

A solution of 2,3-dimethyi-7-(2-phenyl-2-hydroxyethyl)pyrrolo[2,3-b]pyridine (as the base) (266 mg, 1.0 mmol) in 25 ml dry THE was deaerated and treated with 55% NaH dispersion in oil (43 mg, 1.1 mmol) for 30 min. Methyl iodide (62 μΐ, 1.0 mmol) was added and allowed to react for

50 mm. The solvent was evaporated and the residue cart mimed between 100 mi CH„2I., and 20 ml 5% NaCH. The z z mganic layer was dried over MgSO^ and evaporated. The residue was chromatographed (silica, CHvCl., saturated with z z

NH,). Pure fractions were pooled and evaporated leaving a 15 gum which partly crystallized. Trituation with diethyl ether furnished 207 mg (65%¹ pure title compound.

H-NMR, 3 00 MHz ,CCC1,) . 2.29(s,3H), 2.54(s,3H), .14(5,3H), 4.41(dd,iH), 4.86(dd,lH), 4.99(dd,lH), .64(t,lH'·, 7.38 (overlapping signals, 6H) , 7.75(d,lH)

Example 35 , 3-Dimethyl-7-(o-nitrophenacyl)pyrrolo[2,3-bi pyridine .

The title compound was prepared on a 5 mmol scale from 2,3iimethyIpyrrolo]2,3-c]pyridine and c-nitrophenacyl bromide in the same manner as described in example 27 yielding 1.3 g (66%; pure hydrebremide as a yellow solid. Reprocessing ;f the motherliquer gave additional material.

i-H-NMR, 300 MHz. DMSC-dJ. 2.30(s,3H), 0

6.28(s,2H), .68(dd,1H), 7.97(dt,lH), 8

2.47(s,3H), 08(t,IH), dt,2H), 8.37(d,lH), 8.67(d,lH),

12.9(b,IH).

ΑΡ ο 0 0 3 0 9 —27—

Examp1 e 36

2.3- Dimethyl-7 -(o-aminophenacyl)pyrrolo[2,3-b]pyridine.

2.3- Dimethyl-7-(c-nitrophenacyl)pyrrolo[2,3-b]pyridine (1.02 g, 2.6 mmol) was dissolved in 39 ml abs. EtCH and treated with SnCl₂.2H₂O (4.75 g, 21 mmol) and 13 ml cone HCI at 80°C for 3h. The reaction mixture was allowed to cool and then partitioned between 500 ml 2M HCI and 250 ml CH₂C1_2< The organic layer was extracted with additional 150 * 50 mi 2M HCI. The aqueous layers were combined and washed with 4jG ml diethyl ether. The pH was adjusted to 12 and the basified product extracted with 800 + 400 + 200 ml CH₂C1₂· The latter organic layers were combined, dried ever MgSC^, and evaporated leaving 340 mg (46%) pure amine as an intense yellow solid.

(“H-NMR, 3 00 MHz, CDC1-). 2.2S(s,3H), 2.47(s,3H),

6.09(s,2H), 6.21(b,2H), 6.71(m,2H), 6.81(t,lH), 7.33(m,2H), 7.82(d,lH), 7.88{d,lH).

Example 37

2.3- Dimethyl-7-{p-methylohenacyl)pyrrolo[2,3-b]pyridine.

A solution of 2,3-dimethylpyrrolo[2,3-b]pyridine (0.16 g, 1.1 mmol) and p-methylphenacyl bromide (0.26 g, 1.2 mmol) in 4.5 ml CH^CN was warmed to reflux which was enough to initiate crystallisation of the product as a light yellow solid. The precipitate was isolated as described in example 27 furnishing 0.29 g (74%) pure hydrobromide.

(^H-NMR, 3 00 MHz, CDCl-j). 2.27(_S,3H), 2.41(s,3H),

2.5~(s,3H), 6.94(s,2H), 7.32id,2H), 7.37(dd,lH),

7.80(d,lH), 8.17(d,2H), 8.23(d,lH), 13.8(b,lH).

bad original

A

4. » >

* ir-i

-2 8—

Examcles 3 8 ar.d 3 9

R and S.)-2,3-0imethyl-’-(2-phenyl-2-hydroxyethyl)pyrrolo'2,2-0' pyrldinehydrochloride.

* Λ

R ( - :-2 -rr.ethcxy-2-phenylacet ic acid was dissolved in 3 ml SCO., at 0°C ar.d allowed tc react for 4h at room temperature. The excess SOC1₂ was evaporated and the residue treated with a solution of a racemic mixture of 2,2-dimethyl-’- (2-phenyl-2-hydroxyethyl:pyrrolo[2,3b)pyridine prepared according to -xample 11 302 mg, 1.0 mmol; and St,N '27'? μΐ, 2.0 mmol) in 20 mi CH-Ci-. After reacting for 16h at room temperature the mixture was panticned between 150 mi CH_OC1- and 50 mi 2M HCl. The organic layer was collected, washed with 50 ml 5% Na₂CO-, dried over MgSC^, and evaporated. Diastereomers 1 and 2 were separated by ohrom.atogaphy (silica, CH,Ci₂ saturated with NH-/diethyl ether;l/l). Diastereomer 2 was further purified by chromatography (silica, 2H_OC1, saturated with NH- ) . Yields, 14? mg (36%) and 90 mg (22%) cf isomers 1 and

2, respectively. Each iscmer (149 mg, 0.36 mmol 1 and 89 mg, 0.21 mmol 2) was dissolved in a few ml cf MeOH and LiCH (a 5-fcid molar excess) dissolved in a few mi H₂O was added and allowed to react for 1 h at room temperature. The solvent was evaporated and each residue partitioned between 100 mi CH-C1- and 50 mi 5% Na-CO-. Each organic layer was washed once with 50 ml 2M HCl, dried over MgSO^, and evaporated leaving 100 mg ·'92%) enantiomer 1 and 52 mg

82%' enatiomer 2.

-NMR, 3 00 MHc, ZMSC-d.xamc

11.

Example 40 , 3 -Dimethyl-7 - (o-hydroxyohenacy1) pyrrole [2,3 -bi pyridine.

A solution of 2,3-dimethyi-7-(o-methcxyphenacyl) pyrrolo[2, 3-b] pyridine (75 mg, 0.2 mmol) in 20 mi CH₂C1₂ was cooled to 0°C and treater with IM 3Br, in CH₂Ci- (200

AP Ο Ο Ο 3 Ο 9 —29— μΐ, 0.2 mmol). After reacting for an additional hour the reaction mixture was poured into a stirred solution of 5 % NaHCO-j . The aqueous layer was ectracted with 50 + 10 ml and the combined organic layers washed with 50 ml 2M

HCl (reextraction trice with 10 ml C^C^). The combined organic layers were dried over MgSO^ and evaporated. The residue was chromatographed (silica, CH2Cl2/MeOH ; 9/1) affording 35 mg (62%) pure title compound.

(•’’H-NMR, 500 MHz, CDCl_q). 2.27(s,2H), 2.50(s,3H),

6.4C(b,2H), 6.93(b,lH), 6.93(d,lH), 7.14(t,lHi, 7.40;b,lH), 7.65(d,lH), 7.85(b,lH), 3.07(d,lH).

Example 41

2,3-Dimethyl- 6-methylthio-7-phenethylpyrrolo[2,3b]pyridine.

A refluxing solution cf 2,3-dimethyl-6-mehylthiopyrrolo[2,3-b] pyridine (100 mg, 0.5 mmol) in 5 ml CH^CN was treated with five portions of phenethyl bromide (35 μΐ,

1.2 mmol), one each 24 h. The solvent was evpcrated and the residue chromatographed (silica, saturated with

NH^/diethvl ether/petroleum ether; 5/2/3) affording 20 mg (13%) pure title compound.

ΓΗ-NMR, 500 MHz, CDCl-j). 2 . 5 3 ( s , 3 H '1 , 3.25(m,2H), 5

2.27(s,3H), 2.52(s,3H),

10im,2H), 6.75(d,iH), 7.25'm,1H),

7.31 overlapping signals, 4H)

7.68(d,1H).

Examp1e 42

2,3-Dimethyl-7-chenethvl-6-phenethvlthiopyrrolo[2,3b]pyridine hydrochloride

A refluxing solution of 2,3-dimethyl-6-methylthio-pyrrolo 35 [2,3-bjpyridine (391 mg, 2.0 mmol) in 9 ml CH^CN was treated with five portions of phenethyl bromide (553 μΐ, 4.0 mmol), one each 24 h. The solvent was evaporated and bad obv

-3 0the residue chromatographed (silica, CHjCJ^ saturated with \Ή-, < diethyl ether,'petroleum ether; 5/2/3). Pure fractions were peeled, diluted to the double volume with Cf^C^ and washed with 50 ml 2M HCl. The organic layer was dried over MgSO^ and evaporated leaving 221 mg (26%) pure product.

H-NMR, 50C MHz, CDCl-j). 2.29(s,3H), .90(0,ZK), 3.15(t,2H), 3.24(m,2H), 5 .13(d, 2Ηι, 7.23(overlapping signals,

2.55(s,3H),

14(m,2H), 6.92(d,lH), 4H), 7.29 over ng signals, 4H), 7.68(d,lH).

Example 43

2,3-D met hvl-6-methy1thio-7-phenacvlpyrrolo[2,3 -b]pyridine .

A mixture of 2,3-dimethyl-6-methylthiopyrrolo[2,3o’cyridme <100 mg, 0.5 mmol) and phenacyl chloride (804 mg, 5 mmol; in 3 ml CH-CN was refluxed for 72h. The solvent was evaporated and the residue chromatographed (silica, OHyC^/MeCH;59/5). Pure fractions were pooled, evaporated, and taken up ir. 100 ml ¢^¢12- The organic layer was washed with 25 ml 2M HCl, dried ever MgSC^, and evaporated leaving 64 mg <35%; pure product as the hydrochloride.

H-NMR of . 4 5 (3,3 H) .66;m,IH >

the free base, 2.53<5,3H), 6 7.35 f d,IH) , 8

300 MHz, CDC1₃). 2.25(s,3H), 62(b,2H), 7.05(d,lH), 7.55(m,2H), 12(m,2H) .

i.xamc methy1thio-7 -phenacvlpyrrolo[2,3-b]pyridine.

The title compound was prepared on a 0.6 mmol scale from

2,3-dimethyl-5-methylthiopyrrolo[2,3-b]pyridine (prepared azeerding to the procedure described for 2,3-dimethyl-6m.ethyithio-pyrrolo [2,3-b] pyridine) and phenacyl chloride as described in Example 43 yielding 140 mg (63%) pure title zompeund as the hydrochloride.

AP Ο Ο Ο 3 Ο 9

-31— (^LH-NM?, 500 MHz, CDCl,). 2.26(s,3H), 2.57(s,3H),

2.60 s,3H), 6.95'b,2H), 7.60(m,2H), 7.59(m,2H), 8.22(s,lH>, 8.30 . m, 2 K i .

Example 45

2, 3-Dimethyl-5-methylsulfinyl-7-pbenacylpyrrolo[2,3b]pyridine .

A solution cf 2,3-dimethyl-5-methyLthio-710 pher.acylpyrroio [2,3-h] pyridine (35 mg, 0.1 mmol· in 20 ml

OH-Ci^ was cooled to -20°C an treated with 71% m-C?3A (27 z z mg, 0.1 mmol) for 30 mm. The volume was adjusted 50 ml with CH„C1_O and the organic layer washed twice with 50 ml

5% Na~CCc and once with 2M HCI (reextraction trice with 25 z a ml CH^Cl^). The organic layer was dried ever MgSO. and Z Z 4 evaporated leaving 15 mg (41%) pure title compound.

(*K-NMR of the hydrochloride, 300 MHz, CDCl-J. 2.31(s,3H), 2.59(s,3H), 2.95(s,3H!, 7.05(s,2H), 7.54(t,2H), 7.66(t,lH),

8.1c!s,lH), 8.25id,2H), 8.36(s,lH).

Example 46

2, 3-Dimethyl-7-(o-carboxyphenethyl)oyrrolo[2,3-b]pyridine.

A solution of 2,3-dimethylpyrrolo[2,3-b]pyridine (554 mg, 3.8 mmol) and o-bromophenethv 1 bromide (1000 mg, 3.8 mmol) in 11 ml CHyCN was refluxed for 16 h. The solvent was evaporated and the residue chromatographed (silica, CH₇Cl₇-'MeCH ; 9/1) to give 546 mg enriched product. Pure

2,3-dimethyl-7- (c-hromcphenethyli pyrrole[2,3-b]pyridine was obtained by a second chromatography (silica, 0^012 saturated with NH^/petroleum ether ; 7 3) .

A deaerated solution of 2,3-dimethyl-7- (0-bromophenethyl) pyrrolo[2,3-b]pyridine (249 mg, 0.76 mmol) in 25 ml dry THF was cooled to -78°C and treated with 1.6M n-BuLi in hexane (576 μί, 0.91 mmol). After 3 min a vigurous stream of CO₂(g) was bubbled through the solution. The solution was

BAD ORIGINAL

-j zallowed to warm to room temperature and 1.5 ml was added. The solvent was evaporated and the residue chromatographed .'reversed phase silica, MeOH/Hd ; 6/4 > yielding 51 mg <22%. cure amino acid.

(*H-NMR of the hydrcchl 2 . 3 6 ( s , 3 H) , 3 . 5 5 (t, 2 H) , 7.19(m,IH) , 7.24(m,IH), 3.39 id,IH) .

ride, 330 MHz, CDCl^ ) . 5.07(t,2H), 6.86(d,lH) 7.33 (dd,IH) , 7.91(d,IH ( s , 3 H' , 04(m,IH!

Example 47

5-Ercmc-2, 3 -dimeth.vl -chenacvl pyrrolo[2,3-b) cvridine .

A solution cf 5-crorc.c-2 , 3-dimethyl-pyrrolo (2 , 3-o] pyridine 15 (prepared in a similar manner as 6-brcmo-2,3-dimethylpyrrcIc'2 , 3-b'pyridine (200 mg, 0.9 mmol) and phenacyl bromide (200 mg, 1.3 mmcl) in 15 ml CH^CN was refluxed for 16h. The mixture was allowed to cool and the precipitated product filtered off and washed with a small volume of

2C diethyl ether affording 243 mg :.?2%) pure title compound as the hvdrcch1o ride.

i *H-NMR, 500 MHz, DMSO-dg). 2.2S(s,3H), 2.43(s,3H), 6.58's,2H), 7.68:t,2H), 7.31(t,lH), 8.09(d,2H), 3.84's,iH), 3.95 <'s, IH'- .

Example 48

- Zvano-z , 3 pnenaoy. pvrroio . 2 , i -p . cvnuine

A mixtuj cvridine i~7 mg, 0.5 mmcl' and phenacyl chloride (650 mg, 4.2 mmcl) in 12 ml CHyON was refluxed for 62 h. The mixcure was basified with a saturated NayTD, solution and extracted with CH^Cl·,. The organic layer was dried over MgSO^ and evaporated. The residue was chromatographed (silica,

CH.C1₉/diethyl ether;.3) yielding 34 mg (26%) pure title compound .

AP Ο Ο Ο 3 Ο 9 —33—

(DZ-MS, El at 70 (50), 146 :32:, 1	eV) m/z 289 (25), 35:100) .	260 (15), 171 (38),
CH-NMR, 300 MHz,	CDC13) 2.26(s,3H)	, 2.43(s,3H),
6.09(s,2H), 7.54·	t,2H), 7.68(t,lH),	7.75{d,lH), 7.89(d,
8.36( overlapping	signals ,2H).
Examcel 49

Preparation of 3-cyanomethyl-2-methyl-7-phenacylpyrrole :2,3-b¹ovn dine hydrochloride .

A solution of l.G g (5.8 mmol) of 3-cyano-met’nyl-2-methyl pyrrolo[2,3-b]pyridine and 1.03 g (7.0 mmol) of phenacyl chloride in 50 ml acetonitrile was refluxed for 14h. Working up in the same manner as described in example l⁷ gave 0,5 g 53% of the desired title compound.

^H-MMR, 3 00 MHz, DMSO-dg), 2.50{s,3H), 4.25(s,2H), 6.62(s,2H), 7.6-7.83(m,4H), 8.10(d,2H), 8.56(d,lH), 8.73 id,1H) .

Εχ3ΐΓιϋ1θ 50

Preparation of 3- (1-pyrazolo;methyl-2-methy1-7-phenacyl pyrrolo [2,3-b] cvridine .

A solution of 33 mg (0.14 mmol; of 3 - ,1-pyrazolo;methy1-2 methyl pyrrole]2,3-b]pyridine and 32 mg .0.21 mmol; cf phenacyl .ohlcride in 1 mi acetonitrile was refluxed fcr lih.The solvent was evapcraced and the crude product was created with acetonitrile and the product was isolated by filtration. The product was partitioned between methylene chloride and a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and the solvent was evaporated to give 18 mg (39%) of the title compound.

bad ORIGINAL Q 'J ORA

-34—

300 MHz, CD₃OD) , xHCl, 2.60(s,3H), 5.60(s,2H) 6.32<t,lH), o.42(b,2H), 7.5-7.8 f m, 6H! , 8.15(m,2H),

8.33'd,IH) , 3.49(d,IH) .

Example 51

Preparation cf 3-cyancmethyl-2-methyl-'-(4-f luorcphenacvl:

pyrrole ( 2 , 3-b( pyridine hydrochloride .

A scluticr. cf 75 mg (0.44 mmcl) of 3 - cyancmethyl-2methyIpyrrc1c [2, 3-bjpyridine and 99 mg (0.57 mmcl) of 4fiucrcchenacy1 chloride in 1 mi acetonitrile was refluxed for 48 h. The solvent was evaporated and the residue was treated with 0.4 ml aceconitrile. After filtration the solid was treated with 0,3 mi methanol and 0,4 mi acetonitrile to give 75 mg (55%) of the title compound.

^XH-.'O-S., 500 MHz, EMSC-dh, 2.50 s,3H , 4.25(3,OH', o

6.b2's,2H>, 7.53(m,lH), 7.75(m,lH), 8.20;dc,2H),

8.55(d,lH), 8.30(d,lH'.

Examp 1e 5 2

Preparaticn cf 2, 3-dimethy 1-7 ' 2-·· 2-acetaminochenyl)ethylipyrrole (2,3-bjcvridlne hydrobromlde.

A solution cf 73 mg -0,5 mmcl) 2,3 dimethyIpyrrc1cj2 , 3bjpyridine and 122 mg 0,5 mmcl) of (2rromceiny 1' acetan 11 tie m 2 mi acetonitrile was refluxed fcr 10 h. The -elven was evaporated and the crude endue was treated with 5 ml petroleum ether:ether 1:1 and the insoluble fraccicr. was treated with ether. The etheral layer was separated frcm the oily residue, which crystallized from acetronitrile and gave 15 mg -(7,7%) cf the title compound.

(H-NMR, 300 MHz, CTCl-j), 2.20(s,3H), 2.33(s,3H·,

2.42(s,3H), 3.38(t,2H), 5.08t,2H), 6.48(m,lK), 6.73(m,lH), 'J o¹

8^·

AP Ο Ο Ο 3 Ο 9

-357.98(m,ΙΗ), 7.23-7.35(m,2Η), 8.09(d,ΙΗ), 8.55(m,lH), 10.1(s,ΙΗ).

Example 53

Preparat ion of 2,3-dimethyl-7 (2.6-difluorophenacyl)pyrrolo

2,3-b]pyridine hydrobromide

A solution cf IDO mg (0.63 mmol) 2,3-dimethyIpyrrolo[2, 3 blpyridine and 133 mg (0.82 mmol) 2, 6-diflucrophenaoyi bromide in 2 ml acetonitrile were refluxed fcr 3 h. Working up in the same manner as described in example 17 gave 145 mg (54%) of the desired product.

,*H-NMR, 300 MHz, CDClj). 2.28{s,3H), 2.62(s,3H),

6.72is,2H), 7.07(m,2H), 7.38(m,lH), 7.58im,lH), 7.73(d,lH),

8.24'd,IH).

Example 54

Preparation of 3-thiocyano-2-methyl-7-phenacvlpyrroloΓ2,32C b] pvridine hydrochloride

Ul t hiocyanc-2 -methyl

A solution cf 100 mg (0.53 mmol) cf pyrrolo [2,3-blpyridine and 122 mg (0.79 mmol) of phenacyl chloride in 3 ml acetonitrile: dimethylformamide 2:1 was warmed at 70°C for 36 h. The reaction mixture was cooled tc room temperature and the acetonitrile was evaporated. To the residue was added 1j mi diethyl ether. The precipitated produc:

living was ti,tereo < :7 mo 2 3%; of and washed with acetcnitriie ;itie compcun:

-H-NMR, 300 MHz, DMSC-d_g>. 2.65 is, 3H) , 6.66 is, 2K) , 7.7 m, 2H), 7.-0-7.3 (m, 2H), 8.11 (d, 2H; , 3.68 (d, IH) , 8.85 d, IH) .

BAD ORIGINAL bv ϋ

-3 6Examp1e 55

Z-(p-bromopheny1)-3-methyl-7-phenacyl pyrrolo[2,3-b]pyridine

The title compound was prepared from 2 -(p-bromcpheny1)-3methvl-pyrrole-[2,3-b]pyridine and phenacyIbromide on a 1.7

	mmol seal	e accordi	ng co	the	procedure	described in example
	3 y i e 1 d i n	g 629 mg	C4%) .
- *s	;-H-.VME,	5 0 0 ΜΗ o ,	TTCl,:	. 2 .	55 is, 3H)	, 7.35 (s, 2 H) , 7.50
	it, 1H) ,	7.60 it,	ZH), 7	. 55	'd, ZH' , 7	.Ό (t, IH), 7.35 (m
	3 H; , 3.35	'id, 2H) ,	3.45	-* /	IH) .
	Example 56
X J	Methyl-d[	3-methyl-	7-chen	acvl	pvrrolo i 2	, 3-b] -pyridme-Z-vl j

The title compound was prepared from methyl-[p-(-3-mechylpyrrolo[2,3-b]-pyridine)-2jyl benzoate and phenacyIbromide or. a 9.4 mmol scale according to the procedure described in 45% .

2.55 (s, 3H>, 3.90 (s, 2H,, 6.15 55 im, 3 H; , 7.65 (m, 1H!, 3.0 'm, example 3 yielding ,_ mg (^:H-NMR, 300 MHz, CDCi,) (s, 2H), 6.90 it, IH), 3 H, 3.15 m, 2 H) .

-xamp.

The title compound was prepared from isoprcpyl-]p-:3meth.yl-pyrrolo [2 , 3-b]-pyridine'-2 Jyl benzoate and pher.acvIbromide on a 0.2 mmol scale according to the procedure described in example 8 yielding 25 mg (30%''.

AP Ο Ο Ο 3 Ο 9

(-H-NMR, 3	00 MHz,	CDC13). 1,	.35	(S, 3H) , 1,	.40	(s,	3H), 2.	.55
s, 3H), 5	.25 -'m,	IH) , 6.15	' s ,	2H), 6.35	(t,	IH)	, 7.55	(m
3H), 7.65	it, IH)	, 8.05 hm,	5H)	, 8.15 id,	2H)	,

Example 58

-Methyl-2 -pher.yl - ’’-phenacy 1 pvr rolo 12, 3 - b3 pyridine

The title ccmround was prepared from 3-methyl-2-phenylpyrrclo[2,3-b3pyridine and phenacyloromide on a 4 mmol scale according to the procedure described in example 8 yielding 1.33 a t 9”%; .

H-NM?., 501 MHz,

XI, .14

3H) .3:

(several overlapping signals, 3K), 7.~o (t, IH), 7 (overlapping d, 2H), 8.33 (overlapping d, id, IH), 7.93 2H), 8.39 (d, (p .H)

Example 59

3-Methyl-2-io-methyIphenvl)-phenacvlpyrrolo 3 2,3b'pvridine

The title compound was prepared from 3-methyi-2-(pmethylphenyl)-pyrrolo(2,3-b]pyridine and phenacyl bromide on a 3 mmol scale according to the procedure described in example 8 yielding 1.21 g (96%) .

Example 60

-'p-Methoxypheny1i-3-methyl-7-phenacvlpyrrolo'2,3b3 pvridine

The title compound was prepared from 2 -(p-methcxyphenyl)-3methyl-pyrrolo[2,3-b]pyridine and phenacylbrcmide on a 10 bad

ORIGINAL

	mmol scale according to the	procedure described in example
S yielding 4.	02 g	92%) .
	i:H-NMR, 300	MHz ,	cdci3	).2.	50 is, 3H), 3.33 (s, 3H), 7.00
q	id, 2K) , 7.36	f 5 ,	2H) ,	7.42	(dd, IH'. , 7.53 (t, 2H) , 7.63
	it, IH) , 7.32	id,	IH) ,	7.91	(d, 2H;, 3.33 (overlapping
	signals, 3H),	13.5	(b,	IH) .
	Example 61
	2 2-i^metyl-”	_ - r-	he nyl	- 2 -me	thexvimmeety 1) -pyrro lo i 2,3 -
	b'ovridme <E	ar.d	-T - — -CO	mers )

A mixture of 2,3-dimethyl-7-phenacylpyrrolo[2,3-b’pyridine hydrochloride <301 mg, 1 nrocl) and methoxylamine hydrochloride <460 mg, 5 mmol) in 3 ml MeOH and 4.5 ml pyridine was allowed to react for 5 days at room temperature. The methanol was evaporated and the residue partitioned between 150 mi CH2CI2 and 50 ml 2M HC1. The organic layer was collected, dried over MgSO^, and evaporated, Chromatography 'silica, Cr^CJ^/MeCH; 92.5/7.5 ) afforded 179 mg and 74 mg of each isomer, respectively.

Each isomer was dissolved in 100 mi CH2CI2 and washed with 20 ml 2M HCi, dried ever MgSO^, and evaporated leaving 193 mg 60%' tf is:mer 1 and ”0 mg '21%' of isomer 2. No attemets to establish the sterecchenistrv was cone at this

- E - NM?. 01 isomer ., 0 .. 0 MH 0 , C T C _ ; . 2.-/ ' 5, 1H , -.57 5, OH;, 4.10 s, OH;, 6.0 2 is, 2 H. , 6.71 ;t, 1H; , ”.27

IH' , 7.70 im, 2H; , 7.74 ·. d, IH) .

wit.n residua. 0HC.₃, -K) , .23 id, •H-NM?. of isomer 2, 300 MHz, CDCl₃<. 2.22 (s, 3H) , 2.60 <s, 2H), 7.13 it, IH), 7.31 (m, residual CHCI3, 3H), 7.77 (m, 2H) , , 3 K; , 3.36 ' s . 3 H , 6 lignais overlapping with '.35 ^;d, 1H), 7.98 (d, 1H;.

o'?⁵

AP Ο Ο Ο 3 ο 9

-3 9—

Examrle 62

-Chi oro-3 -cyancmethyl-7- ( 2 -phenyl -2 -bydroxyethyi) pyrrole [2,3 -b]oyridine

A solution of 2-chloro-3-cyancmethy1-7-phenacylpyrrolo(2,3bj pyridine (15 mg 0.C5 mmol) in 3 ml MeOH was treated with 13 mg NaHH^ and allowed to react for 30 min at room oemperature. The solvent was evaporated and the residue partioioned between CH₇C1- and water. The organic layer was separated, dried over and evaporated.

Chromatography on silica gel eluting with ether gave the desired product ;7 mg 46%).

300 MHz,

5.3 (dd, 7.95 (d, cd₃co IH) , 7 IH) , 8

4.0 .s, 2H) 05 (dd, IH), 2 (d, IH'

4.55 (dd, IH), 4.95 7.25-7.4 (m, 3H) , 7.5

Example 63

Preparation of 3-(cyanomethvl)-5-fluoro-2-methyl-723 phenacvlpyrrolo[2,3-b]pvridine hydrobromide

A mixture of 3-(cyancmethy1)-5-fluorc-2-methylpyrrolch2,3blpyridine (0.28 g, 1.5 mmol) and phenacyl bromide 0.32 g,

1.6 mmol) in acetonitrile (5 mi was refluxed under argon for 3 h, during which time the initial solution was transformed into a suspension. Then the suspension was coded m an ice bath, filtered and washed with diethyl ether 2x2 ml!. The crystalline product was purified by leerystailization from hot acetonitrile to give 0.52 g

93% of the title compound.

MS m/z (relative intensity) 307 (14, M*), 306(8), 27 2~8i22,, 105(100), 91(41), 77(9?;.

bad ι , ·.

-40—

Example 64

Preparation of 5-bromc-3-methyl-7-phenacyl·-2 phenyIpyrrolo[2,3-b]pyridine

5-3rcmc-5-methyl-2-phenyIpyrrolo[2, 2-b]pyridine (0.34 g,

1.2 mmol; and phenacyl bromide (0.49 g, 2.4 mmol) in acetonitrile (20 ml) was refluxed over night to give a clear solution. The cooled solution was alkalized with sodium carbonate solution (10%) and extracted with methylene chloride. Trying over MgSCu, filtration and evaporation of solvents gave a residue which was dissolved m the minimum amount of ethanol. Crystallization was driven to completeness by keeping crystals and mother liquor in the fridge for a few days. Peorystallization by

15	-3	issolving	in het ethanol and cooling	in the fri	dge	over
		' ;** Γ* C .-3 ’/ °	0.3 5 g (73%) of yellow cry	seals .
		free base	, 1H-NMP., 3 30 MHz, CCC13) 2	.50 is, 3H)	, 6 .	.12 (s,
		H) , 7.29	(dt, IH, Jx 7.5 Hz, J2 1Hz;	, 7.40 !t,	2H,	J7 Hz)
	-	.52-7.60	im, 3H) , 7.63-7.0 im, ih; ,	7.86-7.89	(m,	2H! ,
	3	Λ ' -5	H, J 2 Hz; , 3.12 (d, 2H, C	” Hz ) .

example 65

Preparation of 3-'cyanomethvl -7-phenacy1-2-phenvlpvrrolo '2 .3-b' p-yri dine

-\Cyanomethvl>-2-phenyIpvrro1c:2, 3-b\pyridine (0.3c g, 1.5

bjpyridine hydrebromide [0.46 g, 70% 'Ή-ΝΜΡ., 300 MHz, CMSC-d₅). 4.40 (s, 2H) , 6.68 (s, 2H) ,

AP Ο Ο Ο 3 Ο 9

-41Example 66

Preparation of 3 - joarbamoyimethvl)-7-phenacyl-2phenvipyrrclo[2. 3-bjpyridine hydrcbromide

-(Carbamoyimethy1)-2-phenyIpyrrolo [2,3-b]pyridine (0.35 g,

1.4 mmol! and phenacyl bromide )0.33 g) in acetonitrile (5 mi) were refluxed under argon for 3 h. The resulting yellow suspension was isolated by filtration (0.4 g) . The sparingly soluble raw product was dissolved in a mixture of methanol )20 ml 5 and methylene chloride (4 30 mi), loaded on a flash chromatography column SiC-/CH-Ci-:MeCH 96:4), and eluted with a) 1000 ml MeCK:CH₂Cl₂ 2.5:97.5; b) 1000 mi MeCH:CK'Ci-> 5:95; o 1000 mi MeCH :CH-Ci- 1:9 tc afford cure

-'o arbarneyImethy1)-7-phenacy1-2-chenvIpyrrolo[2,3b’.pvridine which was isolated as its hydrebremide (0.14 g, 22%· .

ree base, ¹H-NMr, 500 MHz, EMSC-dg) 3.70 's, 2H), 6.33 (s, 2H), 6.68-7.71 (t, 2H, J 7 Hz), 7.27 it, IH, J 7.5 Hz), 7.37 (t, 2H, J 7.5 Hz), 7.44 (br s, disappears on addition of E-O. , 7.64 it, 2H, J 8 Hz), .77 it, IH, J 7 Hz), 7.89 d, 2H, J 8 Hz), 8.01 (d, IH, J 6 Hz)', 3.17 (D, 2H, J 7.5 Hz) , 8.2 3 id, IH, J 7.5 Hz) .

Ex amp 1e 67 5 -Ch 1 c r o - 3-ovanome‘ hnv 1 - ~ - 2 -phenvl-2-hydroxyethvi

2, 3-b pvriomi

The title compound was prepared from 5-ohioro-3oyancmet hy1-2-methyl--phenacyipyrrolob[pyridine ) examp 1e 33’ and Na3H^ on a 0.33 mmol scale according to the procedure described in example 11. Chromatography cf the crude material (silica, CH₂Cl₂/MeOH ; 96/4) afforded 45 mg <42%) pure product.

tv j * j *

-42(*H-NMR, 300 MHz, CDCl^). 2.54 is, 3H), 3.78 (s, 2H) , 4.90 (m, 2H) , 5.30 (m, 1H) , 7.32 (coinciding signals, ^.95 (d, 1H) .

Example 68

Preparation of 3-cyancmethvl-2-methyl-7-(2,4diflucrcchenacy1)pyrrolo[2,3-b-pyridine

4.676H) ,

The title compound was prepared from III and 2-chioro2 ' , 4'-diflucrcaceto-phenone on a 2.3 mmol scale according to the procedure described in example 8 yielding 5~0 m.g i 6 5 % i .

;-H-NMR,

6.45 ¹m, 3.13 (m,

300 MHz, DMSO-d_g) . 2.50 ('s , 3H) , 4.25 (s, 2H' , 2H) , 7.40 (dt, 1H) , 7.65 (dt, 1H), 7.75 (t, 1H) , IK , 3.55 d, IK) , 3.33 ..d, IK) .

Example 69

Preparation of 3-cyancmethvl-2-methvl-7-(2m.ethcxyphenacyl) pyrrolo [2, 3-b'cvr idine

The title compound was prepared from III and w-brcmc-2methoxyacetophencne on a 4,2 mmol scale according to the procedure described in example 3 yielding 0.9 g (54%).

; ~ H - NM?, 3 4.25 >3, 2

MHz, DMSO-dg). 6.25 ..3, 2 H ,

7.9 0 dd, IK

3H!, 4.10 IK), 7.40

1H:, 3.3 : ci

r. x a mp e ,

Preparation of 3-ovancmethy1-2-methvl-7 hv droxvphenac'/1pyrrolo[2 , 3-b) pvr i dine

To a deaerated example 69 (3.6 BSr₃ in 0Κ-01₂ was stirred at solution of the g, 8.9 mmol) in (10 , 6 mmo I) wa s room temperature ccmpcund according to 60 mi ΟΗ₂Ο1₂ 10.6 ml of 1 M added dropwise. The solution for 3h and was then cou

J, L X CIi

APΟ Ο Ο 3 ο 9 —43 — intc 50 ml of 1 m NaHCO^. The water layer was extracted three times with 100 ml CH2CI2 ^and ''^r‘^e combined organic layers was washed once with 100 mi 2 m HCl. The organic layer was dried over Na2SO^ and evaporated. The residue was reorystallized from CH^CN affording 2,2 g (73%!.

·: * H-NMF.,	52 0	MHz, DMSO	-d6> ·	2.50 (s,	3H) ,	4.25 s,	.i
6.35 is.	2H)	, 7.0C (t,	1H) ,	7.22 ( ο,	LH) ,	7.60 o,	In
7 Γ j (t,	1H'	, 7.85 (d,	1H! ,	8.60 (d.	- U — * i , ,	8.75 id,	χ H

t r μ -*

-44—

The following Table 1 gives illustrative examples of compounds of toe invention

Table 1 Illustrative compounds of the invention

R²

R¹

AP Ο Ο Ο 3 Ο 9

8 8 & 2 ® « 2 U 2 5 s 8 fe 58 3 U fc 8 * 8

-45ΙΛ <η

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BAD ORIGINAL

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Example

βΜ⁵

S §> 5> «χ OPlQ'^^

AP Ο Ο Ο 3 Ο 9

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U. UL U.

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BAD ORIGINAL

-50The following examples illustrate intermediates useful in the preparation of compounds exemplified in the examples te

Examp1e I

Preparation of 3-[(dimethylamino)methyl]-2methyIpyrrolo[2,3-bi pyridine

A solution of 230 mg (1.5 mmol) 2-methyl-pyrrolo[2,3b]pyridine 200 mg «'2.5 mmol) dimethylaminnydrochloride and 73 mg (2.5 mmol paraformaldehyde in 2,5 ml methanol was refluxed for four days. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. To the residue was added 2 mi water and 2 ml methylene chloride and the pH was adjusted to 11 with 2 M sodium hydroxide. The organic layer was washed once with water dried over sodium sulfate and the solvent was evaporated to give 3.17 (60%) of title oompound.

(^:H-NMR, 500 MHz, CDC1₃) 3.55(s,2H;, 7.03(dd,lH),

2.25(s,6H), 2.50(s,3H), 7.92(d,1H), 8.31/dd,1H).

Example II

Preparation of 3-Htrimethvlamino)methyl 1pyrrolo[2,3-bi pyridine .

A solution of 163 mg (3.86 mmol) of Example Σ and 135 mg (3.95 mmol) cf methyliodide in 1 ml ethanol were stirred for 43 hours at room temperature. The solvent was evapcraced and the crude product 270 mg 35%) was used directly in the next step.

(¹H-NMR, 500MHz, DMSO-dg). 3.10(s,9H), 2.30(s,3H), 4.62(s,2H), 7.12(dd,lH), 8.08(d,lH), 8.19(d,lH).

_bAD oWeiNWAP Ο Ο Ο 3 Ο 9 —51—

Example III

Preparation of 3-cvanomethyl-2-methvlpyrrolof2,3-bl pyridine

To a solution of 270 mg (0.82 mmol) of Example II in 2,5 ml dimethylformamide was added 44 mg (0.90) mmol of sodium cyanide and heated at 100°C for 1,5 hours with stirring the reaction mixture was cooled to room temperature and partitioned between water and methylene chloride. The organic layer was dried over sodium sulfate and the solvent was evaporated to give 130 mg (98%) of the title compound.

Q (¹H-NMR, 500MHz, CDClj). 2.53(s,3H), 3.77(s,2H),

7.12<dd,lH), 7.92(dd,lH), 8.27(dd,lH).

Example IV , Preparation of 3-chloro-2-methyIpyrrolo[2,3-bi pyridine

To a solution of 0,7 g (5.3 mmol) of 2-methyIpyrrolo(2,320 blpyridine in 2,5 ml glacial acetic acid was added dropwise

0,8 g (5.9 mmol) of sulfuryl chloride at room temperature and with stirring. The reaction mixture was stirred for 1 hour. The solvent was evaporated and the residue was partitioned between methylene chloride and a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue was crystallized from ether : ethyl acetate, 5:1 to give 0,45 g (51%) of the title compound.

(¹H-NMR, 500MHz, CDClj). 2.50(s,3H), 7.12(dd,lH), 7.84(dd,lH), 8.25(dd,IH).

AP 0 0 ο 3 0 9 —52—

Example V

Preparation of 2-hydroxymethyl-3-methylpyrrolot2,3b)pvridine w

2,3-dimethylpyrrolot2,3-b)pyridine(0,2 g 0.0014 mol) was treated in 3 ml acetic acid with an equimolecular amount of bromine and after 5 min yellow precipitate was formed. The solid was filtered off and treated with 3 ml water for 60 min. The mixture was made alkaline with bicarbonate and extracted with methylene chloride. When the organic layer had been dried and evaporated the product was isolated as a yellow oil. (0,12 g, 53%).

(^XH-NMR, 300 MHz, CDCl-j). 2.2(s,3H), 4.7(s,2H), 7.0(dd,lH), 7.8(dd,lH), 8.25(dd,lH).

Example VI

Preparation of 2-chloro-3-methylpyrrolo(2,3-blpyridine

3-methylpyrrolo{2,3-b)pyridine (0,5 g 0.0038 mol) was treated in 2 ml acetic acid with an equimolecular amount of sulfuryl chloride at 0°C for 5 min. The mixture was allowed to warm to room temperature and was stirred for 5 min.

After evaporation the residue was dissolved in methylene chloride and was treated with bicarbonate. The organic layer was separated, dried and removed under reduced pressure. Chromatography on silica gel eluting with ethyl acetate gave the desired product. (0,18 g 29%).

(^XH-NMR, 300 MHz, CDClj).

7.75(dd,IH), 8.25(dd,IH).

2.25(s,3H), 7.05(dd,lH),

AP 0 0 0 3 0 9

-53Example VII

Preparation of 2,3-dimethyl-5-trifluoromethyIpyrrolo[2 ,3-b] pyridine

A mixture of 2-chloro-5-trifluoromethylpyridine (10 g 0.055 mol) and hydrazine mono hydrate (2,7 g, 0.055 mol) in 35 ml n-propanol was refluxed for 2 h and was then stirred 20 h at RT. To the solution was added 4,35 g (0.06 mol) methylethylketon and the mixture was refluxed for 30 min. After the solvent was removed under reduced pressure the residue was partitioned between methylene chloride and bicarbonate solution. The organic layer was dried over Na^SO^ and evaporated. The residue was solved in 80 ml diethylene glycol and refluxed for 5 h. The reaction mixture was poured into ice-water and extracted with methylene chloride. The organic layer was separated dried over and evaporated. The residue was treated with warm petroleumether (60-30) wich was decantated and evaporated chromatography twice on silica gel with 1 methylene chloride/ methanol 2 ethyl acetate, gave the desired product. (0,2 g 1.7%).

(¹H-NM?,, 300 MHz, CDCl-j). 2.3(s,3H), 2.45(s,3H), 8.0(s,lH), 8.5(s,IH) .

Example VIII

Preparation of 3-metncxy-2-methvlpyrrolc[2,3-b]pyridine.

A solution of 7,4 g (68 mmol) 2-hydrazinopyridine and 6,0 g (68 mmcl methcxyaceton in 50 mi of ethanol was refluxed for 1 h. The solvent was removed under reduced pressure.

The resulting oil was dissolved in diethylene glycol and refluxed for 1,5 h. The mixture was allowed to cool and was poured into ice-water. Extraction with methylene chloride gave an black oily residue which was treated with boiling petroleumether (60-80). After decanting the solvent was allowed to cool and the precipitated product filtered of BAD ORIGINAL

—54— affordi.ng 4,5 g (41%) pure title compound as a yellow so 1 id .

7.35(d,IH) , 8 .15(d,IH) .

Example IX

2- Chloro-3-cyanomet.hylpyrrolo[2,3-b]pyridine .

3- cyancmethyipyrrclo[2,3-b]pyridine (1,55 g, 0.098 mol) was treated in 5 ml acetic acid with an equimolecular amount of sulfurylchionde at 0°C for 5 min. The mixture was allowed to warm to room temperature and was stirred 5 min. After evaporation the residue was dissolved in methylen chloride and was treated with bicarbonate. The organic layer was separated, dried over Na^SO. and the solvent was removed under reduced pressure. Chromatography on silica gel eluting with ethyl acetate gave the desired product. (0,4 g i’H-NMR, 500 MKc, COCl^. 3.85(s,2H), 7.2(t,lH), 8.05(d,lH) , 8.4(d,IH) .

Example X

2-Methoxymethyl-3-methyIpyrrolo[2,3-blpyridine .

2,3-dimethyipyrrolc[2,3-b]pyridine 0,5 g (0.0034 mol) was treated in 7 ml acetic acid with an equimolecular amount cf bromine and after 5 min a yellow precipitate was formed.

The solid was filtred off and treated with 20 mi methanol. The mixture was refluxed for 30 min. and was then evaporated. The residue was partitioned between methylene chloride and bicarbonate solution. The organic layer was separated dried over Na₂SO^ and evaporated. The residue was treated with boiling petroleumether (60-80) which was decantated and allowed to cool. The precipitated product was filtred off affording 0,13 g (22%) as white so Ini. a.

APΟ Ο Ο 3 ο j —55— (¹H-NMR, 300 MHz, CDCl-j) . 2.3 (s, 3Η) , 3.4(S,3H), 4.65(s,2H), 7.05(dd,lH), 7.85(d,lH), 8.3{d,lH).

Example XI

Preparation of 6-bromo-2,3-dimethyl-pyrrolo[2,3-b]pyridine

A mixture of 2,6-dibromopyridine (47.4 g, 0.3 mol) and hydrazine mono hydrate (97.2 ml, 2.0 mol) in 400 ml propanol was refluxed for 19 h. The solvent was evaporated and the residue taken up in 1000 ml CHjClj. The organic layer was washed with 500 ml 5% Na₂CO₃ {reextraction with 500 + 250 + 250 ml CH₂C1₂), dried over MgSO^, and evaporated. The residue was recrystallized from 100 ml abs. EtOH leaving 30.0 g 2-bromo-6-hydrazinopyridine.

Reprocessing of the mother liquor gave additional 2.5 g. Yield 32,5 g (87%).

A suspension of 2-bromo-6-hydrazinopyridine (32,5 g, 0.17 mol) in abs EtOH was treated with ethyl methyl ketone (20ml, 0.22 mol) for lh at reflux. The reaction mixture was allowed to cool and treated with additional ethyl methyl ketone (10 + 3 + 1 ml) until all starting material had dissapeared according to TLC. The reaction mixture was taken up in 150 ml diethylene glycol and the EtOH evaporated at reduced pressure at 70°C. The remaining solution was deaerated and heated to reflux for 22h. The reaction mixture was cooled and paritioned between 1250 ml CH₂C1₂ and 1000 ml 2M HCI (reextracted with 250 ml CH₂C1₂). The organic layer was washed with further 500 ml 2M HCI and

500 ml H₂O, dried over MgSO^, and evaporated.

Chromatography (silica, CH₂Cl₂/diethyl ether ; 95/5) afforded 6 g 6-bromo-2,3-dimethyl-pyrrolo(2,3-blpyridine. Recrystallization from 120 ml abs EtOH gave 4,2 g (11%).

-56(¹H-NMR, 50 0 MHz, CDCl-j) 2.19(s,3H), 2.42(s,3H), 7.16(d,lH), 7.59(d,lH), 9.12(b,lH).

Example XII

Preparation of 2,3-dimethyl-6-methylthiopyrrolo[2,3b]pyridine

A deaerated solution of 6-bromo-2,3-dimethyl-pyrrolo[2,3-b] pyridine (225 mg, 1.0 mmol) in 25 ml dry THF was cooled to -78°C and treated with 1.6M n-BuLi in hexane (1,5 ml,

2.4 mmol). The reaction mixture was brought to 0°C and the lithiate trapped with dimethyl disulfide (444 μί, 5 mmol). After reacting for 5 min 1.5 ml H₃O was added and the THF evaporated. The residue was taken up in 100 ml and washed with 50 ml 5% NaHCO^, 50 ml 2M HCI {reextracted twice with 25 ml C^C^), and 50 ml 5% NaHCO^. The organic layer was dried over MgSO₄ and evaporated leaving 160 mg (83%) pure 2,3-dimethyl-6-methylthio-pyrrolo[2,3-b]pyridine.

(¹H-NMR, 500MHz, CDC1₃) 2.17(d,3H), 2.36(s,3H),

2.60(s,3H), 6.94(d,lH), 7.58(d,lH), 8.42(b,lH).

Example XIII

Preparation of 3-thiocyano-2-methvlpyrrolof2,3-b]pyridine

To a solution of 300 mg (2.36 mmol) of 2-methylpyrrolo[2,3 b] pyridine and 920 mg (11.3 mmol) in 5 ml acetic acid was added 450 mg (2.8 mmol) bromine in 1 ml acetic acid at 5°C. The reaction mixture was stirred for 30 min at 5°C and thereafter for 16 h at room temperature. The solid was filtered off. To the filtrate was added 20 ml water. The precipitated product was filtered off and washed with water giving 160 mg (37%) of the title compound.

(¹H-NMR 300 MHz DMSO-dg). 2.55(s,3H), 7.22(dd,lH),

7.97(dd,lH), 8.28(dd,lH), 12.5(s,lH).

AP 0 0 0 3 0 9

-57Example XIV

Preparation of 3-(l-pyrazolo)methvl-2-methvlpvrrolo(2,3blpyridine

To a solution of 95 mg (0.29 mmol) of 3[(trimethylammo- nio)-methyl]-pyrrolo(2,3-b]pyridine in 1,0 ml dimethylformamide was added 24 mg (0.35 mmol) of pyrazole and heated at 100°C for 1.5 hours with stirring. The reaction mixture was cooled to room temperature and partitioned between water and methylene chloride. The organic layer was dried over sodium sulfate and the solvent was evaporated to give 30 mg (48%) of the title compound.

¹H NMR (300 MHz, CDClj). 2.55{S,3H), 5.45(s,2H),

6.20(m,lH), 7.03(m,lH), 7.52(m,lH), 7.62(d,lH), 7.7(m,lH), 8.21(m,IH).

Example XV

5-Cyano-2,3-dimethyl-pyrrolo[2,3-blpyridine

An autoclave was charged with 5-bromo-2,3-dimethylpyrrolo [2, 3-b] pyridine (prepared in a similar manner as 6bromo-2,3-dimethyl-pyrrolo(2, 3-b]pyridine (247 mg, 1.1 mmol) and CuCN (135 mg. 1.5 mmol) . The mixture was covered with pyridine and heated to 220°C for 12 h. After cooling the raction mixture was poured into a mixture of FeClj' hexahydrate (0.9 g) , cone HCl (0.5 ml), and water (10 ini). The mixture was heated to 80°C for 1 h and extracted with CHjC^. The organic layer was washed four times with 2M HCl, dried over MgSO^ and evaporated leaving 77 mg (40%) 5cyano-2,3-dimethyl-pyrrolo[2,3-b]pyridine.

^H-NMF., 300 MHz, DMSO-dg) 2.18(s,3H), 2.35{s,3H),

8.32(d,lH), 8.45(d,lH).

►M

-58Example XVI

5-Chlorc-3-oyancmethy1-2-methyl-pyrrolo[2,3-b]pyridine

A mixture of 2,5-dichiorcpyridine (10.7 g, 0.07 mol) and hydrazine mono hydrate (34.0 ml, 0.7 mol) in 140 ml propanol was refluxed for 17h. The solvent was evaporated and the residue taken up in 500 ml C^C^. The organic layer was washed with 200 ml 5% NaHCO^ (reextraction with 100 ml C^C^), dried over MgSO^, and evaporated. The residue was recrystal1ized from 17 ml abs. EtOH leaving 4.7 g 5-chiorc-2-hydrazinopyridine. Reprocessing of the mother liquor gave additional 0.1 g. Yield 4.8 g (48%).

A mixture of 5-chlorc-2-hydrazinopyridine (4.9 g, 34 mmol) and a-(methyIthic) acetone (3.5 g, 34 mmol! in 10 ml abs EtOH was heated to reflux. The reaction mixture was allowed to cool and taken up in 30 ml diethylene glycol. The EtOH was evaporated at reduced pressure at 70°c and the remaining solution deaerated and heated to reflux for 1.5h. The reaction mixture was cooled and taken up in 500 ml

- The organic layer was washed twice with 400 mi H2O (each portion was reextracted with 100 ml C^C^), dried over MgSO^, and evaporated. The residue was filtered through silica eluting with ΟΗ2<212· Fractions containing product were pooled, a small volume of abs EtOH was added, and the evaporated. The precipitated 5-chlcrc-2methyl-3-methylthio-pyrrcio[2,3-b]pyridine was collected and washed with a small volume cf ligroine affording 1.5 g i'20%; pure product. Reprocessing cf the mother liqueur gave additonal material, 1.0 g (14%).

A deaerated solution of 5-chloro-2-methyl-3-methyithiopyrrolo[2,3-b]pyridine (1.1 g, 5.0 mmol) in 45 ml 1,4dioxane was heatet to 70° C and treated with small portions of Raney-Ni until all starting material had disappeared according to GC-MS,(total reaction time: 48h). The catalyst was filtered off and washed with several portions of 5% N^CO^ . Pure 5-c’nioro-2 -methyl-pyrrolo [2 , 3-b]pyridifieA ©AD⁰¹

AP Ο Ο Ο 3 Ο 9

-59appeared as a white precipitate in the filtrate and was collected. A second lot was obtained after evaporating the filtrate, dissolving it in 2M HCl, and carefully basifying the solution with Na^CO^. Yield 0.6 g (74%).

A mixture of 5-chloro-2-methyl-pyrrolo[2,3-b]pyridine (514 mg, 3.1 mmol), paraformaldehyde (102 mg, 3.4 mmol), and dimethylamonium hydrochloride (277 mg, 3.4 mmol), in 12 ml butanol was refluxed for 1.5h. Most of the solvent was evaporated and the remaining moist residue treated with ice cold diethyl ether. The precipitate was collected and dried leaving 707 mg (93%) of a 1:1 mixture of 5-chloro-3dimethylaminomethyl-2-methyl-pyrrolo[2,3-b]pyridine and the corresponding hydrochloride.

A 1:1 mixture of 5-chloro-3-dimethylaminomethyl-2methyl. pyrrolo(2,3-b]pyridine and the corresponding hydrochloride (674 mg, 140 mmol) and cone HCl (1.16 ml, 140 mmol) each 12h until all starting material had disappeared according to DI-MS. The reaction mixture was taken up in 200 ml 5%

Na₂CC>₃ and extracted twice with 200 ml CH₂C1₂. The combined organic layers were dried over MgSO^ and evaporated leaving 147 mg (26%) pure 5-chloro-3cyanomethyl-2-methyl-pyrrolo (2,3-b]pyridine.

(¹H-NMR, 500 MHz, CDCl-j) 2.51(s,3H), 3.72(s,2H),

7.87(d,lH), 8.21(d,lH), 9.16(b,lH).

Example XVII

2-(p-Bromophenyl·)-3-methyl-pvrrolo[2,3-b]pyridine

A mixture of 2-hydrazinopyridine (11.1 g, 0.10 mol) and pbromopropiophenone (25 g, 0.12 mol) in 85 ml 95% EtOH was refluxed for 12 h. Evaporation of the solvent afforded a quantitative yield of the corresponding hydrazone.

(DI-ms, El at 70 ev) m/z 303 (5), 274 (70), 183 (100), 155 (65) .

t ·»' '·* —60—

The residue was dissolved in 100 ml DEG, deaerated and violently refluxed in a nitrogen atmosphere for 6 h. The reaction mixture was allowed to cool and poured into 700 ml H₂O. The precipitated product was collected and reorystallized from EtOH affording 6.48 g (22%) of the desired product.

(¹H-NMR, 300 MHz, CDClj). 2.45 (s, 3H), 7.10 (dd, 1H), 7.50 (d, 2H), 7.65 (d, 2H), 7.90 (dd, 1H), 8.25 (d, 1H).

Example XVIII

2-(p-Carboxyphenyl)-3-methyl-pyrrolo[2,3-blpyridine ©

2-(p-Bromophenyl)-3-methyl-pyrrolo-[2,3-b]pyridine (1 g,

3.5 mmol) was dissolved in 200 ml dry THF, deaerated and cooled to -78° C. n-Butyllithium (5.19 ml, 8.4 mmol) was added dropwise and the mixture was allowed to reach room temperature CO₂ (g) was bubbled through the solution for 10 min.

Excess of n-butyllithium was destroyed with a small amount of water. The solvent was evaporated and the residue partitioned between 100 ml CH₂C1₂ and 100 ml 5% Na₂COj. The water layer was acidified (pH 2) with 2 M HCl. The precipitated product was filtred off and dried affording 0.38 g (44%) of the title compound.

(^H-NMR, 300 MHz, D₂O) . 2.35 (s, 3H) , 7.15 (bs, 1H) , 7.65 (d, 2H), 7.95 (m, 3H), 8.20 (bs, 1H).

Example XIX p-[3-methyl-pyrrolo[2,3-b]-pvridine-2lyl-benzoylchloride

2-(p-Carboxyphenyl)-3-methyl-pyrrolo-[2,3b]pyridine (1 g, 4 35 mmol) was dissolved in 20 ml thionyl chloride at 0° C. The solution was allowed to react at room temperature for 2 h. The solvent was evaporated. The residue was evaporated

AP 0 0 0 3 0 9

-61twice with CH₂C1₂ to remove excess of thionyl chloride to give quantitative yield of the title compound.

(^•H-NMR, 300 MHz, CDC1₃) 7 2.50 (s, 3H) , 7.40 (t, IH) , 7.80 (d, 2H), 8.20 (m, 3H) , 8.40 (d, IH).

Example XX methvl-[p-(3-methyl-pyrrolo[2,3-b] -pyridine)-2]yl benzoate p-(3-methyl-pyrrolo[2,3-b]-pyridine-2]yl benzoylchloride (0.41 g, 1.5 mmol) was chromatographed on silica gel (CH₂C1₂ : MeOH, 95:5) to give 0.28 g (69%) of the title compound.

(¹H-NMR, 300 MHz, CDCl-j). 2.50 (s, 3H) , 3.95 (s, 3H) , 7.10 (dd, IH), 7.75 (d, 2H), 7.95 (d, IH) , 8.15 (d, 2H), 8.20 (d, IH).

Example XXI

Isopropyl-fp(3-methyl-pyrrolo[2,3-b] -pyridine)-2]yl benzoate p-[3-Methyl-pyrrolo(2,3-b]-pyridine-2)yl benzoylchloride (1.1 g, 4 mmol) was dissolved in 20 ml CH₂C1₂. 2-Propanol (1.20, 20 mmol) and triethylamine (0.4 g, 4 mmol) was added and the mixture was allowed to react at room temperature for 24 h. The solvent was evaporated and the residue was purified by chromatography (silica, CH₂C1₂ : MeOH, 97:3) to give 102 mg (9%) of the title compound.

(¹H-NMR, 300 MHz, CDC1₃). 1.40 (s, 3H), 1.45 (s, 3H), 2.55 (s, 3H), 5.35 (m, IH), 7.10 (dd, IH) 7.85 (d, 2H), 7.95 (d, IH), 8.20 (m, 3H).

—62—

Example XXII

3-Methyl-2-phenylpyrrolo[2,3-blpyridine

A mixture of 1-hydrazinopyridine (21.8 g, 20 mmol) and propiophenone (29.3 g, 22 mmol) in 160 ml 95% EtOH was refluxed for 3 h. Evaporation of the solvent afforded a quantitative yield of the corresponding hydrazone.

(DI-MS, El at 70 eV) m/z 225 (8), 196 (100), 148 (15).

The residue was dissolved in 200 ml DEG, deaerated and violently refluxed in a nitrogen atmosphere for 4 h. The reaction mixture was allowed to cool overnight and poured into 1000 ml ^0. The precipitated product was collected and recrystallized from EtOH affording 18.4 g (44%) of the desired product.

(¹H-NMR, 500 MHz, CDCl-j). 2.49 (s, 3H), 7.07 (dd, IH), 7.42 (t, 1H), 7.55 (t, 2H), 7.73 (d, 2H), 7.91 (d, IH), 8.21 (d, IH), 11.38 (b, IH).

Example XXIII

3-Methyl-2-(p-methylphenyl)-pyrrolo[2,3-bi pyridine

The title compound was prepared on a 10 mmol scale following the procedure described in example XXII above. Yield 0.9 g (4%), (DI-MS, El at 70 eV of the hydrazone) m/z 239 (5), 210 (100), 148 (12).

(¹H-NMR, 500 MHz, CDCl-j of the title compound). 2.45 (s, 3H), 2.47 (s, 3H), 7.08 (dd, IH), 7.34 (d, 2H), 7.59 (d,

2H), 7.89 (dd, IH), 8.23 (dd, IH), 10.6 (b, IH).

AP Ο Ο Ο 3 Ο 9 —63—

C‘. Example XXIV

2-(p-Methoxyphenyl)-3-methyl-pyrrolo[2,3-blpyridine *

The title compound was prepared on a 20 mmol scale 5 following the procedure described in example XXII above.

Yield 6.0 g (13%). (DI-MS, El at 70 eV of the hydrazone^ m/z 255 (8), 226 (100), 211 (12).

(¹H-NMR, 500 MHz, CDC1₃ of the title compound). 2.45 (s,

3H), 3.90 (s, 3H), 7.06 (m, 3H), 7.63 (d, 2H), 7.87 (dd,

IH), 8.12 (dd, IH), 10.7 (b, IH).

Example XXV

Preparation of 5-fluoro-2hydrazinopyridine 15

A mixture of 2-chloro-5-fluropyridine (5 g, 0.038 mol) and hydrazine monohydrate (15 ml, 0.32 mol) in n-propanol (40 ml, in a teflon container was purged with argon and heated in a stainless steel bomb at 200°C for 19 h (magnetic stirring,. Evaporation of solvent and excess hydrazine monohydrate in vacuo gave a solid residue (5.9 g) which was dissolved in sodium bicarbonate solution (5%, and extracted with 6x50 ml ethyl acetate. The combined extracts were dried over anhydrous Na₂SO^, filtered and evaporated to give an oil (2.9 g) which proved difficult to purify and was therefore used as such in the next step. The crude product consisted of a ternary mixture of the desired product, 2-chloro-5-hydrazinopyridine, and 5- _ hydrazinopyridine.

(¹H-NMR, 500 MHz, DMSO-dg). 6.73 (dd, IH, 9 Hz, J₂ 3.5 Hz), 7.41 (td, IH, 9.5 Hz, J₂ ^{3 Hz)}' ⁷·^{95 (d}' ^1H' ^J1 ³ Hz)

-64—

Example XXVI

Preparation of 5-fluoro-2-methyl-3-methyltiopyrrolof2,3b]pyridine

A solution of crude 5-fluoro-2hydrazinopyridine (6.7 g, max. 0.053 mol) and (α-methyltio)acetone (6.04 g, 0.058 mol) in ethanol (99.5%, 15 ml) was heated to reflux for a couple of minutes and then evaporated under reduced pressure to afford an oil (11.5 g). A solution of the oil in diethylene glycol (50 ml) was heated at reflux temperature under argon for 8 h. The reaction mixture was cooled to room temperature, diluted with Νβ2θθβ solution (10%, 200 ml), and extracted with diethyl ether (200 ml) and methylene chloride (2x200 ml). The combined extracts were dried over anhydrous Na2SO^ and evaporated in vacuo to give an oil from which the title compound (0.22 g, 2%, two steps) was isolated by flash chromatography (SiO₂/MeOH:CH₂C1₂ 0, 1, and 2%).

MS m/z (relative intensity) 196 (100, M⁺), 181 (100), 137 (58) .

Example XXVII

Preparation of 5-fluoro-2-methvlpyrroloi2,3-blpyridine

Raney-Ni (10 g wet alloy, Aldrich W2, was washed with 10x50 ml deionized water and 5x40 ml dioxane) was suspended in a solution of 5-fluoro-2-methyl-3-methyltiopyrrolo[2, 3bjpyridine (0.5 g, 2.5 mmcl) in dioxane (50 ml). The reaction mixture was stirred under hydrogen for 43 h. More Raney-Ni (5 g wet) was added and stirring under hydrogen was continued over a weekend (69 h). Filtration through Celite and evaporation gave 0.24 g crude product.

Additional crude product (0.48 g) was isolated by Soxhlet extraction of the Raney-Ni. The crude prucuct was used in the next step without prior purification.

AP 0 0 0 3 0 9

-65MS m/z (relative intensity) 150 (75, M⁺), 149 (100), 122 (15).

Example XXVIII ~

Preparation of 3-(cyanomethvl)-5-fluoro-2-methylpyrrolo [2,3-blpyridine

Mannich reagent (0.8 ml, prepared according to Liebigs (1971) Ann. Chem., 743, 95-111, was added under stirring to pre-cooled (~78°C) 5-fluoro-2-methyIpyrrolo[2,3-b]pyridine (0.33 g, 2.2 mmol) under argon. The flask containing the reaction mixture was then placed in an ice bath and stirring was continued to give a white suspension. The ice lumps melted within 2 h and the resulting water bath was allowed attain room temperature. After 24 h almost all suspension had dissolved. The reaction mixture was cooled in an ice bath, diluted with deinionized water (8 ml) and extracted with diethyl ether (2 x 5 ml) to remove some remaining starting material and a by-product (propably the corresponding Mannich dimer). Sodium cyanide (1.08 g, 0.022 mol) was added to the water phase, assumed to contain 3(dimethylaminomethyl)-5-fluoro-2-methyIpyrrolo(2,3b]pyridine, and the resulting solution was refluxed for 2 h to afford a suspension which was isolated by filtration. Purification by flash chromatography (SiO₂/CH₂Cl₂:MeOH 19:1) gave 0.28 g (67%, two steps) of 3-(cyanomethyl)-5fluoro-2-methylpyrrolo[2,3-b]pyridine.

MS m/z (relative intensity) 189 (100, M⁺) , 188 (97), 174 (83), 163 (55), 162 (35), 147 (18), 121 (19).

Example XXIX

Preparation of 5-brcmo-2-hydrazinopyridine

Starting from 2,5-dibromopyridine the title conpound was prepared in the same fashion as 5-chloro-2hydrazinopyridine.

V .· 0 C RA

-66— (¹H-NMR, 300 MHz, CDClj). 3.78 (br s, 2H) , 5.83 (br s, IH) , 6.65 (d, IH, J 9 Hz), 7.54 (dd, IH, 9 Hz, J₂ 2.5 Hz),

8.14 (d, IH, J 2.5).

Example XXX

Preparation of 5-bromo-3-methyl-2-phenylpyrrolo[2.3b)pyridine

5-Bromo-2-hydrazinopyridine (15.6 g, 0.083 mol) and propiophenone (11.1 ml) was heated at 90°C (steam bath) for 30 min. Then toluene (100 ml) was added and the resulting solution was refluxed for 2 h to remove water by azeotropic distillation (Cean Stark apparatus). Evaporation of solvent gave 26.4 g of crude product, assumed to be the desired hydrazone. Crude hydrazone (3.02 g) was dissolved in diethylene glycol (30 ml) and heated at 245° C under argon for 24 h. The reaction mixture was poored crushed ice and extracted with methylene chloride. Drying over MgSO^ and evaporation of solvent left a tary residue which was triturated with diethyl ether to produce 0.84 g (30%) of a brownish, semi-crystalline product.

(¹H-NMR, 300 MHz, DMSO-dg). 2.50 (s, 3H) , 7.41 (t, IH, J 7 Hz), 7.52 (t, 2H, J 7 Hz), 7.71 (d, 2H, J 7 Hz), 8.23 (m,

2H) .

Example XXXI

Preparation of 2-phenylpyrrolo[2,3-b)pyridine

A mixture of acetophenone (28.2 g, 0.24 mcl) and 2hydrazincpyridine (25.7 g, 0.24 mol) was heated on a steam bath for 0.5 h. Toluene (200 ml) was added to give a solution which was refluxed for 2 h to remove water by azeotropic distillation (Dean Stark apparatus). Evaporation of solvent gave 55.4 g of crude product, assumed to be the desired hydrazone. The crude hydrazone was purified by distillation (Vigreux apparatus) to give a yellow oil (38.4

APO 00 3 0 9

-67C¹ g, 77%). Fresh hydrazone (18 g, 0.085 mol) was dissolved in tetraethylene glycol (180 ml) and refluxed under argon for

h. The reaction mixture was cooled, diluted with diethyl *

ether (250 ml) and water (250 ml) under stirring. The 5 phases were separated and the water phase was reextracted with diethyl ether (200 ml). The combined ether phases were dried over anhydrous sodium sulphate, filtered and evaporated to leave a black oil (14.9 g) which was further purified by kugel-rohr distillation, flash chromatography (SiO2/MeOH:CH2Cl2, first none methanol, then gradually more methanol to increase mobility) and recrystallization (methylene chloride) to afford 1.5 g of pure 2phenyIpyrrolo [2,3-blpyridine.

MS m/z (relative intensity) 195 (15, M+1), 194 (100, M⁺), 193 (20), 166 (12), 139 (10), 97 (21), 91 (18), 84 (11).

Example XXXII

Preparation of 3-(cvanomethyl)-2-phenyIpyrrolo[2.320 blpvridine

Aqueous formaldehyde (36%, 1.7 ml) was cooled (ice bath), then acetic acid (3 ml) and aqueous dimethylamine (40%, 2.5 ml) were added. That solution was kept at 0°C for 30 minutes before part of it (2.6 ml) was transfered to a precooled (-78°C) flask containing 2-phenyIpyrrolo[2,3b)pyridine under argon. After 5 min the temperature was changed to 0°C (ice bath) and it was allowed to reach room temperature within 2 h. Stirring of the resulting . 30 suspension was maintained for 110 h. Re-cooling to 0°C and addition of cooled deionized water (25 ml) and diethyl ether (7 ml) under stirring gave two phases which were separated. The organic phase was discarded since it was assumed to contain some remaining starting material and some Mannich dimer.

' v

68Sodium cyanide (3.6 g) was added to the water phase which was assumed to contain 3-(dimethylaminomethyl)-2phenylpyrrolo[2,3-b]pyridine. The mixture was refluxed for 3 h without any noticeable change in TLC apprearance (SiO₂/CH₂Cl₂:MeOH 19:1), indicating that the Mannich base was unchanged. 3-(Dimethylaminomethyl)-2-phenylpyrrolo[2,3b]pyridine was recovered from the reaction mixture by the following procedure. Water (25 ml) was added, solid material was filtered off, and filtrate was extracted with methylene chloride. The major part of the Mannich base was isolated from the filter cake by repeated washing with methylene chloride. The combined washings (3x100 ml), containing the sparingly soluble Mannich base, was dried and evaporated until precipitation just started. The saturated solution was loaded on a flash chromatography column (SiO₂/CH₂Cl₂, prepared in CH₂Cl₂:MeOH 9:1).

Recovered 3-(dimethylaminomethyl)-2-phenylpyrrolo(2,3 b]pyridine (1.26 g, 68%) was isolated by eluting with methylene chloride methanol mixtures (1.500 ml CH₂C1₂ ,-2.500 ml MeOH:CH₂Cl₂ 2:98,-3.500 ml MeOH:CH₂Cl₂ 4:96,-4.500 ml MeOH:CH₂CL₂ 8:92).

Ethyl iodide (1.94 g, 0.012 mol) was added to a solution of recovered Mannich base (1.25 g, 5 mmol) in methanol (10 ml). The solution was stirred under argon for 1.5 h. Then a solution of potassium cyanide (0.81 g, 0.012 mol) in deionized water (1.8 ml) was added. The reaction mixture was heated to reflux for 1 h. Solvents were evaporated and the resulting residue was diluted with water (10 ml) and extracted with ethyl acetate (3x10 ml). The combined extracts were dried (MgSO^) and evaporated in vacuo to give a solid which was purified by flash chromatography (SiO₂/CH₂Cl₂, elution with increasing amounts of methanol, se above) leaving pure title compound (0.85 g, 73%).

(^XH-NMR, 300 MHz, DMSO-dg). 4.18 (s, 2H), 7.17 (q, IH, J_x

7.5 Hz, J₂ 4.5 Hz), 7.43-7.51 (m, IH), 7.54-7.60 (m, 2H), _ΑΡ ο 0 0 3 0 9

-697.67-7.71 (m, 2H), 8.14 (dd, IH, J_x 7.5 Hz, J₂ 1.5 Hz),

8.30 (dd, IH, J! 4.5 Hz, J₂ 1.5 Hz).

Example XXXIII

Preparation of 3-(carbamoylmethvl)-2-phenylpyrrolo[2.3blpyridine

3-(Cyanomethyl)-2-phenylpyrrolo[2,3-b]pyridine (0.37 g,

1.39 mmol), powdered KOH (0.82 g), and t-butanol (5 ml) were heated to reflux under argon for 3 h. The reaction mixture was then cooled to room temperature and diluted with deionized water (6.5 ml) to give a precipitate. The suspension was extracted with methylene chloride and filtered. The filter cake consisted of pure title compound.

(¹H-NMR, 300MHz, DMSO-dg). 3.59 (s, 2H), 6.96-7.03 (m,

2H), 7.33-7.51 (m, 4H) , 7.79-7.84 (m, 2H), 8.13 (dd, IH, J_x

7.5 Hz, J₂ 1.5 Hz), 8.30 (dd, IH, J_x 4.5 Hz, J₂ 1.5 Hz).

For clinical use the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. The pharmaceutical formulation contains a compound of the invention in combination with a pharmaceutically acceptable carrier. The carrier may be in the form of a solid, semisolid or liquid diluent, or a capsule. These pharmaceutical preparations are a further object of the invention. Usually the amount of active compounds is between 0.1-95% by weight of the preparation, between 0.2-20% by weight in preparations for parenteral use and between 1 and 50% by weight in preparations for oral administration.

In the preparation of pharmaceutical formulations containing a compound of the present invention in the form of dosage units for oral administration the compound selected may be mixed with a solid, powdered carrier, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another t V t V V ?

—70—

F suitable carrier, as well as with lubricating agents such as magnesium stearate, calcium stearate, sodium steryl fumarate and polyethylene glycol waxes. The mixture is then processed into granules or pressed into tablets.

Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Hard gelatine capsules may contain granules of the active compound. Hard gelatine capsules may also contain the active compound in combination with a solid powdered carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, arnylopectin, cellulose derivatives or gelatine.

Dosage units for rectal administration may be prepared in the form of suppositories which contain the active substance mixed with a neutral fat base, or they may be prepared in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules, or they may be prepared in the form of a ready-made micro enema, or they may be prepared in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.

²⁵

Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing from 0.2% to 20% by weight of the active ingredient and the remainder consisting of sugar or sugaralcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use .

AP Ο Ο Ο 3 Ο 9

-71Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solven, preferably in a *

concentration from 0.1% to 10% by weight. These solutions 5 may also contain stabilizing unit dose ampoules or vials.

Solutions for parenteral administration may also be prepared as a dry preparation to by reconstituted with a suitable solvent extemporaneously before use.

The typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to

500 mg per day of active substance.

Pharmaceutical formulations containing a compound of the invention as active ingredient are illustrated in the following examples.

Example A. Syrup.

r25

A syrup containing 1% (weight per volume) of active substance was prepared from the following ingredients:

Compound according to Example 49 1.0 g Sugar, powder 30.0 g Saccharine 0.6 g Glycerol 5.0 g Flavouring agent 0.05 g Ethanol 96% 5.0 g Distilled water q.s. to a final volume of 100 ml

Sugar and saccharine were dissolved in 60 g of warm water. After cooling the acid addition salt was dissolved in the sugar solution and glycerol and a solution of flavouring agents dissolved in ethanol were added. The mixture was diluted with water to a final volume of 100 ml.

-72The above given active substance may be replaced with other pharmaceutically acceptable acid addition salts.

Formulation B. Tablets

A tablet containing 50 mg of active compound was prepared from the following ingredients:

I Compound according to Example 49 500 g

Lactose 700 g

Methyl cellulose 6 g

Polyvinylpyrrolidone cross-linked 50 g

Magnesium stearate 15 g

Sodium carbonate 6 g

Distilled water q.s.

II Hydroxypropyl methylcellulose 36 g

Polyethylene glycol 9 g

Colour Titanium dioxide 4 g

Purified water 313 g

I Compound according to example 49, powder, was mixed with lactose and granulated with a water solution of methyl cellulose and sodium carbonate. The wet mass was forced through a sieve and the granulate dried in an oven. After drying, the granulate was mixed with polyvinylpyrrolidone and magnesium stearate. The dry mixture was pressed into tablet cores (10 000 tablets), each tablet containing 50 mg of aorive substance, in a tabletting machine using 7 mm diameter punches .

II A solution of hydroxypropyl methylcellulose and polyethylene glycol in purified water was prepared. After dispersion of titanium dioxide the solution was sprayed onto the tablets I in an Accela Cota®, Manesty coating equipment. A final tablet weight of 175 mg was obtained.

AP 0 0 0 3 0 9

-73Formulation C. Solution for lot ravenous administration λ parenteral formulation. for intravenous use, containing 4 mg of active compound per ml, was prepared from the following ingredients:

Compound according to Example 49 Polyethylene glycol 400 for injection Disodium hydrogen phosphate Sterile water to a final colume of g 400 g q.s.

1.000 ml

Compound according to Example 49 was dissolved in polyethylene glycol 400 and 550 ml of water was added. pH of the solution was brought to pH 7.4 by adding a water solution of disodium hydrogen phosphate and water was added to a final volume of 1000 ml. The solution was filtered through a 0.22 pm filter and immediately despensed into 10 ml sterile ampoules. The ampoules were sealed.

Biological tests

A. Inhibiting effect In vitro on acid secretion in isolated rabbit gastric glands was measured as described by Berqlindh et al.<1976). Acta physiol, soand., 97, 401-414.

Most of the compounds in Table 1 had an ICjq value in the range of 0,2-100 pM.

B. Inhibiting effect in vivo on acid secretion in conscious female rat was measured according to the following method:

Female rats of the Sprague-Dawley strain were used. They were equipped with cannulated fistulae in the stomach (lumen) and the upper part of the duodenum, for collection of gastric secretions and administration of test substances, respectively. A fourteen days recovery period after surgery was allowed before testing commenced.

	‘ n T sa
	—74—
5	Before secretory tests, the animals were deprived of food but not water for 20 h. The stomach was repeatedly washed through the gastric cannula with tapwater (37*C), and 6 ml of Ringer-Glucose given s.c. Acid secretion was stimulated with infusion during 3.0 h (1,2 ml/h, s.c.) of pentagastrin and carbachol (20 and 110 nrool/kg h, respectively), during which time gastric secretions were collected in 30-min fractions. Test substances or vehicle were given iv or id at 60 min after starting the stimulation, in a volume of 1
10	ml/kg. Gastric juice samples were titrated to pH 7.0 with NaOH, 0.1 mol/L, and acid output calculated as the product of titrant volume and concentration. Further calculations
15	were based on group mean responses from 4-5 rats. The acid output during the periods after administration of test substances or vehicle were expressed as fractional responses, setting the acid output in the 30-min period preceding administration to 1.0. Percentage inhibition was calculated from the fractional responses elicited by test compound and vehicle. BD>o-values were obtained from
20	graphical interpolation on log dose-response curves, or estimated from single-dose experiments assuming a similar slope for all dose-response curves. The results are based on gastric acid secretion during two hours after drug/vehicle administration.
25	The compound according to Example 49 had after id administration an ED5O value of 2 ymol/kg.
30	The compound according to Example 63 had after iv administration an EDSO value of 1.3 umol/kg.

AP 0 0 0 3 0 9 €·

Claims (36)

1. A compound of the formula I wherein

0-R⁶ N-O-R⁶

I II

II

X represents -C-, -CH-, -C-, or -CH--;

1 7^

R represents H, lower alkyl, CH₂~O-R ' halogen, phenyl or phenyl substituted with (1-6C) alkyl, (1-6C) alkoxy, (1-6C) acyl, halogen, CF3, CN, NH₂, NO₂, or (1-6C) alkoxycarbony1;

2 U

R represents H, lower alkyl, CH₂CN, CH₂C-NH₂, halogen, fl /

O-R , CH--N

N, s-cn, ch₂oh, ch₂csch, cf₃,ch₂nc or

NH,;

3 g

R represents H, lower alkyl, CFj, 0-R , NH_2> lower alkylamino, di-lower alkylamino, halogen, CN, S-R¹⁰, S-R¹⁰, or NHCOR¹⁰:

R⁴ and R⁵, which are the same or different, represent H, lower alkyl, CN, halogen, 0-R¹¹, NO₂, NH₂, lower

- 76 aikvlamino, dr-lower alkylamino, S-R¹², NHCOR¹³, NHCOR¹^, ’ li

0 0 ¹¹ 15

CF, or C-R ;

¢:^7 q q ii 13

R , R , R , R ' R and R which are the same or different, represent H or lower alkyl;

r¹⁰ represents lower alkyl or phenyl lower alkyl; r!2, _r13 _r14, _which _are the same or different, represent Lower alkyl;

r¹⁵ reoresents H, lower alkyl, OH or lower alkoxy;

1 2 provided that R and R are not simultaneously H, or a pharmaceutically acceptable salt thereof.

2. A compound according to

-CH-, or -CHI 6 ^Z O-R and R is H claim 1 wherein X is -CO-, or (1-60 alkyl.

3. A compound according to claim 1 wherein R¹ is (1-60 7 alkyl, optionally substituted phenyl, -CH_o0R , or halogen, 7 wherein R is H or (1-60 alkyl.

4. A compound according to claim 1 wherein R is H, alkyl, -CH₂CsCH, -CH₂OH, -CH₂CN, -CH₂CONH_2< -CHjNC, (1-6C)

-nh₂.

-SON, halogen, or -CF^.

5. A compound according to claim 1 wherein R^ is H, (1-6C) alkyl, -OR^{6 * * 9}, -NH₂, (1-60 alkyl-amino, (1-60 dialkylamino, CN, -SR^O, halogen, -CF,, or -NHCCR¹^ wherein R^ is H or 10 J (l-6C)alkyl, and R is (l-6Oalkyl or phenyl-(1-60-alkyl.

6. A compound according to claim 1 wherein R^ and R^ are the same or different and selected from H, (1-60 alkyl, CN, halogen, -OR¹¹, -NO₂, ^2' (1-60 alkylamino, (160 dialkylamino, -SR¹², -NHCOR¹³, -CF-j, or -COR¹⁵, wherein

R¹¹ is H or (l-6C)alkyl, R¹² is (1-6C) alkyl, R¹³ is H or (1-60 alkyl and R¹⁵ is H, (l-6C)alkyl, CH, or (1-6C) alkoxy .

_0ADOWO'^NAV

AP 0 0 0 3 0 9 —77—

7. A compound according to claim 1 wherein X is as defined

1 2 m claim 2, R is as defined in claim 3, R is as defined

3 4 5 in claim 4, R is as defined in claim 5, and R and R are as defined in claim 6. *

8. A compound according to claim 1 wherein X is -CO-, -CH(OH)-, -CH(OCH₃)-, -CH{OC₂H₅)-, or -CHj-.

9. A compound according to claim 1 wherein R^ is CH^, C₂H^, CH(CH₃)₂, (CH₂)₂CH₃, Cl, Br, or phenyl.

10. A compound according to claim 1 wherein R is H, CH^, C₂H₅, CH₂CN, CH₂CONH₂, F, Cl, Br, -SCN, CH₂OH, CH^aCH,

CF₃, or CH₂NC.

11. A compound according to claim 1 wherein R^ is H, CH₃, c₂h₅, ch(ch₃)₂, (ch₂)₂ch₃, cf₃, oh, och₃, oc₂h₅, och(ch₃)₂, NH₂, NHCH₃, NHC₂H₅, N(CH₃)₂, N(C₂H₅)₂, F, Cl, Br, SCH₃, SC₂H₅, S-CH₂CH₂ , or NHCOCHj.

4 5

12. A confound according to claim 1 wherein R and R, which are the same or different, are selected from H, CH₃, CjH^, CH(CH₃)₂, F, Cl, Br, OH, OCHj, OC^, OCHfCH.^, NOj, ΝΗ₂, nhch₃, nhc₂h₅, n(ch₃)₂, n(c₂h₅)₂, sch₃, or cf₃.

13. A compound according to claim 1 wherein X is as defined

1 2 m claim 8, R is as defined in claim 9, R is as defined in claim 10, R^ is as defined in claim 11, and R^ and R^ are as defined in claim 12.

<·· ύ .. SA

- 78

14. A compound of the formula or a pharmaceutically acceptable salt thereof.

15. A compound of the formula or a pharmaceutically acceptable salt thereof.

AP Ο Ο Ο 3 Ο 9

79 16. A compound of the formula or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt thereof.

bad original Q

- 80 13. A compound of the formula or a pharmaceutically acceptable salt thereof.

19. A compound of the formula or a pharmaceutically acceptable salt thereof.

AP Ο Ο Ο 3 Ο 9

20. A compound of the formula or a pharmaceutically acceptable salt thereof.

21. A compound of the formula _b#D0W®’^nW· =¹ or a pharmaceutically acceptable salt thereof.

- 32

22. A compound of the forftula ch₂cn ch₃ or a pharmaceutically acceptable salt thereof.

23 .

the formula

A compound of or a pharmaceutically acceptable salt thereof.

AP Ο Ο Ο 3 Ο 9

24. A compound of the formula <Γ·· or a pharmaceutically acceptable salt thereof.

25. A compound of the formula or a pharmaceutically acceptable salt thereof.

gAP original

- 34

26. A compound of the formult or a pharmaceutically acceptable salt thereof.

27. A compound of the formula

CHgCN or a pharmaceutically acceptable salt thereof.

AP Ο 00 30 9

28. A compound of the formula or a pharmaceutically acceptable salt thereof.

29. A compound of the formula or a pharmaceutically acceptable salt thereof.

OftGtt**¹» »·- 86 - or a pharmaceutically acceptable salt thereof.

31. A pharmaceutical composition containing as active ingredient a compound according to any one of claims 1-30.

5

32. A pharmaceutical composition according to claim 31 substantially as hereinbefore described.

33. A compound as defined in any of claims 1-30 for use in therapy.

34. A compound as defined in any of claims 1-30 for use 10 in inhibiting gastric acid secretion in mammals and man.

35. A compound as defined in any of claims 1-30 for use in the treatment of gastrointestinal inflammatory diseases in mammals and man.

36. The use of a compound according to any of claims 115 30 in the manufacture of a medicament for inhibiting gastric acid secretion in mammals and man.

37.

The use of a compound according to any of claims 1-

AP Ο Ο Ο 3 Ο 9

- 87 30 in the manufacture of a medicament for the treatment of gastrointestinal inflammatgry diseases in mammals and man.

38. A process for the preparation of a compound as claimed in any of claims 1 to 30 which process comprises:

5 A. reacting a compound of the formula II in which formulas X, R³·, R², R³, R⁴ and R⁵ are as defined 10 in claim 1 and Y is a leaving group such as a halide, tosyloxy or mesyloxy;

B. to prepare a compound of the formula I wherein R³·, R², R³, R⁴, and R^ are as defined in claim 1 and X is CHOH, reducing a compound as claimed in claim 1 wherein X is CO;

15 C. to prepare a compound of the formula I wherein R² is OH and R³·, R³, R⁴ , R⁵ and X are as defined in claim 1, reacting a compound of the formula I, wherein R³·, R³ , R⁴ ,

R⁵ and X are as defined in claim 1 and R² is -O(1-6C)alkyl, with a dealkylation agent;

BAD

ORIGINAL

D. to prepare a compound of the formula I, wherein R¹, R² , R³, R⁴ and R⁵ are as defined in claim 1 and wherein X is -CHOROH⁶, R^ being as defined in claim 1, reacting a compound of the formula I, wherein R¹, R², R³,

5 R⁴, and R⁵ are as defined in claim 1 and X is -CH(OR⁶)-, R⁶ being as defined in claim 1, with a compound of the formula IV

R⁶ - Ζ IV

I—

L. wherein R⁶ is as defined in claim 1 and Z is a reactive

10 esterified hydroxy group; or

E. to prepare a compound of the formula I wherein X, R¹,

R², and R³ are as defined in claim 1, R⁴ is OH in position 2, and R⁵ is different from R⁴ , reacting a compound of the formula I, wherein X, R¹, R² and 15 R³ are as defined in claim 1, R⁴ is -O(C1-C6)- alkyl, and

R⁵ is different from R⁴, with a dealkylation agent;

whereafter the compound cf the formula I thus obtained if desired is converted to a pharmaceutically acceptable salt.

39. A process for preparing a compound as claimed in

20 claim 1 substantially as described in any one of Examples 1 to 70.

40. A compound as claimed in claim 1 prepared by the process claimed in claim 38 or 39.

sp

AP Ο Ο Ο 3 Ο 9

- 89 ABSTRACT

NOVEL PYRROLOPYRIDINES, PHARMACEUTICAL COMPOSITIONS

CONTAINING THEM AND THEIR PREPARATION

New Pharmaceutically active compounds of the

5 formula wherein

0 O-R⁶ N-O-R⁶

II I U

X represents -C-, -CH-, -C-, or -CH.,-;

R represents H, lower alkyl, CH₂-O-R ' halogen, phenyl or phenyl substituted with (l-6c) alkyl, (l-6c) alkoxy, (l-6c) acyl, halogen, CF₃, CN, NH-, NO₂, or (l-6c) alkoxycarbonyl' ^z O

2 ¹¹ R represents H, lower alkyl, CH₂CN, CHjC-NH^, halogen,

N— q /

O-R°, ^z >_

NH-;

R represents H, , S-CN, ch₂oh, ch₂csch, cf₃,ch₂nc or lower

Q lower alkyl, CF^, O-R , NH₂, original

V' ·. ’ ‘ ' ‘'i+A

Γ'

90 . 0 alkylamino, di-lcwer alkylamino, halogen, CN, S-ΐόθ, S-R^, or NHCOR¹⁰;

R.4 and r5, which are the same or lower alkyl, CN, halogen, O-R^, alkylammc, ii-lower alkylamino, different, represent H, NC^, N^, lower

S-R¹², NHCOR¹³, NHCOR¹⁴,

II ¹¹ 5

CF, or C-R ;

6^J7 3 9 il 13

R , R , R , R ’ R and R which are the same or different, represent H or lower alkyl;

R¹⁰ represents lower alkyl or phenyl lower alkyl; R¹², R¹² and R¹⁴, which are the same or different, represent lower alkyl;

R¹⁵ represents H, lower alkyl, OH or lower alkoxy;

1 2 provided that R and R are not simultaneously H_z and their pharmaceutically acceptable salts inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the prevention and treatment of peptic ulcers.