DE2245929A1 - AZAINDES - Google Patents

Description

Dr. Ing.Walter Abitz

Dr. Dieter hrforf ■ ", ■ ..

Dr. Shark-A. Browns.

8 Munich ου, ri ~ uzo;> aueistr. 28.

MERCK & GO., INC.

126 East Lincoln Avenue, Rahway, New Jersey 07065,

V.S.A.

Azaindenes

The present invention relates to new azaindene compounds, especially those azaindenes in which the aza function Substituted in the 4-, 5- »" 6- or 7-position is. The present invention particularly relates to a-i-aralkylidene-azaindene-J-lower aliphatic acids and their salts, amides and esters. The preferred azainden class form the 4-- ', 5-j 6- and 7-azaindene compounds the formula:

(A)

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in which (a), (b), (c) and (d) each denote C or N, only one of the mentioned symbols (a), (b), (c) and (d) standing for N at any one time. Also mean in the formula above:

Ar aryl;

IL · alkylsulfinyl or alkylsulfonyl;

H ^1,. Hydrogen, halogen, hydroxy, alkoxy, haloalkyl, alkylthio, arylsulfinyl, alkylsulfonyl, haloalkyleneoxy, haloalkylene thio, haloalkylene sulfinyl, cyano, mercapto or sulfonamido;

B _{2 is} hydrogen, alkyl, aralkyl, aryl, heteroaryl, halogen, hydroxy, alkoxy, haloalkyl, alkylthio or arylthio j

B, hydrogen, lower alkyl, halogen-lower alkyl, fluorine, amino, acylamino, di alkylamino, N-morpholino, alkenyl, aralkylthio, hydroxy or alkoxy or together with Β ¹ , a methylene group}

B ¹ , hydrogen or together with B, a methylene group; B ^ ,, B ₁ - and R- each hydrogen, alkyl, alkoxy, nitro, amino, acylamino, alkylamino, dialkylamino, dialkylaminoalkyl, sulfamyl, alkylthio, mercapto, alkylsulfinyl, alkylsulfonyl, halogen, cyano, carboxyl, carbalkoxy, carbamido, aryl , Haloalkyl, alkenyloxy, aralkyloxy, alkenyl, aryloxy, cycloalkyl or cycloalkyloxy and

M hydroxy, lower alkoxy, substituted lower alkoxy, Amino, alkylamino, dialkylamino, N-morpholino, Hydroxyalkylamino, aminoalkylamino or the group OMe, where Me stands for a cation. The 2,3-dihydro derivatives of the compounds mentioned are also included.

The azaindene compounds described above have a high level of anti-inflammatory activity. they are in the treatment of arthritic and dermatological

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Disturbances or the like. Conditions that respond to anti-inflammatory remedies are of value. The azaindenes also have useful levels of analgesic and anti-pyretic activity. Be for these purposes the compounds of the invention normally orally administered in tablets or capsules. The optimal dose depends on the particular compound used and the nature and severity of the condition being treated. Oral dosage levels on the order of 10 to 2000 mg daily is useful for managing the conditions indicated above. The connections can be made with the common, pharmaceutically acceptable carriers for the manufacture of tablets or capsules are mixed. she can also be applied locally, rectally or parenterally, using conventional adjuvants, vehicles and carriers, which are familiar to the specialist, can be used when preparing such preparations. Also here again Dosages on the order of 10 to 2000 mg per day have proven effective. Out with the treatment of warm-blooded animals, such as mice, hats, etc., are the Anti-inflammatory compounds also effective in treating people. Preferred dosages in the treatment of humans and animals range from 3 to 100 mg per kg of body weight per day, depending on the specific compound used and the nature and severity of the condition treated

The compounds used in the process according to the invention are oc-i-aralkylidene-azaindene-J-aliphatic Acids. In particular, they are compounds of the formula (A) given above. The substituents in the 1-position are aralkylidene groups that are different from aromatic aldehydes derive which have an alkylsulfenyl or alkylsulphonyl substituent exhibit. A number of substituents, such as Alkyl, aralkyl, aryl, alkoxy ^ arylthio, nitro, amino, di-

- 3 -309813/1 170

alkylamino, etc., or the 2-position can be unsubstituted, in which case Rp has a different meaning than should have hydrogen.

Since these compounds are azaindenyl-3-aliphatic acids, the 3-position must have an aliphatic acid side chain have, and the azaindenyl nucleus must be on the a-carbon atom the aliphatic acid sit. Usually there is an acetic acid or propionic acid side chain other low-aliphatic acid side chains, such as ß, ß, ß-trifluoro-a-indenylpropionic acids, Alkenoic acids and higher alkanoic acids as well as other aliphatic acids, like Cyclopropanecarboxylic acids, however, can also be used.

The pyridine ring of the azaindene nucleus can have 1 to 3 ßubetituenten carry, preferably hydrogen, alkyl, alkoxy, nitrogen and sulfur derivatives or various functional parts Carboxylic acid derivatives as listed above and are described below. Important only the free acids, but also the esters, amides and salts encompassed within the scope of the present invention.

The compounds of the invention can be used in a variety of ways are produced by working methods. The starting material for one of the methods used in the practical implementation of the present invention can be represented as follows:

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0OR

H ₂ CH (CO ₂ R) ₂ (1)

This connection is known and can after the in Jour. At the. Chem. Soc. 77, (1955) »page 1055» stated procedure using starting materials and intermediates which are known to the person skilled in the art.

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14378

COOR

Br (Cl)

or

/TT.Org. Chem'l CH, 19 (1954), H ° page 1827

.COOR

(for

J.Med.Chem.

(H)

(III)

COOR

COOR

(III) or (IV)

(V)

COOR

CH ₂ Br

(VI)

COOR

CH ₂ C (CO ₂ R) ₂

(VIII)

COOR

HZ '™ "CH ₂ C (COOR) ₂

(VII)

COOR

CH ₂ C (CO ₂ R) ₂

(IX)

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Equivalents:

Z = halogen (Cl, Br, F)

R = esterification group (usually methyl, ethyl or

Benzyl)
Eg has the meaning defined above (other than

Hydrogen and halogen)
Ec has the meaning defined above (including what-.

hydrogen and halogen).

Reagents:

(1) POCl ,, 120 ° C, 4 hours, pouring into crushed Ice cream / jour. Org.Chenu £ 1, (1954-), page 18 ^ 7,

(2) N-bromosuccinimide, benzoyl peroxide, CCl ^, reflux / Jour. Org. Chem. 1 ^., (1954), page 18JT,

(3) 3Yes salt of diethyl malonate, anhydrous benzene, Ice water, concentrated HCl

£ tour. Amer. Chem. Soc. 2Z »0955) ι page 1OJ57,

(4) H ₂ , palladium on charcoal, 3.16 kg / cm ² (45 psi), room temperature,

(5) Potassium methyl thiolate, room temperature, reflux, Filter

It can therefore be seen that the starting material (I) through the compounds (VII) / E ₆ = halogen /; (VIII) YR ₆ = hydrogen ?; and (IX) (R ₆ = has a meaning other than halogen and hydrogen? is represented.

The compounds of the present invention are as follows manufactured: ,

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14578

Flow diagram II

(a) Preparation of compounds according to the invention, at which IL- is as defined above (it has a different meaning than halogen):

COOE

(VIII, IX)

^(XVI)

14578

(b) If Rg is halogen, the reaction proceeds as follows:

halogen

XI-a

XI-b

OH

halogen

R.

.10

Rt

Halogen S ^ iK

XIVa R,

5 \

Halogen <

^ HCO ₂ E

DH

R,

XVIa

s ^ ^ß 1

Nb ¹

or in general

halogen

■ h

2 halogen

XVa

T ^

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Equivalents : f

R, R-, R'yj »Ro» ß * »Bc ¹ ^ d Rg have the meanings given above.

E = esterification group, usually methyl, ethyl or benzyl.

Reagents:

(6) NaH, benzene under Np, boiling under reflux, cooling, the benzene layer is separated off and dried. / Jour. Amer. Chem. 3oc. 22 »(1955)» S · 10? S7

(7) MeJ, NaOEt, reflux, the solvent is evaporated.

(Rp β CH, -). When using this same working method

one will use benzyibromide to obtain Rp = // V ^ -CH _{2 -.} \ - ■ / ;

(8a) HCL

(8b) POCl ₅ . .

(9) Reformatsky reaction, Zn in an inert solvent, Heat.

(10) P ₂ O ₅

(11) Reaction with aldehyde or ketone, using a strong base as a catalyst (K-tert.-butoxide or any alkoxide, NaOH, KOH, NaNHp etc.), heating, if necessary for the formation of the carbanion, in solvents such as liquid ammonia, dimethylformamide, 1,2-dimethoxyethane, pyridine or aqueous alcohol.

(12) The ester is used to obtain the free acid (E «OH) treated with KOH, heated, added HCl until acidic, and cooled. It it should be noted that salts, other esters and amides can be removed from the free acid using methods that belong to the known state of the art can be.

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(c) It should be noted that the "preparation of those azaindenes in which R ^, R ₁ - and Rg are hydrogen, starting from the compound (XIII-a) ^ R ₁ - = # 7" are carried out by the following procedure can:

Halogen'

EAR

9a means H ₂ , palladium on charcoal, 3.16 "kg / cm ² , room temperature (" RT ").

The preparation of the azaindenes of the formula:

5
_ CH ₂ -COOH

is carried out by treating the compound (XIII-b) according to the Working methods of (1O), (11) and (12).

Furthermore, the versatile substituted pyridone (III) can also be used for the preparation of compounds according to the invention can be used according to the following procedure:

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H
(III)

(XVIII)

Flieescliema III

Cl ".""^ ⁰ H ₂ Br

(XII)

CH ₂ C (CO ₂ E).

(XX)

Equivalents:

R, E ₂ and Rc have the meanings given above.

Reagents:

(Ό copper (I) cyanide, dimethylformamide, boiling under reflux, Cool down, FeCl, -HCl solution, filter off the Precipitation (Bc «= cyan).

(2) POCl ₅ (Joür. Org. Chem. I £, (195 ^), p. 18J.

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$ 3 cancellation CJxrtar Kar salt

ζJgu2?. < Arner.

can diana for ale Vei4d.2id; uHgHk ~ Lassen according to the

.- Serc ^ Ψ7 \

: ctea?

Iile ⁱ VesEwenctung vqel
hurry seiir eajverbindueielLesD way z.ux mass "Werbin & uageru, M-ea? lass * sleii gpndei ^ let ^ seBfimaü widen

isrb; di. the end?

14378

^CH

Flow diagram IV

^C0 2 ^ß

(XXII) (1)

(2)

(XXIII)

(3)

CI-

Cl

CO ₂ R

(XXIV) (XXV)

CHCO ₂ H

(XXVI) (XXVII)

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14-378

ts

Equivalents;

R, R ¹ , R ¹ ^ i Εχ and Rr- have the meanings given above.

Reagents ;

(1) POCl ₅ (Jour. Org. Chem. I ^., (1954) p. 183

(2) Bromination .Jour. Org. Chem. 1 ^, (1954) p. 183

(3) Na salt of diethyl malonate (Jour. Amer. Chem. Soc. 77 ”(1955) p. 1035

(^) (5) The way of working is the same as in the flow diagram II, steps 6 to 12, has been defined.

The compound (XXII) can according to the in Chem. Zentrl. II, (1903) »p. 1283j illustrated method.

According to the teachings of Flow Diagrams I and II, a known, substituted pyridone, which has been prepared according to the processes shown in Reports 20 , (1387) »p. 445, has the formula:

CH.

"^ ΝΆ.

CO _n Et

C.

is treated as follows:

CH,

(XXIX)

CH

Rr

TX

(XXIX)

CO ₂ et

Pool

(XXX)

CO ₂ et

₂ E.

NBS

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CO ₂ et

CH ₂ Br

(XXXI)

NaCH (CO ₂ Et) ₂

JH

CO ₂ et

(ΧΧΧΙΙ)

CH ₂ Br

CO ₂ et

CH ₂ C (CO ₂ Et) ₂

COpSt

(XXXIIa)

The chlorine groups can, as illustrated in flow diagram I, to be displaced; the mixture is then separated by column chromatography on silica gel. After the apprenticeship of flow diagram II, the compound (XXXII) gives the 7-aza derivative:

? 3

CHCOOH

(XXXlII)

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14378

while the 6-azainden of the formula:

HCOOH

by converting the compound (XXXII-a) according to the flow diagram II arises.

(c) The same method explained by (a) and (b) above can be used for the preparation of various of the present invention 4-aza and 5-aza compounds applied as follows will:

The compound of the formula:

(XXXV)

CO ₀ GH

is known and according to Jour. Org. Chem. 6, S »566 * can be manufactured using this material is based on the teachings of Flow Diagrams I, II and III made the following 4-aza connection:

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14378

1"

CHCO ₂ E

(XXXVI)

Similarly leads

CH.

CH-

(XXXVII)

its presentation in Jour, Amer. Chem. Soc. 22> (1951) p. 2616 for the formation of the 5-aza material of the formula: H

73

CHCCOMe

(XXXVIII)

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14378

according to the details in flow diagrams I, II and III listed working methods.

As indicated above, can be used for the preparation of the invention Connections numerous paths can be followed. Below is the making of the aza-indene using a compound of the formula

(XXXIX)

> H

their production in Jour. Amer. Chem. Soc. 80, (1958) P. 6254, is shown as the starting material.

Flow diagram V

1 ν

(XXXlX)

(XXXX)

(XXXXI)

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Reagents:

(1) CrO, in pyridine; Honor; Leave; Addition of ether; Filter; Washing the filtrate; Dry over magnesium sulfate.

(2) dissolve in dry dimethoxyethane plus potassium tert-butoxide; after 30 minutes addition of methyl iodide; Boil reflux; Addition of water and ether; Separation and washing of the ether layer.

The connection XXXIX can according to steps 9 ″ to 12 of flow diagram II with formation of the corresponding-4-azaindene of the formula:

Ϊ3

CHCOOH

(XXXXII)

be treated. It is to be understood that substituted derivatives (R ^, R ₁ -, R ^) of the compound (XXXIX), according to Jour. Amer. Chem. Soc 80_, p. 6254- »can lead to the formation of the corresponding substituted 4-azaindenes.

In the same way one can obtain 4-azaindenes, which in of the 2-position members identified as Rp as ßubstituenten wear.

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(XXXXIII)

Ac

R,

E,

(XXXXVa)

OAc

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14378

Reagents:

The preparation of the compound (XXXXIII) is described in HeIv. 22 ,, P. 1170.

(1) H ₂ O ₂ PkCS 80, p. 62547 "

(2) acetic anhydride /J-A.C.S. 80, p. 625V

(3) The mixture of the two acetates is put on a silica gel column separated.

The compounds (XXXXVI) and (XXXXVI-a) can then according to the teachings of flow diagram V with the formation of a 5-azaindene:

? 5

CHCOOH

CH3

and one 6 azainden:

CHCOOH

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implemented.

When introducing the 1-substituent according to the flow chart II described method. can be the appropriate arylaldehyde can be used directly for base condensation.

Although the syntheses described provide esters of the acids of the invention, some desired esters are more readily obtained by forming a simple ester of the final product acid, hydrolyzing it to the free acid, and re-esterifying it. I ¹ The simple lower alkyl or benzyl esters are usually used for the synthesis of the compounds. From the standpoint of therapeutic utility, other esters are more desirable, e.g. B. the methoxymethyl, diethylaminoethyl, dimethylarainoethyl, dimethylaminopropyl, diethylaminopropyl, N-pyrrollidinylethyl, N-piperidinylethyl, N-pyrollidinylmethyl, N-methyl-2-pyrrolidinylmethyl, N-morpholinylethyl, N-ethyl -2-piperidinylethyl, 4-methyl-1-piperazinylethyl, methoxyethoxyethyl ester and the like. These are usually prepared from the corresponding alcohol and azaindenic acid.

The amides, both the simple amides and the substituted amides, are made out in a similar manner the azaindenic acids and the corresponding amines. Morpholide, bis-hydroxyethylamide and the like are particularly useful therapeutically.

Salts are obtained in a similar way by adding the azaindic acids neutralized with bases, or by metathesis of the other salts. The metal salts are particularly useful, like the alkali or alkaline earth salts, and the amine and quaternary ammonium salts that are water soluble. The heavy metal salts, such as iron, 'aluminum to salts, etc., are also useful.

3 ü 9 ² 113/11 7 0

It should also be noted that in preparing many kinds of the compounds of the present invention, preference is given to used a nitro substituent on the benzene ring of the azaindene nucleus and later converted it into a desired one Converts substituents because a lot of substituents are accessible in this way. This is done through reduction the nitro to ier amino group and subsequent implementation the Sandmeyer reaction to introduce chlorine, bromine, cyano or xanthate instead of the amino group. From the Cyano derivatives are obtained by hydrolysis of the carboxamide and the carboxylic acid; other derivatives of the carboxy group, like the esters, can then be made. The xanthates provide the mereapto group by hydrolysis, which easily oxidized to the sulfonic acid or alkylated to an alkylthio group which then oxidizes to alkylsulfonyl groups can be. These reactions can be carried out either before or after the introduction of the 1-substituent will.

The operation of Flowchart II is special then advantageous when other substituents than alkyl groups are to be on the 2-position of the indene ring system. Such Substituents such as phenyl, benzyl, alkoxy, arylthio such as phenylthio, alkylthio such as methylthio and ethylthio and Nitro, are best introduced by having the appropriate azaindanone built up and the keto group by the desired one aliphatic acid side chain is replaced.

The invention is further illustrated by the following examples.

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example 1

A. 2-Carbethoxy-5-chloro-2-meth; yl-4-aza-1-indanone

2.4 g (0.01 mol) of 2-carbätlioxy-5-chloro-4-aza-1-indanone in 50 ml of a solution of absolute ethanol and 0.23 g (0.01 mol) of sodium dissolved. The solution is stirred for 5 minutes at room temperature and then with 20 ml of methyl iodide offset. The mixture is stirred and refluxed for 1 hour. Most of the solvent will removed in vacuo. 50 ml of water are added. The product is extracted with two portions of methylene chloride, dried over magnesium sulfate and after removal of the solvent isolated as a red oil.

5 * 72 (ester) and 5.79 (ketone)

B. 5-Hydroxy-2-methyl-4-aza-1-indanone

2.4 g (9.5 mmol) of the ketone of Example 1-A are dissolved in 30 ml of concentrated hydrochloric acid and the solution is refluxed for 16 hours. The solvent is removed under reduced pressure, and 1.9 g of solid remain, which is washed with ether and dried at 80.degree. C. (Ip 236-238.degree. C.). The ultrared spectrum (Nujol) shows .Bands at 2.9 (sh), 3.1 (broad), 6.0 (sh) and 6.1 11: nuclear magnetic resonance spectrum (DMSO), CH ₃ I, doublet, (7.8T -2H, J = 14 cps); Multiplet 6.6 -7.7T, partially obscured by DMSO, 1 H 3.65T (J = 16 cps) and 1 H - 2.48 0? (J = 16 cps). An analytical sample was obtained from i-propanol. Calculated for C ₉ H ₉ NO ₂ : C 55.31; H 3ö7 \ H 8.57

Found: C, 55.53; H 5.48; N 8.69

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C. 5-Chloro-2-methyl-4-aza-1-indanone

A mixture of 0.5 g (3.0 mmol) of the product of Example 1-B and 20 ml of phosphorus oxychloride is stirred, while the temperature is gradually increased. After a homogeneous solution has been obtained, the reaction mixture becomes cooled and the excess phosphorus oxychloride removed under reduced pressure. The residue will carefully treated with cold water and the precipitate filtered off and dried. The product remains. the Cleaning is done by sublimation in a vacuum. White needles are obtained (melting point 72 to 74 ° C .;

Nujol 5 α ju
max. ^ '/

Nuclear Magnetic Resonance Spectrum, (COCl-,), CEU doublet, 8.61T (3H, J = 11 cps); 3H, multiplet, 6.3 - 7.4T, 1H, doublet, 2.63T (J = 14 cps); IH, doublet, 2.2T (J = 14 cps); Mass spectrum, m / e = 181, calculated 181.

D. Meth yl-5- chloro -4-aza-1- hydroxy-2- nidth.Yl-indanyl-3-ace tat

A well stirred mixture of 0.90 g (5.0 mmol) of the ketone from Example 1-C, 0.6 g (5.2 mmol) of methyl bromoacetate, 400 mg of activated zinc dust and an iodine crystal in 30 ml of dry benzene is added for 20 hours boiled under reflux for a long time. About 30 ml of water are added to the cooled mixture and, after stirring for 10 minutes, the organic layer is separated off and dried over magnesium sulfate. After removing the solvent, a brown oil remains. (^ ^N ^ ° ^X 2.9 (OA), 5.8 (ester) / !;

Mass spectrum, m / e = 255; calculated 255)

E. methyl-6-chloro-2-methyl-7-aza-3-indene acetate and Methyl 6-chloro-2-methyl-7-aza-indanylidene acetate

A solution of 1.0 g of the hydroxy ester of Example 1-D in 50 ml of dry benzene and 5 »0 g of phosphorus pentoxide

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the refluxed for 18 hours, excess phosphorus pentoxide is decomposed with water, and the benzene layer is separated and dried over magnesium sulfate. After the solvent has evaporated in vacuo, a dehydrated material remains (m / e = 2J57ν calculated: 23 7:) The thin-layer chromatography shows two components (λ „, ^ £ ^ο

/' Max.

5.78 (ester), 5.85 (α, β-unsaturated ester); Nuclear Magnetic Resonance Spectrum (CDCl ₅ ), CH, Dablett, 8.65 T (J = 12 cps); CH ₃ singlet, 7.880 ?; Multiplet 6.4 - 7.51, OCH ₃ 6.250? and 6.32T, Vinyl E, 3.80? (J = 4 cps). Multiplet 2.0 2.90? (2 doublets)).

P. methyl 6-chloro-1- (p-methylsulfinylbenzylidene) ~ 2-methyl-7-azaindene-3-acetate

A solution of 0.24 g (1.0 mmol. 1) of the isomer mixture of the Example 1-E (approximately 0.20 mmol endocyclic isomer), 1iQ mmol ρ-Me thy Is ul finy! Benzaldehyde and 0.10 g (2.0 mmol) Sodium methoxide in 15 ml of anhydrous methanol is taken under a sticks placed in the atmosphere and placed under for 3 hours Boiled under reflux. The mixture is then poured into water and weakly acidified using dilute HCl. the aqueous solution is extracted three times with methylene chloride and dried over magnesium sulfate. After evaporation of the solvent remains an oil. The oil is dissolved in 25 ml of anhydrous methanol and 1 drop more concentrated Sulfuric acid is added. The solution is refluxed for 12 hours and then in vacuo evaporated to a small volume. Water is added and the mixture is extracted with methyl en chloride. The extracts are dried over magnesium sulfate, and methyl 6-chloro-1- (p ~ methylsulfinylbenzylidene) -2-methyl-7-azaindene-3-acetate results.

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G. Preparation of i-p-Methylsulfinylbenzylidene-2-methyl-6-chloro-7-azaindene-3-acetic acid

100 mg of the methyl ester of Example 1-F. Are in 15 ml a methanol + (80 ^ -water mixture. 2 ml of a 10% KOH solution are added and the solution is dissolved heated in the steam bath for 10 to 15 minutes. About 25 ffll water and enough 10% HCl solution to dissolve the yellow solution just acidic are added. On cooling, the acid separates out of the solution as a yellow one

Powder off.

Kr

NaSCH ₅ p

NS.

NaOH

These compounds can be made according to the procedures of the examples 1-D, 1-E, 1-F and 1-G to form the desired Azaindenacetic acid are implemented.

Example 2

A. Preparation of ethyl 2- (2 ', 2'-dicarbethoxy) ethyl nicotinate

A solution of 3.58 g (0.01 mol) of ethyl 2- (2 ', 2'-dicarb-

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1 * 378 »μ

ethoxy ^ ethyl-ö-chloronicotinate in 50 nil ethanol using 0.5 g palladium (10%) - on-charcoal Hydrogenated at 45 p.s.i. for 8 hours. After this The time span is the hydrogen uptake according to the theory completely finished. The catalyst is filtered off and the piltrate is evaporated to dryness. The product remains as a the hydrochloride salt back. The salt is dissolved in a small amount of water and the solution is made basic with E ^ CO. The oily pyridine is extracted into CEpCIp, over MgSCL dried and then evaporated until the free base remains. The hydrochloride has a melting point of 14-5 Dis 146 ° C.

B. Preparation of ethyl 2- (2. ^f , 2'-dicarbethoxy) ethyl 6-methylthionicotinate

A solution of 0.05 mol of Ealiunuaethylthiolat is made from methyl mercaptan, 100 ml of ethanol and 2.8 g (0.05 mol) of KOH were prepared in the course of 2 hours at 0 ° C. 17.9 g (0.05 mol) Ethyl 2- (2 ', 2'-dicarbethoxy) -ethyl-6-chloronicotinate added with stirring. After 10 minutes at room temperature, the mixture is refluxed for 2 hours. After cooling, the precipitated EGI salt is through a Filter the celite pad and evaporate the piltrate. The product remains as a white solid.

In the same way, R ^ substituents, such as dialkylaminoalkyl, Cyan and alkoxy, can be obtained by displacing the halogen derivative by adding the following reactants can be used accordingly:

(a) Dialkylamine in EtOH

(b) KCN in EtOH - HpO

(c) Alkyllithium in ethyl ether

(d) RONa in ROH, where R = alkyl

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O · Production of 2-carbetho x y ~ 5 ~ niethylthio-4-aza-1- ynon

A stirred suspension of 0.025% by volume of sodium hydride (56 %) in 200 ml of benzene is added dropwise with stirring to a solution of 0.02 mol of the compound of Example 2-B in 50 ml of benzene under Np. After the addition, the mixture is refluxed for 17 hours, cooled and poured into JOO ml of cold water. The benzene layer is separated and dried over magnesium sulfate. After evaporation of the solvent, the desired product remains as a white solid.

D. Preparation of 2-methyl-2-carbethoxy-5-methyltnio-4-aza-1-indanone

(a) 0.01 mol of the ester of Example 2-C is in 50 ml Ethanol containing 0.01 mol of sodium ethoxide dissolved. 0.01 mol of methyl iodide are added, and the reaction mixture. is refluxed for 45 minutes. After evaporation of the solvent, the product remains as an oil return. Using the procedure described above, benzyl bromide can be used in place of methyl iodide be to the corresponding benzyl radical in the R ^ position to win.

(b) The corresponding chlorine derivative, which can be obtained as follows:

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can be used for the further production of '^ "groupings, like -SCH, and -OH, can be used.

Example 5

A. Preparation of 7-aza-1-indanone

1.0 g of 7-aza-1-indanol (J.A.C.S. 80, p. 6254) in 10 ml of byyridine is added to a stirred slurry of 1.0 g of chromium trioxide in 10 ml of pyridine. The thick slurry darkens slightly and becomes less viscous. Stirring is continued for 1 hour and then the reaction mixture is allowed to stand for 22 hours. 50 ml of ether are added, and the mixture is filtered. The filtrate is washed with water and then dried over magnesium sulfate. After evaporation, an oily ketone remains.

B. Preparation of 2-methyl-7-aza-1-indanone

0.01 mol of the ketone of Example 3-A is dissolved in 50 ^{ml of} dry methoxyethane and 0.012 mol of potassium t-butoxide is added with stirring and under an inert atmosphere.

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After 50 minutes, 20 ml of methyl iodide are added, and the reaction mixture is refluxed for 6 hours cooked. Water is added and then ether. The ether layer is separated, washed twice with water, over Magnesium sulfate dried and evaporated. A colorless liquid remains.

The indanone described above is prepared by following the procedures of Examples 1-D, 1-E, 1-F and 1-G to form 1-p-methylsulfinylbenzylidene-2-methyl-7-azainden-3-acetic acid implemented.

Example 4 Manufacture; of 2-methyl-5-methylthio-4-aza-1-indanone

The ester of Example 2-C is dissolved in 25 ml of concentrated HCl dissolved, and the solution is refluxed for 12 hours. The solvent is removed in vacuo, and the remaining hydrochloride is dissolved in a small volume of water. A saturated solution of potassium carbonate is added until the solution has become basic. The ketone is then obtained by extracting with CHpCIo.

The indanone described above is according to the procedures of Examples 1-D, 1-E, 1-P and 1-G to produce 1-p-Methy] sulfinylbenzylidene-2-methyl-5-methylthio-4-azaindene-3-acetic acid implemented.

Example ^

1-p-Methylsulfinylbenzylidene-2-methyl-6-chloro-7-azaindene acetmorpholide

A mixture of 0.01 moles of i-p-methylsulfinylbenzylidene-2-methyl-5-methylthio-4-azaindene-acetic acid and 0.03 moles

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Thionyl chloride is put in a dried flask with attached cooler and drying tube on the steam bath like this! heated for a long time until the evolution of gas has ceased. Excess thionyl chloride is then removed in vacuo, and the residue is taken up in a slight excess of anhydrous Ither and slowly added to a vigorously stirred, ice-cooled solution of 0.035 mol of dry morpholine in 100 ml of ether. The mixture is stirred overnight at room temperature and filtered, the morpholine hydrochloride is washed with excess ether, and the combined ether filtrates are washed with 2 × 100 ml of water, dried over anhydrous sodium sulfate and filtered, and the ether is removed in vacuo. Chromatography of the crude product on a silica gel column using 50-100% (v / v) ether in petroleum ether as the eluent gives the desired morpho] id.

Similarly, if one replaces morpholine with an equivalent amount of the following amines, the corresponding amides.

Dirnethylamine

Ethanol emin

Benzylamine

N, N-diethylethylenediamine.

Example 6

Esters of i-p-methylsulfinylbenzylidene ^ -methyl-e-chloro-7-azaindene-acetic acid

(a) Simple Esters - A mixture of 0.1 mole of 1-p-methylsulfinylbenzylidene-2-methyl-6-chloro-7-azain4en-acetic acid, 0.2 g of p-toluenesulfonic acid, 100 ml of absolute ethanol and 75 ml of dry benzene is taking on a steam bath

-33-309813 / 1170

Boiled to reflux while the solvent slowly distilled off will. After 17 hours the remaining solvent is removed under reduced pressure. The residue is in aqueous sodium bicarbonate and then with water, until he's neutral, slammed up. The resulting ethyl ester Can be recrystallized from organic solvents such as ethyl acetate, benzene and the like. When you get to the The working method described above uses methanol, propanol, t-butanol and benzyl alcohol instead of ethanol, the corresponding methyl, propyl, t-butyl and benzyl esters are obtained.

(b) alkoxyalkyl esters. - 0.055 ^M ol chloromethyl methyl ether are p-Metbylsulfinylbenzyliden-2-methyl-6-chloro-7-aza-inden-1 acetic acid to a suspension of 0.05 mol and 0.15 WOI of anhydrous potassium carbonate in 250 ml of anhydrous acetone. The mixture is stirred overnight at room temperature. About 20 ml of diethyl ether are added and the mixture is filtered. The filtrate is washed once with 100 ml of saturated sodium bicarbonate solution and twice with 100 ml of water and dried over anhydrous sodium sulfate. It is then filtered and the solvent is removed in vacuo. The residue is chromatographed on 200 g of acid-washed clay using ether-petroleum ether (varying from 10 to 60% by volume of ether) as the eluent. Methoxymethyl-ip-methylsulfinylbenzylidene ^ -methyl-G-chloro ^ - azaindene acetate is obtained.

(c) Dialkylamino-alkyl esters. - A solution of 0.0054 mol of N ₁ N'-dicyclohexylcarbodiimide in 6 ml of anhydrous tetrahydrofuran becomes a solution of 0.005 mol of 1-p-methylsulfinylbenzylidene-2-methyl-6-chloro-7-azaindene-acetic acid and 0.0054 Added mol of 2-diethylaminoethanol in 17 ml of anhydrous tetrahydrofuran. The mixture is stirred at ambient temperature overnight. The dicyclohexyl urea

13/1170

is removed by filtration and 2 ml of glacial acetic acid is added to the filtrate. After allowing the mixture to stand the mixture is filtered for 1 hour, and 200 ml of ether are added to the filtrate. The solution will then extracted three times with 100 ml of 2.5 & -HCl, and the extracts are combined, washed twice with 100 ml of ether, cooled with ice, weakly alkaline with concentrated NHqOH made and extracted three times with 100 ml of ether. ' The ether extracts are combined, washed zehranal with 100 ml of water, to remove traces of starting amine, dried over anhydrous potassium carbonate, filtered and in vacuo evaporated. The oily residue is ß-diethylaminoethyl-1-p-methylsulfinylbenzylidene ^ -methyl-G-chloro ^ -azaindenacetat.

If, in the procedure described above, 2-dimethylaminoethanol, 3-dimethylaminopropanol (l) 3-diethylaminopropanol- (1} N-ß-hydroxyethylpiperidine, N-ß-hydroxyethylpyrrolidine, N-hydroxymethylpyrrolidine, N-methyl 1-2- If hydroxymethylpyrrolidine, N ~ ethyl-2-hydroxymethylpiperidine, 1-ß-hydroxyethyl-4'-methylpiperazine or N-ß-hydroxyethylmorpholine is used instead of 2-diethylaminoethanol, the corresponding ß-dimethylaminoethyl, γ-dimethylaminopropyl, γ-diethylamine are obtained -, ß-N-piperidinylethyl, ß-N-pyrrolidinylethyl, N-pyrrolidinylmethyl, 2 ^f - (1'-methylpyrrolidinylmethyl) -, 4-methyl-i-piperazinyl ethyl, N-ethyl ~ 2- piperidinyl ethyl and N-morpholinyl ethyl esters.

(d) Phenyl-ip-methylsulfinylbenzylidene ^ -methyl-ö -chloro-7-azaindene acetate. - A solution of 0.0054 mol of N, N ¹ -dicyclohexylcarbodiimide in 6 ml of anhydrous tetrahydrofuran becomes a solution of 0.005 mol of 1-p-chlorobenzylidenyl-2-methyl-6-chloro-7-azaindene-acetic acid and 0.0054 mol Phenol was added to 17 ml of anhydrous tetrahydrofuran. That

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Mixture is shaken vigorously with the bottle stopped let stand overnight at room temperature to settle.

After filtering off the Ν, Ν'-dioyclohexylurea, 2 ml of glacial acetic acid are added to the filtrate and the mixture is left to stand for 1 hour. After filtration, 200 ml of ether are added to the filtrate, and the ether solution is washed with 2 × 100 ml of saturated sodium bicarbonate solution and 3 × 100 ml of water and then dried over anhydrous sodium sulfate. The mixture is filtered, concentrated in vacuo to 25 ml and chromatographed on an acid-washed alumina column (150 g) using ether-petroleum ether (v / v 10-60 ⁰ Jo) as the eluent. Phenyl-ip-methylsulfinylbenzylidene-2-methyl-6-chloro-7-azaindene acetate is obtained.

If, in the above procedure, 2- (2-methoxyethoxy) ethanol, Glycol or N-acetylethanolamine used in place of phenol is obtained in a similar manner 2- (2-methoxyethoxy) -ethyl-1-p-methylsulfinylbenzylidene-2-methyl - ^ - methoxy-J-azaindene acetate, β-Hydroxyethy1-1-pmethyl3ulfinylbenzylidene-2-methyl-6-chloro-7-azaindene acetate or ß-acetamidoethyl-i-p-methylsulfinylbenzylidene-2-methyl-6-chloro-7-azaindene acetate.

A mixture of 0.06 moles of sodium 1-p-methylsulfinylbenzylidene-2-methyl-6-chloro-7-azaindene acetate and 0.05 moles of trityl bromide in 100 ml of anhydrous benzene is added rapidly Stir and reflux under nitrogen for 5 hours. The hot reaction mixture is filtered and the filtrate was concentrated in vacuo. The remaining oil is recrystallized from methyl ethyl ketone and gives Trityl-i-p-methylsulfinylbenzylidene ^ -methyl-o-chloro -? - azaindene acetate.

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If you have any of the other 7 - A-zainden-acids »found in other examples are described in lieu of the above The acid described is used for any of the preparation methods given above, the corresponding ones are obtained Ester.

Example 7

K- (i-p-Methylsulfinylbenzylidene-2-methyl-6-chloro-7-azaindenylacetyl) glycine

(a) Benzyl F-1- (p-methylsulfinylbenzylidene-2-methyl-6-. chloro-7-az (aindenacetyl) glycinate. the The procedure of Example 5 is followed using benzylaminoacetate in place of the morpholine. It educates the above connection ..

(b) N- (i-p-Methylsulfinylbenzylidene-2-methyl-6-chloro-7-indene-acetyl) -glycine. -.

0.003 mol of benzyl N- (ip-methylsulfinylbenzylidene-2-methyl-6-chloro-7-azaindene acetyl) -glycinate is left in a mixture of 25 ml of anhydrous ethanol and 2.5 ¹ ^ l "of sodium hydroxide at room temperature for 18 hours The solution is diluted with water and extracted with ether. The aqueous layer is acidified with dilute hydrochloric acid and the organic product is extracted with ethyl acetate, washed with water and dried over sodium sulfate. Evaporation of the solution gives N- (ip-methylsulfinylbenzylidene ^ -methyl-G-chloro ^ -azaindenacetylglycine.

If you have any of the other i-aralkylidene-7-azaindenaliphatic Acids, which are described in the other examples of this description, according to those given above Procedure instead of 1-p-methylsulfinylbenzylidene-2-methyl-6-chloro-7-azaindene-acetic acid used, received

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one the corresponding indenylacylglycine. Example 8

i-p-Methylsulfinylbenzylidene ^ -methyl-G-chloro ^ -azaindena-alkyl-acetic acid

(a) 1-p-Methylsulfinylbenzylidene-2-methyl-6-chloro-7-azaindene acetamide. -

Using the procedure of Example 5 an ethereal solution of ammonia was followed instead of the morpholine. The amide mentioned above is formed.

(b) i-p-Methylsulfinylbenzylidene ^ -methyl-G-chloro -? - azaindenacetonitrile.-

A mixture of 10 g of the amide from section (a) and 20 cm ^ POCl, is kept at 90 to 100 ° C for 4 to 5 hours heated. The mixture is then poured into ice wax and extracted with 100 ml of ether. The extract is made with sodium bicarbonate washed, dried over NapSO ^ and evaporated. The above-mentioned nitrile is obtained

(c) 1-p-Methylsulfinylbenzylidene-2-methyl-6-chloro-7-azaindene-α-allylacetonitrile. -

A mixture of 0.01 mol of the nitrile from section (b) and 0.01 mol NaNHp in 100 cnr toluene is at room temperature touched. 0.015 moles of allyl chloride are added and the mixture is stirred for 3 to 4 hours. It will then poured into a large volume of water and extracted with ether. The extract is dried and dried to dryness evaporated. The α-allyl nitrile is obtained.

(d) i-p-Methylsulfinylbenzylidene ^ -methyl-G-chloro -? - azainden-a-allyl-acetic acid. -

The α-allyl nitrile from section (c) is refluxed for 8 hours in a large volume of 6N sulfuric acid

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cooked. The mixture is then cooled, by 4 to 5 parts by volume Diluted water and extracted with ether. The extract is dried and evaporated to dryness. You get the a-allylacetic acid.

Example9

A. Preparation of methyl 2-methyl-7-aza-1-hydroxyindane-3-acetate

The 2.0 g of methyl ^ -methyl-G-chloro ^ -aza-i-hydroxyindan ^ - acetate of Example 1-D are in 20 ml of ethyl alcohol using 0.2 g of palladium (10%) - on charcoal 3.16 kg / cm hydrogenated. After the theoretical amount of hydrogen has been taken up, the filtrate is evaporated and there remains the methyl-2-methyl-7-aza ~ 1-hydroxyindan-3-acetate as oil back.

B. Preparation of methyl 2-methyl-7-aza-3-indene acetate and Methyl 2-methyl-7-aza-indanylidene acetate

1.8 g of methyl ^ -methyl ^ -aza-i-hydroxyindan - ^ - acetate of Example 9-A are dissolved in 25 ml of benzene, and 2.0 g of phosphorus pentoxide are added. The mixture is 21 hours boiled under reflux for a long time and filtered. Evaporation of the piltrate results in a mixture of methyl-. 2-methyl-7-azaindenyl-3-acetate and methyl-2-methyl-7-azaindanylidene acetate, which are separated by chromatography on silica gel.

C. Preparation of methyl 2-methyl-1- (p-methylsulfinylbenzylidene; -7-azaindene-J-acetate

A solution of 0.24 g (1.0 mmol) of the isomer mixture of the Example 9-B (about 0.20 mmol endocyclic isomer), 1.0 ml p-methylsulfinylbenzaldehyde and 0.10 g (2.0 mmol)

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Sodium methoxide in 15 ml of anhydrous methanol is placed under a nitrogen atmosphere and under for 3 hours Boiled under reflux. The mixture is then poured into water and made weakly acidic with dilute HCl. The aqueous solution is extracted three times with methylene chloride and dried over magnesium sulfate. The result is what you want Product. The free acid, namely 1-p-methylsulfinylbenzylidene-2-methyl-7-azaindene-3-acetic acid, is produced according to Example 1-G.

Example 1 0

A. Preparation of ethyl 5-bromo-6-hydroxy-2-methylnicotina t

4.0 g of ethyl 2-methyl-6-hydroxynicotinate are used as described by Adams and Schrecker in Jour. Amer. Chem. Soc. 211 (1949) S. 1194, described, brbmiert without the solution being made alkaline at the end of the reaction. The crystalline Ethyl 5-bromo-6-hydroxy-2-methylnicotinate is filtered off (4.4 g).

B. Preparation of ethyl 5-bromo-6-chloro-2- methyl nicotinate

4.4 g of ethyl - ^ - bromo-G-hydroxynicotinate and 10.0 g of phosphorus oxychloride are held at 120 to 130 ° C for 4 hours. The crystalline material is filtered off and dried and sublimed under reduced pressure (1 mm Hg). 2.3 g of ethyl bromo-G-chloro-methyl nicotinate are obtained.

C. Preparation of ethyl 5-bromo-2-methyl nicotinate

The compound prepared in Example 10-B is prepared as in Example 9-A described, with palladium-on-charcoal too the above compound implemented.

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3U9813 / 1170

14,378 ha

D. Preparation of ethyl ~ ^ -bromo-2-methylnicotinate

A mixture of 4.8 g of Itbyl ^ -bromo-ß-ehlor ^ -methylnicotinate from Example 10-C, 3.5 g of recrystallized H-bromosuccinimide, 25 nig recrystallized in benzoyl peroxide and 40 ml of carbon tetrachloride (dried over phosphorus pentoxide and distilled) is irradiated with a 100 watt lamp and refluxed under anhydrous conditions for 4 hours. The cooled mixture is filtered and the 3? filtrate evaporated under reduced pressure. Ethyl 5-bromo-2-bromo-methyl nicotinate is obtained.

E. Preparation of ethyl 5-bromo-2- (2 ', 2'-dicarbethoxy) ethyl nicotinate

A solution of ethyl 5-bromo-2-bromomethyl nicotinate in 40 ml of anhydrous benzene is added over 0.5 hours to the stirred mixture of the sodium salt of diethyl malonate, which is kept at room temperature. Stirring is continued for an additional 16 hours at room temperature. The reaction mixture is poured into 400 ml of ice-water containing 4 ml of concentrated hydrochloric acid. The organic layer is separated and combined with benzene extracts from the aqueous layer. The organic solvent is distilled off and the remaining oil is heated to 100 ° C. (0.3 mm) in order to remove diethyl malonate. The residue is recrystallized from petroleum ether (boiling point 30 to 60 ° C.) and yields ethyl 5-bromo-2- (2 ^l , 2'-dicarbethoxy) ethyl nicotinate.

F. Preparation of 6-bromo-2-carbethoxy-4-aza-1-indanone

That made by the procedure of Example 10-E Compound is reacted according to the procedure of Example 2-C and gives 6-bromo-2-carbethoxy-4-aza-1-indanone.

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G. Preparation of e-bromo ^ -carbethoxy ^ -methyl ^ -aza-1-indanone

That prepared according to the procedure of Example 10-F Compound is reacted according to the procedure of Example 2-D and gives e-bromo ^ -carbethoxy ^ -methyl - ^ - aza-1-indanone.

H. Preparation of 6-bromo-2-methyl-4-aza-1-indanone

That prepared according to the procedure of Example 10-G Compound is reacted according to the procedure of Example 1-B and gives 6-bromo-2-methyl-4-aza-1-indanone.

I. Manufacture of

az aindanyl-J-acetate

That prepared according to the procedure of Example 1O-H Compound is made according to the procedure of Example 1-D converted and gives methyl-6-bromo-1-hydroxy-2-methyl-4-azaindanyl-3-acetate.

J. Preparation of methyl 5-bromo-2-methyl-7-azaindenyl-3-acetate

That prepared according to the procedure of Example 10-I Compound is reacted according to the procedure of Example 1-E and gives methyl ^ -bromo ^ -methyl ^ -azaindenyl-3-acetate.

K Preparation of methyl-cis-5-bromo-2-methyl-1- (pmethylthiobenzylidene; ~ 7-azaindenyl-3-acetate

That made by the procedure of Example 10-J Compound is made following the procedure of Example 1-F using p-methylthiobenzaldehyde instead of p-methylsulfinylbenzaldehyde reacted and yields methyl

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14378 * ί \

cis-5-l ^> rom-2-methyl-1- (p-methylthio'benzylidene) -7 * -azaiiidenyl-3-acetate.

L. Preparation of methyl cis -5-bromo-2-methyl-1- (pmethylsulfinylbenzylidene) -7-azaindenyl-3-acetate

3j72 g of that prepared according to the procedure of Example 10-K Compound are added to stirred solutions of 11.36 (0.0422 mol) sodium meta-periodate trihydrate in 240 ml of methanol given in 85 ml of water at room temperature. That Mixture is stirred overnight to a small volume concentrated, diluted with water, filtered, dried in air and then in vacuo at 50 ° C. and extracted from ethyl acetate-hexane recrystallized. Methyl-cis-5-bromo-2-methyl-1- (p-methylsulfinylbenzylidene) -7-azaindenyl-3-acetate is obtained.

M. 5 ~ BiO ^m -2-methyl-1- (p-methylsulfinylbenzylidene) -7-aziaindenyl-acetic acid

The compound (1 g) prepared according to Example 10-L is Stirred in 50% aqueous pyridine for 48 hours and subsequently diluted and acidified. 5-Bromo-2-methyl-1- (p-methylsulfinylbenzylidene) ~ 7-azaindenyl-acetic acid is formed.

Example 11

A. Preparation of ethyl 3-fluoro-6-chloro-2-methyl nicotinate

The compound prepared according to Example 10-A is under the one in Jour. Medicinal Chem. (1967), p. 38I ff. Conditions described with potassium difluoride with the formation of Ethyl 5-fluoro-6 ~ hydroxy-2-methylnicotinate implemented. These Compound then becomes ethyl 5-fluoro-6-chloro-2-methylnicotinate as described in Example 10-B above implemented.

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309813/1170

B. Production of Ethyl ^ -fluoro-e-chloro ^ -methylnicotinate

4.4 g of ethyl 5-fluoro-6-hydroxynicotinate and 10.0 g of phosphorus oxychloride are for 4 hours at 120 to 150 ° C held. The crystalline material is filtered, dried and sublimed under reduced pressure (1 mm Hg). Man receives 2.3 g of ethyl 5-fluoro-6-chloro-2-methylnicotinate.

C- Production of ethyl 3-i * luoro-2-methyl nicotinate

The compound prepared in Example 11-B is reacted, as described in Example 9-A , with palladium-on-charcoal to give the abovementioned compound.

D. Preparation of ethyl 5-fluoro-2-bromomethyl nicotinate

A mixture of 4.8 g of ethyl 5-fluoro-6-chloro-2-methyl nicotinate from Example 11-C, 3 * 5 6 recrystallized N-bromosuccinimide, 25 nig recrystallized benzoyl peroxide and 40 ml of carbon tetrachloride (dried over phosphorus pentoxide and distilled) with a 100 watt lamp irradiated and under anhydrous conditions for 4 hours refluxed. The cooled mixture is filtered and the piltrate evaporated under reduced pressure. Ethyl 5-fluoro-2-bromomethyl nicotinate is obtained.

E. Preparation of ethyl 5-fluoro-2- (2 ', 2'-dicarbethoxy) ethyl nicotinate

A solution of ethyl - ^ - fluor ^ -bromomethylnicotinate in 40 ml of anhydrous benzene is added to the stirred mixture maintained at room temperature over 0.5 hour given of the sodium salt of diethyl malonate. Stirring is continued for an additional 16 hours at room temperature. The reaction mixture is poured into 400 ml of ice-water containing 4 ml of concentrated hydrochloric acid. The organic layer is separated and combined with benzene extracts from the aqueous layer. The organic solution

_ 44 _
309813/1170

medium is distilled off and the remaining oil is heated to 100 ° C. (0.3 mm) in order to remove diethyl malonate. The residue is recrystallized from petroleum ether (boiling point 30 to 60 ° C.). Ethyl-5-fluoro-2- (2 ', 2'-dicarbethoxy (-äthylni co tinate.

F. Preparation of 6-fluoro-2-carbethoxy-4-aza-1-indanone

That made by the procedure of Example 11-E Compound is converted to 6-luoro-2-carbethoxy-4-aza-1-indanone according to the procedure of Example 2-C.

G. Preparation of 6-i ¹ luor-2-carbätho2cy-2-methyl-4-aza-1-indanone

That made by the procedure of Example 11-3P Compound is reacted according to the procedure of Example 2-D to 6-E'iuor-2-carbäthoxy-2-methyl-4-aza-1-indanone.

H. Preparation of 6-ffluoro-2-meth: yl-4-aza-1-indanpn

That made according to the procedure of Example 11-IP Compound is converted to 6-fluoro-2-methyl-4-aza-1-indanone according to the procedure of Example 2-D.

I. Preparation of methyl 6-fluoro-1-hydroxy-2-methyl-4-azaindanyl-3-acetate

That made by the procedure of Example 11-H Following the procedure of Example 1-D, compound is converted to methyl 6-fluoro-1-hydroxy-2-methyl-4-azaindanyl-3-acetate implemented.

J. Preparation of methyl 5-fluoro-2-methyl-7-azaindenyl-3-acetate

That made according to the procedure of Example 11-1

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309813 / 117Ö

Connection is made following the procedure of Example 1-E converted to methyl 5-fluoro-2-methyl-7-azaindenyl-3-acetate.

K. Preparation of Methvl ~ cis-5-fluoro-2-methyl-1- (pmethylthiobenzylidene) -7-azaindenyl-3-acetate

That made by the procedure of Example 11-J Compound is made following the procedure of Example 1-F using p ~ methylthiobenzaldehyde instead of ρ-Methylsulfinylbenzaldehyde. to methyl-cis-5-fluoro-2-methyl-1- (p-methylthiobenzylidene) -7-azaindenyl-3-acetate implemented.

Preparation of methyl cis-5-fluoro-2-methyl-1- (pmethylsulfinylbenzylidene) -7-azaindenyl-3-acetate

3172 g of that prepared according to the procedure of Example 11-K Compound in 240 ml of methanol are stirred. Solutions of 11.3 g (0.0422 moles) sodium meta-periodate trihydrate given in 85 ml. water at room temperature. That Mixture is stirred overnight, concentrated to a small volume, diluted with water, filtered, and in air then dried in vacuo at 50 ° C and from ethyl acetate-η-hexane recrystallized. Methyl cis-5-fluoro-2-methyl-1- (p-methylsulfir.ylbenzylidene) -7-azaindenyl-3-acetate is obtained.

M. 5-i'liior-2-methyl-1- (p-methylsulfinylbenzylidene) -7-azaindenyl-acetic acid

The compound (1 g) prepared according to Example 11-L is stirred for 48 hours in 50% strength aqueous pyridine and then diluted and acidified. It forms a 5-i ^l luor-2-methyl-1- (p-methylsulfinylbenzylidene) -7-azaindenyl-acetic acid.

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Claims (20)

Claim e in which (a), (b), (c) and (d) each denote C or N, where .only one of the mentioned Eeste (a), (b), (c) and (d) stands for N at any time, and furthermore means:. Ar
E ¹ , Hydrogen, halogen, hydroxy, alkoxy, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl ₃ haloalkyleneoxy, haloalkylene thio, haloalkylene sulfinyl, cyano, mercapto or sulfonamido; Hydrogen, alkyl, aralkyl, aryl, heteroaryl, halogen, hydroxy, alkoxy, haloalkyl, alkylthio or arylthio; Hydrogen, lower alkyl, halo-lower alkyl, fluorine, amino, acylamino, dialkylamino, N-morpholino, Alkenyl, aralkylthio, hydroxy or alkoxy or together with R'-, a methylene group; Hydrogen or together with R ₁ - and ^ a methylene group; each hydrogen, alkyl, alkoxy, nitro, amino, acylamino, alkylamino, dialkylamino, dialkylaminoalkyl, SuIfamyl, alkylthio, mercapto, aryl-eulfinyl, Alkylsulfonyl, halogen, cyano, carboxyl, - 47 -3ϋ9ΰ13 / 1 170 ORtGINAL INSPECTED Carbalkoxy, carbamido, aryl, haloalkyl, alkenyloxy, Aralkyloxy, alkenyl, aryloxy, cycloalkyl or cycloalkyloxy and M hydroxy, lower alkoxy, substituted lower alkoxy, amino, alkylamino, dialkylamino, N-morpholino, Hydroxyalkylamino, aminoalkylamino or the group OMe, where Me stands for a cation. 2. Compounds according to claim 1, characterized in that Ar aryl; R. lower alkyl sulfinyl or lower alkyl sulfonyl; E ^ 'hydrogen; E ₂ alkyl; R-, and R ¹ , hydrogen; 3 3 * M hydroxy or lower alkoxy; and R ^, R ₁ - and Eg are each hydrogen, halogen or lower alkoxy
mean. 3. i-p-Chlorobenzylidene ^ -methyl-G-chloro-y-azaindene-J-acetic acid according to claim 2. 4. 1-p-chlorobenzylidene-2-methyl-7-aza-inden-3 ^"e ssigsäure according to claim. 2 5 x 5-fluoro-2-methyl-1- (p-methylsulfinylbenzylidene) -7-azaindenyl-3-acetic acid according to claim 2. 6. 5 »6-Difluoro-2-methyl-1- (p-methylsulfinylbenzylidene) -7-azaindenyl-3-acetic acid according to claim 2. 7 x 5-Bromo-2-methyl-1- (p-methylsulfinylbenzylidene) -7-azaindenyl-3-acetic acid according to claim 2. 3J9813M170 14378 8. 5-Bromo-6-clilor-2-methyl-1- (p-methylsulfinyl'beiizylidene) -7-azaindenyl-3-acetic acid according to claim 2. 9. 5- ^il luoro-6-chloro-2-methyl-1- (p-methylsulfinylbenzylidene) -7-azaindenyl-3-acetic acid according to claim 2 «. 10. 5-Bromo-6-fluoro-2-methyl-1- (p-methylsulfinylbenzylidene) -7-azaindenyl-J-acetic acid according to claim 2. 11. Composition containing an effective 'anti-inflammatory amount' of a compound of the formula: CH R ' and a pharmaceutically acceptable carrier therefor, in which (a), (b), (c) and (d} _ are each C or Ή , with only one of said radicals (a), (b), (c) and ( d) at any time stands for N, and in which further "means: Ar aryl; R. alkylsulfinyl or alkylsulfonyl; R ^1,. Hydrogen, halogen, hydroxy, alkoxy, haloalkyl, alkylthio, arylsulfinyl, alkylsulfonyl, haloalkyleneoxy, haloalkylene thio, haloalkylene sulfinyl, cyano, mercapto or sulfonamido; - 49 - 3ü93 13/1170 Κ, -, hydrogen, alkyl, aralkyl, aryl, heteroaryl, Halogen, hydroxy, alkoxy, haloalkyl, alkylthio, or arylthio, E, hydrogen, lower alkyl, halo-lower alkyl, fluorine, amino, acylamino, dialkylamino, N-morpholino, alkenyl, aralkylthio, hydroxy or alkoxy or together with R ¹ , a methylene group; fi ¹ . Hydrogen or together with E, a methylene group; R ^, E _r and Hg each hydrogen, alkyl, alkoxy, nitro, amino, acylamino, alkylamino, dialkylamino, dialkylaminoalkyl, sulfamyl, alkylthio, mercapto, arylsulfinyl, alkylsulfonyl, halogen, cyano. Carboxyl, carbalkoxy, garbamido, aryl, haloalkyl, Alkenyloxy, aralkyloxy, alkenyl, aryloxy, cyclo -alkyl or cycloalkyloxy and M hydroxy, lower alkoxy, substituted lower alkoxy, Amino, alkylamino, dialkylamino, N-morpholino, Hydroxyalkylamino, ■ Aminoalkylamino or the Group OMe, in which Me stands for a cation. 12. Means according to claim 11, characterized in that the compound i-p-chlorobenzylidene-2-methyl-6-chloro-7-azaindene-5-acetic acid is. 13. Means according to claim 11, characterized in that the connection. i-p-chloro "benzylidene-2-methyl-7-azaindene-3-acetic acid is. 14. Agent according to claim 11, characterized in that the compound is 5-l ^l 'l ^uor ~ 2-methyl-1- (p-methylsulfinylbenzylidene) -7-azaindenyl-3-acetic acid. 15- means according to claim 11, characterized in that the compound 5,6-difluoro-2-methyl-1- (p-methylsulfinylbenzylidene) -7-azaindenyl-3-acetic acid is. - 50 -3J9Ö 1 3 / I 170 14-378 S1 16. Medium after. Claim 11, characterized in that the compound 5-B3? om - 2-niethyl-1- (p-meth.ylsulfinylt »enzylidene) -7-azaindenyl-3-acetic acid is. 17 · Means according to claim 11, characterized in that the compound 5-bromo-6-chloro-2-methyl-1- (p-methylsulfinylbenzylidene) -7-azaindenyl-3-acetic acid is. 18. Composition according to claim 11, characterized in that the compound 5-I ^l lu.or-6-chloro-2-methyl-1- (p-niethylsulfinylbenzyliden) -7-azaindenyl-3-acetic acid is. 19- means according to claim 11, characterized in that the compound 5-bromo-6-fluoro-2-methyl-1- (p-methylsulfinylbenzylidene) -7-azaindenyl-3-acetic acid is. 20. Process for preparing compounds of the formula: In which (a), (b), (c) and (d) each mean G or W, where only one of the radicals (a), (b), (c) and (d) mentioned is at any time for N, and in the further mean: 3J9813 / 1170 Ar aryl; R. alkylsulfinyl or alkylsulfonyl; R ¹ . Hydrogen, halogen, hydroxy, alkoxy, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyleneoxy, haloalkylene thio, haloalkylene sulfinyl, cyano, mercapto or sulfonamido; R2 hydrogen, alkyl, aralkyl, aryl, heteroaryl, Halogen, hydroxy, alkoxy, haloalkyl, alkylthio or arylthio; R, hydrogen, lower alkyl, halo-lower alkyl, fluorine, amino, acylamino, dialkylamino, N-morpholino, alkenyl, aralkylthio, hydroxy or alkoxy or together © it R ¹ -, a methylene group; R ' -ζ hydrogen-f or together with R, a methylene group; R ^, Rf- and R ^ each hydrogen, alkyl, alkoxy, nitro, amino, acylamino, alkylamino, di alkyl amino, dialkylaminoalkyl, sulfamyl, alkylthio, mercapto, arylsulfinyl, alkylsulfonyl, halogen, cyano, carboxyl, carbalkoxy, carbamido, Aryl, halo ^ - alkyl, alkenyloxy, aralkyloxy, alkenyl, aryloxy, cycloalkyl or cycloalkyloxy and M hydroxy, lower alkoxy, substituted lower alkoxy, Amino, alkylamino, dialkylamino, N-morpholino, hydroxyalkylamino, aminoalkylamino or the group OMe, in which He stands for a cation, characterized in that the corresponding ester is acidified- W .j \ i i> UM 1 V (J