DK141201B - Analogous process for the preparation of derivatives of pyranoindole, oxazinoindole and indenopyran as well as their thioanalog or acid addition salts thereof. - Google Patents

Description

(wi \ Ra / (η "PUBLICATION 11 * 1201 & 07 o 3 tt / 78 ΠΔΝΜΔΡΚ (51) Intel.3 C 07 D SS5 / 0A UAINIViAnIV c 07 B 491/04 0 07 B 496/04" (21) Application No. 209/73 '(22) Exit' * 'on 12 Jan 1973 (23) Running day 12 yrs *, 1973 (44) The application submitted and I on the presentation letter published on 4 Feb 1980

DIRECTORATE OF

PATENT AND TRADEMARK (3 °) Priority requested from it

Jan 13 1972, 217627 * US

Feb 14 1972, 226287, US

Oct 12 1972, 297129, US

Oct 12 1972, 297150, US

(71) AYERST MCKENNA & HARRISON LIMITED, 1025 Laurent I and Boulevard, Saint-Haurent, Quebec, CA.

i72) Inventor: Christopher Alexander Demerson, 390 Co. of Vertu St. ,, St. Lau «rent, CA: Leslie George Humber, 75 Maple Circle Road, DQllard des Or = meaux, CA: Andre Alfred TCsselin, 231 Charron Street, Lemoyne, CA: Ivo Ladislav Jirkovsky, 321Cf Forest Hill Road, Montreal 247, CAi George San * by, 4850 Cote de Neiges Road, Montreal, CA: Thomas Albert Dobson, 259 BIscaye Street, Dollard des Ormeaux, CA: Charles Pelz, 115fTBarclet St., Montreal 382, CA. : 74 (74) Plenipotentiary:

The engineering company Budde, Schou & Co.

(54) Analogous process for the preparation of derivatives of pyranolndole, oxazinolndole and indenopyran and their thioanalog or acid addition * salts thereof.

The present invention relates to an analogous process for the preparation of novel derivatives of pyranoindole, oxazino-indole and indenopyran, as well as their thio-analog or acid addition salts thereof. The derivatives prepared by the analogous process of this invention are useful antidepressants of low toxicity. Furthermore, some have anti-ulcer activity.

Pyrano [3,4-b] indole, 1,4-oxazino [4,3-a] indole and indeno [2,1-c] pyran derivatives and their thio analogs have been the subject of little attention so far. In the few literature sites that actually exist, such as H.Plieninger, Chem. Bér., (53, 2; 71 (1950); S. Sakurai and T. Ito, Nippon Kagaku Zagghi, 78, 1665 (1957), [Chem Abstr., 54, 1488 f (I960)]; JA Elvrldge and P.S. Spring, 2 141201 J. Chem., Soa., 2935 (1949) WR Smith and R. Y. Moir, Can. J. Chem., 30, 411 (1952); and N, Campbell et al., J. Chem. Soc. 993 (1963), these derivatives are treated more like chemical curiosities, in which case the known derivatives can be readily distinguished from compounds of the process of the invention by the unsaturation associated with the pyran moiety of their ring system.

Danish Patent Application No. 2719/72 discloses a process for the preparation of anti-inflammatory active compounds by cyclizing tryptophol or indole-3-ethanthiol or substituted derivatives thereof with various aeto acids, keto esters and ketoamides for the preparation of indole derivatives with a pyranindole or thiopyran derivative which carries a substituent at the 1-position containing an acid, ester or amide function. These known compounds also have analgesic, antibacterial and antifungal effects.

It has now been found that application of the process in question to appropriate starting materials can lead to tricyclic pyranindole, oxazinoindole and indenopyran derivatives with an alkylamine side chain.

The novel and therapeutically useful compounds prepared by the present process have, as the free compounds, the general formula CEL · / m

V

R 2 / v (CR 2) n-NR 6 R 7 wherein R 1 is alkyl, R 2 and R 7 are the same or different and represent hydrogen or alkyl, or R and R form together with the nitrogen atom to which they are attached; a heterocyclic amine radical which is 1-pyrrolidinyl, piperidino, morpholino, piperazino, 4-alkyl-1-piperazinyl or 4-hydroxyalkyl-1-piperazinyl, n is an integer of from 1 to 4, x means oxy or thio, and A represents a divalent radical that is 17 • “-ζχΧ -“ - Ca · “· -u- € u (

u I

A1 A2 A3 141201 3

16 17 IS

wherein κ is hydrogen or alkyl, R + is alkyl, and R is hydrogen, alkyl, hydroxy, alkoxy of 1-4 carbon atoms, benzyl-oxy or halogen, wherein said alkyl groups may be straight-chain of 1-6 carbon atoms or branched by 3-4 carbgnatomer.

The present analogous process for preparing the novel compounds of formula (I) is characterized in that a) a compound of formula ch2ch2y (Ha) R16 R17

CH2CH2Y

CH2CH2Y

or R (Πο) 16 17 18 wherein R, R and R have the meaning given above and Y means hydroxy, mercapto, -S-SOgNa or -S-SO 2 -K, in the presence of an acidic catalyst is treated with a compound of formula R1CO- (CH2) n-NR6R7 (III) 167 wherein R, R, r 'and n have the meaning given above, or b) a compound of formula CEL · /'> \ x (iv) \ Wherein R, A, E, X and n are as defined above and R is lower alkyl, hydrolyzed to form the corresponding acid whereupon the acid, if desired after an alkylation at the N atom, is treated with a (lower alkyl) chloroformate to form the corresponding mixed anhydride, the mixed anhydride is treated with an amine of the formula HNR R wherein R and R has the meaning given above to form the corresponding amide and the latter compound is treated with a reducing agent, or c) a compound of the formula

CEL

\ i <*>

V

wherein N, X, R, R, R and n are as defined above, are treated with a reducing agent, or d) a compound of the formula CH0 A f * ( VI) \ / x

C

R · ® (CH,) -O-COR₂O 4 n where A, X, R ^ and n have the meaning given above and R ® ® represents hydrogen or lower alkyl are treated with a hydrolyzing agent to form the corresponding primary alcohol which is treated with a halogenating, mesylating or tosylating agent to form the corresponding halide, mesylate or two-sylate, and this latter compound is treated with an amine of the formula HNR6R7 6 7 wherein R and R are as defined above, or e) a compound of formula 5,

/ 'V

A (VII) \ C ^

X (CH2) n-L

wherein A, X, R and n have the meaning given above / and L means halogen, are treated with an amine of the formula HNR ^ R7 wherein R6 and R7 have the meaning given above, or f) a compound of the formula CH ®2

A I

\ X (VIII) R 2 Ns (CH 2) n-NR 6 C R R 21 where A, X, R 2 ·, R 2 and n have the meaning given above and 21 R represents hydrogen or alHyl of 1-5 carbon atoms, is reduced, or g ) a compound of the formula CH, / CH, AI 2 (IX) ty \ (CH 2) n -B0j where A, X, R 2 and n have the meaning given above are reduced, g 7, then a compound prepared wherein R and / or R is hydrogen, if desired, is alkylated and the compounds prepared, if desired, are converted to a pharmaceutically acceptable acid addition salt.

The acid addition salts are prepared by reacting the corresponding base form of the compound of formula (I) with predominantly one or two equivalents, depending on the number of basic nitrogen atoms in the compound, or preferably with an excess of the appropriate acid in an organic solvent, e.g. or a mixture of ethanol and ether. When administered to mammals, these salts have the same pharmacological effects as the corresponding bases. It is preferred for many purposes to administer the salts rather than the base compounds. Among the acid addition salts suitable for this purpose are such salts as sulfate, phosphate, lactate, tartrate, maleate, citrate, hydrobromide and hydrochloride. Both the base compounds and the salts have the particular advantage of having a relatively low degree of toxicity.

The present invention also relates to the stereochemical isomers of the compounds of formula (I) derived from asymmetric centers contained in these compounds. These isomeric forms can be prepared by various methods and are easily purified by crystallization or chromatography.

Individual optical isomers that can be separated by fractional crystallization of the diastereoisomeric salts formed therefrom, e.g. by D- or L-tartaric acid or D - (+) - α-bromocarbon sulfonic acid are also encompassed by the invention.

The useful antidepressant effect of the compounds of formula (I) and their acid addition salts with pharmaceutically acceptable acids can be demonstrated by standard pharmacological tests, e.g. the experiments described by F. Hafliger and V. Burckhart in "Psychopharma-cological Agents," M. Gorden, published by Academic Press, New York and London, 1964, pages 75-83.

As indicated in the latter literature reference, the antidepressant properties of a compound may be more specifically demonstrated by the compound's ability to counteract the depressant effects of reserpine. Furthermore, it is well documented that reserpine produces a pattern depression in animals which can be used to detect antidepressant properties. Accordingly, the compounds of this invention counteract reserpine effects in mice at doses of from ca. 1 to 100 mg / kg. Several of the preferred compounds, e.g. 1- [2- (Dimethylamino) -ethyl] -1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] -indole oxalate (Example 1), 1-methyl-1- [ 3- (methylamino) propyl] -1,3,4,9-tetrahydropyrano (3,4-b] indole oxalate (Example 9), 1- [2- (dimethylamino) ethyl] -9-ethyl -1-methyl-1,3,4,9-tetrahydrothiopyrano- [3,4-b] indole hydrochloride (Example 41), 1,10-dimethyl-1- [3- (methylamino) propyl] - 3,4-dihydro-1H-1,4-oxazino [4,3-a] indole hydrochloride (Example 55), 1- (3-aminopropyl) -1,10-dimethyl-3,4-dihydro-1H- 1,4-oxazino (4,3-a] indole hydrochloride (Example 56) and Ν, Ν, Ι-trimethyl - 1,3,4,9-tetrahydroindeno [2,1c] thiopyran-1-ethylamine hydrochloride 7 141201 (Example 74), counteracts the effects of reserpine in mice at a dose of from about 1 to 15 mg / kg.

When the present compounds are used, scan antidepressants are used in warm-blooded animals, e.g. rats and mice, they can be used alone or in combination with pharmacologically acceptable carriers, the amount of which is determined by the solubility and chemical nature of the compound, the route of administration chosen, and standard biological practice. For example, they can administered orally in solid form containing such excipients as starch, milk sugar and certain types of clay. They may also be administered orally in the form of solutions or may be injected parenterally. For parenteral administration, they can be used in the form of a sterile solution containing other solvents, e.g. salt or glucose in a sufficient quantity to make the solution isotonic.

The dosage of therapeutic agents containing compounds of formula (I) varies with the form of administration and the specific compound selected. It also varies with the specific host being processed. Generally, the treatment is initiated at small doses that are substantially less than the optimal dose of the compound. Thereafter, the dosage is increased in small portions until the optimal effect according to circumstances is reached. In general, it is most desirable to administer the compounds of this invention at a concentration level which usually yields effective results without causing any harmful or annoying side effects, and preferably at a level ranging from about 10 to about 100. 0.1 mg to approx.

50 mg per kg per today, although as mentioned above, variations occur. A dosage level in the range of approx. 0.5 mg to approx. 25 mg per kg per today is most desirably used to achieve effective results.

1 2

The compounds of formula (I) wherein A and A or A have another useful pharmacological property, i. they are useful anti-ulcer agents. More specifically, the compounds of this invention exhibit anti-ulcer activity in standard pharmacological studies, e.g. the experiment described by D.A. Brodie and L.S. Valitski, in Broc. Soc. Exp.

Biol. Med., 113, 998 (1963), and which is based on the prevention of stress-induced ulcers.

When these compounds of formula (I) are used as anti-ulcer agents, they can be formulated and administered in the same manner as described above for their use as antidepressants.

The starting materials required for the practice of the present process are either known or readily prepared in one of the following ways: When the starting materials have the formula (IIa) wherein Y is hydroxy, they are either known, e.g. tryptophol, described by H.R.

Snyder and F.J. Pilgrim, in J. Am. Chem. Soc. 7, 3770 (1948), or they can be prepared by the following procedure: 7-N-NHO + OH-CEL-CHO-CH-OH-k (X) (XI) I

Referring to this process, phenyl hydrazines of formula (X) and hydroxyaldehyde of formula (XI) are reacted with one another under the conditions of the "Fischer-indole synthesis", cf.

eg. PL Julian, E.N. Myer and H.C. Printy, "Heterocyclic Compounds," R.C. Elderfield, Ed., Volume 3, John Wiley and Sons, Inc.,

New York, 1952, pages 8-11, to form the desired starting material [(IIa), Y = OH].

The phenylhydrazines of formula (X) are either known or can be prepared by known methods. A suitable method involves diazotizing the appropriately substituted aniline to form the corresponding diazo derivative. The latter compound is then reduced with stannous chloride or sodium sulfite to give the corresponding phenylhydrazine, cf. L.F. Fieser and M. Fieser, "Advanced Organic Chemistry," Reinhold Publishing Corporation, New York, 1961, page 734.

The hydroxy aldehydes of formula (XI) are either known, cf. "Rodd's Chemistry of Carbon Compounds," S. Coffey, Ed., Volume 1d, 2nd Edition, Elsevier Publishing Co., Amsterdam, 1965, pages 44-49, or they can be prepared by known methods. A suitable method involves reducing an appropriate lactone of the formula

I I

o-c-ch 2 -ch 2 -ch 20 with bis- (3-methyl-2-butyl) -borane, H.C. Brown and D.B. Bigley, J. Am.

9 141201

Chem. Soc., £ 3, 486 (1961), diisobutyl aluminum hydride, L.T. Zakharkin and I.M. Khorlina, Tetrahedron Letters, 619 (1962), or sodium hydride hydride, L.I. Zakharkin et al., Tetrahedron Letters, 2087 (1963).

The appropriate lactones used in this condensation are either commercially available, e.g. 6-valerolactone, or they are described together with a variety of methods for their preparation in organic chemistry manuals, e.g. the "Methods of Organizational Chemistry" manuals, Houben-Weyl, E. Muller, Ed., Vol. VI / 2,

Georg Hierne Verlag, Stuttgart, 1963, pages 561-852, or L.F. Pieser and M. Fieser, "Advanced Organic Chemistry," mentioned above.

Alternatively, the starting materials of formula (IIa) wherein R R-6 represents hydrogen and Y represents hydroxy can be prepared by lithium aluminum hydride reduction, N.G. Gaylord, "Reduction with Complex Metal Hydrides," Interscience Publishers, Inc., Sew York, 1956, pages 322-370, of compounds of formula (XII) described by T.Y. Shen in U.S. Patent No. 3,161,654: r18-t-CH2COO- (lower alkyl) (XII) 18 wherein R has the meaning given above.

The starting materials of formula (IIa) wherein Y is more than 18-capo, -S-SO 2 -Na or -S-SO 3 ~ K, and R is as defined above, are obtained by the following procedure: The appropriate compound described above of formula (IIa) wherein Y = OH is treated with phosphorus tribromide in an inert solvent, for example, ether, carbon tetrachloride, methylene dichloride or toluene, to give the corresponding 3- (2-bromomethyl) indole derivatives. The latter compound is then converted to the desired starting material of formula '(IIa)' wherein Y = SH, -S-SO3Na or -S-SO3 -K, by a method similar to that of NN Suvorov and VN Buyanov, Khim.- Farm.Zh., 1 ^ 4 (1967), [Chem.

Abstr. 6_7, 73474a (1967)] to convert 3- (2-bromomethyl) indole to indole-3-ethanthiol. Accordingly, the appropriate 3- (2-bromethyl) indole derivative is treated with sodium or potassium thiosulfate to form the corresponding sodium or potassium β- (3-indolyl) ethylthiosulfate derivative, namely the desired starting materials of formula (IIa), where Y = -S-SOgNa or -S-SOgK. Treatment of the latter derivative with strong alkali, e.g. sodium or potassium hydroxide, converting the derivative to the corresponding bis- [Q - (3-indolyl) ethyl] disulfide derivative. Reduction of the latter compound by lithium aluminum hydride gives the desired compounds of formula (IIa) where Y = SH.

Alternatively, the above thiosulfate derivative is treated with acid, e.g. dilute aqueous solutions of hydrochloric acid, sulfuric acid or phosphoric acid to give the latter compound of formula (IIa).

It should be noted that the above process is not entirely feasible in practice for the preparation of the compounds of formula (IIa) wherein Ϋ means mercapto and -S- SO-Na or -S-SO, K, 18 means hydroxy. For this reason, the preferred starting materials of formula (IIa) are for the final preparation of the 18 compounds of formula (I) wherein R is hydroxy, the corresponding 18 compounds of formula (II) wherein R is benzyloxy, and Y is - SH, -S-SOgNa or -S-SOgK, and are readily prepared by the process of the present invention. When the latter compounds are used as starting materials in this way, they are first subjected to the process [(IIa) + (III) -) (I)] described below. The benzyloxy group is then removed by hydrogenation in the presence of a catalyst, e.g. 10S palladium on carbon to give the corresponding compound of formula (I) wherein R is hydroxy. In the same way, it should be noted that a similar application of the 18 designs is preferred

process materials of formula (IIa), where Y is hydroxy, and R

means benzyloxy, to form the corresponding compound of formula (I) wherein R is hydroxy.

Further, when a necessary starting material of formula (IIb) is desired, this starting material is readily prepared from a corresponding indole precursor of formula (XIII) wherein R and R have the meaning given above.

H

The precursors of formula (XIII) are either well known, e.g. skatole and 3-ethylindole, or they can be prepared from indole or known indole derivatives, cf. P-L. Julian at al., "Heterocyclic Compounds", R.C. Elderfield, Ed., Volume 3, John Wiley and ^ ons, Inc.,

New York, 1952, page 1, according to the method of R.; Robinson et al., Described in U.S. Patent No. 2,407,452. ·.

The indole precursor (XIII) is then converted to the desired starting material of formula (IIb) wherein R and R are as defined above and Y is hydroxy, -capto, -S-SOgNa or -S-SO_k 3 - i '^ R17 (Ilb) ch2ch2y

This transformation can be accomplished in several ways. A general method involves reacting the appropriate lithium derivative of the indole precursor (XIII) with ethylene oxide to give the corresponding desired compound of formula (IIb) wherein Y is hydroxy. The desired compound is also obtained by treating the appropriate indole precursor (XIII) with ethylene oxide by the method of M. Julia et al., Bull. Soc. Chim. Fri., 2291 (1966).

An alternative method for the preparation of the necessary starting material of formula (IIb) involves treating the indole precursor (XIII) with an α-haloacetic acid (lower alkyl) ester of the formula LCH2COO- (lower alkyl), where L means halogen in presence of a suitable proton acceptor and preferably using an inert solvent for the reaction. The α-Haloacetic acid (lower alkyl) esters are well known, cf. "Rodd's Chemistry of the Carbon Compounds," S. Coffey, Ed., Volume 1, 2nd ed. Elsevier Publishing Co., Amsterdam, 1965, pages 201-205. Suitable proton acceptors include sodium hydride, alkali metal carbonates and triethylamine. Suitable inert solvents include tetrahydrofuran, benzene, toluene and dimethylformamide. Preferred conditions for the N-alkylation include the use of sodium hydride as proton acceptor and Ν, Ν-dimethylformamide or tetrahydrofuran as inert solvent. Although the optimum temperature and reaction time vary depending on the reactants used, the reaction is usually carried out at the boiling point of the reaction mixture for a period of from 30 minutes to 48 hours.

12 141201

The indole-1-acetic acid (lower alkyl) ester derivative obtained by the above N-alkylation reaction is then hydrolyzed, preferably with a solution of potassium hydroxide in methanol / water, to form the corresponding indole-1-acetic acid derivative which, upon reduction with lithium aluminum hydride gives the desired starting material of formula (IIb) where Y is hydroxy.

When desiring the corresponding starting materials of formula (IIb), where Y is mercapto, -S-SO 2 Na or -S-SO 2 K, a method similar to that of N.N. Suvorov and V.N. Buyanov in the above literature site. More specifically, the present starting material of formula (IIb) wherein Y is hydroxy is treated with phosphorus tribromide in an inert solvent, e.g. ether or carbon tetrachloride, followed by treatment of the product with sodium or potassium thiosulfate to give the corresponding sodium or potassium β- (1-indolyl) ethyl-thiosulfate derivative, respectively, the desired starting material of formula (IIb) wherein Y = -S-SO3Na or -S-SO3K. Treatment of the latter product with strong alkali, e.g. sodium or potassium hydroxide, gives the corresponding bis [cu (indolyl) ethyl] disulfide derivative. Finally, reduction of the latter compound with lithium aluminum hydride gives the desired starting material of formula (IIb) where Y is mercapto.

Alternatively, the above thiosulfate derivative is treated with acid, e.g. dilute aqueous solutions of hydrochloric acid, sulfuric acid and phosphoric acid, to directly form the latter compound of formula (IIb).

Alternatively, the latter starting materials of formula (IIb) wherein Y is mercapto are prepared by oxidation of the corresponding compound of formula (IIb) wherein Y is hydroxy, as described above, with Ν, Ν-dicyclohexylcarbodiimide and dimethylsulfoxide in the presence of a suitable acid , eg. trifluoroacetic acid, cf. K.E. Pfitzner and J.G. Moffat, J. Amer. Chem. Soc., 87, 5670 (1965) to form the corresponding aldehyde derivative. The same aldehyde derivative is also obtained by N-alkylation of the appropriate indole precursor (XIII) with an appropriate α-halo-acetaldehyde derivative (cf. "Rodd's Chemistry of the Carbon Compounds", cited above, vol. 1c, pages 24-26 ) under the conditions described above for N-alkylation with α-haloacetic acid (lower alkyl) esters.

The latter aldehyde derivative is converted to the corresponding gem-dithiol derivative with hydrogen sulfide which is reduced with lithium aluminum hydride by that of T.L. Cairns et al. in J. Amer. Chem. Soc., 13, 141201 74, 3982 (1952), described the method of forming the desired starting material of formula (IIb) wherein Y is

It should also be noted here that the above methods may not be entirely feasible in practice for the preparation of the compounds of formula (IIb) wherein Y is hydroxy, mercapto, 18 -S-SOgNa or -S-SOgK, and R is hydroxy. For this reason, the preferred indole precursors (XIII) for the final preparation 18 of the compounds of formula (I) wherein R is hydroxy are the indole 18 precursors of formula (XIII) where R is benzyloxy, i.e. hydroxyl with a protective benzyl group or other suitable protecting group (cf. JFW McOmie, "Advances in Organic Chemistry", Vol. 3, RA Raphael, et al., Eds., Interscieace Publishers, New York, 1963, pages 191-294) . Following the appropriate conversions described below, the benzyloxy group is removed by hydrogenation in the presence of a catalyst, e.g. 10% palladium on carbon, immediately preceding the preparation of the desired corresponding compound of formula (I) wherein R is hydroxy.

Furthermore, the necessary starting materials of formula (Ile) are either known or can be readily prepared. More specifically, the starting material of formula (Ile), indene-3-ethanol is well known, and the synthesis of it by a variety of methods is described, cf. GR Clemo et al., J. Chem, Soc., 863 (1951) and P.H.

Howell and D.A.H. Taylor, J. Chem. Soc., 3011 (1957). Suitable for the preparation of this starting material as well as the other necessary starting materials of formula (Ile) wherein Y is hydroxy are the following two general methods.

The first process for preparing the present starting material of formula (Ile) is illustrated as follows:

Cl

CH CH COOH

«IV) 2C00R

On,

(XVI) -r-CH, CH, OH

^ —F ___ ζ f \ ΓΤ 2 2 CHC00R27 ^^^ R18 (XV) R1 (IIC)

Y = OH

R18 (XVII) 14 141201

With reference to this first process, the cyclization of the appropriate phenylpropionic acid derivative (XIV), see "Chemistry of Carhon Compounds", Vol. IIIA, E.H. Rodd, Ed.,

Elsevier Publishing Co., Amsterdam, 1954, pages 593-598, in treating with an acid, e.g. anhydrous hydrogen fluoric acid, under those of J.A. Elvidge and R.G. Foster in J. Chem. Soc., 590 (1963) described conditions for forming the corresponding indanone of formula (XV).

The latter compound is treated with an appropriate Reformat 22 skii reagent of the formula LCH 2 COOR wherein L represents bromine or chlorine and R represents lower alkyl, followed by dehydration of the product, cf. "Organic Reactions", Volume 1, R. Adams et al., eds.,

John Wiley and Sons, Inc., New York, 1942, and K. Brewster et al., J. Chem. Soc., 941 (1972), to form a mixture of the "Endo" ester (XVI) with the "exo" ester (XVII). The ester (XVI) or the mixture of esters (XVI) and XVII) is then reduced with lithium aluminum hydride and the desired compound of formula (Ile) where Y = OH is separated from the reaction product by conventional methods such as chromatography or recrystallization.

The second process for preparing the present starting material of formula (Ile) is illustrated as follows:

Cd +. * r18 '(XVIII) (XIX)

r18_0 [j] -CH2CH2OH

(IIe)

Y = OH

Referring to this second method, the appropriate indene derivative of formula (XVIII), cf. "Chemistry of the Carbon Compounds", Vol. Chem., 4859 (1961), and M.L. Tamayo and N.D. Robles, Anales Real Soc. Espan. Fis. Y Quim., 52B, 117 (1956) [Chem. Abst., 50, 14676 (1956)], to the corresponding lithium derivative by treatment with butyllithium in tetrahydrofuran.

The corresponding lithium derivative is then treated with ethylene oxide to give the desired starting material of formula (11c) where Y is hydroxy. The desired starting materials can also be obtained by treating the appropriate indene derivative of formula (XVril) with ethylene oxide by the method of M. Julia et al., Bull. Soc.

Chim. Pr., 2291 (1966) for reaction of ethylene oil with indole.

The starting materials of formula (Ile) wherein Y is mer-capto, -S-SO 2 Na or -S-SO-jK are prepared by the following procedure: The appropriate compound of formula: (IIc) wherein Y * OH, described above , is treated with phosphorus tribromide in an Indifferent solvent, e.g. ether or carbon tetrachloride to form the corresponding 3- (2-bromomethyl) indene derivative. When R is hydrogen, the corresponding corresponding 3- (2-bromethyl) indene derivative is itself the 3- (2-bromethyl) indene, also described by R. Clemo et al., J. Chem. Soc. 863 (1951). The 3- (2-bromomethyl) indene derivative thus obtained is then converted to the residual desired starting material of formula (Ile) by a similar procedure to that of N.N. Suvorov and V.N. Buyanov in Khim.-Farm. Zh., 1, (1967), [Chem. Abstr. 6T_t 73474a, (1967) 1 described for the conversion of 3- (2-bromomethyl) indole to indole-3-ethanthiol. In accordance *? In doing so, the appropriate 3- (2-bromomethyl) indene derivative is treated with sodium or potassium thiosulfate to give the corresponding sodium or potassium β- (3 "indenyl) ethyl-thiosulphate derivative, respectively, the desired starting materials of formula ( £ Ic), where Y means -S-SO3 Na or -S-SO ^ K. Subsequent treatment of the latter derivative with strong alkali, e.g. sodium or potassium hydroxide, converts the derivative to the corresponding bis- [co- (3-indenyl) ethyl] disulfide derivative. Reduction of the latter compound by lithium aluminum hydride gives the corresponding desired compound of formula (Ile) where Y = SH.

Alternatively, the above thiosulfate derivative is treated with acid, e.g. dilute aqueous solutions of hydrochloric acid, sulfuric acid or phosphoric acid, to directly produce the latter compound of formula (Ile).

It should again be noted that the above process is not entirely feasible in practice for the preparation of the compounds of formula (Ile) where Y is mercapto and R is hydroxy. For this reason, the preferred starting materials of formula (Ile) to 18 are the final preparation of the compounds of formula (I) wherein R is hydroxy, the corresponding compounds of formula (Ile) wherein R is benzyloxy, i. a hydroxyl having a protecting benzyl group or other suitable protecting group, cf. J.F. McOmie, discussed above.

-When the latter compounds are used as starting materials in this way, they are first subjected to the procedure described below [(IX) + (III) -► (I)]. Then the benzyloxy group is removed by hydrogenation in the presence of a catalyst, e.g. 10% palladium on carbon, immediately preceding the preparation of the desired corresponding compound of formula (I) wherein R is hydroxy.

Similarly, it should be noted that a similar use of the starting materials of formula (Ile) wherein 18 Y is hydroxy and R is benzyloxy is preferred, to give 18 the corresponding compound of formula (I) where R is hydroxy .

In the practice of the condensation [(II) + (III) - (1)], it is generally advantageous to use practically equimolar amounts of the starting material of formula (II) and the aminoketone compound of formula (III) in the presence of an acidic catalyst. .

Usually, a solvent is used as the reaction medium for the condensation. Suitable solvents include, e.g. aromatic hydrocarbons such as benzene or toluene, ethers and cyclic ethers such as diethyl ether, dioxane or tetrahydrofuran, and halogenated hydrocarbons such as methylene dichloride or carbon tetrachloride. Benzene and toluene are particularly suitable and useful for this application. For this condensation, a variety of suitable acidic catalysts, e.g. the type of catalyst used in a Friedel-Crafts reaction, i.e. p-toluenesulfonic acid, aluminum chloride, phosphorus pentoxide, boron trifluoride, zinc chloride, hydrochloric acid, perchloric acid, trifluoroacetic acid, sulfuric acid and the like. Among the preferred acidic catalysts are p-toluenesulfonic acid, aluminum chloride, boron trifluoride and phosphorus pentoxide. The amount of acid catalyst used is not very critical and may range from 0.01 molar equivalents to 100 molar equivalents; however, a range of 0.1 to 10 molar equivalents is usually preferred. It should also be noted that in the case where the reactants (II) and / or (III) contain basic nitrogen atoms (different from the indolic nitrogen atom), the amount of acidic catalyst used should be greater than that required to neutralize such nitrogen atoms. . The reaction time can range from 10 minutes to 60 hours and the preferred range is from 1/2 to 24 hours. The reaction temperature can range from -20 ° C to the boiling point of the reaction mixture. Preferred temperature ranges are at 20 to 160 ° C.

A more detailed description of the preparation of the annelled indole and indene derivatives of formula (I) and their corresponding thio analogs as well as the intermediates of the methods; b) to g) and their conversion to the desired compounds of formula (I) are given below.

(a) Preparation of Compounds of Formula (I)

The starting materials of formula (II) described above are condensed in the presence of an acidic catalyst with an amino ketone of the formula R RO-tCEL) -NR6R7, wherein R,, n, R6 and R7 have the above-mentioned mt I producing the compounds of formula (I).

The required amino ketones for this reaction are either known, e.g. 1-dimethylamino-3-butanone and 1-methylamino-3-penta-non, cf. F.F. Sheets referred to above or they can be produced by known methods, cf. "The Method of Organic Chemistry", discussed above, Vol. XI / I, 1957, pages 58-62, 285-289 and 508-509.

In the practice of this condensation, it is usually advantageous to use practically equimolar amounts of the starting material of formula (II) and the amino ketone in the presence of an auric catalyst. At this specific condensation, the amount to be used of the above acidic catalyst generally ranges from about 1 to about 1. 1.01 to 100 molar equivalents, attributed to the amount of the aminoketone reactant, with a range of 1.05 to 10 molar equivalents being preferred. It should be noted that the lower limit of the amount of acid catalyst used is dependent on the number of basic nitrogen

6 T

atoms present in the amino ketone. If R and R in the amino ketone together with the nitrogen atom to which they are attached represent a piperazine radical (i.e., there are two basic nitrogen atoms present), e.g. a minimum of 2.01 mb equivalents of acidic catalyst is used. Optionally, the acid addition salts of the above amino ketones, e.g. hydrochloride or sulfate salt is used. In this case, the amount of acid catalyst may range from 0.01 to 100 molar equivalents, preferably from 0.1 to 10 molar equivalents. Boron trifluoride is a preferred acid catalyst for the condensation. The reaction can be conveniently and advantageously carried out without a solvent, although a higher boiling solvent, e.g. toluene, o-xylene or isobutyl ether. When the solvent is omitted, it is desirable to heat the reactants to a melt and to stir the melt in an inert atmosphere, e.g. nitrogen or helium. Reaction time and temperature depend on the specific reactants used and can be varied.

The most convenient reaction time is from 1/2 to 48 hours, preferably from 1/2 to 4 hours, and the most convenient reaction temperatures are from 20 to 200 ° C, preferably 60 to 140 ° C. In each case, the reaction is preferably carried out at the lowest temperature at which the reaction proceeds smoothly and rapidly with a minimum of decomposition.

When the starting material is a material of formula (II) wherein Y is -S-SO 2 Na or -S-SO 2 K, it is preferred that there is at least one equivalent of water present in the reaction mixture. This water may be added directly to the reaction or it may be included as part of the acidic catalyst. Examples of the latter case are those cases where p-toluenesulfonic acid containing crystallization water or concentrated hydrochloric acid is used as the acidic catalyst.

Intermediates of formula (IV) are readily obtained by condensing compounds of formula (II) with keto esters of formula R1-C0- (CH2) n_1 -COOR19 (XX) in an analogous manner as described under (a).

Ester intermediates of formula (IV) are readily converted to their corresponding acids by treatment with a hydrolyzing agent, e.g. a suitable alkali, e.g. potassium hydroxide or sodium carbonate, in aqueous methanol or aqueous ethanol or by treatment with lithium iodide in a suitable organic solvent, e.g. collidin, cf. L.F.

Fieser and M. Fieser, "Reagents for Organic Synthesis," John Wiley and Sons, Inc., New York, 1967, pages 615-617.

The α-, β- / Y and δ-ketoacid esters of formula (XX) used in the condensation are either known, e.g. pyruvic acid ethyl ester, ethyl α, α-dimethylacetoacetate and β, β-dimethyllevulinic acid ester, or they can be prepared by known methods described in common organic chemistry manuals. A comprehensive account of the properties and preparation of such α, β, γ and δ ketoacetic esters can be e.g. can be found in "Rodd's Chemistry of the Carbon Compounds", cited above, Vol. Id, pages 226-274.

19 141201

The acid intermediate is then subjected to a treatment with a (lower alkyl) chloroformate, preferably ethyl chloroformate, in the nitrate of triethylamine to produce the corresponding mixed anhydride which is converted by treatment with the appropriate g 7 g of 7 amine of the formula HNR R wherein R and R 'has the meaning given above, e.g. ammonia, methylamine or dimethylamine, to produce the corresponding amide.

Then, the amides thus obtained are treated with a reducing agent, e.g. a suitable complex metal hydride, to prepare the desired compounds of formula (I). Examples of suitable complex metal hydrides are lithium aluminum hydride, lithium aluminum hydride aluminum chloride, aluminum aluminum hydride aluminum chloride, dlborane and sodium borohydride alumina chloride. Lithium aluminum hydride is preferred.

Two aspects of the latter reduction of the amides are worth noting. The first aspect relates to the reduction of the above amides wherein R is hydrogen and R is lower alkyl, i.e. secondary amides, for their corresponding compounds of formula (I)> ie. secondary amines. In this case, a modification of the above method in the manner below is among the preferred methods. The above acid or ester intermediate is reacted with g 7 g 7 amine of the formula HNR R wherein R is benzyl and R is lower 7 alkyl corresponding to R in the desired amine. This step is performed in accordance with the amidation step described above. The resulting amide is then reduced with a complex metal hydride according to the above procedures. Then the benzyl group is removed by hydrogenolysis in the presence of a catalyst, preferably 10% palladium on carbon, to give the desired secondary amine compounds of formula (I).

The second aspect relates to a more general modification of the reduction of the above amides. This modification can be applied to the reduction of the tertiary, secondary and primary amides and is a preferred modification for the reduction of the latter two. In carrying out this modification, the above amide is treated with triethyl oxonium fluoroborate, cf. R.F. Borch, Tetrahedron Letters, no. 1, 61 (1968), or dimethyl sulfate, cf. H. Bredereck et al., Chem. Ber., 98, 2754 (1965) in an Indifferent solvent, e.g. mephchylene dichloride to give the corresponding iminoether fluoroborate and methyl sulfate salt, respectively. Subsequent reduction of the salt thus obtained with a complex metal hydride by the above-described amide reduction process gives the desired compounds of formula (I). Alternatively, the above fluoroborate or methyl sulphate salt originating from a secondary or primary amide can be decomposed by treatment with base, e.g. with 10% sodium hydroxide solution or triethylamine to give the corresponding imino ether derivative which is then similarly reduced to the desired compound of formula (I).

Alternatively, the compound of formula (I) wherein 1 16 A is A and R is lower alkyl is prepared by subjecting the acid or ester intermediate, wherein R is H to N-alkylation by treatment with a molar excess of an appropriate alkylation. agent, e.g. a (lower alkyl) halide, in an inert solvent in the presence of a proton acceptor. Suitable inert solvents include tetrahydrofuran, benzene, toluene and dimethylformamide. Suitable proton acceptors include sodium hydride, alkali metal carbonate and triethylamine. Preferred conditions for carrying out this N-alkylation involve the use of sodium hydride as proton acceptor and tetrahydrofuran as inert solvent. Although the optimum temperature and reaction time vary depending on the reactants used, the reaction is generally conducted at the boiling point of the reaction mixture for a period of from 30 minutes to 48 hours.

In this way, the corresponding N-alkylated derivatives of the above acid and ester derivatives are obtained. Next, these derivatives are subjected to the amidation and reduction steps under the conditions described above in this section to produce the desired compounds of formula (I) wherein A is A 1 and R 6 is lower alkyl.

Although the above step sequence for the conversion of the acid 16 and ester intermediates, where R = H, to the corresponding compounds of formula (I) is convenient and effective, gives a change in the order in which the amides are treated with the appropriate organic halide at the above described N-alkylation conditions, followed by reduction with a complex metal hydride, as described above, likewise the aforementioned desired compounds X 16 of formula (I) wherein A is A and R is lower alkyl.

Using the above steps in the preparation of 18 compounds of formula (I) wherein R is hydroxy, it is preferable to use corresponding intermediates where R is benzyl oxy, followed by the appropriate conversions as previously indicated to produce the desired compounds of formula (I). (C) Preparation and conversion of intermediates of formula (V)

The intermediates of formula (V) are prepared by condensing the appropriate starting materials of formula (II) and ketoamides of formula.

R ^ OiCHj) .JCONR ^ R7 (XXI)

The ketoamides required for this condensation are either known, e.g. pyruvic acid amide or α, α-dimethylacetoacetamide, or they can be prepared by known methods, cf. "Rodd's Chemistry of the Carbon Compounds," mentioned above, Vol. Id, pages 226-274.

Next, these amides of formula (V) are converted by the above-described reduction process to the compounds of formula (I).

ld) Manufacture and conversion of ^ llex products ^ icfed fgrmel ^^ yi).

Intermediates of formula (VI) are obtained when a starting material of formula (II) is condensed with a ketoalcohol (lower alkanoic acid) ester of formula R formOiCH. OCOR20 (XXII) 2 n 20 2 where R and R have the above meaning, in the presence of 3, a suitable acid catalyst under the conditions described above 4 for the condensation [(11) + (III) -> (I) J. The keto alcohol (lower 5 alkyl) esters are either known, e.g. acetonyl acetate or 5-acetoxy-pentan-2-one, or they can be prepared by known methods, cf. "Rodd's Chemistry of the Carbon Compounds," cited above, Vol. Id, pages 49-54.

6

These intermediates of formula (VI) can then be used for the preparation of compounds of formula (I) of the present invention in the following manner. The intermediate is hydrolyzed by treatment with a hydrolyzing agent, e.g. an aqueous alcoholic solution of a suitable alkali, e.g. sodium hydroxide in aqueous methanol to give the corresponding primary alcohol.

7

The primary alcohol is then treated with a suitable halogenating, mesylating or tosylating agent to produce a reactive intermediate / namely the corresponding halide, mesylate or tosylate, respectively, which can then be reacted with two or more 6 7 6 7 molar equivalents of an amine of the formula HNR R wherein R and R are as defined above. This reaction is preferably carried out in a suitable inert solvent, e.g. tetrahydrofuran, at 40-100 ° C or at the boiling point of the reaction mixture for a period of from 8 to 24 hours. In the case of alkylations of amines of the formula HNR R, wherein R is hydrogen and R is lower alkyl, as described above, it is generally more advantageous to perform the alkylation with the corresponding N-benzyl derivative of the amine, i.e. . an amine of the formula HNR R 'wherein R is 7 benzyl and R is lower alkyl. When all appropriate conversion is complete, the N-benzyl group can then be removed by hydrogenolysis with a catalyst, preferably 10% palladium on carbon, to give the desired compounds of formula (I).

6 7

Compounds of formula (I) wherein R and R are hydrogen can be N-alkylated at the nitrogen atom of the primary amine with the appropriate (lower alkyl) halide for the corresponding compounds.

of formula (X) wherein R is hydrogen or lower alkyl, and R

means lower alkyl (i.e., secondary or tertiary amines). Depending on the specific desired derivative, the N-alkylation in this case can be carried out with one or two moles of the alkyl halide to produce the secondary and tertiary amines, respectively. On the other hand, the N-alkylation can be carried out in two steps, introducing a different alkyl group each time to provide the corresponding tertiary amine, wherein R and R are different lower alkyls.

When it is desired to prepare the above-described tertiary amine compounds wherein one of R and R 'or both means methyl, an alternative alkylation method comprises reacting the appropriate corresponding primary or secondary amine with an aqueous mixture of a substantial excess of formaldehyde and formic acid under the conditions of the Eschweiler-Clarke reaction, cf. ML Morre, Organic Reactions, 5, 301 (1949), thereby conducting N-methylation.

Another N-alkylation method that can be applied to the primary and secondary amines described above involves keylation with a (lower alkanoic acid) anhydride or acid halide and subsequent reduction of the amide formed.

23 141201

The above primary amines can also be used to produce corresponding compounds of formula (I) wherein R and R together with the nitrogen atom to which they are attached form a heterocyclic amine radical as defined above. When the primary amines are used in this way, the known N-alkylation methods, e.g. by treatment with a divalent alkylating agent, cf. Method J. described by R.B. The Moffet in J. Org. Chem., 14, 862 <1949), with the appropriate α, ω-dibromides, e.g. tetramethylene dibromide, pentamethylene dibromide, bis (2-chloroethyl) ether, bis- (2-chloroethyl) benzylamine, followed by hydrogenation in the reaction of 10% palladium on carbon to remove the protecting benzyl group, a bis- (2). -chlorethyl) - (lower alkyl) amine or a bis- (2-chloroethyl) - -N- [hydroxy- (lower alkyl)] amine to give the corresponding compound of formula (I) wherein R and R together with the nitrogen atom to which they are attached form a heterocyclic amine radical, i.e. a pyrrolidino, piperidino, morpholino, piperazino, 4- (lower alkyl) -1-piperazinyl or 4- [hydroxy (lower alkyl)) -1-piperazinyl group, respectively.

Intermediates of formula (VII) are obtained when a starting material of formula (II) is condensed with a β-, γ- or δ-halogen ketone of formula R1-C0 (CH2) nL (XXIII) in the presence of a suitable acidic catalyst under the conditions , described above for the condensation [(II) + (III) - ► (I)]. The halogen ketones are either known, e.g. 4-chlorobutan-2-one or they can be prepared by known methods, cf. Rodd's Chemistry of Carbon Compounds, cited above, Vol Ic.r pages 70-71, and "Methoden der Organischen Chemie", Houben-Weyl, E. Muller, Ed., Vol V / 3,

Georg Thieme Verlag, Stuttgart 1962, pages 511-1076.

Then these intermediates of formula (Vil) 6 7 6 are treated with a 2 molar excess of an amine of the formula HNR ° R, wherein R and R have the meaning given above, to produce the compounds of formula (I). This reaction is preferably carried out in a suitable inert solvent, for example, tetrahydrofuran, at the boiling point of the reaction mixture for a period of from 8 to 24 hours.

24 141201

Intermediates of Formula (VIII) are readily obtained by condensing the compound of Formula (II) with ketoamides of Formula R 2 CO (CHO) NR 6COR21 (XXIV) 2 n

The ketoamides used herein are either known, e.g. formamidoacetone [A. Treibs and W. Sutter, Chem., Ber., £ 8, 96 (1951)], cf. also R.H. Wiley and Q.H. Borum, J. Amer. Chem. Soc., TQ_, 2005 (1948), or they can be prepared by known methods, cf. "The Method of Organizational Chemistry," mentioned above, Vol. XI / 1, 1957, especially pages 58-62, 285-289 and 508-509, and F.F. Blikke, Organic Reactions, 1, 303 (1942).

Thereafter, treatment with a complex metal hydride converts the present intermediates of formula (VIII) into the compounds of formula (I).

(g) Preparation and preparation of intermediates by formula _ (IX)

Intermediates of formula (IX) are obtained by condensing the starting materials of formula (II) and appropriate α, β, γ and ό nitroketones of formula R 2 CO (CHO) -NOO (XXV) 2 n 2 in the presence of a suitable acidic catalyst. In this case, trifluoroacetic acid is the preferred acidic catalyst.

The nitroketones used herein are either known, e.g. 1-nitro - 2-propanone, N. Levy and C.W. Scaife, J. Chem. Soc., 1100, (1946) and 5-nitro-2-hexanone, H. Shechter et al., J. Amer. Chem. Soc. J7, 3664 (1952), or they can be prepared by known methods, cf.

Levy and Scaife, cited above, Shechter et al., Cited above, "Rodd's Chemistry of Carbon Compounds," cited above, Vol. Ic, pages 71-72, and "the method of Organizational Chemistry" cited above, Vol. X / l, 1971, page 203.

Next, these intermediates of formula (IX) are reduced by a complex metal hydride, preferably lithium aluminum hydride, 67 to provide the compounds of formula (I) wherein R and R are hydrogen.

If desired, the latter compounds can be N-alkylated by the methods described in section (d) for the preparation of the compounds of formula (I), wherein R and R are as defined in claim 1.

25 141201

The following examples serve to further illustrate the process of the present invention. ·

Example_l Step_A. Section 1).

1-Methyl-l, 3,4,9-tetrahydro-pyrano [3,4-b] indole-l-acetic acid [(IV); A = A1, where R16 and R18 - H, g1 * CHj, X »O, n * 2, R19 = H].

23.4 g (0.18 mol) of ethyl acetoacetate are added to a solution of the starting material of formula (IIa), 10.0 g (0.06 mol) of tryptophol, in 20 ml of benzene. After standing for 10 minutes, 1.3 g of p-toluenesulphonic acid and ca. 5 g of hydrated alkali-aluminum silicate (molecular sieve # 4). The mixture is refluxed for 30 minutes, an additional 600 mg of p-toluenesulfonic acid is added and the reflux is continued for 2 1/2 hours. The molecules are collected and the benzene solution is washed successively with 5% sodium bicarbonate and water, dried over sodium sulfate and evaporated under reduced pressure to dryness to give an oil. The oil is subjected to chromatography on silica gel. Elution with 5% ether in benzene gives the ester, 1-methyl-1,3,4,9- -tetrahydropyrano [3,4-b] indole-1-acetic acid ethyl ester, in the form of an oil, 0 1715 cm -1.

* max

Hydrolysis of this ester to the title compound is carried out as follows; The ester is dissolved in 230 ml of methanol. To this is added 10 g of KOH in 30 ml of 0, and the mixture is allowed to stand at room temperature overnight. The methanol evaporates to which water is added and the solution is washed with benzene. The aqueous phase is acidified with 6 N HCl and extracted with benzene. This organic phase is washed with water, dried over sodium sulfate and evaporated to dryness to give an oil which is crystallized from benzene containing a trace of petroleum ether to give the title compound (No. A1), m.p. 150-152 ^, ^^^^ 3 3325 and 1705 cm

An equivalent amount of methyl acetoacetate may replace ethyl acetoacetate in the implementation of this section. In this case, 1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] ipdole acetic acid methyl ester is obtained, m.p. 87-90 ° C after recrystallization from a mixture of benzene and hexane as the ester.

An equivalent amount of propylacetoacetate can replace ethyl acetoacetate by the process of this section. In this case, 1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid propyl ester is obtained as the ester.

26 141201

An equivalent amount of N-methyltryptophol may replace tryptophol by the method of this section. In this case, 1,9-dimethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid is obtained, m.p. 105-108 ° C after recrystallization from benzene. The product is identical to the product described as Compound No. A10 with the same name.

A similar substitute with N-ethyltryptophol gives 9-ethyl-1-methyl - 1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid identical to that described as Compound No. All product.

Section 2).

1-Methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-propionic acid [(IV);

A = RliOvC

i16 where R16 and R18 = H, R1 = CH3, X = O, n = 3, R19 = H].

A mixture of the starting material of formula (IIa), 500 mg tryptophol, 580 mg levulinic acid, 75 ml benzene, 1.7 g phosphorus pentoxide and ca. 0.5 g of diatomaceous earth (celite) is magnetically stirred at room temperature for 15 minutes and then at 70 ° C for 1 1/2 hours. The reaction mixture is filtered. The filtrate is washed three times with 5 N NaOH. The combined aqueous phase is washed twice with ether and then acidified with cold 50% HCl. The aqueous phase is extracted with chloroform. The chloroform extract is dried (Na 2 SO 4) and evaporated to dryness. The residue is crystallized from a mixture of ethyl acetate and petroleum ether to give the title compound (No. A2), m.p. 104-110 ° C, NMR (CDCl 3) δ 1.47 (3H), 21.8 (4H), 2.74 (2H), 3.96 (2H), 7.18 (4H), 7.85 ( 1H) and 9.60 (1H).

The title compound is also obtained by proceeding in the manner specified in section 1), but replacing ethyl acetoacetate with an equivalent amount of ethyl levulinate. In this case, 1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] -indole-1-propionic acid ethyl ester is obtained, m.p. 116-118 ° C, 9 ^ ax ^ 8 1716 cirT ^, after crystallization from a mixture of benzene and petroleum ether as the ester prior to hydrolysis.

Section 3).

1-Methyl-1,3,4,9-tetrahydrothiopyrano [3,4-b] indole-1-acetic acid [(IV); A = A1, where R16 and R18 = H, R1 = CH3, X = S, n = 2, R19 = H].

1.5 g of indole-3-ethanethiol and methyl acetoacetate are mixed with 50 ml of benzene and the solution is heated for 30 minutes (bath temperature 27-70 ° C). 0.15 g of p-toluenesulfonic acid is added and the reaction mixture is refluxed and stirred for 12 hours. The water formed in the reaction mixture during this time is collected by means of a water separator. After cooling, the benzene solution is washed with a 10% solution of sodium bicarbonate, water and saturated brine, and dried over sodium sulfate. Evaporation of the benzene solution gives the ester, 1-methyl-1,3,4,9-tetrahydrothiopyrano [3,4-b] indole-1-CHCl-1-acetic acid, as a semi-solid, -? 3 1715 cm, mdx

This ester is then treated with aqueous alcoholic KOH in the manner described for the esters in sections 1) and 2) to provide the title compound (No. A3), m.p.

147-149 ° C, NMR (CDCl 3) δ 1.86 (S, 3H), 306 and 812 (6H), 7.35 (multiplet, 4H), 8.71 (1H), 10.31 (1H) after recrystallization from a mixture of benzene and hexane.

Proceed as described in section 1) or 3) for the preparation of other compounds of formula (IV). Examples of such compounds of formula (IV) are listed in Table I.

In each of these examples, an equivalent amount of the starting material of formula (Ila) is used instead of the starting material of formula (Ila) described by the method of sections 1) and 3).

Similarly, the method described in section 2) is used to produce the products listed in Table I. In this case, an equivalent amount of the starting material of formula (Ila), instead of the starting material of formula (Ila) described in the tables, is used, and an equivalent amount of the corresponding keto acid ester is used instead of the section 2) listed keto ester.

28 141201 ό Ρ * - ρ g - o α o o O (0 M ** - O O 00>, p co H co O CN -a1 Μ m - B a m «a * o m oo

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Step B.

N, N, 1-Trimethyl-1,3,4,9-tetrahydropyrano [3,4-b] indp-1-acetamide [(V), A = A1, where R16 and R18 = H, R1 = CHEg, X = O, n = 2, R6 and R7 = CH3].

To a stirred solution of 15 g (0.061 mol) of 1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid, prepared in the manner described in step A, section 1) , in 300 ml of dry tetrahydrofuran, cooled to -5 ° C, is added 18.5 g (0.183 mol) of triethylamine followed by 16.6 g (0.153 mol) of ethyl chloroformate. The mixture is stirred at -5 ° C for 2 hours. This mixture, now containing the mixed anhydride of the above starting material, is added dropwise to 225 ml of cooled 40% aqueous solution of the amine, dimethylamine. The resulting mixture is stirred at room temperature for 1/2 hour. Most of the tetrahydrofuran is evaporated and the residue is partitioned between chloroform and water.

The organic phase is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel. Elution with 20% ethyl acetate in benzene, followed by crystallization of the eluate from ethyl acetate gives the title compound (No. B1), m.p. 149-r51 ° C,> 33 ° 3333, η max 1634 cm.

Similarly, replacing the 40% aqueous solution of dimethylamine with an equivalent amount of concentrated ammonium hydroxide, 30% aqueous solution of methylamine, 30% aqueous solution of diethylamine, 70% * aqueous solution of Ethylamine, 50% aqueous solution of pyrrolidine, piperidine, morpholine or N-methyl-piperazine is obtained respectively 1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acephamide (compound No. B2), m.p. 158-160 ° C, N> 1-dimethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetamide (Compound No. B3), m.p. 138-140 ° C, N, N-diethyl-1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetamide (Compound No. B4), m.p. 99 ° ^^ 3 3350, 1-620 cm -1, max N-ethyl-1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetamide (Compound no. B5), mp 152-153 ° C, 1 - [(1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) -acetyl] -pyrrolidine, (compound No. B6), mp 119-120 ° C, 1-t (1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) -acetyl] -piperidine ( Compound No. B7), mp 148-149 ° C, 1 - [(1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) -acetyl] -morpholine, (Compound No. B8), mp 141-142 ° C, and 1-methyl-4 - [(1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole) 1-yl) -acetyl] -piperazine (Compound No. B9) When used in the manner described above in Step B, but using as the starting material an equivalent amount of one of the acid compounds No. A2-A9 of formula ( IV) described under Step A instead of 1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid and using an equivalent amount of an appropriate amine such as ammonia or a primary or secondary amine, described In step B above, the corresponding amide compound of formula (V) is obtained. Examples of such amides are listed as products in Tables II and III together with the starting material and amine used to prepare the amide.

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Step C.

1- [2- (Dimethylamino) -ethyl] -1-methyl-1,3,4 (9-tetrahydropyrano- [3,4-b] indole [(I); A = A1, where R16 and R3.8. * S, R1 - C4, X -O, n = 2, R6 and R7 = CH-].

__________________: 2 --..--, ----------- Λ .- '' -, ----------------

A solution of 5.0 g (0.01 $ mole) of N, N, i-trimethyl-T, 3,4,9 * -tetrahydropyrano [3,4-b] indole-1-acetamide, prepared as described below Step B, Compound No. B1, is added to a cooled, well-stirred mixture of 1.4 g (0.036 mol) of lithium oil aluminum carbohydrate in 200 ml of ether. Stirring is continued at room temperature at room temperature and the mixture is heated under reflux for 12 hours.

After cooling in an ice-water bath, 6.2 ml of water is added dropwise to destroy excess hydride. Next, an additional 100 ml of water is added and the ether phase is decanted. The aqueous phase is extracted once with benzene. The combined organic phases are washed with water, dried over sodium sulfate and evaporated to dryness to give 5 g of oil which crystallizes on standing. 133-135 ° C, NMR (CDCl 3) δ 1.53 (s, 3H), 2.07 (2H), 9.74 (1H), 10.55 (6H).

The corresponding oxalic acid addition salt (oxalate), 1 - [(2-dimethylamino) ethyl] -1-methyl-1,3,4,9-tetrahydzopyrano [3,4-b] indole oxalate, has m.p. 181-183 ° C after crystallization from a mixture of methanol and ether.

Similarly, but replacing lithium aluminum hydride with an equivalent amount of lithium aluminum hydride-aluminum chloride, aluminum hydride-aluminum chloride, diborane and sodium borohydride-aluminum chloride, the title compound is also obtained.

Example 2-8 In the manner described in Example 1, step C, but substituting Ν, Ν, Ι - trimethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetaraide with an equivalent amount of the amides No. B2, No. B3, No. B4, No. B6, No. B7, No. B8, and No. B9, respectively, are given in 1- (2-aminoethyl) in Example 1 - 1-methyl-1,3,4,9-tetral} ydropyrano [3,4-b] indole, m.p. 80-84 ° C ·? 3455, 3280 CNF1 (Example 2), max. 1-methyl-1- [2- (methylamino) ethyl] -1,3,4,9-tetrahydropyrano- [3,4-b] indole, m.p. 160 ° C 163¾ (m.p. for the corresponding oxalic acid addition salt 140-144 ° C) (Example 3), 34 141201 1- [2- (diethylamina) ethyl] -1-methyl-1,3,4,9-tetrahydro -pyrano [3,4-b] indole, m.p. 74-76 ° C, m.p. for the corresponding maleic acid addition salt 98-100 ° C (Example 4), 1-methyl-1- [2- (1-pyrrolidinyl) ethyl] -1,3,4,9-tetrahydro-pyrano [3.4- b] indole, NMR (CDCl 3) δ 1.62 (3H), 2.00 (m, 4H), 4.05 (m, 2H), m.p. for the corresponding maleic acid addition salt (maleate) 192-192 ° C (Example 5), 1-methyl-1- (2-piperidinoethyl) -1,3,4,9-tetrahydropyrano- [3,4-b] indole, m.p. 146-148 ° C, m.p. for the corresponding maleic acid addition salt 147-149 ° C (Example 6), 1-methyl-1- (2-morpholinoethyl) -1,3,4,9-tetrahydropyrano- [3,4-b] indole, NMR (DMSO -DG). é 1.50 (3H), 6.07 (2H), 6.87-7.65 (m, 4H), 10.86 (1H), m.p. for the corresponding maleic acid addition salt 192--193 ° C (Example 7) and 1-methyl-1- [2- (4-methyl-1-piperazinyl) ethyl] -1,3,4,9-tetrahydropyrano [3 , 4-b] indole, NMR (CDCl3) δ 1.47 (3H), 2.58 (3H), 3.87 (t, 2H) [m.p. for the corresponding maleic acid addition salt (i.e., maleate) 208-21 ° C] (Example 8).

Example 9-9 Proceeding in the manner described in Example 1, step C, but using as an starting material an equivalent amount of one of the amide compounds of formula (V) described in Example 1, instead of N, N, 1-trimethyl-1,3,4,9-tetrahydropyrano [3,4-b] -indole-1-acetamide gives the corresponding compounds of formula (I). Examples of such compounds of formula (I) are listed as products in Tables IV and V together with the starting material used, amides of formula (V), m. -Ρ d Μ 05 -P - 0 ΤΤ I U -ϋ H '-' • ri

-r HO <0 W -P

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ft a! USP 00 (I). U 05 P

0 Q00O P ft Q Ή (d P Λί U '-' O oo id g Uoiil

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Example_13 Step A.

1,9-Dimethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid [(IV); A = A1, where R16 = CH, and R18 * H, R1 = CH ,, X = O, n - 2, 19 JJ '__________________________________________________i______ 10 g (0.04 mole) of 1-methyl-1,3,4,9 Tetrahydropyrano [3,4-b] -indole-1-acetic acid, prepared in Example 1 as Compound No. A1, in 150 ml of tetrahydrofuran is added dropwise to a stirred suspension of 4.4 g of 55% sodium hydride dispersion in 200 ml. ml of tetrahydrofuran. This mixture is heated at 50 ° C with stirring for 2 hours. 14.2 g (0.1 mole) of methyl iodide are added dropwise and heating and stirring are continued for an additional 2 hours.

After cooling, add water until the solution is clear. The tetrahydrofuran is evaporated under reduced pressure and the residue is partitioned between water and benzene. The aqueous phase is washed once with benzene, acidified with HCl and extracted 3 times with benzene. The organic phase is washed with water, dried over sodium sulfate and treated with charcoal. The organic layer is evaporated. The residue is crystallized from benzene and then a mixture of ether and petroleum ether to give the title compound (No. A10), m.p. 105 105-108 ° C, NMR (CDCl 3) δ 1.73 (S, 3H), 2.83 (t, I = 5.5, 2H), 3.0 (2H), 3.68 (3H) , 4.08 (t, I = 5.5 2H), 7.34 (4H), 9.47 (1H).

Similarly, but replacing methyl iodide with an equivalent amount of ethyl iodide or propyl iodide, the N-ethyl analog of the title compound, 9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano [respectively] is obtained, respectively. 3,4-b] indole-1-acetic acid (Compound No. All), m.p. 134-136 ° C, and the N-propyl analog of the title compound 1-methyl-9-propyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid ( compound No. A12), m.p. 120-122 ° C.

Proceeding in the manner described in Example 13, Step A, but using as the starting material an equivalent amount of acid compounds of formula (IV) described in Examples 1-12 and using an equivalent amount of a suitable organic halide, the corresponding N-alkylated acid compounds of formula (IV) are obtained. Examples of these latter compounds are listed as products in Tables VI and VII of the gamma having the starting material of formula (IV) and the organic halide used for their preparation.

38 141201

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X) Φ di μ οι h OH <ao) When used in the manner described in Example 13, Step A, but using as starting material, an equivalent amount of the ester compounds obtained prior to the hydrolysis of Example 1, instead of 1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid, and using an equivalent amount of the appropriate organic halide gives the corresponding N-alkylated ester compound.

Step B.

Proceeding in the manner described in Example 1, Step B, but using as the starting material an equivalent amount of one of the N-alkylated acid compounds of No. A10-A19 instead of 1-methyl-1,3,4, 9-tetrahydropyrano [3,4-b] indole-1-acetic acid, and using an equivalent amount of an appropriate amine such as ammonia or a primary or secondary amine, described in Example 1, step B, gives the corresponding amide compound with formula (V) wherein 16 R is lower alkyl. Examples of such amides are listed as products in Tables VIII, IX and X together with the starting material used and the amine used.

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Step C.

1,9-Dimethyl-1- [2- (dimethylamino) -ethyl3-1,3,4,9-tetrahydropyrano- [3,4-b] indole, [(I); A = A1, where R16 = CH3 and R18 = H, R1 - CH3, X = O, n = 2, R6 and R7 - CH3J.

A solution of 12.0 g of N, N, 1,9-tetramethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetamide described above as Compound No. B1, in 100 Dry ml of tetrahydrofuran is added dropwise to a mechanically stirred mixture of 5 g of lithium aluminum hydride in 100 ml of dry tetrahydrofuran (THF). The mixture is heated under reflux for 20 hours under nitrogen. 50 ml of water / THF in a ratio of 1: 1 is added to destroy the excess hydride. The mixture is filtered through cells, diluted with 300 ml of water and extracted three times with ether. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure to give the title compound, NMR (CDCl3) <δ 1.66 (3H), 2.70 (6H), 3.83 (3H) .

The corresponding hydrochloric acid addition salt, 1,9-dimethyl-1- [2- (dimethylamino) ethyl] -1,3,4,9-tetrahydropyrano [3,4-b] indole hydrochloride, has m.p. 229-230 ° G after crystallization from a mixture of methylene dichloride and benzene.

The title compound is cleaved using D- and L-di-p-toluoyl tartaric acid for the optical isomer, (-) - 1,9-dimethyl-1- [2- (dimethylamino) ethyl] -1 , 3,4,9-tetrahydropyrano- [3,4-b] indole, [α] HCl = -41.5 ° and the corresponding (+) antipode with [α] HCl - 34.6 ° C.

Example Gel 14-34 Proceeding in the manner set forth in Example 13, Step C, but using as the starting material an equivalent amount of one of the N-alkylated amide compounds of formula (V) described in Example 13 as the compounds no. B15-B35, instead of N, N, 1,9-tetramethyl-1,3,4,9-tetrahydro [3,4-b] indole-1-acetamide, gives the · corresponding N-alkylated amine compound of formula (I). Examples of such compounds are listed as products in Tables XI and XII 'together with the starting material used.

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Example_35.

1-Methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-carboxamide [(V); A = A1, where R16 and R18 = H, R1 = CH3, X = Ο, n = 1, R6 and R7 = H].

Proceeding in the manner described in Example 1, but using boron trifluoride etherate as an acid catalyst and an equivalent amount of pyruvic acid amide in place of ethyl acetoacetate, 1-methyl-1,3,4,9-tetrahydropyrano [3.4 -b] indole-1-carboxamide, m.p. 188-189 ° C after recrystallization from a mixture of benzene and hexane, which product is identical to product No. Car of Example 1, Step B.

Similarly, but using an equivalent amount of the appropriate starting material of formula (II) together with the appropriate α, β, γ or 6-ketoamide, the products listed in Tables II and III are obtained. Using tryptophol [(IIa);

-I c 1 Q

wherein R and R = H, and Y - OH] and the β-ketoamide, N, N-dimethylacetoacetamide, by the method of this example, are obtained N, N, 1-trimethyl-1,3,4, 9-Tetrahydropyrano [3,4-b] -indole-1-acetamide identical to Product No. B1 of Example 1, Step B.

By reduction as described in Example 1, Step C, the end products listed in Examples 1-12 are obtained.

Example 36 1-Methyl-1- [3- (1-pyrrolidinyl) propyl] -1,3,4,9-tetrahydropyrano - [3,4-b] indole t (I); A = A1, where R16 and R18 = H, R1 = CH3, X = 0, n = 3, and -NR6R7 = -N (CH2) 4].

To a solution of 15 g (0.09 mol) of tryptophol in 150 ml of benzene is added 12 g (0.10 mol) of 5-chloro-2-pentanone. The mixture is heated in the presence of 200 mg of p-toluenesulfonic acid and hydrated alkali-metal-aluminum silicate (molecular sieve # 4). After 1 hour reflux, an additional 400 mg of acid is added. After a total of 2 hours, the reaction mixture is cooled, filtered and washed with 5% sodium bicarbonate and water and dried over sodium sulfate. Evaporation under reduced pressure gives an oil. This oil is purified by chromatography on silica gel. Elution with benzene and concentration of the eluent gives 1- (3-chloropropyl) -1-methyl-1,3,4,9-tetrahydropyrano- [3,4-b] indole, NMR (CDCl3) <$ 1.33 (3H), 1.93 (4H), 2.75 (2H).

A solution of 250 ml (0.9 mmol) of the latter compound in 10 ml of THF and 1.5 ml of pyrrolidine is heated at reflux for 16 hours. The mixture is concentrated under reduced pressure and the residue is partitioned between 5% sodium carbonate and chloroform. The organic phase is washed with water, dried (Na 2 SO 4), filtered and evaporated under reduced pressure to give the title compound, m.p. 124-127 ° C.

Proceeding in the manner described above, but using as an starting material an equivalent amount of a starting material of formula (IV), e.g. those described as Compound No. A2-A9, inclusive, instead of tryptophol, and using an equivalent amount of an appropriate β-, γ- or <3-halogenketane 67 and an appropriate amine of the formula NHR R, are obtained. the respective compounds of formula (I), e.g. those described in Examples 2-12, inclusive.

Example 37 - 1 - [(Ethylamino) methyl] -1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole [(I); A = A1, where R16 and R18 = H, R1 = CH3, x = O, n = 1, r6 = c2h5, R7 = H].

A mixture of 3.86 g of tryptophol and 3.0 g of acetamidoacetone, cf. R.H. Wileg and O.H. Borum, J. Amer. Chem. Soc., 7Ό, 2005 (1948), in 300 ml of dry benzene is stirred and heated at reflux. Water is collected in a Dean-Stark water collector. After removing the water, 5 drops of boron trifluoride etherate are added and the mixture is refluxed for 30 minutes again using the water separator. After stirring at room temperature overnight, the reaction mixture is evaporated to dryness. The solid residue is dissolved in chloroform and washed successively with 10% aqueous sodium bicarbonate, water and brine. The chloroform solution is dried over magnesium sulfate, filtered and evaporated. The residue is crystallized from benzene to give 1- (acetamido-methyl) -1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole, m.p. 100-102 ° C. This product is dried under reduced pressure at 27 ° C. Spectroscopic and analytical data show that the compound is dissolved with 1 mole of benzene which can be removed completely entirely by melting. R ^ values for the amide and tryptophol are major.

Dissolve 2.4 g of the latter product in 80 ml of dry THF and add to a suspension of lithium aluminum hydride in 200 ml of THE.

The resulting slurry is stirred and heated to reflux for 2 hours and cooled, and 2.4 g of lithium aluminum hydride is added to 52141201. The mixture is then refluxed with stirring overnight. The reaction mixture is decomposed with 22.4 ml of water added dropwise over 3 hours with stirring and cooling. Stirring is continued for 1 hour, the precipitate is separated by filtration and the filtrate is dried (MgSO4). Removal of the solvent by evaporation gives the title compound, NMR (DMSO-dg) <5 1.18 (t, 3H), 1.62 (s, 3H), 2.80 (t, 2H).

The corresponding hydrochloric acid addition salt, 1 - [(ethylamino) methyl] -1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole hydrochloride, has m.p. 242-243 ° C after recrystallization from a mixture of isopropanol and ether.

Proceeding in the manner described in Example 37, but using as the starting material an equivalent amount of the appropriate starting material of formula (IIa) and using an equivalent amount of a suitable ketoamide of the formula (XXIV)

ISLAND

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Example 38 1-Methyl-1-aminomethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole [(I); A = A1, where R16 and R18 = H, R1 = CH3, X = O, n = 1, R6 and R7 = H].

To a solution of 322 mg of the compound of formula (IIa), tryptophol, and 248 mg of the nitroketone, nitro-2-propanone, in 100 ml of benzene are added 5 drops of boron trifluoride etherate and 3 drops of trifluoroacetic acid. The reaction mixture is stirred and heated under reflux under water separator for 18 hours. The benzene solution is cooled, washed with 10% sodium bicarbonate solution, water and saturated brine, and dried over magnesium sulfate. The solvent is removed and the residue is subjected to chromatography on silica gel. Elution with chloroform gives 1-methyl-1-nitromethyl-1,3,4,9-tetrahydropyrano- [3,4-b] indole,> 3 3450, 1550 cm "1, NMR (CDCl„) δ 1.68 ( s, 3H), 2.84 (t, 2H), 4.10 (t, 2H).

Reduction of the latter compound with lithium aluminum hydride in the manner described in Example 1, step C gives 1- (amino-methyl) -1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole, which is identical to the product of Example 10.

1: 53 141201 When used in the manner described in Example 38, ) 0 in "R - C - described above, the respective primary amine compounds of formula (I) are obtained.

Example_39 1- [2- (Dimethylamino) ethyl] -9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indol-6-ol-hydrochloride

A mixture of 5.3 g (0.015 mole) of 6-benzyloxy-1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid, prepared as described in Example 1, compound No. A7, in 250 ml of anhydrous ethanol and 1.1 g of 10% palladium on carbon are stirred at room temperature under a hydrogen atmosphere until no more hydrogen is absorbed by the reaction mixture. The catalyst is removed by filtration through diatomaceous earth (Celite) and the filtrate is concentrated. The residue is recrystallized from a mixture of ethanol and benzene to give 6-hydroxy-1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid, m.p. 170-171 ° C.

The corresponding benzylamine salt is prepared by mixing equimolar ethereal solutions of benzylamine and the above product. The resulting solid is recrystallized from acetonitrile to give 6-hydroxy-1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid benzylamine salt, m.p. 191-193 ° C.

Proceeding in the manner described in this example, but replacing 6-benzyloxy-1-methyl-1,3,4,9-tetrahydropyrario- [3,4-b] indole-1-acetic acid with an equivalent amount 6-Benzyloxy-1- [2- (dimethylamino) -ethyl] -9-ethyl-1-methyl-1- 3,4,9-tetrahydropyrano- [3,4-b] indole hydrochloride, described in Example 24 , 1- [2- (dime thylamino) -ethyl] -9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano-3,4-b] -indole-6-ol hydrochloride is obtained, m.p. 213-214 ° C. The corresponding free base of the latter compound has NMR (CDCl3) δ 1.36 (t, I = 7, 3H), 1.6 (s, 3H), 2.18 (s, 6H). Similarly, replacement with 6-benzyloxy-1,9-dimethyl-1- [2- (dimethylamino) ethyl] -1,3,4,9-tetrahydro-pyrano [3,4-b] indole 1-Hydrochloride, described in Example 26, 1,9-dimethyl-1- [2- (dimethylamino) -ethyl] -1,3,4,9-tetrahydropyrano-3,4-b] -indole-6 ol hydrochloride, m.p. 242-244 ° C. The corresponding free base has NMR (CDCl3) δ 1.6 (s, 3H), 2.2 (s, 6H), 3.7 (s, 3H).

Example 40 1- (2-Aminoethyl) -1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole [(I); A = A1, where R16 and R18 = H, R1 = CH3 # X = O, n = 1, R6 and R7 = H].

20.0 g (0.817 mol) of 1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetamide, described in Example 1 as Compound No. B1, are dissolved in 400 ml of dry methylene chloride and 17.00 g (0.894 mol) of freshly prepared triethyloxonium fluoroborate are added in one portion to the solution. The reaction mixture is stirred at room temperature for 2 hours. The methylene chloride solution is washed with cold 30% aqueous potassium carbonate followed by brine, and the dried organic layer is concentrated under reduced pressure. The residue is dissolved in 150 ml of ether. The solution is filtered and the crystallization proceeds at room temperature to give ethyl 1-methyl-1,3,4,9-tetrahydropyrano- [3,4-bindole-1-acetimidate, m.p. 139.5 to 141 ° C.

4.79 g (0.0176 mol) of the latter compound dissolved in 100 ml of dry tetrahydrofuran is added dropwise to a stirred and ice-cooled suspension of 1.75 g (0.046 mol) of lithium aluminum hydride in 50 ml of THF. The reaction mixture is stirred overnight at room temperature, and then diluted sodium hydroxide is added dropwise to decompose, of excess hydride. The precipitate is collected by filtration and the filtrate is concentrated under reduced pressure to give a residue extracted with methylene chloride. The organic layers are washed with brine and dried (MgSO4), and the concentration of the solvent and crystallization from ether give the title compound, m.p. 80-84 ° C, 3455, 3280 cm 1, which is identical to the compound of Example 2 with the same name.

Example 41 1- [2- (Dimethylamino) -ethyl] -9-ethyl-1-methyl-1,3,4,9-tetrahydrothio-pyrano [3,4-b] indole [(I); A = A ^, where R ^ 8 = ° 9 = H, R ^ = CH3, X = S, n = 2, R6 and R7 = CH3].

822 mg of the compound of formula (I), 1- [2- (dimethylamino) -ethyl] -1-methyl-1,3,4,9-tetrahydrothiopyrano [3,4-b] indole, described in Example 12, dissolve in 15 ml DMF and 15 ml benzene. To remove all possible traces of water, a portion of this benzene is distilled.

After cooling to 0 ° C, 140 mg of sodium hydpide (54% suspension in mineral oil) is added and the mixture is stirred for 15 minutes. The alkylation is carried out by adding 350 mg of ethyl bromide and stirring the reaction mixture at 0 ° C for 20 minutes. The resulting suspension is poured onto crushed ice and extracted with chloroform, and the organic layer is washed repeatedly with water and evaporated. Chromatography of the residue on 20 g of silica gel using a mixture of chloroform and methanol (0-10%) gives the title compound which after crystallization from ether-hexane has m.p. 86-886, 3 2820, 2765, 1600, 1568, 1537 cm -1, NMR (CDCl

IQaX J

<5 2.20 (s, 6H), 2.30 (m, 4H).

The corresponding hydrochloric acid addition salt of the title compound, 1- [2- (dimethylamino) ethyl] -9-ethyl-1-methyl-1,3,4,9-tetrahydrothiopyrano [3,4-b] indole hydrochloride , m.p.

220-222 ° C.

Proceeding in the manner indicated and using an appropriate compound of formula (I) (A ** A1 where R 16 means hydrogen) together with the appropriate organic halide, other compounds of formula (I) are obtained (A = A1 where R 1 represents lower alkyl).

For example, the use of the same compound of formula (I) as described in Example 41 with an equivalent amount of methyl bromide instead of ethyl bromide in the process of Example 41 gives 1,9-dimethyl-1- [2- (dimethylamino) ethyl] -1 , 3,4,9-tetrahydrothiopyrano [3,4-b] indole, NMR (CDCl3) <δ 3.72 (s, 6H), 6.40 (s, 3H) identical to the product of Example 33. The corresponding hydrochloric acid addition salt of the latter compound, 1,9-dimethyl-1- [1- (dimethylamino) ethyl] -1,3,4,9-tetrahydrothiopyrano [3,4-b] indole hydrochloride has m.p. 244-246 ° C.

Similarly, the use of the same compound of formula (I) as described in Example 41 gives an equivalent amount of propyl bromide instead of ethyl bromide 1- [2- (dimethylamino) ethyl] -1-methyl-9-propyl 1,3,4,9-tetrahydrothiopyrano [3,4-b] indole, NMR (CDCl3) δ 1.03 (t, 3H), 1.83 (s, 3H), 2.22 (s, 6H) , 4.14 (m, 2H), 7.22 (m, 4H). The corresponding hydrochloric acid addition salt has m.p. 243-245 ° C.

56 141201

Example 42 1 - [(2-Dimethylamino) -ethyl] -1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] -indole, ______________________________________________________________

To a solution of 2.28 g of p-toluenesulfonic acid in 40 ml of toluene is added 1.61 g of the starting material of formula (IIa), tryptophol, and 1.27 g of the amino ketone, 4- (dimethylamino) -2-butanone. The mixture is evaporated under reduced pressure and the residue is stirred under nitrogen at 130 ° C (bath temperature) for 45 minutes. The mixture is cooled, 20 ml of water is added and the mixture is extracted with toluene. The toluene extract is washed with 5 ml of 5% sulfuric acid and 5 ml of water. The aqueous layer containing a dark viscous oil is combined with the aqueous washing liquids. 10 ml wife. NH 2 OH is added and the mixture is extracted with 10 ml and 2 x. 5 ml of toluene. The combined toluene solution is washed with 2 x 5 ml of water, dried (Na 2 SO 4), treated with charcoal and evaporated under reduced pressure. The residue is recrystallized from ether to give the pure, title compound which is identical to the product described in Example 1 with the same name.

Example Gel 43 1,9-Dimethyl-1- [2- (dimethylamino) -ethyl] -1,3,4,9-tetrahydropyrano-black-blind _____________________________________________________

To a mixture of 0.50 g of the starting material of formula (IIa), N-methyltryptophol, and 0.363 g of the amino ketone, 4-dimethylamino-2-butanone, is added portionwise 0.650 g of p-toluenesulfonic acid and the mixture is stirred under nitrogen at 130 ° C for 1 1/2 hours. After cooling, add 10 ml of water and extract the mixture with 2 x 5 ml of toluene. The combined toluene solution is washed back with water and discarded. The aqueous phase containing a thick brown oil is made alkaline with 10 ml of wife. ammonium hydroxide and extracted with 3 x 10 ml benzene. The combined benzene extract is washed with 2 x 10 ml of water, dried (Na 2 SO 4), treated with charcoal and evaporated under reduced pressure to give the title compound identical to the product of Example 13 of the same name.

57 141201

Example Gel-44 1,9-Dimethyl-1- [2- (dimethylamino) ethyl) -1,3,4,9-tetrahydrothio

A mixture of 0.75 g of the starting material of formula (IIa), 1-methylindole-3-ethanethiol, 0.72 g of 4-dimethylamino-2-butanone hydrochloride, ca. 1 ml of toluene and 1.00 g of p-toluenesulfonic acid are stirred under nitrogen at 125 ° C for 1/2 hour. After cooling, 20 ml of water and 0.5 ml of wife are added. hydrochloric acid and the mixture is then extracted with 3 x 10 ml of toluene. The combined toluene solution is washed back with water. The aqueous phase containing a brown oil is made alkaline with wife. NH 4 OH and extracted with 3 x 15 ml of toluene. The combined toluene solution is washed with water, dried (Na 2 SO 4), treated with charcoal and evaporated under reduced pressure to give the title compound identical to the product of Example 33 of the same name.

Example_45 1- [2- (Dimethylamino) ethyl] -9-ethyl-1-methyl-1,3,4,9-tetrahydro

To a stirred solution of 57.0 g of p-toluenesulfonic acid monohydrate in 400 ml of toluene at 80 ° C under nitrogen is added 13.8 g of the amino ketone 4- (dimethylamino) -2-butanone. Then, 30.7 g of the starting material of formula (IIa), sodium 1-ethylindole-3-ethylthiosulfate prepared from 1-ethyl-indole-3-ethanol by the method of Suvorov and Buyanov, are added portionwise over 5 minutes. above. The mixture is kept at 80 ° C for 1 1/4 hour with stirring, then cooled and diluted with 66 ml of 20% sodium hydroxide followed by 100 ml of water and extracted with toluene. The toluene extract is washed with 3 x 30 ml of 20% sulfuric acid and with 5 x 30 ml of water. The combined aqueous phases plus solid precipitating therefrom are made alkaline with 20% sodium hydroxide and then extracted with 4 x 50 ml of toluene.

The combined toluene solution is washed with water, dried (Na 2 SO 4) and evaporated. The residue is recrystallized from a mixture of ether and hexane to give the title compound identical to the product of Example 41. The corresponding hydrochloric acid addition salt of the title compound has m.p. 225-227 ° C after recrystallization from isopropanol.

Similarly, but using an equivalent amount of potassium 1-ethylindole-3-ethylthiosulfate, the title compound is also obtained.

Example_46 Step A.

2lMethylindol-l-ethanol

FremgangsmådeAj

Commercial n-butyllithium in hexane (3.05 mol) is diluted with 1000 ml of dry tetrahydrofuran (THF). To this cooled (-10-0 ° C) solution is added dropwise 393 g (3.0 moles) of the indole precursor of formula (XIII), skatole, in 1000 ml of dry THF. The reaction mixture is stirred at the same low temperature for 1 hour, then 300 ml of ethylene oxide in 300 ml of dry THF is added to the mixture. The temperature is allowed to rise to room temperature. Then, the reaction mixture is stirred overnight.

The THF is evaporated and the residue is dissolved in methylene chloride and washed with concentrated HCl. The methylene chloride solution is then washed with .10% 1s sodium bicarbonate and water and dried (MgSO4). The solvent is evaporated and the product distilled off at reduced pressure to give the title compound, b.p. 124 ° C / 0.25 mm Hg.

Method B; 35 g (0.276 mol) of the indole precursor of formula (XIII), skatole, in 300 ml of dimethylformamide (DMF) is added dropwise to a stirred mixture of 14.0 g of sodium hydride (55% oil dispersion) in 325 ml of DMF. The mixture is heated at 40 ° C for 2 hours. After cooling in an ice-water bath, 116.5 g (0.7 mol) of ethyl bromoacetate are added dropwise, keeping the temperature below 20 ° C. After the addition, stirring is continued for 5 minutes and then gently added water to destroy any excess hydride. The reaction mixture is partitioned between water and ether. The ether layer is washed with water, dried (MgSO 4) and evaporated under reduced pressure.

The residue, 3-methyl-indole-1-acetic acid ethyl ester, is dissolved in 900 ml of methanol and then 90 g of potassium hydroxide is added in 400 ml of 1: 1 methanol / H2 O mixture. The mixture is stirred at room temperature for 1 1/2 hours. The methanol is evaporated under reduced pressure U1201 59. The residue is diluted with 800 ml of water and extracted 3 times with ether. Acidification with 6N HCl of the aqueous phase gives 3-methyl-indole-1-acetic acid, m.p. 174-176 ° C.

47.5 g (0.25 mol) of the latter compound in 1000 ml of ether are slowly added to a stirred mixture of 12.5 g (0.32 mol) of lithium aluminum hydride in 700 ml of ether. The reaction is kept below 15 ° C using ice water bath. The reaction mixture is stirred for 15 minutes after the addition, excess hydride is destroyed with water and the precipitate is collected. The ether filtrate is washed with water, dried over sodium sulfate and evaporated under reduced pressure to give an oil. Chromatography on silica gel using 15% ethyl acetate in benzene as the eluant gives the title compound identical to the product of process A.

Proceeding in the manner described in the liner process A, other indole-1-ethanol intermediates of formula (IIb), e.g. those listed in Table XIII, and by appropriate selection of the indole of formula (XIII) and the ethylene oxide derivative. When skatole and ethylene oxide are replaced by equivalent amounts of 3,7-dimethylindole, respectively, cf. Robinson et al., Cited above, and 3,3-dimethyl-1,2-epoxybutane, cf. V. Franzen and H.E. Driesen, discussed above, is obtained e.g. a mixture of β-isopropyl-α, 3,7-trimethyl-indole-1-ethanol and α-isopropyl-0,3,7-trimethyl-indole-1-ethanol. Such mixtures of position isomers can be separated by fractional distillation, fractional recrystallization or chromatography. Similarly, replacing skatole with 3-isopropylindole, R. Robinson et al., Discussed above, by process A gives 3-isopropylindole-1-ethanol.

Proceeding as described under process B, other indole-1-ethanol intermediates of formula (IIb) can be prepared by appropriate selection of the indole of formula (XIII) and the α-haloacetic acid (lower alkyl) ester of formula LCH2C00 - (lower alkyl) where L is halogen. Thus, replacing skatole with 3-butylindole, cf. R. Robinson et al., Discussed above, by Method B gives 3-butylindole-1-ethanol.

1,10-Dimethyl-3H-4-dihydro-1H-1,14-oxazino [4,3-a] indole-1-acetic acid

A mixture of 26.5 g (0.15 mol) of the starting material of formula (IIb), 3-methylindole-1-ethanol, in 600 ml of toluene, 36 g (0.20 mol) of ethyl acetate and 2.0 g of toluene sulfonic acid is heated under reflux for 6 hours using a water separator. The toluene solution is washed with water, 5% bicarbonate solution and again with water. The solution is then dried over sodium sulfate and the solvent is evaporated under reduced pressure to give an oil. The oil is subjected to chromatography on silica gel. Elution with 10% ethyl acetate in benzene and concentration of the eluate gives the ester 3,4 - dihydro-1,10-dimethyl-1H-1,4-oxazino [4,3-a] indole-1-acetic acid - ethyl ester , in the form of an oil, ^ 1725 cm

Hydrolysis of this ester to the title compound is carried out as follows: 39.9 g of the ester is dissolved in 800 ml of methanol containing 22.5 g of KOH in 20 ml of water. After stirring for 5 hours at 50 ° C and for 12 hours at room temperature, the solvent is evaporated under reduced pressure. The residue is taken up in water and washed twice with ether, acidified with 6 N HCl and extracted with ether. The ether solution is washed once with water, dried (Na 2 SO 4) and evaporated under reduced pressure to give a solid.

The solid is recrystallized from petroleum ether to give the title compound (No. A20), m.p. 138-139 ° C, NMR (CDCl 3) δ 1.75 (s, 3H), 2.86 and 3.18 (d, 1 * 14.5 cp, 2H), 4.07 (m, 4H).

An equivalent amount of methyl acetoacetate can replace ethyl acetoacetate by the method of this example. In this case, ester 3,4-dihydro-1,10-dimethyl-1H-1,4-oxazino [4,3-a] indole-1-acetic acid methyl ester is obtained as ester.

An equivalent amount of propylacetoacetate can replace ethyl acetoacetate by the method of this example. In this case, ester 3,4-dihydro-1,10-dimethyl-1H-1,4-oxazino [4,3-a] indole-1-acetic acid propyl ester is obtained as ester.

1,10-Dimethyl-3,4-dihydro-lH-l, 4-oxazino [4,3-a] indol-l-propionic acid

Process A:

A mixture of 29.7 g (0.17 mol) of the starting material of formula (IIb), 3-methylindole-1-ethanol, 26.96 g (0.187 mol) of ethyl levulinate and 2.25 g of p-toluenesulfonic acid in 650 Dry ml of dry benzene is refluxed with hydrated aluminum silicate for 12 hours (Molecular Sieve No. 4). The benzene solution is washed with 5% aqueous NaHCO 3 followed by varid. The concentration of the solution gives a residue which is passed through a silica gel column using 15% ethyl acetate in benzene to give the ester 3,4-dihydro-1,1,4-dimethyl-1H-1,4-oxazino [4.3 -a] indole-1-propionic acid ethyl ester in the form of an oil,> 3 1730 cm 41.9 g of this ester is dissolved in 650 ml of methanol containing 23 g of KOH in 50 ml of water and heated at 50 ° C. 1 hour. The solvent is evaporated and the residue is poured into water. The aqueous solution is washed twice with ether, acidified with 6 N HCL and extracted three times with ether. The ether solution is washed once with water, dried over MgSO 4 and evaporated under reduced pressure to give a solid. The solid is recrystallized from a mixture of ethyl acetate and petroleum ether to give the title compound (No. A21), mp 115-116 ° C, NMR (CDCl 3) δ 1.62 (s, 3H), 2.30 (m, 7H), 4.04 (4H), 7.21 - 7.52 (m, 4H), 10.93 (1H).

Fremgangsmåde_B:

A mixture of 500 ml of the starting material of formula (IIb>, 3-methylindole-1-ethanol, 580 mg of levulinic acid, 75 ml of benzene, 1.7 g of phosphorus pentoxide and about 0.5 g of diatomaceous earth (Cellte) is magnetically stirred at room temperature for 1 hour. The reaction mixture is filtered, the filtrate is washed three times with 5 N NaOH, the combined aqueous phase is washed twice with ether and then acidified with cold 50% HCl. The chloroform extract is dried (Na 2 SO 4) and evaporated to dryness. Recrystallization of the residue from a mixture of ethyl acetate and petroleum ether gives the title compound identical to Compound No. A21 of Process A.

Processes A can be used to prepare other 2 intermediates of formula (IV) where A = A. Examples of such compounds are listed in Table XIII. In each of these cases, the starting material of formula (IIb) and the indicated keto ester are used in an amount equivalent to the starting material of formula (IIb) and the keto esters listed in process A. It should be noted that in all these cases an ester is obtained prior to the hydrolysis. This ester is the corresponding intermediate of formula (IV).

Similarly, Methods B can be used to prepare the products listed in Table XIII with the exception that in this case an equivalent amount of the corresponding ketoacid is used instead of the ketoester listed in the table.

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Hiiii2lS £ i5i2 £ ilZil2LilÉiiiY5E2liSlIii ^ 25S ^ i32 ^ i-6. | I; SliSå2iliZS £ SiSSi ^ 6 g of triethylarain and then 5 g of ethyl chloroformate are added to a cooled solution (-5 ° C) of 10 g of 1,10-dimethyl-3 , 4-Dihydro-1H-1,4-oxazino [4,3-a] indole-1-acetic acid, described as Compound No. Ά20, in 150 ml of tetrahydrofuran (THF). After stirring for 2 hours at 10 ° C, the suspension is further cooled to room temperature. -10 ° C and treated with 66 ml of 40% aqueous solution of methyl ami and stirred at a given temperature for an additional 1 hour. Most of the THF is evaporated and the residue is partitioned between ether and water. The ether solution is washed with water, dried (MgSO4) and concentrated to give a solid. The solid is recrystallized from ethyl acetate to give the title compound (No. B36), m.p. 131-133 ° C.

Similarly, but the 40% aqueous solution of methylamine is replaced by an equivalent amount of the amines of formula 8 9 HNR R, ammonium hydroxide (concentrated), dimethylamine (30% aqueous solution), diethylamine (30% aqueous solution), ethylamine (70% aqueous solution), pyrrolidine (50% aqueous solution), piperidine, morpholine and N-methylplperazine, respectively, 1,10-dimethyl-3,4-dihydro-1H-1,4 is obtained. -oxazino [4,3-a] indole-1-acetamide (Compound No. B37), m.p. 156-157 ° C, NMR (CDCl 3) δ δ 1.69 (3H), 2.33 (3H), Ν, Ν, 1,10-tetramethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indole-1-acetamide (Compound No. B38), NMR (CDCl3) δ 1.78 (3H), 2.33 (3H), 2.95 (6H), N, N- diethyl-1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indole-1-acetamide (Compound No. B39), 1,10-dimethyl-N-ethyl-3 , 4-dihydro-1H-1,4-oxazino [4,3-a] indole-1-acetamide (Compound No. B40), m.p. 114-116 ° C, 1 - [(1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indol-1-yl) -acetyl] -pyrrolidine ( Compound No. B41), 1 - [(1,10-Dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indol-1-yl) -acetyl] -piperidine (Compound No. B42), 4 - [(1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indol-1-yl) -acetyl] -morpholine (compound no. B43), and 1-methyl-4 - [(1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino- [4,3-a] indol-1-yl) -acetyl] - piperazine (Compound No. B44).

64 141201 When proceeding in the manner indicated, but using as the starting material an equivalent amount of one of the acid compounds of No. A21-A24 in place of 1,10-dimethyl-3,4-dihydro-1H-1, 4-bxazino [4,3-a] indole-1-acetic acid, and using an equivalent amount of a suitable amine such as ammonia or a primary or secondary amine, gives the corresponding amide compound of formula (V). such amides are listed as products in Tables XIV and XV together with the starting material concerned and the amine used to prepare the amide.

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Step C.

1,10-Dimethyl-1- [2- (methylamino) -ethyl] -3,4-dihydro-1H-1,4-oxazino-1 H -a-indole 11.0 g of it as compound no. B36 described amide, Ν, Ι, ΙΟ - trimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indole-1-acetamide in 200 ml of THF is added dropwise to a stirred mixture of 6 3 g of lithium aluminum hydride in 200 ml of THF. The reaction mixture is refluxed for 2 hours and cooled. Excess hydride is destroyed by water. The mixture is filtered and the filtrate is evaporated. The residue is poured into ether, washed with water and the solution is evaporated to give the title compound, NMR (CDCl3) δ 1.62 (s, 3H), 2.34 (s, 3H).

The corresponding hydrobromic acid addition salt, 1,10-dimethyl-1- [2- (methylamino) ethyl] -3,4-dihydro-1H-1,4-oxazino [4,3-a] indole hydrobromide, has m.p. 249-251 ° C after recrystallization from isopropanol.

Similarly, but replacing lithium aluminum hydride with an equivalent amount of lithium aluminum hydride-aluminum chloride, aluminum hydride-aluminum chloride, diborane and sodium borohydride-aluminum chloride, the title compound is also obtained.

Example_47 In the manner described in Example 46, step C, but substituting an equivalent of N, 1,10-trimethyl-3,4-dihydro-1H-1,4-oxazinoI4,3-a] indole-1-acetamide amount of the amides described above as Compounds No. B37-B44 is obtained respectively 1- (2-aminoethyl) -1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino- [4,3-a ] indole, NMR (CDCl 3) δ 1.62 (3H), 2.34 (3H) (Example 47), 1,10-dimethyl-1 - [(2-dimethylamino) ethyl] -3,4-dihydro-1 -1,4-oxazilio [4,3-a] indole, NMR (CDCl3) δ 1.60 (3H), 2.30 (3H) (Example 48), the corresponding hydrochloric acid addition salt (hydrochloride) having m.p. 237-239 ° C after recrystallization from a mixture of methanol and ether, 1- [2- (diethylamino) ethyl] -1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino [4, 3-a] indole, NMR (CDCl 3) δ 1.60 (3H), 2.30 (3H) (Example 49), the corresponding hydrobromic acid addition salt (hydrobromide) has m.p. 191-193 ° C after recrystallization from a mixture of isopropanol and ether, 1,10-dimethyl-1- [2- (ethylamino) ethyl] -3,4-dihydro-1H-1,4-oxazino [4,3- α] indole, NMR (CDCl 3) δ 1.58 (3H), 2.32 (3H), (Example 68), the corresponding hydrobromic acid addition salt has m.p. 196-198 ° C after recrystallization from a mixture of isopropanol and ether, 1,10-dimethyl-1- [2- (1-pyrrolidinyl) ethyl] -3,4-dihydro-1H-1,4-oxazino [4, 3-a] indole ·, NMR (CDCl 3) δ 1.60 (3H), 2.30 (3H) (Example 51), the corresponding hydrochloric acid addition salt having m.p. 223-225 ° C after recrystallization from a mixture of isopropanol and ether, 1,10-dimethyl-1- (2-piperidinoethyl) -3,4-dihydro-1H-1,4-oxazino [4,3-a] indole, NMR (CDCl3) δ 1.61 (3H), 2.33 (3H) (Example 52), the corresponding hydrobromic acid addition salt having m.p. 253-255 ° C after recrystallization from methanol.

1,10-dimethyl-1- (2-morpholinoethyl) -3,4-dihydro-1H-1,4-oxazino [4,3-a] indole, NMR (CDCl3) <δ 1.60 (3H), 2.31 (3H) (Example 53), the corresponding hydrochloric acid addition salt has m.p. 234-236 ° C after recrystallization from a mixture of isopropanol and ether, and 1,10-dimethyl-1- [2- (4-methyl-1-piperazinyl) ethyl] -3,4-dihydro-1H-1,4 -oxazino [4,3-a] indole, NMR (CDCl 3) δ 1.62 (s, 3H), 2.32 (s, 3H) (Example 54), the corresponding maleic acid addition salt (dimaleate) having m.p. 196-198 ° C after recrystallization from methanol.

Example 55 Proceeding in the manner described in Example 46, Step C, but using as the starting material an equivalent amount of one of the amide compounds of formula (V), described as Compounds No. B45-B57, instead of N 1,10-Trimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indole-1-acetamide gives the corresponding compounds of formula (I). Examples of such compounds of formula (I) are listed as products in Table XVI together with the starting material used.

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Example 68 1.10- Dimethyl 1,3,4-dihydro-1H-1,6-oxa2ino [4- (3-a] indole-1-propanol)

Process A: 10.4 g of the acid intermediate 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indole-1-propionic acid, described as Compound No. A20 in Example 46, step A, in 100 ml of THF is slowly added to a stirred mixture of 2 g of lithium aluminum hydride in 100 ml of THF. The reaction mixture is maintained at 0 ° C using an ice / water bath.

After adding the acid, the excess hydride is destroyed with water and the precipitate is collected on a filter disc. The filtrate is evaporated. The residue is taken into ether and the ether phase is washed with water, dried (Na 2 SO 4) and evaporated under reduced pressure to give an oil. Chromatography of the oil on silio gel using a mixture of ethyl acetate and chloroform in a 1: 1 ratio gives the title compound, 0 ^^ 3 3610, 3450, 1080 cm

Process _g:

Alternatively, the title compound is also obtained by proceeding in the manner described in Example 46, Step A, (Method A), but replacing ethyl levulinate with an equivalent amount of the keto-alcohol (lower alkyl) ester, 5-acetoxypentane. -2-one.

It should be noted that the process of Example 46, Step A, includes hydrolysis of the intermediate ester.

1,10-Dimethyl-1- [3- (methylamino) -propyl] -3,4-dihydro-1H-1,4-oxazino-9.5 g 1,10-dimethyl-3,4-dihydro-1H -1,4-oxazino [4,3-a] indole-1-propanol is dissolved in 20 ml of dry pyridine. 7.4 g of p-toluenesulfonyl chloride are added portionwise to the vigorously stirred and cooled solution. The mixture is further stirred at 0 ° C for 1 hour, adding ice and water, and the aqueous mixture is extracted with ether.

The combined ether extracts are washed with 10% ice-cold hydrochloric acid, water, 5% sodium bicarbonate, and water and dried (Na 2 SO 4). Concentration of the extracts yields 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indole-1-propyl tosylate.

^ CHC13 1600 '1370' 1190 1170 cm '1.

Dissolve 12.3 g of the latter tosylate in 100 ml of dry acetone, and treat the resulting solution with 15 g of sodium iodide. The mixture is stirred at room temperature for 24 hours. Most of the acetone is removed at reduced pressure / water and ice is added and the resulting brownish solution is extracted with ether. The combined ether extracts are washed with 10% sodium thiosulfate solution and water and dried (Na 2 O 4). The solvent is evaporated under reduced pressure to give a yellow oil. The oil is subjected to chromatography on silica gel and eluted with benzene. Concentration of the eluate affords 1,10-dimethyl-1- (3-iodopropyl) -3,4-dihydro-1H-1,4-oxazino [4,3-a] indole, NMR (CDCl3) ό 1.59 (3H) , 3.13 (2H).

A mixture of 10.2 g of the latter compound in 100 ml of THF and 199 ml of 40% aqueous methylamine is stirred at room temperature for 6 hours. Most of the tetrahydrofuran is removed at reduced pressure, the milky aqueous solution is extracted with ether and washed with water until samples show that the water is neutral. The extract is dried (Na 2 SO 4) and evaporated to give the title compound which is identical to the product of Example 55.

Proceeding in the order described above, but using as the starting material an equivalent amount of the appropriate ester intermediate of formula (IV) (by Process A) or a suitable starting material of formula (II) and a suitable ketoalcohol ( lower alkyl) ester of formula (XXII) (by Process B), followed by the use of a suitable amine of formula HNR R, the respective compounds of formula (I) are obtained.

More specifically exemplified is obtained by proceeding in the manner described in Method A, but having 1,10-dimethyl-3,4-dihydro-1R-1,4-oxazino [4,3-a] indole-1 proplonic acid is replaced by 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino (4,3-a] indole-1-butyric acid, described as Compound No. A24,10,10-dimethyl-3,4- dihydro-1H-1,4-oxazino [4,3-a] indole-1-butanol, 3600 3460 cm @ -1, which is then converted to its corresponding tosylate, 1600, 1370, 1190, -1 1170 cm, then treated with sodium iodide to give 1,10-dimethyl-1- (4-iodobutyl) -3,4-dihydro-1H-1,4-oxazlno [4,3-a) indole, m.p. . 60-62 ° C. Subsequent treatment of the latter compound with ethylamine gives 1,10-dimethyl-1- [4- (ethylamino) -butyl] -3,4-dihydro-1H-1,4-oxazino [4,3-a] indole, NMR (CDCl 3) 1.54 (s, 3H), 2.25 (s, 3H), 3.98 (m, 4H); its corresponding hydrochloric acid addition salt has m.p. 144-146 ° C.

74 141201

Eksingel_69 1- [2- (Diethylamino) -ethyl] -10-methyl-1-propyl-3,4-dihydro-1H-1,4-

A solution of 3.5 g (0.0185 mole) of triethyloxonium fluoroborate and 5.5 g (0.016 mole) of the amide described as Compound No. B52 of formula (V), N, N-diethyl-10-methyl -1-Propyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indole-1-acetamide in 100 ml of methylene chloride is evaporated under reduced pressure and the residue is dissolved in 50 ml of absolute ethanol . 1.35 g (0.035 mol) of sodium borohydride is added portionwise to the stirred solution at 0 ° C. After the addition is complete, stirring is continued for 18 hours at 25 ° C. The solution is poured into 250 ml of water and extracted with 3 x 30 ml portions of ether. The combined extracts are washed with ether, dried (MgSO4) and evaporated to give the title compound identical to the product of Example 62.

Similarly, other amides of formula (V) can be reduced to their corresponding oxazino indoles of formula (I).

Eksempel_70.

ixIQ.zSiSSthyl-l ^ n-iodgrogyl ^ -S ^ J ^ -dihydro-lH - ^^ - ^ oxazingRil-a indole

To a solution of 15 g of 3-methylindole-1-ethanol in 150 ml of benzene is added 12 g of 5-iodo-2-pentanone. The mixture is heated under reflux with 200 mg of p-toluenesulfonic acid and hydrated alkali-aluminum silicate (Molecular Sieve No. 4). After 1 hour, an additional 400 mg of acid is added. After a total of 2 hours, the reaction mixture is cooled, filtered and washed with 5% sodium bicarbonate and water and dried over sodium sulfate. Evaporation under reduced pressure gives an oil. This oil is purified by chromatography on silica gel. Elution with benzene and concentration of the eluate gives the title compound which is identical to the compound of Example 68 of the same name.

Proceeding in the manner described, but using as a starting material, a suitable starting material of formula (II), described above, together with a suitable β, γ or ε-halogen ketone of formula (XXIII) described above, the corresponding intermediates of formula (VII) are obtained.

Next, the latter intermediates of formula (VII) can be treated under the conditions described in Example 68 with a suitable amine of formula HNR R, wherein R and R 'have the meaning given above 75 to produce the corresponding oxazino indoles with formula (I), e.g. the products of Examples 46-67.

5SSS§SE§i_Zi 1.10- Dimethyl-1- [3- (ethylamino) propyl] -3,4-dihydro-1H-1,4-oxazino-__________________________________________________;

A mixture of 4.2 g of 3-methylindole-1-ethanol and 3.7 g of N- (4-oxopentyl) acetamide, described by L.P. Kuhn et al., J. Am, Chem. Soc. 8_9, 3858 (1967), in 300 ml of dry benzene is stirred and heated at reflux. After removing the water, 5 drops of boron trifluoride etherate are added and the mixture is refluxed for 30 minutes again using the water separator. After stirring at room temperature overnight, the reaction mixture is evaporated to dryness. The solid residue is dissolved in chloroform and washed successively with 10% aqueous sodium bicarbonate, water and brine. The chloroform solution is dried over magnesium sulfate, filtered and evaporated to give 1- [3- (acetamido) propyl] -1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a ] indole, 3,650 cm 2,6 g of the latter product in 80 ml of dry THF is added to a suspension of lithium aluminum hydride in 200 ml of THF. The resulting slurry is stirred and heated under reflux for 2 hours, cooled and 2.4 g of lithium aluminum hydride is added. The mixture is heated at reflux for 16 hours. The mixture is then decomposed with 22.4 ml of water added over 3 hours while stirring and cooling the mixture. The precipitate is separated by filtration. The filtrate is dried (MgSO4). Removal of the solvent gives the title compound which is identical to the product of Example 58.

When proceeding in the manner described, but using as an starting material an equivalent amount of the appropriate starting material of formula (II), e.g. those described in Example 46 as Compound No. A20-A24, and using an equivalent amount of a suitable ketoamide of formula (XXIV), the respective secondary amine compounds of formula (I) are obtained.

Example 72 72 Dimo-1- (3-aminopropyl) -3,4-dihydro-1H-1,4-oxazino [4,3-a] indole

To a solution of 352 mg of 3-methylindole-1-ethanol and 273 mg of 76 141201 c of the nitroketone, 5-nitro-2-pentanone, cf. H. Shechter et al., Discussed above, in 5 ml of benzene are added 5 drops of boron trifluoride etherate. and 3 drops of trifluoroacetic acid. The reaction mixture is stirred and heated under reflux under a water separator for 18 hours. The benzene solution is cooled, washed with 10% sodium bicarbonate solution, water and saturated brine, and dried over magnesium sulfate. The solvent is removed and the residue is subjected to chromatography on silica gel. Chloroform elution gives 1,10-dimethyl-1- (3-nitro-propyl) -3,4-dihydro-1H-1,4-oxazino [4,3-a] indole. ^^ 3 3450, 1500 cm

Reduction of the latter compound with lithium aluminum hydride in the manner described in Example 69 gives 1- (3-aminopropyl) -1,1-dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a ] indole identical to the product of Example 56.

Proceeding in the manner described, including the reduction described, but using as an starting material an equivalent amount of the appropriate starting material of formula (II), e.g. those described in Example 46 as Compound No. A20-A24, and using an equivalent amount of a suitable nitro-ketone of formula (XXV), the respective primary amine compounds of formula (I) are obtained.

Example 73 1,10-Dimethyl-1- [3- (methylamino) propyl] -3,4-dihydro-1H-1,4-oxazino- [4- (3-a] indole)

To a solution of 2.28 g of p-toluenesulfonic acid in 40 ml of toluene is added 1.6 g of the starting material of formula (II), 3-methylindole-1-ethanol, and 1.3 g of the amino ketone, 5- (methylamino) -2-pentanone. The mixture is evaporated under reduced pressure and the residue is stirred under nitrogen at 130 ° C (bath temperature) for 45 minutes. The mixture is cooled, 20 ml of water is added and the mixture is extracted with toluene. The toluene extract is washed with 5 ml of 5% sulfuric acid and 5 ml of water. The aqueous layer, containing a dark, heavy oil, is combined with the aqueous washings. 10 ml wife. NH 4 OH is added and the mixture is extracted with 10 ml and 2 x 5 ml of toluene. The combined toluene solution is washed with 2 x 5 ml of water, dried (Na 2 SO 4), treated with charcoal and evaporated under reduced pressure to give the title compound identical to the product of Example 55.

Similarly, but substituting an equivalent amount of sodium or potassium 3-methylindole-1-ethyl-thiosulphate for 3-methylindole-1-ethanol, the title compound is also obtained.

When proceeding in the manner described, but using as an starting material an equivalent amount of the appropriate starting material of formula (II), e.g. those described in Example 46 as Compound No. A2Q-A24, and using an equivalent amount of the appropriate amino ketone of formula (III), the corresponding oxazino indoles of formula (I) are also obtained.

Example 74 Step A.

Indene-3-ethanethlol 17 g of 3- (2-bromethyl) indene, prepared from indene-3-ethanol in dry ether on ice boat by reaction with phosphorus tribromide in dry ether, stirring for 36-48 hours at room temperature, decomp. ice and water, washing the ether layer with 10% sodium bicarbonate solution and then water, drying over CaCl 2, decanting and drying over MgSO4 and finally evaporating the filtrate, reflux for 3 hours with a solution of 13.3 g sodium thiosulfate in 100 ml. ml of water and 2000 ml of ethanol. The solvents are removed under reduced pressure to give the corresponding sodium-indenethyl-thiosulfate derivative [(Ile), = Η, Y = -S-SO 2 Na]. The latter derivative is dissolved in a solution of 15 g NaOH in 100 ml of water. Add 300 ml of ethanol. The solution is heated to reflux for 2 hours, allowed to cool and extracted with 3 portions of ether. The combined extracts are washed with saturated brine and concentrated. The residue is passed through a column filled with silica gel and eluted with a 1: 3 ratio of benzene and hexane to give bis-β - [(3-indenyl) ethyl] disulfide, NMR ( CDClg): ό 3.02 (s, 8H), 3.33 (m, 4H), 6.25 (Μ, 2H), 7.30 (m, 8H), in the form of an oil, 12 g of the latter compound in anhydrous ether is added dropwise with vigorous stirring to suspension of 2.5 g of lithium aluminum hydride in 200 ml of ether. The reaction mixture is stirred at room temperature overnight, decomposed with 10 ml of water and the precipitate is collected on a filter. The filtrate is dried (MgSO4). Evaporation of the solution gives the title compound, NMR (CDCl3) <δ 1.48 (t, 1H), 2.83 (m, 4H), 3.32 (m, 2H), 6.25 (m, 1H), 7.30 (m, 4H).

Proceeding in the manner described in this example, other starting materials of formula (Ile) (Y = SH) are prepared by appropriate selection of the appropriately substituted 3- (2-bromoethyl) indene derivative prepared from their corresponding starting materials of formula (Ile) (Y = OH) by treatment with phosphorus tribromide in carbon tetrachloride.

For example, when the 3- (2-bromomethyl) indene. is replaced by an equivalent amount of 3- (2-bromomethyl) -5-methoxyindene by the method of this example, 5-methoxyindene-3-ethanthiol is obtained. By substituting the 3- (2-bromethyl) indene with the 3- (2-bromo-1-methylpropyl) indene, the same way, α, p-dimethylindene-3-ethanthiol-1-methyl-1,3,4 is obtained. , 9-tetrahydroindeno [2 f 1-cl ^ pyran-1-acetic acid

To a solution of 8 g of indene-3-ethanol and 6 g of methyl acetoacetate in 250 ml of dry benzene containing ca. 2 g of hydrated alkali-aluminum silicate (molecular sieve # 4) is added 1 ml of boron trifluoride etherate and the mixture is stirred at room temperature for 4 hours. An additional 1 ml of boron trifluoride etherate is added, the reaction mixture is stirred at ambient temperature overnight and then refluxed for 1 hour. The hydrated alkali-aluminum silicate is collected and the filtrate is washed with 10% solution of sodium bicarbonate and water. After drying over magnesium sulfate, benzene is removed under reduced pressure to give 1-methyl-1,3,4,9-tetrahydroindeno- [2,1-c] pyran-1-acetic acid methyl ester, 1724 cm -1.

Hydrolysis of this ester to the title compound is carried out as follows: 11.5 g of the latter ester are dissolved in 400 ml of methanol and the solution is mixed with a solution of 12 g of sodium hydroxide in 100 ml of water. The resulting mixture is kept at room temperature overnight. Methanol is removed by evaporation. Dilute the residue with water. The aqueous solution is repeatedly extracted with ether and acidified with 6N hydrochloric acid.

The resulting precipitate is extracted with ether. The ether extract is dried (MgSO4), filtered and concentrated. The residue is crystallized from benzene to give the title compound (No. A25), m.p. 179-180 ° C, NMR (CDCl 3) δ 1.45 (s, 3H), 2.51 (m, 2H), 2.73 (s, 2H), 3.25 (t, 2H), δ , 02 (t, 2H), 7.26 (m, 4H), 9.80 (wide, 1H).

An equivalent amount of ethyl acetoacetate can replace methyl acetoacetate by the method of this example. In this trap 79141201 is obtained as ester 1-methyl-1,3,4,9-tetrahydroindeno (2,1-c3 pyran-1-acetic acid ethyl ester).

An equivalent amount of propylacetoacetate can replace methyl acetoacetate by the method of this example. In this case, as ester 1-methyl-1,3,4,9-tetrahydroindeno [2,1-ejpyran-1-acetic acid propyl ester is obtained.

9-Tetrahydroindeno [2,1-cJ pyran-1-propionic acid

A mixture of 15 g of indene-3-ethanol, 300 ml of dry benzene, 22.6 g of levulinic acid, 3 ml of boron trifluoride etherate and hydrated alkali-aluminum silicate (Molecular Sieve No. 4) is stirred at room temperature for 2 hours.

The reaction mixture is filtered. The filtrate is washed 3 times with 5 N NaOH. The combined aqueous phase is washed twice with ether and then acidified with cold diluted HCl. The aqueous phase is extracted with chloroform. The chloroform extract is dried (^ 280 ^) and evaporated to dryness. The residue is crystallized from a mixture of ether and hexane to give the title compound (No. A26), m.p. 97-996, ½½ 1700, NMR (CDCl 3) δ 1.4 (s, 3H), 2.2 (m, 4H), 2.5 (m, 2H), 3.25 (t, 2H) ).

1-Methyl-l, 3,4,9-tetrahydroindeno [2,1-c] thiopyran-l-acetic acid

A mixture of 8.0 g of indene-3-ethanethiol, 6 g of methyl acetoacetate and 0.8 g of p-toluenesulfonic acid in 200 ml of benzene is heated under reflux using a water separator for 5 hours.

After cooling, the reaction mixture is washed with 10% solution of sodium bicarbonate and water. The benzene is removed under reduced pressure. The residue is the corresponding methyl ester of the title compound, 1-methyl-1,3,4,9-tetrahydroindeno [2,1-c] thio-CHrl1 pyran-1-acetic acid methyl ester, max 3 1730 cm .

The latter ester is dissolved in 200 ml of methanol and 100 ml of 1.25 N NaOH is added. After stirring under reflux for 3 hours, the methanol is removed by evaporation and the aqueous residue is extracted with ether. The aqueous layer is then acidified with 6N HCl and extracted with ether. The ether extract is dried (MgSO4), filtered and evaporated to dryness. The residue is crystallized from ether to give the title compound (No. A27) m.p. 119-121 ^, 0 ^^ 3 3000, 1700 cm "1.

Proceed in the manner described to prepare 3 other compounds of formula (IV) wherein A is A, Examples of such compounds of formula (IV) are listed in Table XVII together with the necessary starting materials of formula (II) and (XX). It should be noted that the ester obtained prior to hydrolysis in each of these examples is a corresponding ester of the product obtained there.

Similarly, the products listed in Table XVII can be prepared if an equivalent amount of the corresponding keto acid is used instead of the keto ester listed there.

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Ν f Ν, 1-Trimefchyl-1,3 ^ 4,9-tetrahydroindeno [2 f-c] pyran-1-acetamide 12.0 g of triethylamine and then 13 g of ethyl chloroformate in 50 ml of tetrahydrofuran (THF) are added to a cooled solution (- 5 ° C) of 97 g of 1-methyl-1,3,4,9-tetrahydroindeno [2,1-c] pyran-1-acetic acid, described as Compound No. A25, in 150 ml of THF. After stirring for 90 minutes, the mixture is further cooled to ca. -10 ° C, treat with 230 ml of 40% aqueous dimethylamine solution and stir at -10 ° C for an additional 30 minutes. Most THF is evaporated and the residue is partitioned between chloroform and water. The chloroform layer is washed with water, dried (MgSO 4) and concentrated to give the title compound (No. B58) as an oil, v3 1625, in ΧαΧ 1400, 1075 cm cm 1, NMR ( CDCl3) δ 1.55 (S, 3H), 3.07 and 2.53 (m, 2H), 2.74 (s, 2H), 2.92 and 3.07 (s, 6H), 3.42 (m, 2H), 3.96 (t, 2H), 7.25 (m, 4H).

N, N, 1-Trimethyl-1,3,4,9-tetrahydroindeno [2,1-c] thiopyran-1-acetamide 4.0 g of 1-methyl-1,3,4,9-tetrahydroindeno [2,1-c ] Thiopyran-1-acetic acid, described as Compound No. A27, is dissolved in 60 ml of anhydrous THF. This solution is treated with 4.7 g of triethylamine at -5 ° C.

5.0 g of ethyl chloroformate in 30 ml of THF is added dropwise to the solution and the resulting mixture is stirred at -5 ° C for 90 minutes. 60 ml of a 40% aqueous solution of dimethylamine are added and stirring is continued at room temperature for 30 minutes. The solvent is removed under reduced pressure. The remaining suspension is partitioned between chloroform and water. The organic phase is separated, washed with water, dried (MgSO 4) and concentrated to give the title compound (No. B59) as a solid, NMR (CDCl3) δ 1.75 (s, 3H), 2.95 (broad m, 12H), 3.50 (t, 2H), 7.26 (m, 4H).

Proceeding in the manner described, but using as the starting material an equivalent amount of another acid compound of formula (IV) (A - A) instead of 1-methyl-1,3,4,9- tetrahydroindeno [2,1-c] pyran-1-acetic acid or its thio analog, and using an equivalent amount of an appropriate amine, e.g. ammonia or a primary or secondary amine, the amides are listed as products in Table XVIII together with the starting material of formula (Ile) and the amine used for the preparation of the amide.

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A mixture of 500 mg of intra-3-ethanol, 580 mg of N, N-dimethylpyruvic acid amide, described by W.F. Gresham, U.S. Patent No. 2,429,877, 1.7 g of phosphorus pentoxide and 0.5 g of diatomaceous earth (Celite) in 75 ml of benzene are stirred at room temperature for 15 minutes and then at 70 ° C for 1 1/2 hours. The reaction mixture is filtered. The filtrate is washed with water, dried (MgSQ4) and concentrated to give the title compound, which is identical to Compound No. B61.

£ 3 same made t but as cLei? If equivalent amount of the appropriate starting material of formula (Ile) is used instead of within-3-ethanol together with the appropriate α, β, Y or S ketoamide, the products listed as Compounds B58-B61 are obtained.

Step C.

NiNil-Trimethyl-lihi [14] -tetrahydroindeno] l2il; c] gyryl-1-ethylamine Lamin 6.0 g of the amide, N, N, 1-trimethyl-1,3,4,9-tetrahydroindeno- [2,1c] pyranic acid 1-Acetamide, described as Compound No. B58 in 50 ml of dry tetrahydrofuran is added dropwise to a stirred mixture of 3.0 g of lithium aluminum hydride in 50 ml of ether. The reaction mixture is stirred at room temperature for 90 minutes. Hydride excess is decomposed with 24 ml of water. 100 ml of THF is added and the mixture is filtered and the filtrate is dried (MgSO 4), filtered and the filtrate is evaporated. The residue is evaporated to give the title compound, NMR (CDCl3) ό 1.42 (s, 3H), 1.70 - 2.80 (6H), 2.22 (s, 6H), 3.30 ( t, 2H), 3.97 (t, 2H), 7.30 (m, 4H).

The corresponding hydrochloric acid addition salt, Ν, Ν, Ι-trimethyl-1,3,4,9-tetrahydroindeno [2,1-c] pyran-1-ethylamine hydrochloride, has m.p. 266-268 ° C after recrystallization from ethanol.

Similarly, but replacing lithium aluminum hydride with an equivalent amount of lithium aluminum hydride-aluminum chloride, aluminum hydride-aluminum chloride, diborane and sodium borohydride-aluminum chloride, the title compound is likewise obtained.

NiN ^ l-Trimethyl-l ^ S ^^ g-tetrahydro-indeno [^ l-cHiogyran ^ l -ethylamine 2.7 g of the amide N, N, l-trimethyl-1,3,4,9-tetrahydroindeno [ 2,1-c] thiopyran-1-acetamide, described as Compound No. B59 in 200 ml of anhydrous ether, is added dropwise to a stirred suspension of 1.0 g of lithium aluminum hydride in 100 ml of anhydrous ether. The mixture is stirred at room temperature for 30 minutes. Excess hydride disintegrate with 4 ml of water. The mixture is filtered. The filtrate is dried (MgSO 4) and concentrated to give the title compound, NMR (CDCl 3), δ 1.45 (s, 3B), 3.50 (ra, 2H), 7.32 (m, 4H).

The corresponding hydrochloric acid addition salt, N, N, 1,1 trimethyl - 1,3,4,9-tetrahydroindeno [2,1-c] thiopyran-1-ethylamine hydrochloride, has m.p. 265-267 ° C after recrystallization from ethanol.

Similarly, but replacing lithium aluminum hydrohydride with an equivalent amount of lithium aluminum hydride-aluminum chloride, aluminum hydride-aluminum chloride, diborane and sodium borohydro-aluminum chloride, the title compound is likewise obtained.

EXAMPLE 2 75-7§ When used in the manner described in Example 74, Step C, but using as an starting material an equivalent amount of another amide compound of formula (V) in place of N, N, 1-trimethyl-1 , 3,4,9-tetrahydroindeno [2,1-c] pyran-1-acetamide or its thio analog, the corresponding compounds of formula (I) are obtained. Examples of such compounds of formula (I) are listed as products in Table XXIX together with the starting material used.

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Example Gel-Z7 1-Methyl-1H-Si-Si-g-tetra-droindgno-g-1-glEjrrgs ^ J.-Niethanol E-SS2ASSSSA2 S-S in 10.4 g of the acid intermediate of formula (IV), -1,3,4,9-tetrahydroindeno [2,1-c] pyran-1-carboxylic acid, described as Compound No. A28, in 100 ml of THF is slowly added to a stirred mixture of 2 g of lithium aluminum hydride in 100 ml of TUF. The reaction is maintained at 0 ° C using an ice-water bath. After addition of the acid, the excess of the hydride is destroyed with water and the precipitate is collected on a filter plate. The filtrate is evaporated. The residue is taken into ether and the ether phase is washed with water, dried (Na 2 SO 4) and evaporated at reduced pressure to give an oil. Chromatography of the oil on silica gel using chloroform gives the title compound, 3580, 3440, 1470, 1120, 1095, 1075, 1050 in IRaO cm, NMR (CDCl3) δ 1.32 (s, 3H), 2.02 (broad, 1H), 2.49 (m, 2H), 3.26 (t, 2H), 3.62 (s, 2H), 3.95 (t, 2H), 7.21 (m, 4H) .

Fremgangsmåde_B:

Alternatively, the title compound is also obtained by proceeding in the manner described in Example 74, step A, but replacing methyl acetoacetate with an equivalent amount of the keto-alcohol (lower alkyl) ester, acetoxyacetone. It should be noted that the process of this example includes hydrolysis of the intermediate ester.

NiNil-Trimethyl-1,3-3,4-tetrahydroindeno [2ilgc] 2 Acid; 1; methylamine 9.0 g of 1-methyl-1,3,4,9-tetrahydroindeno [2,1-c] pyran-1-methanol is dissolved in 20 ml of dry pyridine. 7.4 g of p-tpluenesulfonylohloride are added portionwise to the vigorously stirred and cooled solution. The mixture is stirred at 0 ° C for an additional hour, ice and water are then added and the aqueous mixture is extracted with ether. Pe combined ethereal extracts are washed with 10% ice-cold hydrochloric acid, water, 5% sodium bicarbonate, and water and dried (Na 2 SO 4). Concentration of extracts gives 1-methyl-1,3,4,9-tetrahydroindeno [2,1-c] pyran-1-methyl tosylate.

Dissolve 11.7 g of the latter tosylate in 100 ml of dry acetone and treat the resulting solution with 15 g of sodium iodide. The mixture is stirred at room temperature for 24 hours. Most of the acetone is removed at reduced pressure, water and ice are added and the resulting brownish solution is extracted with ether. The combined etheric extracts are washed with 10% sodium thiosulfate solution, water and dried (Na 2 SO 4). The solvent is evaporated under reduced pressure to give a yellow oil. The oil is chromatographed on silica gel and eluted with benzene. Concentration of the eluate gives 1- (3-iodomethyl) -1-methyl-1,3,4,9-tetrahydroindeno [2,1-c] pyran.

A mixture of 11.7 g of the latter compound in 100 ml of THF and 199 ml of 40% rs aqueous dimethylamine is stirred at room temperature for 6 hours. Most of the tetrahydrofuran is removed at reduced pressure, the milky aqueous solution is extracted with ether and washed with water until analyzes show that the water is neutral. The extract is dried (Na 2 SO 4) and evaporated to give the title compound which is identical to the product of Example 76.

Proceeding in the manner described in that order, but using as an starting material an equivalent amount of the appropriate ester intermediate in Process A or a suitable starting material of formula (Ile) and an appropriate ketoalcohol (lower alkyl) ester at Process B followed by the use of a suitable amine of formula HNR R in the process of Example 77 yields the respective compounds of formula (I), e.g. those described in Examples 74-76.

Example 78 1- (3-Iodomethyl) -1-methyl-1,3,4-f9-tetrahydrindindo [2,1-c] pyran

To a solution of 15 g of indene-3-ethanol in 150 ml of benzene is added. 12 g of iodoacetone. The mixture is heated under reflux with 5 ml of boron trifluoride etherate and hydrated alkali-aluminum silicate (Molecular Sieve # 4). After 1 hour, an additional 400 mg of acid is added. After a total of 2 hours, the reaction mixture is cooled, filtered, washed with 5% sodium bicarbonate and water and dried over sodium sulfate. Evaporation under reduced pressure gives an oil.

This oil is purified by chromatography on silica gel. Elution with benzene and concentration of the eluate gives the title compound which is identical to the compound of the same name described in Example 77.

Proceeding in the manner described, but using as starting materials an appropriate starting material of formula (Ile) described above, together with an appropriate β, γ or ό halogen ketone of formula (XXIII) described above, is obtained. 89 141201 the corresponding intermediates of formula (VII).

These latter intermediates of formula (VII) are then treated under the conditions described in Example 77 with a suitable amine of the formula HNR R, wherein R and R are as defined above, to produce the corresponding compounds of formula (I). ), eg. the products of Examples 74 and 75.

Example 79 N-Ethyl-1-methyl-1,3,4,9-tetrahydroindeno [2,1-gpyran-1-propylyamine

A mixture of 4.2 g of indene-3-ethanol and 3.7 g of N- (4-oxo * pentyl) acetamide, described by L.P. Kuhn et al., In J. Am. Chem. Soo., 89, 3858 (1967), in 300 ml of dry benzene is stirred and refluxed under reflux. Water is collected in a Dean-Stark separator. After draining the water, 5 drops of boron trifluoride etherate are added and the mixture refluxed for 30 minutes, again using the water separator. After stirring at room temperature overnight, the reaction mixture is evaporated to dryness. The solid residue is dissolved in chloroform and washed successively with 10% aqueous sodium bicarbonate, water and brine. The chloroform solution is dried over magnesium sulfate, filtered and evaporated to give 1- [3- (acetamido) propyl] -1-methyl-1,3,4,9-tetrahydroindeno [2,1c] pyran, $ 1650 cm .

2.6 g of the latter product in 80 ml of dry THF is added to a suspension of lithium aluminum hydride in 200 ml of THF. The resulting slurry is stirred and heated at reflux for 2 hours, cooled, and then 2.4 g of lithium aluminum hydride is added. The mixture is heated at reflux for 16 hours. The mixture is then decomposed with 22.4 ml of water added dropwise over 3 hours with stirring and cooling of the mixture. The precipitate is separated by filtration. The filtrate is dried (MgSO 4). Removal of the solvent gives the title compound, MMR (CDCl3) δ 1.1 (t, 1 = 7, 3H), 1.50 (s, 38), 3.3? (m, 2H), 2.9 (q, 1 = 7, 2H).

Alternatively, 2.6 g of the latter product is added to a solution of 1.8 g of triethyloxonium fluoroborate in 50 ml of methylene chloride.

The resulting solution is evaporated under reduced pressure and the residue is dissolved in 25 ml of absolute ethanol. 0.7 g of sodium borohydride is added portionwise to the stirred solution at 0 ° C. After the addition is complete, stirring is continued for 18 hours at 25 ° C. The solution is poured into 250 ml of water and extracted with 3 portions of ether of 30 ml each. The combined extracts are washed with water, dried (MgSO 4) and evaporated to give the title compound.

Proceeding in the manner described, but using as an starting material an equivalent amount of the appropriate starting material of formula (XIc), e.g. those described in Example 74 as Compounds No. A25-A28, and using an equivalent amount of a suitable ketoamide of formula (XXIV) described above, the respective secondary amine compounds of formula (I) are obtained.

Example 80 1-Methyl-1- (3-aminopropyl) -1,3,4,9-tetrahydroindeno [2 T1-c [pyran

To a solution of 352 mg of intra-3-ethanol and 273 mg of the nitroketone, 5-nitro-2-pentanone, cf. H. Shechter et al., Discussed above, in 5 ml of benzene are added 5 drops of boron trifluoride etherate and 3 drops. trifluoroacetic acid. The reaction mixture is stirred and heated at reflux under a water separator for 18 hours. The benzene solution is cooled, washed with 10% sodium bicarbonate solution, water and saturated brine, and dried over magnesium sulfate. The solvent is removed and the residue is subjected to chromatography on silica gel. Chloroform elution gives 1-methyl-1- (3-nitropropyl) -1,3,4,9-tetrahydroindeno [2,1-c] pyran, 0

Reduction of the latter compound by lithium alumininium hydride by the procedure of Example 79 gives 1-methyl-1- (3-aminopropyl) -1,3,4,9-tetrahydroindeno [2,1-c] pyran, NMR (CDCl 1.51 (s, 3H), 3.32 (m, 2H), 7.28 (m, 4H).

. Proceeding in the manner described including the reduction described therein, but using as an starting material an equivalent amount of the appropriate starting material of formula (Ile), e.g. those described in Example 74 as Compounds No. A25-A28, and using an equivalent amount of a suitable nitroketone of formula (XXV) described above, the respective primary amine compounds of formula (I) are obtained.

Eksempel_81

NjN ^ l-Tr imethy 1-1,3,4 ^ -tetrahydroindeno [2 Al-c ^ pyran-1-e thylamine

To a solution of 1.0 g of 1-dimethylamino-3-butanone dissolved in 10 ml of toluene is added 1.3 g of p-toluenesulfonic acid. The suspension is stirred for 10 minutes, 1.0 g of indene-3-ethanol in 5 ml of toluene is added to the suspension and the resulting solution is stirred for 2 hours. 0.25 ml of 91 141201 boron trifluoride etherate is added together with ca. 0.5 g of hydrated alkali-aluminum silicate. The mixture is heated at 80 ° C for 30 minutes. The mixture is cooled and diluted with water. The organic layer is separated and the aqueous layer is extracted with toluene. The organic layers are washed with water. The combined aqueous phase is made alkaline down wife. NH 2 OH and extracted with toluene. The latter extract is treated with charcoal and then concentrated to give the title compound which is identical to the same compound described in Example 74.

When proceeding in the manner described, but using as an starting material an equivalent amount of the appropriate starting material of formula (Ile), e.g. those described in Example 74 as compounds of A25-A28, and using an equivalent amount of the appropriate amino ketone of formula I6 7 R CO- (CH2) n-NR R, respectively, the indopyranic and indenothiopyranalkylamines are obtained with formula (I).

Claims (3)

92 141201 Patent Claims. 1. An analogous process for the preparation of derivatives of pyranoindole, oxazinoindole and indenopyran and their thioanalogues or acid addition phenyl salts thereof, the derivatives of which are of the general formula CH2, I2 (I) \ / x C / \ 67 R (CH2) n- HK R '17 where R is alkyl, R and R are the same or different and 6 7 means hydrogen or alkyl, or R and R together with the nitrogen atom to which they are attached form a heterocyclic amine radical which is 1- pyrrolidinyl, piperidino, morpholino, piperazino, 4-alkyl-1-piperazinyl or 4-hydroxyalkyl-1'-piperazinyl, n is an integer of from 1 to 4, X is oxy or thip, and A is a divalent radical, there is * "- € £ Χ -“ - CigC * · “* -“ - OcX il6 · I 1 K 2 3 wherein R 6 represents hydrogen or alkyl, R 7 represents alkyl, and R 18 represents hydrogen, alkyl, hydroxy, alkoxy of 1-4 carbon atoms, benzyloxy or halogen, wherein said alkyl groups may be straight chain with 1-6 carbon atoms or branched with 3-4 carbon atoms, characterized in that a) a compound of the formula _ / H2CH2Y ί (Ila) R16 R17 r1 ^ 0CnJi (IIb) CH2CH2y 93 141201 ch2ch2y or (Ile) 16 17 18 wherein R, R and R are as defined above and Y is hydroxy, mercapto, -S-SO3Na or -S-SO3 -K, in the presence of an acidic catalyst treated with a compound of the formula R3 CO- (CH2 ) n ~ NR6R7 (III) 16 7 wherein R, R and R and n are as defined above, or b) a compound of the formula CH0 / χς®2 \ I (ro) R1 · ^ "\ (CH2) n_rCO0R19 1 19 where A, R, X and n are as defined above and R is lower alkyl, hydrolyzed to form the corresponding acid, whereupon the acid, if desired after an alkylation at the N atom, is treated with a (low (alkyl) chloroformate to form the corresponding mixed anhydride, the mixed anhydride treated with an amine of the formula HNR ° Ry, wherein R and r 'have the meaning given above to form the corresponding amide and the latter compound is treated with a reducing agent, or c) a compound of the formula CHO / CH2 O2 (CH2), -CONR6R7 r n-1 16 7 wherein A, X, R, R, R and n are as defined above are treated with a reducing agentX, or d) a compound of the formula / CH2 / Xch2 \ in (VI) R1 / \ (CH9) O-COR20 "Π" 94 where A, X, R and n are as defined above, and R is hydrogen or lower alkyl, is treated with a hydrolyzing agent to form the corresponding primary alcohol which is treated with a halogenating, mesylating or tosylating agent to form the corresponding halide, mesylate or tosylate, and this latter compound is treated with an amine with the formula HNR6R7 6 7 wherein R and R have the above or e), or e) a compound of the formula CH0 / ^ /? H, AI 1 (VII) \ 1 / CX R where A, X, R1 and n have the meaning given above and L means halogen is treated with a amine of formula hnr6r7 6 7 wherein R and R are as defined above, or f) a compound meets the formula CH- /% AI (VIII) \ X R3 ^ X (CH2) n-NR6COR21 1 6 21 where A, X, R, R and n are as defined above and R is hydrogen or alkyl of 1 to 5 carbon atoms, reduced, or g) a compound of the formula CHO / AI (IX) yx NcH2 -SO wherein A, X, R1 and n has the meaning set forth above, reduced, 7 7 after which a compound prepared wherein R and / or R means