CH605959A5 - (thio)pyrano-indole derivs - Google Patents

Abstract

(thio)pyrano-indole derivs with antidepressant and antiulcer activity

Description

  

  
 



   The invention relates to a process for the preparation of condensed indole and indene derivatives having useful pharmacological properties. In particular, the invention relates to the preparation of pyranoindole, oxazinoindole and indenopyran derivatives and their analogues.



  The compounds produced by the process according to the invention have antidepressant properties and at the same time a low toxicity. In addition, some have anti-ulcer efficacy.



   So far, very little attention has been paid to the pyrano [3,4-b] indole, 1,4-oxazino F4,3-a] indole and indeno [2,1-clpyran derivatives and their thio analogs.



  In the few publications that exist, such as the reports by H. Plieninger, Chem. Ber., 83, 271 (1950); S. Sakurai and T. Ito, Nippon Kagaku Zasshi, 78, 1665 (1957), Chem Abstr., 54, 1488f (1960); YES. Elvridge and F.S. Spring, J. Chem. Soc., 2935 (1949); W.R. 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 as chemical curiosities. In these cases, the known derivatives can easily be distinguished from the compounds according to the invention, because the pyrene portion of the ring system is unsaturated.



   In addition, the previously published methods of preparation of the compounds which have one of the ring systems mentioned have absolutely no resemblance to the process according to the invention. For example, the known processes lead to heterocyclic systems with a higher degree of oxidation and / or, in contrast to the process according to the invention, do not allow easy and direct introduction of a large number of substituents into the oxygen or sulfur-containing ring. See, for example, the J.A. Elvridge and F.S. Spring, or M.C. Freed et al., J. Med. Chem., 7, 628 (1964).



   Indeed, the reaction of a condensed indole or indene bearing an ethanol or ethanethiol substituent with a ketone appears to be a tricyclic heterocycle without a precursor. One has to delve into the remote field of furopyran chemistry before one can find a process which has some similarity, i.e. for example the reaction of furan-3-ethanol with certain ketones, which leads to bicyclic heterocycles (DT-OS 2 051 496, published on April 29, 1971).



   The present invention therefore provides a process for the preparation of a compound of the formula I.
EMI1.1
 wherein R1 is alkyl of 1 to 6 carbon atoms;
R2, R3, R4 and R5 are identical or different and are hydrogen or alkyl with 1 to 6 carbon atoms; R6 and R7 are the same or different and are hydrogen or alkyl of 1 to 6 carbon atoms or R6 and R7 together with the nitrogen atom to which they are attached form a heterocyclic ring, e.g. a l-pyrrolidinyl; Piperidino, morpholino, piperazino, S-lower alkyl-1- piperazinyl or 4- (hydroxy-lower alkyl) -1-piperazinyl radical;

  ;
Alk CR8R9, CR3R9CRl0Rll, CR8R9CRl0RllcRl2R13 or CR8ROCRlORUCRI2RuCRHRli, in which R8, R9, R10, R11, R12, R13, R14 and R15 represent hydrogen or alkyl having 1 to 6 carbon atoms;
X oxygen or sulfur;

   and
A is a divalent radical of the formula
EMI1.2
 where R16 is hydrogen or alkyl having 1 to 6 carbon atoms, R17 is alkyl having 1 to 6 carbon atoms and R18 is hydrogen, alkyl having 1 to 6 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms, alkanoyloxy having 2 to 6 carbon atoms or halogen, which is characterized in that a compound of the formula II
B-CR4R5CRêR Y (II), where B is a monovalent radical of the formula
EMI1.3
  
EMI2.1

B, wherein Y represents hydroxy, mercapto, -S-SO3Na or -S-SO3-K, with a compound of the formula m Rlco z (m) wherein Z a) Alk-NR6R7;

  ; b) CONR6R7 or Alk1-CONR0R7, where Alk1 represents CR3R9 CR1OR11 or CRsRCRloRllCRl2R13; or c) Alk NR6COR21, in which R21 is hydrogen or alkyl having 1 to 5 carbon atoms, in the presence of an acid catalyst to give a corresponding compound of the formula IV
EMI2.2
 reacts, and if a compound of the formula III is used in which Z has the meaning given under (b) or (c), the compound of the formula IV is reduced.



   The term lower alkyl used in this specification denotes straight-chain alkyl radicals with 1 to 6 carbon atoms and branched-chain alkyl radicals with 3 to 4 carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and the like.



   The term lower alkoxy denotes both straight and branched-chain alkoxy radicals having 1 to 4 carbon atoms and includes methoxy, ethoxy, isopropoxy and the like.



   The term lower alkanoyloxy denotes both straight and branched chain alkanoyloxy radicals having 2 to 6 carbon atoms and includes acetoxy, propionyloxy, hexanoyloxy and the like.



   The term halogen includes fluorine, chlorine, bromine and iodine.



   The compounds of the formula I can form acid addition salts with pharmaceutically acceptable salts. Such salts also belong to the compounds prepared according to the invention.



   The acid addition salts are generally prepared by adding the corresponding basic form of the compounds of the formula I with one or two equivalents, depending on the number of basic nitrogens in the compound, but preferably with an excess of a suitable acid in an organic solvent, e.g. Ether or an ethanol-ether mixture. When administered to mammals, these salts exhibit the same pharmacological activity as the corresponding bases. For some purposes it is advantageous to administer salts instead of the basic compounds. Salts suitable for this purpose include the sulfate, phosphate, lactate, tartrate, maleate, citrate, hydrobromide and hydrochloride.



  Both the basic compounds and the salts have the great advantage of relatively low toxicity.



   The compounds prepared according to the invention also include the stereochemical isomers of the compounds of the formula I, which can be attributed to the asymmetric centers contained therein. These isomeric forms can be prepared in several ways and can be easily purified by crystallization or chromatography.



   This also includes individual optical isomers which are formed by fractional crystallization of the diastereoisomeric salts formed from them, e.g. with d- or l-tartaric acid or D - (+) - a-bromocamphonic sulfonic acid, can be separated.



   The useful antidepressant properties of the compounds of formula I and their acid addition salts can be demonstrated in standard pharmacological tests, e.g. in the experiments described by F. Hafliger and V. Burckhart in Psychopharmacological Agents, M. Gordon, Ed., Academic Press, New York and London, 1964, pp. 75-83.



   As described in the latter reference, the antidepressant properties of a compound can be demonstrated, in particular by its ability to counteract the depressive effects of reserpine. Indeed, it is well known that reserpine induces a characteristic depression in animals which can be used to demonstrate antidepressant properties. The compounds prepared according to the invention now act against reserpine depression in mice in doses in the range from about 1 to 100 mg / kg.

  Several of the preferred compounds, e.g. 1- [2-Q) imethylamino) ethyl] -1- methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole oxalate (Example 54), 1-methyl -1- [3- (methylamino ) propyl] - 1,3,4,9-tetrahydropyrano [3,4-b] indole oxalate (Example 55), 1- [2- (dimethylamino) ethyl] -9-ethyl-1-methyl-1,3,4 , 9-tetrahydrothiopyrano [3,4-b] indole hydrochloride (Example 137), 1,10-dimethyl-1- [3 (methylamino) propyl] -3,4-dihydro-IH-1,4-oxazino- [4, 3-a] indole hydrochloride (Example 173), 1- (3-aminopropyl) 1,1 0-dimethyl-3,4-dihydro-IH-1, 4-oxazino [4,3-aindole hydrochloride (Example 174),

   and N, N, 1-trimethyl-1,3,4,9-tetrahydro-indeno [2, 1-c] thiopyrano-1-ethylamine hydrochloride (Example 220), are already effective at doses in the range from about 1 to 15 mg / kg.



   When using the antidepressants prepared according to the invention in warm-blooded animals, e.g. in rats and mice, they can be used alone or in combination with pharmacologically acceptable carriers, the proportion of these carriers depending on the solubility and chemical nature of the compound, the route of administration chosen and on common biological practice. You can e.g. be administered orally in solid form using carriers such as starch, lactose, certain types of clay, etc. They can also be administered orally in the form of solutions or injected parenterally.

 

  For parenteral administrations, sterile solutions containing other solutes, e.g. contain enough saline or glucose to make the solution isotonic.



   The dosage of the active ingredients depends on the type of administration and on the particular compound chosen.



  In addition, it naturally depends on the recipient. Generally, treatment is started with a small dose, well below the optimal dose of the compound. The dose is then increased in small steps until the optimum effect is achieved under the given circumstances. In general, the compounds prepared according to the invention are administered in a concentration which brings effective results without, however, having adverse side effects, preferably in a dose which is in the range from about 0.1 to about 50 mg per kilogram and day, although as mentioned, different amounts can be used. However, a dose in the range from about 0.5 to about 25 mg per kilo and day is most expedient if a satisfactory effect is to be achieved.



   The compounds of the formula I in which A is A1 or A2 have other valuable pharmacological properties. They are useful anti-ulcer agents. This efficacy against ulcers is particularly evident in standard pharmacological tests, e.g.



  the D.A. Brodie and L.S. Valitski, Proc. Soc. Exptl.



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



   When the compounds of formula I are used as anti-ulcer agents, they can be prepared and administered in the same manner as when used as antidepressants.



   The required starting materials of the formula B-CR4RG CR2R3Y aI) are either known or, depending on the meaning of B, can easily be prepared by one of the following methods:
When B is B1, the required starting materials of formula II, wherein Y is hydroxy, are either known, e.g. Tryptophol, described by H.R.



  Snyder and F.J. Pilgrim, J. Am. Chem. Soc. 70, 3770 (1948) or can be obtained by the following procedure:
EMI3.1

In this process phenylhydrazines of formula V and hydroxyaldehydes of formula VI are reacted according to the conditions of the Fischer indole synthesis, see e.g. P.L. Julian, E.N. Myer and H.C. Printy, Heterocyclic Compounds, R.C. Elderfield, Ed., Vol. 3, John Wiley and Sons, Inc., New York, 1952, pp. 8-11, the desired starting material of the formula II (B = B1 and Y = OH) being formed.



   The phenylhydrazines of the formula V are either known or can be prepared by known methods.



  One of the most popular methods is the diazotization of a suitably substituted aniline, the corresponding diazo derivative being obtained. This compound is then reduced to the corresponding phenylhydrazine with tin chloride or sodium sulfite. See L.F. Fieser and M. Fieser, Advanced Organic Chemistry, Reinhold Publishing Corporation, New York, 1961, p. 734.



   The hydroxy aldehydes of formula VI are either known, see e.g. Rodd's Chemistry of Carbon Compounds, S. Coffey, Ed., Vol. 1d, 2nd ed., Elsevier Publishing Co., Amsterdam, 1965, p. 4449 or can be prepared by known processes. This includes the reduction of a suitable lactone of the formula
EMI3.2
  with bis (3-methyl-2-butyl) borane, H.C. Brown and D.B.



  Bigley, J. Am. Chem. Soc., 83, 486 (1961), diisobutylaluminum hydride, L.1.Zakharkin and 1.M. Khorlina, Tetrahedron Letters, 619 (1962) or sodium aluminum hydride, L 1.



  Zakharkin et al., Tetrahedron Letters, 2087 (1963). The lactones suitable for this condensation are either commercially available, e.g. Valerolactone, α-methyl-butyrolactone or numerous processes for their preparation are described in textbooks on organic chemistry; Such textbooks are: Methods of Organic Chemistry, Houben-Weyl, E. Muller, Ed., Vol. VI / 2, Georg Thieme Verlag, Stuttgart, 1963, pp. 561-852 or L.F. Fieser and M. Fieser, Advanced Organic Chemistry.



   On the other hand, the starting materials of the formula II, in which B = B1, R2, R3, Ro and R16 is hydrogen and Y is hydroxy, can be obtained by lithium aluminum hydride reduction, N.G. Gaylord, Reduction with Complex Metal Hydrides, Interscience Publishers, Inc., New York, 1956, pp. 322-370, of compounds of Formula VII, page 12, described by T.Y. Shen in U.S. Patent No. 3,161,654 dated December 15, 1964.



   The starting materials of the formula II, in which B is B1 and Y is mercapto, can be obtained with the aid of the following processes: The suitable compound of the formula II (Y = OH) is dissolved in an inert solvent, e.g. Ether, carbon tetrachloride, methylene dichloride or toluene, reacted with phosphorus tribromide to give the corresponding 3- (2-bromoethyl) indole derivatives. This compound is then converted into the desired starting material of Formula II (Y = SH) or Formula 2 (Y = -S-SO3Na or -S-SOsK), wherein B is B1, using a procedure similar to that of N.N. Suvorov and V.N. Buyanov, Khim. Farm. Zh., 1,4 (1967), Chem.

  Abstr. 67, 73474a (1967) for the conversion of 3- (2-bromoethyl) indole to indole-3-ethanethiol (2; B = B1, R2, R3, R4, R5, R13 and R19 = H and Y = SH) . The suitable 3-2 (bromoethyl) indole derivative is treated accordingly with sodium or potassium thiosulfate, the suitable sodium or potassium ss- (3-indolyl) ethyl thiosulfate derivative, in particular the desired starting materials of the formula II (Y = -S- SOaNa or -S-SO, K), where B is B1. If this derivative is treated with a strong alkali, e.g. Sodium or potassium hydroxide, it is converted into the corresponding bis- [sa- (3-indolyl) - ethyl] disulfide derivative. Reduction with lithium aluminum hydride then leads to the desired starting material of the formula II.



   On the other hand, the foregoing thiosulfate derivative can be mixed with acid, e.g. dilute, aqueous solutions of hydrochloric acid, sulfuric acid or phosphoric acid, treated, the compound of formula II being obtained directly.



   It must be noted that this process is not particularly practical for preparing compounds of Formula II wherein Y is mercapto, -S-SOaNa, or -S-SO3K and R13 is hydroxy or lower alkanoyloxy.



  Therefore, the preferred starting materials of the formula II for the preparation of the compounds of the formula I in which R18 is hydroxy or lower alkanoyloxy and Y is mercapto, -S-SOaNa or -S-SO3K, those compounds of the formula II in which R18 is benzyloxy, which according to can be easily manufactured using the present processes.



  When the latter compounds are used as starting materials, they are first subjected to the process (11 + m + m, as described below. Then the benzyloxy group is removed by hydrogenation in the presence of a catalyst, e.g. 10% palladium on carbon , and one obtains the corresponding compound of the formula I in which R18 is hydroxy. This can, if desired, be converted into the corresponding compound of the formula I in which R18 20 is lower alkanoyloxy, for example by treatment with the suitable lower alkanoic acid anhydride, preferably in the presence of Pyridine.

  However, it should also be noted that a similar use of the starting material of the formula II, in which Y is hydroxy and R 1 is benzyloxy, for the preparation of a corresponding compound of the formula I in which R 18 is hydroxy or lower alkanoyloxy, is preferred.



   If, however, a starting material of the formula II, in which B = B2, is desired, this can easily be obtained from a corresponding indole precursor of the formula VIII
EMI4.1
 getting produced.



   The precursors of formula WI are either known, e.g. Skatole and 3-ethylindole, or can be made from indole or known indole derivatives. See e.g.



  P.L. Julian, et. al., Heterocyclic Compounds, R.C. Elderfield, Ed., Vol. 3, John Wiley and Sons, Inc., New York, 1952, p. 1, following the method of R. Robinson et al., Described in U.S. Pat. No. 2 407 452, dated September 10, 1946.



   The indole precursor of the formula VIII can then be converted into the desired starting material of the formula II
EMI4.2
 where B = B2 and Y is hydroxy, mercapto, -S-SOaNa or -S-SOaK, can be converted.



   This can be done in a number of ways. A customary process is the reaction of the suitable lithium derivative of the indole precursor of the formula VIII with ethylene oxide or a suitable lower alkyl-substituted ethylene oxide to give the desired compound of the formula II, in which Y is hydroxy. The desired compound can also be obtained by treating the appropriate indole precursor of Formula VIII with the appropriate ethylene oxide derivative by the method of M. Julia et al., Bull. Soc. Chim. Fr., 2291 (1966).

 

   The lower alkyl-substituted ethylene oxides are prepared by known methods. See e.g. V. Franzen and H.E. Driesen, Chem. Ber., 96, 1881 (1963).



   Another process for preparing the required starting materials of the formula II (B = B2), where R2 and R3 are hydrogen, is the treatment of the indole precursor of the formula WI with a lower alkyl ester of an α-haloacetic acid of the formula LCR4R5COO-lower alkyl, where L is halogen, in the presence of a suitable proton acceptor, an inert solvent being preferably used for the reaction. The lower alkyl esters of α-haloacetic acid are well known.



  See e.g. Rodd's Chemistry of the Carbon Compounds, S. Coffey, Ed., Vol. Ic, 2nd ed., Elsevier Publishing Co., Amsterdam, 1965, pp. 201-205. Suitable proton acceptors are sodium hydride, alkali metal carbonates and triethylamine. Suitable inert solvents are tetrahydrofuran, benzene, toluene and dimethylformamide.



  Preferred conditions for the N-alkylation include the use of sodium hydride as the proton acceptor and N, N-dimethylformamide or tetrahydrofuran as the inert solvent. Although the optimum temperature and reaction time will vary depending on the reagents used, the reaction is generally carried out at the boiling point of the reaction mixture and over a period of from 30 minutes to 48 hours.



   The indole-1-acetic acid lower alkyl ester derivative, which is obtained in the above N-alkylation, is then hydrolyzed, preferably with a solution of potassium hydroxide in methanol-water, and leads to the corresponding indole-lessetic acid derivative, which is converted into the desired by reduction with lithium aluminum hydride Starting material of the formula II (B = B3, where R2 and R3 are hydrogen and Y is hydroxyl, is converted.



   The mentioned indole-1-acetic acid derivative can also be mixed with two equivalents of a lower alkyl Grignard reagent, e.g. Methylmagnesium bromide, are reacted, the corresponding desired compound of formula II (R2 = R3 = lower alkyl and Y = hydroxy) being obtained after hydrolysis of the magnesium-halogen derivative. See L.F. Fieser and M. Fieser, Advanced Organic Chemistry, Reinhold Publishing Corp., New York, 1961, p. 272.



   If the corresponding starting material of Formula II (B = B2), wherein Y is mercapto, -S-SONa or -S-SO'K, is desired, a procedure similar to that cited above by N.N. Suvorov and V.N. Buyanov apply. The starting material of the formula II (B = where Y is hydroxy is then reacted with phosphorus tribromide in an inert solvent, e.g. ether or carbon tetrachloride, and then treated with sodium or potassium thiosulphate, the corresponding sodium or potassium ss- ( l-indolyl) ethyl thiosulfate derivative, namely the desired starting material of the formula II (Y = -S-SOaNa or -S-SO3K), in which B = B2, is obtained.



  If the latter product is treated with a strong alkali, e.g. Sodium or potassium hydroxide, the corresponding bis- [n- (indolyl) ethyl) disulfide derivative is obtained. Finally, reduction with lithium aluminum hydride gives the desired starting material of the formula II, in which Y is mercapto.



   The aforementioned thiosulfate derivative can also be mixed with acid, e.g. dilute, aqueous solutions of hydrochloric acid, sulfuric acid or phosphoric acid, are treated, this compound of formula II being obtained directly.



   These starting materials of the formula II (B = B2), where R2 and R3 are hydrogen and Y is mercapto, can also be prepared by reacting a corresponding compound of the formula II, where Y is hydroxy, with N, N-dicyclohexylcarbodiimide and dimethyl sulfoxide in the presence a suitable acid, e.g. Trifluoroacetic acid, oxidized to the corresponding aldehyde derivative. See K.E. Pfitzner and J.G. Moffat, J. Amer. Chem. Soc., 87, 5670 (1965).

  This aldehyde derivative is obtained by N-alkylation of the suitable indole precursor of the formula VIII with a suitable α-halo-acetaldehyde derivative (see Rodd's Chemistry of the Carbon Compounds, Vol. 1c, pp. 24-26), the above for the N-ALkylation with a-halo-acetic acid lower alkyl esters used conditions described.



   The aldehyde derivative is converted into the corresponding gem-dithiol with hydrogen sulfide, which is prepared according to the method of T.L. Cairns, et al., J. Amer. Chem. Soc., 74, 3982 (1952) to the desired starting material of the formula II, in which B = B2, and R2 and R3 are hydrogen and Y is mercaptoX.



   It should be noted that the foregoing methods are not necessarily practical for the preparation of compounds of Formula II wherein Y is hydroxy, mercapto, -S-SOaNa or -S-SO3K and R19 is hydroxy or lower alkanoyloxy. Therefore, the preferred indole precursors of the formula VIII for the preparation of the compounds of the formula I in which R18 is hydroxy or lower alkanoyloxy are those compounds of the formula WI in which R13 is benzyloxy, i. have a hydroxyl with a benzyl protecting group or other suitable protecting group (see JFW McOmie, Advances in Organic Chemistry, Vol. 3, RA Raphael, et al., Ed., Interscience Publishers, New York, 1963, pp. 191-294) .

  After the reaction steps described above, the benzyloxy group is hydrogenated in the presence of a catalyst, e.g.



     10% palladium on carbon, removed again. The compound of formula I obtained in this way, in which R18 signifies hydroxy, can, if desired, be converted into the corresponding compound of formula I in which R18 signifies lower alkanoyloxy, e.g. by treatment with a suitable lower alkanoic anhydride, preferably in the presence of pyridine.

 

   The starting material of the formula II, in which B = B3, is either known or can easily be prepared.



  In particular, the starting material of Formula II indene-3 ethanol is known and its synthesis has been carried out by a variety of methods. (See, e.g., G.R. Clemo et al., J. Chem. Soc., 863 (1951), and F.H. Howell and D.A.H.



  Taylor, J. Chem. Soc., 3011 (1957). For the preparation of this starting material, as well as for the preparation of other starting materials of the formula II (B = 33), in which Y is hydroxy, the following two general processes are suitable.



   The first method is illustrated by the following formula scheme:
EMI6.1

The cyclization of the suitable phenylpropionic acid derivative of the formula IX (see Chemistry or Carbon Compounds, Vol. III A, EH Rodd, Ed., Elsevier Publishing Co., Amsterdam, 1954, pp. 593-598) is achieved by adding an acid, e.g. anhydrous hydrofluoric acid, according to the conditions of J.A. Elvidge and R.G. Foster, J. Chem. Soc., 590 (1963) to the corresponding indanone of the formula X. This compound is reacted with the appropriate Reformatzky reagent of the formula LCR4R5COOR22, where L is bromine or chlorine and R22 is lower alkyl, and then dehydrated. See Organic Reactions, Vol. 1, R. Adams et al., Eds., John Wiley and Sons, Inc., New York, 1942, p. 1 and K. Brewster et al., J. Chem. Soc., 941 (1972).

  The endo -Ester XI or its mixture with the exo -Ester XII is obtained in the event that R5 is hydrogen. The ester XI or the mixture of these esters is then reduced with lithium aluminum hydride. The desired compound of the formula II obtained (B = B3, Y = OH, and R2 and R3 = 11) are then separated off from the reaction product using suitable methods such as chromatography or recrystallization.



   The second procedure is illustrated in the following equation:
EMI6.2

The suitable indene derivative of the formula XIII (Chemistry of the Carbon Compounds, Vol. 3 B, 1956, pp. 1256-1261, A. Panetta and SC Bunce, J. Org. Chem., 4859 (1961), and ML Tamayo and ND Robles, Anales Real Soc. Espan. Fis. Y Quim., 52B, 117 (1956), Chem. Abst., 50, 14676 (1956) 1 is converted into the corresponding lithium derivative by treatment with butyllithium in tetrahydrofuran treated with ethylene oxide or a lower alkyl-substituted ethylene oxide of the formula MV and gives the desired starting material of the formula II, wherein Y is hydroxy.

  This starting material can also be obtained by combining the suitable indene derivative of the formula XIII with the suitable ethylene oxide derivative of the formula MV according to the method of M. Julia et al., Bull. Soc. Chim. Fr., 2291 (1966) for the reaction of ethylene oxide with indole.



   The lower alkyl-substituted ethylene oxides are prepared by known methods. See e.g. V. Franzen and H.E. Driesen, Chem. Ber., 96, 1881 (1963).



   The starting material of the formula II, in which Y is mercapto, -S-SONa or -S-SO3K and B is B3, can be obtained by the following process: The above-described compound of the formula II (B = B3 and Y = OH) is with Phosphorus tribromide in an inert solvent, e.g.



  Ether or carbon tetrachloride, which gives the corresponding 3- (2-bromoethyl) indene derivative. If Y is hydroxy and R2, R3, R4, Ro and R18 are hydrogen, the 3- (2-bromoethyl) indene derivative is 3- (2-bromoethyl) indene itself, which is also described by R. Clemo, et al, 863 ( 1951). The 3- (2-bromoethyl) indene derivative obtained in this way is then converted into the desired starting material of the formula II. This is done according to a procedure similar to that of N.N. Suvorov and V.N. Buyanov, Khim. Farm. Zh., 1,4, (1967), [Chem. Abstr. 67, 73474a, (1967) 1 for the conversion of 3- (2-bromoethyl) indole into indole-3-ethanethiol.



  The suitable 3- (2-bromoethyl) indene derivative is treated with sodium or potassium thiosulphate and gives the corresponding sodium or potassium 8- (3-indenyl) ethylthiosulphate derivative, namely the desired starting material of the formula II, where B = B3 and Y means -S-SO3Na or -S-SO3K The subsequent treatment with strong alkali, e.g. Sodium or potassium hydroxide causes the conversion into the corresponding bis- [ID- (3-indenyl) ethyl] disulfide derivative.



  Reduction of this compound with lithium aluminum hydride gives the desired compound of formula II (B = B3 and Y = SH).



   The aforementioned thiosulfate derivative can also be mixed with acid, e.g. dilute, aqueous solutions of hydrochloric acid, sulfuric acid or phosphoric acid, treated, the compound of formula II being obtained directly.



   It should again be noted that the foregoing process for preparing compounds of Formula II wherein Y is mercapto and R13 is hydroxy or lower alkanoyloxy is not necessarily practical. Therefore the preferred starting material of formula 2 for the preparation of compounds of formula I in which R13 is hydroxy or lower alkanoyloxy and X is thio is those compounds of formula II in which R18 is benzyloxy, i. have a hydroxyl with a benzyl protecting group or other suitable protecting group (see J.F. McOmie cited above).



   If the letiter compounds are used as starting materials, they are first subjected to the procedure Ql + m -t IV) described below. Then the benzylo-xy group is hydrogenated in the presence of a catalyst, e.g. 10% palladium on carbon, removed before the desired compound of the formula I, in which R18 is hydroxy, is obtained. If desired, this can be converted into the corresponding compound of the formula I in which R15 is lower alkanoyloxy, e.g. by treatment with the appropriate lower alkanoic anhydride, preferably in the presence of pyridine.



   It should also be noted that the similar use of the starting material of Formula II (B = B3) where Y is hydroxy and R13 is benzyloxy to prepare a compound of Formula I where R18 is hydroxy or lower alkanoyloxy is preferred.



   When carrying out the condensation QI + m + m, it is generally advantageous to use equimolar amounts of the starting material of the formula II and the aminoketone compound of the formula m in the presence of an acid catalyst.



   In general, a solvent is used as the reaction medium for the condensation. Suitable solvents are aromatic hydrocarbons, e.g.



  Benzene or toluene, ethers and cyclic ethers, e.g.



  Diethyl ether, dioxane or tetrahydrofuran, halogenated hydrocarbons, e.g. Methylene dichloride or carbon tetrachloride and the like. Benzene and toluene are particularly suitable for this purpose. A variety of suitable acid catalysts can be used for the condensation. For example, the type of catalyst used in Friedel-Crafts reactions comes into question; p-toluenesulfonic acid, aluminum chloride, phosphorus pentoxide, boron trifluoride, tin chloride, hydrochloric acid, perchloric acid, trifluoroacetic acid, sulfuric acid and the like. p-Toluenesulfonic acid, aluminum chloride, boron trifluoride and phosphorus pentoxide are among the preferred acid catalysts. The amount of acid catalyst used is not particularly critical and can vary from 0.01 to 100 molar equivalents.



  However, a range of 0.1 to 10 mole equivalents is generally preferred. It should also be noted that if the reagents II and / or m contain certain basic nitrogens (other than indolian nitrogen), the amount of acid catalyst used should be greater than the amount required to neutralize such nitrogens. The reaction time can vary from 10 minutes to 60 hours, the preferred duration being between half an hour and 24 hours. The reaction temperature can vary from -20.degree. C. to the boiling point of the reaction mixture. The preferred temperature range is between 20.degree. And 1600.degree.



   A more detailed description of the preparation of the above compounds of the formula IV and a description of their subsequent conversion into the condensed indole and indene derivatives of the formula I and the corresponding thio analogs follows. For convenience, these descriptions are grouped into subsections based on the group selected for Z in the intermediate of Formula IV.



   a) Preparation of compounds of the formula Lv (Z = Alk-N115R7) = compounds of the formula I.
The above-described starting materials of the formula II are condensed directly to compounds of the formula I with an aminoketone of the formula Rl-CO-Alk-NR6R7 in the presence of an acid catalyst.



   The amino ketones required for this reaction are either known, e.g. l-Dimethylamino-3-butanone, l-methylamino-3-pentanone, see the above-cited F.F .; Views, or can be prepared by known processes. See e.g. Methods of Organic Chemistry, Vol. XI / I, 1957, pp. 58-62, 285-289 and 508-509.



   When carrying out this condensation, it is generally advantageous to use equimolar amounts of the starting material of the formula II and of the aminoketone in the presence of an acid catalyst. In this particular condensation, the amount of acid catalyst used will vary in the range of about 1.01 to 100 molar equivalents relative to the amount of aminoketone, with a range of 1.05 to 10 molar equivalents being preferred. It should be noted that the lower limit of this amount of acid catalyst depends on the number of basic nitrogens present in the aminoketone.

 

  If e.g. in the aminoketone R6 and R7 together with the nitrogen atom to which they are attached represent a piperazino radical (i.e. that two basic nitrogen atoms are present), a minimum of 2.01 molar equivalents of acid catalyst must be used.



  The acid addition salts of the aminoketones mentioned can also be used, e.g. the hydrochloride or sulfate.



  In this case the amount of acid catalyst can vary from 0.01 to 100 molar equivalents, preferably from 0.1 to 10 molar equivalents. In the present condensation, boron trifluoride is the preferred acid catalyst. The reaction can conveniently and advantageously be carried out without a solvent, although a high-boiling solvent, e.g. Toluene, O-xylene or isobutyl ether can be used. If no solvent is used, it is advisable to fuse the reagents and remove the melt in an inert atmosphere, e.g. under nitrogen or helium to stir. The reaction time and temperature depend on the respective starting materials.



   The most expedient reaction time is in the range from 0.5 to 48 hours, preferably 0.5 to 4 hours, and the reaction temperatures in the range from 20 to 200.degree. C., preferably 60 to 140.degree. In either case, the reaction is carried out at the lowest temperature at which the reaction will readily proceed with a minimum of decomposition.



   If a compound of the formula II in which Y denotes -S-SOsNa or -S-SOsK is used as starting material, it is advantageous if at least one equivalent of water is present in the reaction mixture. This water can be added directly or it can be part of the acid catalyst.



   An example of the latter case is p-toluene sulfonic acid with
Crystal water or concentrated hydrochloric acid.



   b) Preparation and reactions of the intermediate products of the formula IV (Z = CONR6R7 and Alkl-CONR6R7)
The intermediates of the formula IV, in which Z is CONR6R7 and Alkl-CONR6R7, which are mentioned in the preceding
Section described can also be produced directly if one uses the appropriate starting materials
Formula II and a-, ss-, 7-, or a-ketoamides of the formula
EMI8.1
 wherein Z is CONR6R7 or Alkl-CONR6R7 is used. The ketoamides required for this condensation are either known, e.g. Pyruvic acid amide or a, a-dimethylacetoacetamide, or can easily be prepared by known methods. See Rodd's Chemistry of the Carbon Compounds, Vol. Ld.

  Pp. 226-274.



   These amides of the formula IV are then reduced by the method described above to compounds or formula I in which Alk-NR6R7 is amino (lower) alkyl, in which Alk is CH2 or Alkl is CH2.



   c) Preparation and reactions of the intermediates of the formula IV (Z = AlkNR6COR21)
Intermediate products of the formula IV, in which Z denotes AlkNR6COR21, are obtained by condensation (II + III + IV) of ketoamides of the formula
EMI8.2
 - Easily obtained NR6COR21 with the appropriate starting material of Formula II.



   The ketoamides used here are either known, e.g. Formamidoacetone (A. Treibs and W. Sutter, Chem.



  Ber., 84, 96 (1951), see also R.H. Wiley and O.H. Borum, J. Amer. Chem. Soc., 70, 2005 (1948) or can be prepared by known processes. See e.g.



   Methods of Organic Chemistry, Vol. XI / 1, 1957, in particular pp. 58-62, 285-289 and 508-509, and F.F. Views, Organic Reactions, 1, 303 (1942).



   The intermediates of the formula IV are then converted with a complex metal hydride into the compounds of the formula I in which -Alk-NR6R7 is amino (lower) alkyl, in which R7 is lower alkyl.



   All changes and modifications of the embodiment of the method according to the invention which fall within the scope of the present invention are also to be protected. Such changes and modifications are e.g. those changes which depend on the known conversions of amines, amides, acids and esters into one another or on the change in the sequence of reaction steps.



   The following examples are intended to further illustrate the process according to the invention.



   Example 1 1-Methyl-1,3,4,9-tetrahydropyrano [3,4b] indole-1-acetic acid (4; A = A1, where RIO and18 = H, R1 = CH3, R2, R3,
R4 and R3 = H, X = 0 and Z = CH2 CO OH)
23.4 g (0.18 mol) of ethyl acetoacetate are added to a solution of the starting material of formula 2, 10.0 g (0.06 mol) of tryptophol in 200 ml of benzene. After standing for 10 minutes, 1.3 g of p-toluenesulfonic acid and about 5 g of hydrated alkali aluminum silicate (No. 4 molecular sieves) are introduced. The mixture is refluxed for 30 minutes, a further 600 mg of p-toluenesulfonic acid are added and refluxing is continued for 2 1/2 hours.

  The molecular sieves are collected and the benzene solution is washed successively with 5% sodium bicarbonate and water, dried over sodium sulfate and evaporated to dryness under reduced pressure. An oil is obtained which is subjected to chromatography on silica gel. After eluting with 5% ether in benzene, the ester, l-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid ethyl ester, is obtained as an oil, VCHcl3 = 1715 cm- l.



   The hydrolysis of this ester to the title compound is achieved as follows: The ester is dissolved in 230 ml of methanol.



  10 g of KOH in 30 ml of H30 are added and the solution is left to stand overnight at room temperature. The methanol is evaporated, water is added and the solution is washed with benzene. The aqueous phase is acidified with 6N hydrochloric acid and extracted with benzene. The organic phase is washed with water, dried over sodium sulfate and evaporated to dryness. An oil is obtained which crystallizes from benzene, which contains a trace of petroleum ether, to give the title compound with a melting point of 1500 to 152 ° C.



     v ,, C13 = 3325 and 1705 cm¯1.



   An equivalent amount of methyl acetoacetate can replace ethyl acetoacetate in the procedure of this example.



  In this case, 1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-acetic acid methyl ester, melting point 87 "to 90" C, is obtained after recrystallization from benzene / hexane.



   An equivalent amount of propyl acetoacetate can replace ethyl acetoacetate in the procedure of this example.

 

  In this case, 1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid propyl ester is obtained.



   An equivalent amount of N-methyltryptophol can replace tryptophol in the operation of this example. In this case, 1,9-dimethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid with a melting point of 105 to 108 "C is obtained after conversion from benzene. This product is with the product of the same name, which is described in Example 65. A similar replacement by N-ethyltryptophol gives 9-ethyl-1-methyl-1, 3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid, which is identical to the product of the same name described in Example 65.



     Example 2
1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-propionic acid (4; A = A1, where R16 and R18 = H, R1 = CH3, R2, R3,
R4 and R5 = H, X = 0 and Z = CH2CHoCOOH are)
A mixture of the starting material of formula 2, 500 mg tryptophol, 580 mg levulinic acid, 75 ml benzene, 1.7 g phosphorus pentoxide and about 0.5 g diatomaceous earth (Celite) are magnetized for 15 minutes at room temperature and then for 1 1/2 hours at 70 C stirred.



  The reaction mixture is filtered, the filtrate is washed three times with Sn sodium hydroxide solution and the combined aqueous phase is washed twice with ether and acidified with cold 50% hydrochloric acid. The aqueous phase is extracted with chloroform. The chloroform extract is dried over sodium sulfate and evaporated to dryness. The residue is crystallized from ethyl acetate / petroleum ether and gives the title compound with a melting point of 104 to 110 ° C., nuclear magnetic resonance spectrum (CDC13) 8 1.47 (3H), 2.18 (4H).



  2.74 (2H), 3.96 (2H), 7.18 (4H), 7.85 (1H), 9.60 (1H).



   The above title compound can also be obtained if the procedure of Example 1 is followed, but using an equivalent amount of ethyl levulinate instead of ethyl acetoacetate. In this case, the 1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1 propionic acid ethyl ester, melting point 116 to 118 ° C., VC3HXCl3 = 1716 cm-1, falls after recrystallization from benzene / petroleum ether than the ester before hydrolysis.



   Example 3
1-methyl-1,3,4,9-tetrahydrothiopyrano [3,4-b] indole-1-acetic acid (4; A = A1, where R16 and R18 = H R1 = CH3, R2, R3,
R4 and R5 = H, X = S and Z = CH2COOHsH)
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 70 to 80 ° C.). 0.15 g of p-toluenesulfonic acid are added and the reaction mixture is heated to reflux temperature for 12 hours while stirring. The water that forms in the reaction mixture during this period is collected in a water separator.



   After cooling, the benzene solution is washed with 10% sodium bicarbonate solution, water, saturated sodium chloride solution and dried over sodium sulfate. After evaporation of the benzene solution, the ester, 1-methyl-1,3,4,9-tetrahydrothiopyrano [3,4-b] indole-1-acetic acid methyl ester, is obtained as a semisolid substance, Vmax 13 = 1715 cm-1.



   This ester is then treated with aqueous alcoholic KOH in the manner described for the esters in Examples 1 and 2 to give the title compound, melting point 147 to 149 C, nuclear magnetic resonance spectrum (CDC13) 61.86 (S, 3H), 3.06 and 8 , 12 (6H), 7.35 (multiplet, 4H), 8.71 (1H), 10.31 (1H) after recrystallization from benzene / hexane.



   The processes of Examples 1 or 3 are used to prepare other compounds of the formula IV in which A = A1 and R1, R2, R3, R4, R5 and X have the meaning defined in the first case and Z = COOR19 or Alk1-COOR19 , where R19 and AlKÚ have the meaning defined in the first case. Examples of such compounds of the formula IV are listed in Tables I and II.



  In each of these examples, an equivalent amount of the starting material of Formula II indicated therein is used in place of the starting material of Formula II as indicated in the procedures of Examples 1 and 3.



  It should be noted that in each example the ester obtained before hydrolysis is a corresponding ester compound of Formula IV
Similarly, the procedure of Example 2 can be used to prepare the products listed in Tables I and II. In this case, an equivalent amount of the starting material of the formula II, which is given therein, instead of the starting material of the formula II, as described in Example 2, and an equivalent amount of the corresponding keto acid of the formula m instead of the ketoester of the formula given therein III uses TABLE I
EMI9.1


 <tb> example <SEP> source material <SEP> the <SEP> formula <SEP> II <SEP> ketoester <SEP> the <SEP> formula <SEP> III <SEP> product:

   <SEP> [(prefix) -1,3,4,9
 <tb> <SEP> (B. <SEP> = <SEP> = <SEP> B1 <SEP> and <SEP> R16 <SEP> = <SEP> H) <SEP> 0 <SEP> tetrahydropyrano <SEP> [3,4-b]
 <tb> <SEP> II <SEP> indole-l- (Sufflx)]
 <tb> <SEP> Rl-C-AIkl <SEP> cooRlD
 <tb> <SEP> R1 <SEP> R3 <SEP> R4 <SEP> RS <SEP> R18 <SEP> X <SEP> R1 <SEP> Alk1-CO <SEP> Rl9 <SEP> prefix // suffix
 <tb> <SEP> 4 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> O <SEP> CH3 <SEP> CO <SEP> C2HS <SEP> 1-methyl // carboxylic acid
 <tb> <SEP> (see <SEP> example <SEP> 132)
 <tb> <SEP> 5 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> O <SEP> C2H5 <SEP> CH2CO <SEP> C2H <SEP> 1-ethyl // acetic acid
 <tb> <SEP> Smp. <SEP> 137-140 "C
 <tb> <SEP> 6 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> O <SEP> n-C3H7 <SEP> CH2CO <SEP> C2HS <SEP> l-propyl // acetic acid,
 <tb> <SEP> Smp.

   <SEP> 148-151 "C
 <tb> <SEP> 7 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> O <SEP> i-C3H7 <SEP> CH2CO <SEP> C2H5 <SEP> l-isopropyl / acetic acid,
 <tb> <SEP> Smp. <SEP> 150-152 "C
 <tb> <SEP> 8 <SEP> CH3 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> O <SEP> n-C3H? <SEP> CH2CO <SEP> C2H5 <SEP> 3-methyl-l-propyl // acetic acid;
 <tb> <SEP> Smp. <SEP> 75-800C <SEP> (isomer <SEP> A),
 <tb> <SEP> Smp. <SEP> 146-148 "C <SEP> isomer <SEP> B)
 <tb> <SEP> 9 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> O <SEP> CH2 <SEP> CH (CH2) CO <SEP> C2H5 <SEP> a, <SEP> l-dimethyl // acetic acid;
 <tb> <SEP> Smp. <SEP> 154-156 "C. <SEP> (isomer <SEP> A),
 <tb> <SEP> Smp. <SEP> 163-165 "C <SEP> (isomer <SEP> B)
 <tb> <SEP> 10 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> O <SEP> t-C4Hs <SEP> CH2CO <SEP> C2H5 <SEP> l-t-butyl // acetic acid,
 <tb> <SEP> Smp.

   <SEP> 210-212 C
 <tb> TABLE I (continued)
EMI10.1


 <tb> example <SEP> source material <SEP> the <SEP> formula <SEP> II <SEP> ketoester <SEP> the <SEP> formula <SEP> III <SEP> product: <SEP> [(prefix) -l, 3,4,9
 <tb> <SEP> (B = <SEP> B1 <SEP> and <SEP> R16 <SEP> = <SEP> H) <SEP> O <SEP> tetrahydropyrano <SEP> [3,4-b]
 <tb> <SEP> - [l <SEP> indole-l- (suffix)]
 <tb> <SEP> Rl-C-Alkl-COOR19
 <tb> <SEP> R2 <SEP> R3 <SEP> R4 <SEP> Rs <SEP> R18 <SEP> X <SEP> R1 <SEP> Alk-CO <SEP> R19 <SEP> prefix // suffix
 <tb> <SEP> 11 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> O <SEP> n-C4Hs <SEP> CHICO <SEP> C2H5 <SEP> 1-butyl // acetic acid,
 <tb> <SEP> Smp. <SEP> 124-127 C
 <tb> <SEP> 12 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 7-CH3 <SEP> O <SEP> n-CsH7 <SEP> CH2CO <SEP> C2H5 <SEP> 8-methyl-l-propyl // acetic acid,
 <tb> <SEP> Smp.

   <SEP> 127-128 C
 <tb> <SEP> 13 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 5-Br <SEP> O <SEP> C2Hs <SEP> CH2CO <SEP> CH5 <SEP> 6-bromo-l-ethyl // acetic acid,
 <tb> <SEP> Smp. <SEP> 182-184 "C.
 <tb> <SEP> 14 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 5-OCH2 <SEP> O <SEP> CH3 <SEP> CH2CO <SEP> CH3 <SEP> 6-methoxy-l-methyl // acetic acid,
 <tb> <SEP> Smp. <SEP> 142-143 C
 <tb> <SEP> 15 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 5-OCOCHs <SEP> O <SEP> CH3 <SEP> CH3CO <SEP> C2H5 <SEP> 6-acetoxy-l-methyl // acetic acid,
 <tb> <SEP> Smp. <SEP> 142-143 "C
 <tb> <SEP> 16 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 5-benzyloxy <SEP> O <SEP> CH3 <SEP> CH3CO <SEP> C2H5 <SEP> 6-benzyloxy-1-methyl //
 <tb> <SEP> acetic acid, <SEP> Smp. <SEP> 163.5 "C
 <tb> <SEP> 17 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 4-CHs <SEP> O <SEP> n-C3H7 <SEP> CH2CO <SEP> CsHs <SEP> 5-methyl-l-propyl // acetic acid,
 <tb> <SEP> Smp.

   <SEP> 177-178 "C
 <tb> <SEP> 18 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 6-CH3 <SEP> O <SEP> n-CsH7 <SEP> CH3CO <SEP> CsHs <SEP> 7-methyl-l-propyl // acetic acid,
 <tb> <SEP> 157-158 "C
 <tb> <SEP> 19 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 5-NO2 <SEP> O <SEP> n-CsH7 <SEP> CH2CO <SEP> CsH5 <SEP> 6-nitro-l-propyl // acetic acid,
 <tb> <SEP> Smp. <SEP> 119-120 C
 <tb> <SEP> 20 <SEP> H <SEP> H <SEP> CH2 <SEP> CH3 <SEP> H <SEP> O <SEP> n-CsH7 <SEP> CH2CO <SEP> CsH5 <SEP> 4,4-dimethyl-l-propyl //
 <tb> <SEP> acetic acid, <SEP> Smp. <SEP> 184-185 C
 <tb> <SEP> 21 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 4-CH3 <SEP> O <SEP> CH3 <SEP> CH2CO <SEP> CsH5 <SEP> 1,5-dimethyl // acetic acid,
 <tb> <SEP> Smp. <SEP> 150-152 C
 <tb> <SEP> 22 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 4-CI <SEP> O <SEP> CH2 <SEP> CH2CO <SEP> CH3 <SEP> 5-chloro-l-methyl // acetic acid,
 <tb> <SEP> Smp.

   <SEP> 183-1840C
 <tb> <SEP> 23 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> O <SEP> CH3 <SEP> (CH2) 2CO <SEP> CsHs <SEP> l-methyl // butyric acid,
 <tb> <SEP> Smp. <SEP> 132-135 "C
 <tb> TABLE II
EMI10.2


 <tb> example <SEP> source material <SEP> the <SEP> formula <SEP> II <SEP> ketoester <SEP> the <SEP> formula <SEP> III <SEP> product:

   <SEP> [(prefix) -1,3,4,9
 <tb> <SEP> (13 <SEP> = <SEP> B1 <SEP> and <SEP> R15 <SEP> = <SEP> H) <SEP> O <SEP> tetrahydropyrano <SEP> [3,4-b]
 <tb> <SEP> II <SEP> indole-l- (suffix)]
 <tb> <SEP> Rl-C-Alkl-COOR19
 <tb> <SEP> R2 <SEP> R3 <SEP> R4 <SEP> Rs <SEP> R18 <SEP> X <SEP> R1 <SEP> Alkl-CO <SEP> R15 <SEP> prefix // suffix
 <tb> <SEP> 24 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> O <SEP> CH3 <SEP> CO <SEP> CsHs <SEP> l-methyl // carboxylic acid
 <tb> <SEP> 25 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> O <SEP> CsH5 <SEP> CH2CO <SEP> CsHs <SEP> l-ethyl // acetic acid,
 <tb> <SEP> Smp. <SEP> 138 "C
 <tb> <SEP> 26 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> O <SEP> n-CsH7 <SEP> CH3CO <SEP> CsHs <SEP> l-propyl // acetic acid,
 <tb> <SEP> Smp.

   <SEP> 127-129 C
 <tb> <SEP> 27 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> O <SEP> i-GH7 <SEP> CH2CO <SEP> CsHs <SEP> l-isopropyl // acetic acid
 <tb> <SEP> 28 <SEP> CH3 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> O <SEP> n-C3H7 <SEP> CH3CO <SEP> CsHs <SEP> 3-methyl-l-propyl // acetic acid
 <tb> <SEP> 29 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> O <SEP> CH3 <SEP> CH (CH3) CO <SEP> CsH5 <SEP> a-l-dimethyl // acetic acid
 <tb> <SEP> 30 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> O <SEP> t-C4H9 <SEP> CH2CO <SEP> CsHs <SEP> l-t-butyl // acetic acid
 <tb> <SEP> 31 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> O <SEP> n-C4Ho <SEP> CH2CO <SEP> CsH5 <SEP> l-butyl // acetic acid
 <tb> <SEP> 32 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 7-CH2 <SEP> 0 <SEP> n-C3H7 <SEP> CH2CO <SEP> CsHs <SEP> 8-methyl-l-propyl // acetic acid
 <tb> <SEP> 33 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 5-Br <SEP> 0 <SEP> CsH5 <SEP> CH2CO <SEP>

   CsH6 <SEP> 6-bromo-l-ethyl // acetic acid
 <tb> <SEP> 34 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 5-OCHs <SEP> O <SEP> CH2 <SEP> CH2CO <SEP> CH2 <SEP> 6-methoxy-l-methyl // acetic acid
 <tb> <SEP> 35 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 5-OCOCH3 <SEP> O <SEP> CH3 <SEP> CH2CO <SEP> CsHs <SEP> 6-acetoxy-methyl // acetic acid
 <tb> <SEP> 36 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 5-benzyloxy <SEP> O <SEP> CH3 <SEP> CH2CO <SEP> CsHs <SEP> 6-benzyloxy-l-methyl //
 <tb> <SEP> acetic acid
 <tb> <SEP> 37 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 4-CH2 <SEP> 0 <SEP> n-C3H7 <SEP> CH2CO <SEP> CsHs <SEP> 5-methyl-l-propyl // acetic acid
 <tb> <SEP> 38 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 6-CHs <SEP> O <SEP> n-CsH7 <SEP> CH2CO <SEP> CsHs <SEP> 7-methyl-l-propyl // acetic acid
 <tb> <SEP> 39 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 5-NO2 <SEP> O <SEP> n-CsH? <SEP> CH2CO <SEP> CsHs <SEP> 6-nitro-l-propyl // acetic acid
 <tb> <SEP>

   40 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> O <SEP> CH3 <SEP> (CH2) 2CO <SEP> C2H5 <SEP> l-methyl // propionic acid
 <tb> <SEP> 41 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 4-CH2 <SEP> O <SEP> CH2 <SEP> CH2CO <SEP> C5H5 <SEP> 1,5-dimethyl // acetic acid
 <tb> <SEP> 42 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 4-CI <SEP> O <SEP> CH3 <SEP> CH2CO <SEP> CH3 <SEP> 5-chloro-l-methyl // acetic acid
 <tb>
Example 43 N, N-1-Trimethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetamide [4;

  A = A1, where R16 and R13 = H, R1 = CH3, R2, R3, R4 and IZS = H, X = 0 and Z = CH3CON (CH3) 3 j
To a stirred solution of 15 g (0.061 mol) of 1-methyl1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid, prepared as described in Example 1, in 300 ml of cooled to -5 ° C dry tetrahydrofuran are added 18.5 g (0.183 mol) of triethylamine and then 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 from the above starting material, is added dropwise to a cooled 40% aqueous solution of the amine, 225 ml of dimethylamine. The resulting mixture is stirred for half an hour at room temperature.

  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. After elution with 20% ethyl acetate in benzene and subsequent crystallization of the eluate from ethyl acetate, the title compound is obtained with a melting point of 149 to 151 ° C., CHCl3 / Vmax = 3375, 1634 cm-1.



   In the same way, but replacing the 40% aqueous dimethylamine solution with an equivalent amount of concentrated ammonium hydroxide, methylamine (30% aqueous solution), n-hexylamine (20 0% aqueous solution), diethylamine (30% aqueous solution) , Isopropylamine (40% aqueous solution), ethylamine (70% aqueous solution), pyrrolidine (50% aqueous solution), piperidine, morpholine or N-methylpiperazine are 1-methyl-1,3,4,9- tetrahydropyrano [3,4-b] indole-1-acetamide,
Melting point 158 to 1600C, N, 1-dimethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1 acetamide,

   Melting point 138-140 ° C, N-hexyl-1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1 acetamide, N, N-diethyl-1-methyl-1,3,4 , 9-tetrahydropyrano [3,4-b] indole-1-acetamide, m.p. 99 C, VmMCl3 = 3350, 1620 cm-1.



  N-Isopropyl-1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1 acetamide, melting point 151 to 153 C, N-ethyl-1-methyl-1,3,4; 9 -tetrahydropyrano [3,4-b] indole-1-acetamide, m.p. 152-153 ° C, 1 - [(1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl ) acetyl] pyrrolidine, melting point 119 to 1200C, 1 - [(1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) acetyl] piperidine, melting point 148 to 149 ° C , 1 - [(1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1] acetyl] morpholine, melting point 141 to 142 C, and 1-methyl-4 - [(1- methyl-1,3,4,9-tetrahydropyrano [3,4-b] indol -1-yl) acetyl] piperazine.



   Following the procedure of Example 43, but using an equivalent amount of one of the acid compounds of the formula 4, as described in Examples 2 to 42, instead of 1-methyl-1,3,4,9-tetrahydropyrano [3 , 4-b] indole-1-acetic acid and using an equivalent amount of a suitable amine, such as ammonia or a primary or secondary amine, as described in Example 43, the corresponding amide compound of the formula IV is obtained. Examples of such amines are as products listed in Tables m and IV along with the appropriate starting material and the amine used to make the amide. In each case the starting material is indicated by the example in which it was prepared.



   TABLE III Example No. of Example in which Amine Product: [(Prefix-1,3,4,9-Tetrahydropyrano [3,4-b]
Starting material produced is indole-1- (suffix)
Prefix // suffix
44 2 CHaNH2 N, 1-dimethyl // propionamide, m.p. 149-150
45 2 (CHa) 2NH N, N, 1-trimethyl // propionamide
46 4 NHO 1-methyl // carboxamide, m.p. 188-189 C
47 4 CaHsNH2 N-ethyl-1-methyl // carboxamide
48 6 (CH3) 2NH N, N-dimethyl-1-propyl // acetamide, m.p. 159-162 C
49 2 Pyrrolidine 1 - [(- 1Methyl // propionyl)] - pyrrolidine
TABLE IV Example No. of the example in which amine product:

   [(Preflx-1,3,4,9-tetrahydropyrano [3,4-b] -
Starting material produced is indole-1- (suffix)] prefix // Stnnx
50 3 CHaNH2 N, 1-dimethyl // acetamide
51 3 (CH3) 2NH N, N, 1-trimethyl // acetamide, m.p.

   182 C
52 24 NHa l-methyl // carboxamide
53 26 (CHa) aNH N, N-dimethyl-l-propyl // acetamide
Example 54 1-t, 2- (dimethylamino) ethyl] -1-methyl-1,3,4,9-tetrahydropyrano- [3,4-b] indole [1, A = A1, where R16 and R15 = H, R1 = CH3,
Rê, R, R4 and R5 = H, X = 0 and AlkNR6R7 = CH2CH2N (CH) 2]
A solution of 5.0 g (0.018 mol) of N, N, 1-trimethyl 1, 3,4,9-tetrahydropyrano [3, 4-b] indole-1-acetamide, prepared as described in Example 43, is added dropwise a cooled, well-stirred mixture of 1.4 g (0.036 mol) of lithium aluminum hydride in 200 ml of ether was added.

  Stirring is continued for one hour at room temperature and then the mixture is refluxed for 2 hours.



   After cooling in an ice-water bath, 6.2 ml of water are added dropwise3 to destroy the excess hydride. Then another 100 ml of water are introduced 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. 5 g of oil are obtained, which crystallizes after standing. The crystallized product is recrystallized from ether and gives the pure title compound, melting point 1330 to 135 ° C, nuclear magnetic resonance spectrum (CDCla) a 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-tetrahydropyrano- [3,4-b] indole oxalate, has a melting point of 181 to 183 ° C Crystallization from methanol / ether.



   The title compound is also obtained in the same way, but by using an equivalent amount of lithium aluminum hydride aluminum chloride, aluminum hydride aluminum chloride, diborane and sodium borohydride aluminum chloride instead of lithium aluminum hydride.



   In the same way, but using an equivalent amount of the following amides described in Example 43 instead of N, N, 1-trimethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetamide 1- Methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetamide, N, 1-dimethyl-1, 3,4,9-tetrahydropyrano [3,4-b] indole-1 - acetamide, N-hexyl-1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1 acetamide, N, N-diethyl-1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1 acetamide, N-isopropyl-1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1 acetamide, N-ethyl4-methyl-1,3 , 4,9-tetrahydropyrano [3,4-b] indole-1-acetamide, 1 - [(1 -methyl-l,

   3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) acetyl] pyrrolidine, II-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl ) acetyl] piperidine, 1-l-methyl-1,3, 4,9-tetrahydropyran03, Cb] indol-l -yl) acetyl] morpholine and 1-methyl-4 - [(1-methyl-1,3, 4,9-tetrahydropyrano [3,4-b] indol -1-yl) acetyl] piperazine becomes 1- (2-aminoethyl) -1-methyl-1,3,4,9-tetrahydropyrano [3,4-b ] indole, melting point 80 to 84 C, VCaHCl3 = 3455, 3280 cm-1, 1-methyl-1- [2-methylamino) ethyl] -1,3,4,9-tetrahydropyrano [3,4-b] indole, Melting point 1600 to 163 C (melting point of the corresponding oxalic acid addition salt 140 to
144 C), 1- [2- (hexylamino) ethyl] -1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole,

   1- [2- (diethylamino) ethyl] -1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole, melting point 74 to 76 ° C., melting point of the corresponding maleic acid addition salt
98 to 100 ° C., 1 - [2- (isopropylamino) ethyl] -1-methyl-1,3, 4,9-tetrahydropyrano [3,4-b] indole, 1- [2- (ethylamino) ethyl] -1 -methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole, 1-methyl-1- [2- (1-pyrrolidinyl) ethyl] 1,3,4,9-tetrahydropyrano [3,4 -b] indole, nuclear magnetic resonance spectrum (CDC13) 3 1.62 (3H),
2.00 (m, 4H), 4.05 (m, 2H), melting point of the corresponding maleic acid addition salt (maleate) 192 "C, l-methyl-1- (2-piperdinoethyl) -1,3,4,9- tetrahydropyrano [3,4-b] indole, melting point 146 to 148 C,

   Melting point of the corresponding maleic acid addition salt 147 to 149 ° C, 1-methyl-1- (2-morpholinoethyl) -1,3,4,9-tetrahydropyrano [3,4-b] indole, nuclear magnetic resonance spectrum (dimethylsulfoxide-ds) 61.50 (3H) , 6.07 (2H), 6.87 to 7.65 (m, 4H), 10.86 (1H),
Melting point of the corresponding maleic acid addition salt 192 to 193 C, and 1-methyl-1- [2- (4-methyl-1-piperazinyl) ethyl] 1,3,4,9 tetrahydropyrano (3,4-b] indole, Nuclear Magnetic Resonance Spectrum (CDC13) 3 1.47 (3H), 2.58 (3H), 3.87 (t, 2H), [melting point of the corresponding maleic acid addition salt (ie, dimaleate) 208 to 210 C].



   Following the procedure of Example 54, but using an equivalent amount of one of the amide compounds of the formula IV, as described in Examples 44 to 53, instead of N, N, 1-trimethyl-1,3,4,9-tetrahydropyrano [3,4-b] -indole-1-acetamide as starting material, the corresponding compounds of the formula I are obtained. Examples of such compounds of the formula I are listed as products in Tables V and VI together with the appropriate starting material, amides of the formula IV. In each case the starting material is provided with the number of the example in which it is manufactured.

 

   TABLE V Example No. of Example, Product: (Prefix) -1,3,4,9 in which tetrahydropyrano [3,4-b] -indole
Starting material is produced
55 44 1-methyl-1- [3- (methylamino) propyl], NMR (CDCl3) 3 1.48 (3H),
1.87 (4H), 2.47 (3H), corresponding oxalic acid
The addition salt has m.p. 1,100C
56 45 1 -Methyl-1- [3- (dimethylamino) propyl], m.p. 114-116 C, corresponding oxalic acid
Addition salt has m.p. 168-172 ° C
57 46 l- (aminomethyl) -l-methyl, VmCHaxCl3 3465, 3400, 3180, 2930, corresponding hydrochloric acid
Addition salt (hydrochloride) has
M.p. 251-2520C
TABLE V (continued) Example No. of Example, Product:

   [(Prefix) -1,3,4,9- in which tetrahydropyrano [3,4-b] -indole
Starting material is produced
58 47 l - [(ethylamino) methyl] -l-methyl,
NMR (DMSO-d0) 8 1.18 (3H),
1.62 (3H), 2.80 (2H); corresponding hydrochloric acid
The addition salt has m.p. 242-243 C
59 48 1- [2- (dimethylamino) ethyl] -1 propyl, NMR (CDCl3) 0.84 (t, 3H),
1.21 (3,6H), 2.79 (t, J = 5.5 cps,
2H) corresponding maleic acid
Addition salt has m.p. 152-154 ° C
60-49 l-methyl-1- [3- (1-pyrrolidinyl) propyl], m.p. 124-127 C
TABLE VI Example No. of Example, Product:

   (Prefix) -1,3,4,9 in which tetrahydropyrano [3,4-b] indole
Starting material is produced
61 50 1-methyl-1- [2- (methylamino) ethyl
62 51 1- [2- (dimethylamino) ethyl] -1-methyl, m.p. 119-121 C
63 52 1- (aminomethyl) -l-methyl
64 54 1- [2- (dimethylamino) ethyl] -l-propyl
Example 65
1,9-Dimethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid (4;

  A = A1, where R16 = CH3 and R13 = H, R1 = CH3, R2, R3, R4 and R5 = H, X = O and Z = CH2COOH)
10 g (0.04 mol) of 1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] -indole-1-acetic acid, prepared according to the procedure of Example 1, in 150 ml of tetrahydrofuran are added dropwise to a stirred suspension of 4.4 g (55% strength dispersion) of sodium hydride in 200 ml of tetrahydrofuran was added. The mixture is heated at 50 ° C. for 2 hours with stirring. 14.2 g (0.1 mol) of methyl iodide is added dropwise and heating and stirring are continued for an additional 2 hours.



   After cooling, water is added until the solution is clear. The tetrahydrofuran is evaporated under reduced pressure and the residue is partitioned between water and benzene. The aqueous layer is washed once with benzene, acidified with hydrochloric acid, and extracted three times with benzene. The organic phase is washed with water, dried over sodium sulfate and treated with activated charcoal.



  The organic layer is evaporated, the residue is crystallized from benzene and then from ether / petroleum ether and gives the title compound, melting point 105 to 108 C, nuclear magnetic resonance spectrum (CDC13) S 1.73 (s, 3H), 2.83 (t, J = 5.5 (2EI), 3.0 (2H), 3.68 (3H), 4.08 (t, J = 5.5, 2H), 7.34 (4H), 9.47 (111).



   In the same way, but with the difference that methyl iodide is replaced by 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 [3,4 -b] indole-1-acetic acid, melting point 134 to 136 ° C, and the N-propyl analog of the title compound, 1-methyl-9-propyl-1,3,4,9-tetrahydropyrano [3, b] indole-1-acetic acid , Melting point 1200 to 122 ° C.



   Following the procedure of Example 65, using as starting material an equivalent amount of the appropriate acid compounds of formula 4 (A = A1), e.g. those as described in Examples 1 to 42, and using an equivalent amount of a suitable organic halide, then the corresponding N-alkylated acid compounds of the formula IV are obtained. Examples of the latter compounds are given as products in Tables VII and VIII, together with the suitable starting material of the formula IV and the organic halide used for their preparation. In each case the starting material is indicated by the example according to which it was prepared.



   TABLE VII Example No, of the Example in which Organic Halides Product: [(Prefix) -1,3,4,9-Tetrahydropyrano [3,4-b]
Starting material produced is indole- (suffix)] prefix // suffix
66 2 CHal 1-9-dimethyl // propionic acid, m.p. 129-130 C
67 21 CHal 1,5,9-trimethyl // acetic acid, m.p. 132-134 "C
68 16 C2HsBr 6-benzyloxy-9-ethyl-1-methyl // acetic acid, NMR (CDC13) 8 # 1.73 (s, 3H), 5, 12 (s, 2H)
69 22 CHaT 5-chloro-l, 9-dimethyl // acetic acid, m.p. 105-110 C.
70 16 CH3I 6-benzyloxy-1,9-dimethyl // acetic acid, m.p. 167-168 C
71 14 CH 3 Cl 1,9-dimethyl-6-methoxy // acetic acid, m.p. 129-132 C
TABLE VIII Example No.

   of the example in which organic halides product: [(prefix) -1,3,4,9-tetrahydropyrano [3,4-b]
Starting material produced is indole- (suffix)] prefix // suffix
72 3 CH3I 1,9-dimethyl // acetic acid, m.p. 145-146 C
73 3 C2H5Br 9-ethyl-1-methyl // acetic acid
74 40 n-C3H7I l-methyl-9-propyl // propionic acid
75 40 CH3I 1,9-dimethyl // propionic acid
76 34 CHaCl 1, 9-dimethyl-6-methoxy // acetic acid
Following the procedure of Example 65, but using an equivalent amount of the ester compounds of the formula IV (A = A1, where R16 = H) obtained in Examples 1 and 3 to 42 before the hydrolysis as starting material,

   instead of l-methyl-1,3,4,9-tetrahydro pyrano [3,4-b] indole-1-acetic acid and an equivalent amount of the appropriate organic halide used, then the corresponding N-alkylated ester compound of the formula IV ( A = A1, where R16 = lower alkyl).



   Following the procedure of Example 43, but using an equivalent amount of one of the N-alkylated acid compounds of the formula IV, as described in Examples 65 to 76 incl., Instead of 1-methyl-1,3,4, 9-tetrahydropyrano [3,4-b] indole-1-acetic acid and an equivalent amount of a suitable amine, such as ammonia or a primary or secondary amine, as described in Example 43, are used to obtain the corresponding amide compound of the formula IV, wherein A = Al and R16 are lower alkyl. Examples of such amides are listed as products in Tables M, X, XI and XII together with the appropriate starting material, numbered with the example according to which it was prepared, and the amine used to prepare the amide.



   TABLE IX Example No. of Example in which Amine Product: [Prefix) -1,3,4,9-Tetrahydropyrano [3,4-b]
The starting material is indole-1- (suffix)] prefix // suffix
77 65 (title compound) (CH3) 2NH N, N, 1,9-tetramethyl // acetamide, vCHCl3 1620, 1070 cm
78 65 (title compound) CH3NH2 N, 1,9-trimethyl // acetamide, m.p. 136-138 C
79 65 (title compound) NH3 1,9-dimethyl // acetamide, m.p. 105-106 C
80 65 (title compound) (C2H5) 2NH N, N-diethyl-1,9-dimethyl // acetamide, maxCHCl3 1625 cm
81 65 (titanium compound) (CU3) 2NH 9-ethyl-N, N, 1-trimethyl // acetamide, vmaxCHCl3 1620 cm-1
82 65 (title compound) CH3NH2 N, 1-dimethyl-9-ethyl // acetamide, m.p. 108-109 C
83 65 (N-ethyl analog) NH3 9-ethyl-1-methyl // acetamide, m.p.

   130-133 C
84 65 (N-Propyl Analog) (CH2) 2NH 9-Propyl-N, N, 1-trimethyl // acetamide, m.p. 84-87 C
85 66 (CH3) 2NH N, N, 1,9-tetramethyl // propionamide, VmaxCHCl3 1620 cm-1
86 66 CH3NH2 N, 1,9-trimethyl // propionamide, m.p. 148-150 C 87 67 (CH3) 2NH N, N, 1,5,9-pentamethyl // acetamide, NMR (CDC13) S 1.75 ( s, 3H), 2.66 (s, 3H), 2.96 (s, 3H), 3.08 (s, 3H),
3.78 (s, 3H)
88 68 (CH3) 2NH 6-benzyloxy-9-ethyl // acetamide,
VmaxCHCl3 1650 cm-1
89 69 (CH3) 2NH 5-chloro-N, N, 1,9-tetramethyl // acetamide, NMR (CDCl3) 3 1.72 (s, 3H), 2.93 (s, 3H), 3.80 ( s, 3H), 3.77 (s, 3H)
90 70 (CH3) 2NH 6-Benyloxy-N, N, 1,9-tetramethyl // acetamide,
NMR (CDCl3) 3 1.73 (s, 3H), 2.95 (s, 3H), 3.05 (s, 3H),
3.75 (s, 3H), 5.12 (s,

   2H)
91 71 CH3NH2 6-methoxy-N, N, 1,9-tetramethyl // acetamide,
M.p. 118-120 C
TABLE X Example No. of Example in which Amine Product: [(Prefix) -1,3,4,9-Tetrahydropyrano [3,4-b]
Starting material produced is indole-1- (Stnnx)] prefix / suffix
92 65 (title compound) pyrrolidine 1 - [(1,9-dimethyl // acetyl)] - pyrrolidine NMR (CDC13) s 1.77 (3H), 2.82 (2H), 3.78 (3H)
93 65 (title compound) piperidine 1 - [(1,9-dimethyl // acetyl)] - piperidine, VmaxCHCl3 1635 cm
94 65 (title compound) morpholine 1 - [(1,9-dimethyl // acetacetyl)] - morpholine,
NMR (CDC13) 8 1.73 (3H), 3.03 (2H),

   3.70 (3H)
95 65 (title compound) N-methyl-piperazine 1-methyl-4- [1,9-dimethyl // acetyl] piperazine,
VmaxCHCl3 1640 cm-1
96 65 (title compound) N-piperazine-ethanol 1- (2-hydroxyethyl) -4- [1,9-dimethyl // acetyl] piperazine, v "1625 cm-1
TABLE XI Example No. of Example in which Amine Product:

   [(Prefix) -1,3,4,9-tetrahydropyrano [3,4-b] -
The starting material is indole-1- (Sufflx)]
Prefix // suffix
97 72 (CH3) 2NH N, N, 1,9-tetramethyl // acetamide, v 1625 cm
98 72 CH3NHa N, 1,9-trimethyl // acetamide, m.p. 127-128 C
99 73 (CH3) 2NH 9-ethyl-N, N, 1-trimethyl // acetamide
100 74 (C2H5) 2NH N, N-Diethyl-1-methyl-9-propyl // Propionaqmid
101 75 CH3NHa N, 1,9-trimethyl // propionamide
102 76 (CH3) 2NH 6-methoxy-N, N1,9-tetramethyl // acetamide
TABLE XII Example No. of Example in which amine product:

   [(Prefix) -1,3,4,9-tetrahydropyrano [3,4-b] -
The starting material is indol-1-Yl) - (suffix)]
Prefix // Sufix
103 72 piperidine 1 - [(1,9-dimethyl // acetyl)] piperidine
104 74 Pyrrolidine 1 - [(1-methyl-9-propyl // propionyl)] pyrrolidine
Example 105
1,9-dimethyl-1- [2- (dimethylamino) ethyl] -1,3,4,9-tetrahydropyrano- [3,4b] indole [1; A = A1, where R16 = CH3 and
R18 = H, RÚ = CH3, Rê, R, R4 and R5 = H, X = 0 and AlkNR6R7 = CH2CH2N (CH3) 2]
A solution of 12.0 g of N, N, 1,9-tetramethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetamide, as described in Example, in 100 ml of dry 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 refluxed under nitrogen for 20 hours. A 1: 1 mixture of 50 ml of water / tetrahydrofuran is added to destroy excess hydride.



  The mixture is filtered through Celite, 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. The title compound is obtained, nuclear magnetic resonance spectrum (CDCls) 8 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 a melting point of 2290 to 230 ° C. after crystallization from methylene dichloride / benzene.



   The title compound is converted to the optical isomer, (-) - 1,9 dimethyl-1- [2- (dimethylamino) ethyl] -1,3,4,9-tetrahydropyrano, through the use of d- and l-di-p-tolu-yltartaric acid [3,4-b] indole dissolved, [α] DCHCl3 = -41.5. Its corresponding (+) antipode has [α] DCHCl3 = 34.6.



   Following the procedure of Example 105, but using an equivalent amount of one of the N-alkylated amide compounds of the formula IV, as described in Examples 77 to 104, instead of N, N, 1,9-tetramethyl-l, 3,4,9-tetrahydro- [3,4-b] indole-1-acetamide is used to obtain the corresponding N-alkylated amine compound of formula I. Examples of such compounds are listed as products in Tables XIII and XIV together with the appropriate one Source material specified.



  In each case the starting material bears the number of the example according to which it was manufactured.



   TABLE XIII Example No. of Example, Product: (Prefix) -1,3,4,9 in which tetrahydropyrano [3,4-b] indole
Starting material is produced
106 78 1,9-dimethyl-1- [2- (methylamino) ethyl], NMR (CDC13) S 1.10 (111),
1.66 (s, 3H), 2.33 (s, 3H), the corresponding hydrobromic acid addition salt
M.p. 223-225 C
107 79 1- (2-aminoethyl) -1,9-dimethyl
VmaxCHCl3 3369, 1570 cm 1
108 80 1- [2- (Dimethylaunno) ethyl] -9-ethyl-1-methyl, NMR (CDC1a) # 1.39 (3H), 1.70 (3H), 2.73) m, 12H), the same hydrochloric acid
Addition salt has m.p.

   202-205 C
109 81 1- [2- (dimethylamino) ethyl]
9-ethyl-1-methyl, NMR (CDCl3) s 1.39 (3H), 1.70 (3H), 2.73 (m, 12H), corresponding hydrochloric acid
Addition salt has m.p. 202-205 C
110 82 9-ethyl-1-methyl-1- [2 (methylamino) ethyl],
NMR (CDCl3) # 1.6 (3H), 2.30
111 83 1- (2-aminoethyl) -9-ethyl-1-methyl,
NMR (CDC13) 8 1.02 (t, 3H),
1.62 (s, 3H)
111a 84 1- [2- (dimethylamino) ethyl] -1 methyl-9-propyl, NMR (CDC13),
61.00 (t, 3H), 1.65 (s, 3H) corresponding maleic acid
Addition salt has 125-126 C.
112 85 1,9-Dimethyl-1- [3- (dimethylamino) propyl], NMR (CDCl3) # 1.60 (3H)
2.68 (6H), equivalent
Has maleic acid addition salt
M.p.

   115-118 C
113 86 1,9-Dimethyl-1- [3- (methylamino) propyl], NMR (CDCl3) 8 1.6 (3H),
2.9 (3H), 3.6 (3H), equivalent
Hydrochloric acid addition salt
M.p. 194-196 C
TABLE XIII (continued) Example No. of Example, Product: (Prefix) -1,3,4,9- in which tetrahydropyrano [3,4-b] -indole
Starting material is produced
114 87 1- [2- (dimethylamino) ethyl] -1,5,9-trimethyl, NMR (CDC13) 8 1.63 (s, 3H), 2.20 (s, 6H), 2.67 (s, 3H), 3.74 (s, 3H), maleate salt has m.p. 144-145 ° C
115 88 6-Benzyloxy-1- [2- (dimethylamino) ethyl] -9-ethyl-1-methyl,
NMR (CDCl3) # 1.38 (t, J = 7, 3H),
1.62 (s, 3H), 2.18 (s, 6H),
Has hydrochloride salt
M.p.

   216-217 C
116 89 5-chloro-1- [2- (dimethylamino) ethyl] -1,9-dimethyl, NMR (CDC13) 8 1.63 (s, 3H) 2.18 (s, 6H),
3.72 (s, 3H), maleate salt
M.p. 148-151 C
117 90 6-benzyloxy-1,9-dimethyl-1- [2 (dimethylamino) ethyl],
NMR (CDC13) 6 1.60 (s, 3H),
2.17 (s, 6H), 3.68 (s, 3H),
Has 5.12 (s, 2H), hydrochloride salt
M.p. 238-239 C
118 91 1,9-dimethyl-1- [2- (dimethylamino) ethyl] -6-methoxy, NMR (CDCl3)
8 2.60 (s, 3H), 3.85 (s, 3H), corresponding maleic acid
The addition salt has m.p. 109-111 ° C
119 92 1,9-Dimethyl-1- [2- (1-pyrrolidinyl) ethyl], NMR (CDCl3) 8 1.62 (s, 3H), 3.74 (s, 3H),
M.p.

   of the corresponding
Hydrochloric acid addition salt
230-231 C
120 93 l, 9-dimethyl-1- (2-piperidinoethyl),
NMR (CDCl3) 8 1.61 (s, 3H),
2.32 (m, 6H), 9.81 (m, 2H), m.p.



   of the corresponding hydrochloric acid
Addition salt 233-235 C
121 94 1,9-dimethyl-1- (2-morpholinoethyl)
NMR (CDCl3) # 1.62 (3H),
2.77 (2H), 3.72 (3H),
Hydrochloric acid addition salt
M.p. 230-231 C
122 95 1,9-dimethyl-1- [2- (4-methyl-1-piperazinyl) ethyl],
NMR (CDC13) ô 1.56 (s, 3H),
2.22 (s, 3H), 2.3 (m, 8H),
Has dimaleate addition salt
M.p. 194-195 C
TABLE X1H (continued) Example No. of example, product:

   (Prahx) -1,3'4'9- in which tetrahydropyrano [3,4b] indole
Starting material is produced
123 96 1,9-dimethyl-1- {2- [4- (2-hydroxyethyl) -1 -piperazinyl] ethyl},
NMR (CDC1s) Ï 1.60 (s, 3H),
3.70 (s, 3H), has the corresponding dihydrochloride salt
M.p. 219-220 C
TABLE X1V Example No. of the example, product:

   (Prefix) -1,3,4,9 in which tetrahdyropyrano [3,4-b] indole
Starting material is produced
124 97 1,9-Dimethyl-1- [2- (dimethylamino) ethyl], NMR (CDCl3) 8 3.72 (s, 6H), 6.40 (s, 3H) corresponding hydrochloric acid
The addition salt has m.p. 244-246 C
125 98 1,9-Dimethyl-1- [2- (methylamino) ethyl], NMR (CDC13) 8 1.82 (3H), 3.01 (m, 4H)
126 99 1- (2-aminoethyl) -1,9-dimethyl
127 100 1,9-dimethyl-1- [2- (hexylamino) ethyl]
128 101 1- [2- (diethylamino) ethyl) -1,9-dimethyl
Example 129
1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-carboxamide (4;

  ; A = A1, where R16 and R18 are H, 11 '= CH3 R2, R3, R4 and R' = H, X = 0 and Z = CONH2]
Following the procedure of Example 1, but using boron trifluoride etherate as acid catalyst and an equivalent amount of pyruvic acid amide instead of ethyl acetoacetate, 1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1 is obtained -carboxyamide, melting point 188 to 189 C after recrystallization from benzene / hexane, which is identical to the product obtained in Example 46.



   In the same way, but using an equivalent amount of the appropriate starting material of formula 2 together with the appropriate α-, β-, y- or 8-ketoamide, the products listed in Tables III and IV are obtained. For example, when using tryptophol (2; B = B1, where R16 and R18 = H, R2, R3, R4 and R5 = H, and Y = OH) and the ß-ketoamide, N, N-dimethylacetoacetamide, in the procedure of this example N, N, 1-trimethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetamide, which is identical to the product of Example 43.



   Example 130
1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-carbhoxaldehyde
A mixture of 32.2 g (0.2 mol) of the tryptophol used as starting material, 23.2 g (0.2 mol) of acetonylacetate and 3.2 g of p-toluenesulfonic acid in 500 ml of benzene is added in the presence of a Dean-Stark Water separator refluxed 1l / 2 hours. The benzene solution is washed with 5% sodium bicarbonate and water, dried and evaporated to an oil. The oil is chromatographed on a silica gel column using 10% ethyl acetate in benzene as the eluent.



  The acetate, 1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-methanol acetate, is obtained as an oil, Nuclear Magnetic Resonance Spectrum (CDCla) x 1.52 (s, 3H), 2.08 (s, 3H), 4.35 (211).



   This acetate is dissolved in 250 ml of methanol and stirred at room temperature. 20 ml of 10N NaOH are added dropwise to this solution. The hydrolysis occurs immediately.



  Most of the methanol is removed under reduced pressure and water is added. The mixture is made neutral and extracted with chloroform. The chloroform extract is dried and evaporated to the primary alcohol, 1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-methanol, melting point 145 to 147 ° C, Nuclear Magnetic Resonance Spectrum (CDCl3) 8 1.43 (s, 3H), 2.68 (t, J = 5.5 cps., 2H), 3.65 (d, J = 6 cps., 2H), 3.86 ( t, J = 5.5 cps., 2H) after crystallization from benzene / petroleum ether.



   17.36 g (0.084 mol) of N, N-dicyclohexylcarbodiimide are added to the cooled, stirred solution of the above primary alcohol (6.09 g, 0.028 mol) in 63 ml of dimethyl sulfoxide / benzene (2: 1), the 1.12 ml (0.014 mol) of trifluoroacetic acid and 2.24 ml (0.028 mol) of pyridine were introduced.



  The reaction mixture is stirred under nitrogen for 5 hours at room temperature. It is then diluted with 600 ml of ether, and then a solution of 7.56 g of oxalic acid in 21 ml of methanol is added dropwise. After 30 minutes, 600 ml of water are added and the insoluble material is collected. The organic phase is washed twice with water, twice with 5% aqueous sodium bicarbonate and twice with water. After drying over magnesium sulfate, the organic phase is evaporated and yields an oil. This is purified by chromatography on silica gel.

  After eluting with 10% ether in benzene, the title compound is obtained as an eluate, nuclear magnetic resonance spectrum (CDC13) 8 1.59 (s, 3H), 2.84 (t, J = 5.5 cps., 2H), 4, 15 (t, J = 5.5 cps., 2H).



   Example 131 1 - [(AethylaminoJ methyl] -1-methyl-1,3,4,9-tetrahydropyrano [3,4b] indole (1; A = A1, in which R16 and R13 = H, RÚ = CH3,
Rê, R, R4 and R5 - H, X = 0 and Alk-NR6R7 = HC2NHCoH3 are)
A mixture of 3.86 g tryptophol (2; R2, R3, R4, R5 and R6 = H and X1 = OH) and 3.0 g acetamidoacetone, see R.H. Wileg and O.H. Borum, J. Amer. Chem. Soc. 70, 2005 (1948), in 300 ml of dry benzene, is stirred and heated to reflux temperature. Water is collected in a Dean-Stark trap.

  After removing the water, 5 drops of boron trifluoride etherate are added and the mixture is refluxed for 30 minutes, the water separator being used again. After stirring overnight at room temperature, the reaction mixture is evaporated to dryness. The solid residue is dissolved in chloroform and washed successively with 10% strength aqueous sodium bicarbonate, water and concentrated sodium chloride solution. The chloroform solution is dried over magnesium sulfate, filtered and evaporated. The residue is crystallized from benzene and gives 1- (acetamidomethyl) -1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole, melting point 100 "to 102" C.



  This product is dried under reduced pressure at 27 ° C. The spectroscopy and the analytical data show that the compound is solvated with 1 mol of benzene, which can only be completely removed by melting.



  The Rf values of the amide and tryptophol are the same.



   2.4 g of the latter product are dissolved in 80 ml of dry tetrahydrofuran and added to a suspension of lithium aluminum hydride in 200 ml of tetrahydrofuran
The resulting slurry is stirred and refluxed for two hours, cooled, and 2.4 g of lithium aluminum hydride is added. The mixture is refluxed with stirring overnight. The reaction mixture is decomposed with 22.4 ml of water, which is added dropwise over 3 hours with stirring and cooling. Stirring is continued for 1 hour, the precipitate is separated off by filtration and the filtrate is dried over magnesium sulfate.

  After removal of the solvent by evaporation, the title compound is obtained, nuclear magnetic resonance spectrum (DMSO-d6) 8 1.18 (t, 3H), 1.62 (s, 3H), 2.80 (t, 2H), the product of Example 58 is identical.



   The corresponding hydrochloric acid addition salt, 1 [(ethylamino) methyl] -1 -methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole hydrochloride, has a melting point of 242 to 243 ° C. after recrystallization from isopropanol -Ether
Following the procedure described in this example using as starting material an equivalent amount of the appropriate starting material of Formula II, e.g. those described in Examples 1 to 42 and an equivalent amount of a suitable ketoamide of the formula
0
II R1-C-Alk-NRsCOR21, used as described above, gives the corresponding secondary amine compounds of the formula 1 (A = A1).



   Example 132
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, the starting material of the formula II, 1.61 g of tryptophol and 1.27 g of the aminoketone 4- (dimethylamino) -2-butanone are added. The mixture is evaporated under reduced pressure and the residue is stirred for 45 minutes under nitrogen at a bath temperature of 130.degree.



  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 washing liquids.



  10 ml conc. NH40E are introduced and the mixture extracted once with 10 ml and twice with 5 ml of toluene each time.



  The combined toluene solution is washed twice with 5 ml of water each time, dried over sodium sulfate, treated with activated charcoal and evaporated under reduced pressure. The residue is recrystallized from ether and gives the pure title compound, which is identical to the product of the same name described in Example 54.



   Example 133
1,9-dimethyl-1- [2- (dimethylamino) ethyl] -1,3,4,9-tetrahydropyrano [3,4-b] indole
To a mixture of the starting material of the formula II, 0.50 g of N-methyltryptophol and 0.363 g of the aminoketone.



  4-Dimethylamino-2-butanone are added to 0.650 g of p-toluenesulphonic acid in portions and the mixture is stirred at 130 ° C. for 1½ hours under nitrogen. After cooling, 10 ml of water are added and the mixture is extracted twice with 5 ml of toluene each time. The combined toluene solution is washed again with water and discarded. The aqueous phase, which contains a heavy brown oil, is made alkaline with 10 ml of concentrated ammonium hydroxide and extracted three times with 10 ml of benzene each time. The combined benzene extract is washed twice with 10 ml of water each time, dried over sodium sulfate, treated with activated charcoal and evaporated under reduced pressure to give the title compound, which is identical to the product of the same name described in Example 105.



   Example 134
1,9-dimethyl4- [2- (dimethylamino) ethyl] -1,3,4,9-tetraXydro-thiopyrano [3,4-b] indole
A mixture of 0.75 g of the starting material of the formula II, 1-methylindole-3-ethanethiol, 0.72 g of 4-dimethylamino -2-butanone hydrochloride, approx. 1 ml of toluene and 1.00 g of p-toluenesulfonic acid is used for half an hour stirred at 125 ° C. under nitrogen. After cooling, 20 ml of water and 0.5 ml of concentrated hydrochloric acid are added. The mixture is then extracted three times with 10 ml of toluene each time. The combined toluene solution is washed again with water.



  The aqueous phase, which contains a brown oil, is concentrated with. NH40H made alkaline and extracted three times with 15 ml of toluene each time. The combined toluene solution is washed with water, dried over sodium sulfate, treated with activated charcoal and evaporated under reduced pressure to give the title compound, which is identical to the product of the same name, which is described in Example 124.



   Example 135
1- [2- (dimethylamino) ethyl-9-ethyl-1-methyl-1,3,4,9-tetrahydrothiopyrano [3,4-b] indole
To a stirred solution of 57.0 g of p-toluenesulfonic acid monohydrate in 400 ml of toluene, 13.8 g of the aminoketone 4- (dimethylamino) -2butanone are added at 80 "C. under nitrogen. Then 30.7 g of the starting material of the formula II, Sodium l-ethylindole-3-ethyl thiosulfate, prepared from l-ethylindole-3-ethanol according to the above-mentioned process by Suvorov and Buyanov, was added in portions over the course of 5 minutes. The mixture is kept at 80 ° C. for 11/4 hours while stirring , then cooled and first diluted with 66 ml of 20% sodium hydroxide and then with 100 ml of water and extracted with toluene.

  The toluene extract is washed five times with 30 ml of 20-0% sulfuric acid each time and five times with 30 ml of water each time. The combined aqueous phases and the solid precipitated therefrom are made alkaline with 20% strength sodium hydroxide and then extracted four times with 50 ml of toluene each time. The combined toluene solution is washed with water, dried over sodium sulfate and evaporated.



  The residue is recrystallized from ether / hexane and gives the title compound, which is identical to the product of Example 137. The corresponding hydrochloric acid addition salt of the title compound has a melting point of 225 to 227 ° C. after recrystallization from isopropanol.



   The title compound is also obtained in the same way, but using an equivalent amount of potassium 1-ethylindol-3-ethyl thiosulfate.



   Following the procedure of Examples 132, 133, 134 or 135 and using an appropriate starting material of Formula II together with the appropriate aminoketone, other compounds of Formula I, e.g. those as described in Examples 54 to 64 and 106 to 128 are obtained.



   Example 136 3-methylindole-I-ethanol
A. 3.05 moles of commercial n-butyllithium in hexane are diluted with 1000 ml of dry tetrahydrofuran.



  The indole precursor of the formula 8, skatole (393 g, 3.0 mol) in 1000 ml of dry tetrahydrofuran, is added dropwise to this solution, which has been cooled to -10 "to 0 C. The reaction mixture is stirred at the same low temperature for 1 hour. 300 ml of ethylene oxide in 300 ml of dry tetrahydrofuran are then added to the mixture, the temperature is allowed to rise to room temperature, and the reaction mixture is then stirred overnight.



   The tetrahydrofuran is evaporated, the residue is dissolved in methylene chloride and washed with concentrated hydrochloric acid. The methylene chloride solution is then washed with 10% sodium bicarbonate and water and then dried over magnesium sulfate.



  The solvent is evaporated and the product is distilled under reduced pressure to give the title compound, boiling point 124 "C / 0.25 mm Hg.



   B. 35 g (0.276 mol) of the indole precursor of formula VIII, skatole, in 300 ml of dimethylformamide are added dropwise to a stirred mixture of 14.0 g of sodium hydride (55% strength oil dispersion) in 325 ml of dimethylformamide. The mixture is heated at 40 ° C. for two hours.



  After cooling in an ice-water bath, 116.5 g (0.7 mol) of ethyl bromoacetate are added dropwise, the temperature being kept below 200.degree. After the addition is complete, stirring is continued for 5 minutes and then water is carefully added to destroy any excess hydride present. The reaction mixture is divided between water and ether. The ether layer is washed with water, dried over magnesium sulfate and evaporated under reduced pressure.



   The residue, 3-methyl-indole-1-acetic acid ethyl ester, is dissolved in 900 ml of methanol, whereupon 90 g of potassium hydroxide in 400 ml of methanol / water (1: 1) are added. The mixture is stirred for 1 1/2 hours at room temperature.



  The methanol is evaporated under reduced pressure.



  The residue is dissolved in 800 ml of water and extracted three times with ether. Acidification of the aqueous phase with 6N HCl gives 3-methylindole-1-acetic acid, melting point 174 "to 176" C.



   47.5 g (0.25 mol) of the latter compound in 1000 ml of ether are slowly introduced into a stirred mixture of 12.5 g of lithium aluminum hydride (0.32 mol) in 700 ml of ether. The reaction mixture is kept below 15 ° C. by means of an ice-water bath. The reaction mixture is stirred 15 minutes after the addition, the excess hydride is destroyed with water and the precipitate is collected.



  The ether filtrate is washed with water, dried over sodium sulphate and evaporated to an oil under reduced pressure. After chromatography on silica gel using 15% strength ethyl acetate in benzene as the eluent, the title compound, which is identical to the product of A, is obtained.



   After procedure A of the present example, other indole-l-ethanol intermediates of the formula II (B = B2), for example. those listed in Examples 146 and 148 can be obtained by suitable choice of the indole of the formula VIII and the ethylene oxide derivative. If you e.g. Skatole and ethylene oxide by equivalent amounts of 3,7-dimethylindole, R. Robinson et al., Supra, and 3,3-dimethyl-1,2-epoxybutane, V. Franzen and H.E. Driesen, op. Cit., A mixture of ß-isopropyl, 3,7-trimethylindole-1-ethanol and α-isopropyl-ß, 3,7-trimethylindole-1-ethanol is obtained.

  Such mixtures of stereoisomers can be separated by fractional distillation, fractional recrystallization or chromatography. In the same way, by replacing skatole with 3-isopropylindole, R. Robinson et al., Op. Cit., Using the procedure A, 3-isopropylindole-1-ethanol is obtained.



   According to procedure B of the present example, other indole-1-ethanol intermediates of the formula II, in which R2 and R3 are hydrogen, by suitable choice of the indole of the formula WI and a-haloacetic acid lower alkyl ester of the formula LCR4R5COO- (lower alkyl), in which L is halogen and R4 and R5 are hydrogen or lower alkyl. If you e.g. Skatole and ethyl bromoacetate by equivalent amounts of 3-ethylindole, R. Robinson et al., Op. Cit., And 2,3-epoxybutane, F.G. Bordwell and P.S. Landis, J. Amer. Chem. Soc., 79, 1593, (1957), a, 13-dimethyl-3-ethylindol-1-ethanol is obtained. In the same way, by replacing the skatole with 3-butylindole, R.

  Robinson et al., Op. Cit., Obtained 3-butylindole-1-ethanol in the procedure B.



   Example 137 3-methylindole-1-ethanethiol
A. 9.0 g of N, N-dicyclohexalcarbodiimide are added to a cooled stirred solution of 3.0 g of 3-methylindole-l ethanol in 30 ml of dimethyl sulfoxide / benzene (2: 1), the 0.6 ml of trifluoroacetic acid and 1.12 ml containing pyridine was added.



  The reaction mixture is stirred for 5 hours at room temperature under nitrogen. The reaction mixture is then diluted with 300 ml of ether. This is followed by the dropwise addition of 3.78 g of oxalic acid in 11 ml of methanol.



  After 30 minutes, 300 ml of water are added and the insoluble material is collected. The organic phase is washed twice with water, twice with 5% aqueous sodium bicarbonate and twice again with water. After drying over magnesium sulphate, the organic phase is evaporated to give 3-methylindole-acetaldehyde. The latter compound is then converted to its corresponding gem-dithiol with hydrogen sulfide and treated with lithium aluminum hydride according to the method of T.L. Carins et al, J. Amer. Chem. Soc., 74, 3982 (1952). The title compound is obtained, VCaH "Cl3 = 2570 cm-1.

 

   B. 1.2 ml of phosphorus tribromide in 100 ml of dry ether are slowly added to a stirred solution of 7.2 g of 3-methylindole-l-ethanol, as described in Example 136, in 500 ml of dry ether (ice bath).



  A dark red oily complex is deposited.



  The reaction mixture is stirred for 36 to 48 hours at room temperature and then decomposed with ice and water. The separated ether layer is washed quickly with the above sodium bicarbonate solution and with water, dried over calcium chloride for 2 minutes, decanted and dried over magnesium sulfate for 30 minutes. After evaporation, the filtrate gives 1 - (2-bromoethyl) -3-methyl-indole.



   A solution of 10.4 g of sodium thlosulfate in 60 ml of water and 100 ml of ethanol is poured onto 8.6 g of 1- (2-bromoethyl) -3-methylindole. The reaction mixture is stirred and refluxed for 31/2 hours, allowed to cool and evaporated to dryness. The solid residue is dissolved in boiling isopropanol, dried with a hydrated alkali aluminum silicate (molecular sieves) and filtered. After rapid cooling of the filtrate, 6.4 g of sodium indolethylthiosulfate derivative are obtained as a precipitate.



  This material is collected by filtration and washed with ether. The isolated intermediate is heated under reflux with a solution of 9 g of sodium hydroxide, 60 ml of water and 140 ml of ethanol for 3 hours.



  The ethanol is removed under reduced pressure, the aqueous residue is diluted with water and extracted with three portions of ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. After evaporation, the filtrate gives bis [2- (3-methylindol-1-yl) ethyl] disulfide.



   1.4 g of the latter product in 100 ml of dry ether is added dropwise to a stirred suspension of 600 mg of lithium aluminum hydride in 80 ml of dry ether. The reaction mixture is refluxed for 3 hours and then kept at room temperature for 15 hours. The decomposition with 2.8 ml of water takes place in a stream of nitrogen. After stirring for 60 minutes, a white precipitate is filtered off with suction, the cake is washed with ether and the filtrate is dried over magnesium sulfate. The clear ether solution is evaporated to give the title compound.



   On the other hand, 6.4 g of the collected sodium indolyl ethyl thiosulfate derivative can be suspended in 100 ml of 50/00 phosphoric acid and 35 ml of ether. The mixture will
Stirred for 18 hours at room temperature. The ether layer is separated off and the aqueous layer is stirred with 35 ml of fresh ether for 18 hours at 40 ° C. The combined ether layers are then dried over magnesium sulfate, filtered and evaporated to give the title compound.



   Following procedure A or B of the present example, other indole-1-ethanethiol intermediates of formula II, e.g. those described in Examples 143 and 144 are prepared by suitable choice of the indole-1-ethanol intermediate of the formula II. If you e.g. Replacing 3-methylindole-1-ethanol by an equivalent amount of β-isopropyl-α, 3,7-trimethyl-1-ethanol, one obtains β-isopropyl-α, 3,7-trimethylindole-1-ethanethiol.



  In the same way, using an equivalent amount of 3-isopropylindole-1-ethanol instead of 3-methylindole-1-ethanol-34sopropylindole-1-ethanethiol is obtained.



   Example 138 1,10-Dimethyl-3,4-dihydro-1H, 1,4-oxazino [4,3-a] -indole-1-acetic acid
A mixture of 26.5 g (10.15 mol) of the starting material of the formula II, 3-methylindole-1-ethanol, described in Example 136, in 600 ml of toluene, 36 g (0.20 mol) of ethyl acetoacetate and 2.0 g of p-toluenesulfonic acid is refluxed for 6 hours using a water separator.



  The toluene solution is washed with water, 5% sodium bicarbonate solution and again with water. It is then dried over sodium sulfate and the solvent is evaporated off under reduced pressure. An oil is obtained which is subjected to chromatography on silica gel.



  After eluting with 10% ethyl acetate in benzene and concentrating the eluate, the ester, 3,4-dihydro 1,10-dimethyl-1H-1,4-oxazino [4,3-a] indole-1-acetic acid ethyl ester, is obtained as an oil, VmFioImx 1725 cm-l.



   The hydrolysis of this ester to give the title compound is carried out as follows: 39.9 g of the ester are dissolved in 800 ml of methanol which contains 22.5 g of KOH in 20 ml of water.



  After stirring for five hours at 50 ° C. and stirring for 12 hours at room temperature, the solvent is evaporated under reduced pressure. The residue is taken up in water, washed twice with ether, acidified with 6N HCl and extracted with ether. The ethereal solution is washed once with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The solid obtained is recrystallized from petroleum ether and gives the title compound, melting point 138 to 139 ° C, nuclear magnetic resonance spectrum (CDC10) 8 1.75 (s, 3H), 2.86 and 3 , 18 (d, J = 14.5 cps., 2H), 4.07 (m, 4EI).



   In the procedure of this example, an equivalent amount of methyl acetoacetate can replace the ethyl acetoacetate.



  In this case, 3,4-dihydro-1,10-dimethyl-1H-1, 4-oxazino [4,3-a] indole-1-acetic acid methyl ester is obtained.



   If an equivalent amount of propyl acetoacetate is used instead of ethyl acetoacetate in the procedure of this example, the ester obtained is 3,4-dihydro-1,10-dimethyl-1 H-1, 4-oxazino [4, 3-a] -indole- l-propyl acetate.



   Example 139 1,10-Diinethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indole-1-propionic acid
A. A mixture of 29.7 g (0.17 mol) of the starting material of the formula II, 3-methylindole-1-ethanol, described in Example 136, 26.96 g (0.187 mol) of ethyl levulinate and 2.25 g of p- Toluenesulfonic acid in 650 ml of dry benzene is refluxed with hydrated alkali aluminum silicate (molecular sieves No. 4) with stirring for 12 hours. The benzene solution is washed with 5% strength aqueous NaHCO 3 and then with water.

  After concentrating the solution, a residue is obtained which is passed through a silica gel column using 15% strength ethyl acetate in benzene, which contains the ester, 3,4-dihydro-1,10-dimethyl-1H-1,4-oxazino [ 4,3-a] ethyl indole-1-propionate is obtained as an oil, VCaHCl3 = 1370 cm-1.



   41.9 g of this ester are dissolved in 650 ml of methanol containing 23 g of KOH in 50 ml of water and heated for 1 hour at 50 ° C. The solvent is evaporated and the residue is taken up in water. The aqueous mixture is washed twice with ether washed, acidified with 6N HCl and extracted three times with ether. The ethereal solution is washed once with water, dried over magnesium sulfate, evaporated under reduced pressure and gives a solid which, after recrystallization from ethyl acetate-petroleum ether, gives the title compound, melting point 115 to 116 " C, Nuclear Magnetic Resonance Spectrum (CDC13) 8 1.62 (s, 3in), 2.30 (m, 7H), 4.04 (4H), 7.21 to 7.52 (m, 4H), 10.93 (1H ).

 

   B. A mixture of 500 mg of the starting material of formula II, 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 (Celite) is 15 minutes at room temperature and then stirred magnetically for 11/2 hours at 70 ° C. The reaction mixture is filtered and the filtrate is washed three times with Sn / NaOH. The combined aqueous phase is washed twice with ether and then acidified with cold 50% hydrochloric acid. The aqueous phase is made extracted with chloroform The chloroform extract is dried over sodium sulfate and evaporated to dryness.



  After recrystallization of the residue from ethyl acetate / petroleum ether, the title compound is obtained, which is identical to the product of A of this example.



   The procedure of Examples 138 and 139 (A) is used to prepare other intermediates of the formula IV, in which B = B2 and Z COLOR'9, or Alkl-COOR19 where R19 and Alkl have the meanings given first. Examples of such compounds are given in Tables XV and XVI. In each case, the starting material of the formula II and the keto ester given therein are used in an amount equivalent to the starting material of the formula II and the keto ester mentioned in Examples 138 and 139 (A). It should be noted that in each case an ester is obtained before hydrolysis. This ester is the corresponding intermediate of formula 1V.



   In the same way, the procedure of Example 139 can be used to prepare the compounds listed in Tables XV and XVI, with the exception that in this case an equivalent amount of the corresponding keto acid of formula m is used instead of the ketoester mentioned in the table.
EMI21.1


 <tb>



  example <SEP> source material <SEP> the <SEP> formula <SEP> II <SEP> ketoester <SEP> the <SEP> formula <SEP> m <SEP> product: <SEP> (prefix) -3,4-dihydro
 <tb> <SEP> (B. <SEP> = <SEP> B2 <SEP> rev <SEP> Y <SEP> = <SEP> OH) <SEP> O <SEP> 1H-1,4-oxazino <SEP> [4,3-a]
 <tb> <SEP> II <SEP> iudol-l- (Sufflx)]
 <tb> <SEP> Rl-C-A1kl-CO-oRt9
 <tb> <SEP> R2 <SEP> Rs <SEP> R4 <SEP> Rs <SEP> R18 <SEP> R17 <SEP> R1 <SEP> Allcl-CO <SEP> Rl9 <SEP> prefix // Sutlix
 <tb> <SEP> 140 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> CH3 <SEP> n-C3H7 <SEP> CHaCO <SEP> C2HS <SEP> 10-methyl-l-propyl // acetic acid,
 <tb> <SEP> Smp. <SEP> 146-1480C
 <tb> <SEP> 144 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> C2H5 <SEP> CH3 <SEP> CH2CH2CO <SEP> C2H5 <SEP> 10-ethyl-1-methyl //
 <tb> <SEP> propionic acid, <SEP> Smp.

   <SEP> 119-121 "C
 <tb> <SEP> 142 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> CH3 <SEP> CH3 <SEP> (CH2) 3CO <SEP> C2H5 <SEP> 1,10-dimethyl // butyric acid,
 <tb> <SEP> Smp. <SEP> 104-106 C
 <tb> TABLE XVI
EMI21.2


 <tb> example <SEP> source material <SEP> the <SEP> formula <SEP> II <SEP> ketoester <SEP> the <SEP> formula <SEP> III <SEP> product: <SEP> (Prltix) -3,4Dihydro
 <tb> <SEP> (B-B2andY = S11) <SEP> O <SEP> B2 <SEP> us <SEP> Y <SEP> = <SEP> 1H4 <SEP> 0 <SEP> 1H-1,4-thiazino <SEP> [4,3-a]
 <tb> <SEP> ll <SEP> indole-l- (suffix)
 <tb> <SEP> Rl-C-AlkI-CO-ORt
 <tb> <SEP> R2 <SEP> R3 <SEP> R4 <SEP> R5 <SEP> R15 <SEP> R17 <SEP> R1 <SEP> ALtcl-CO <SEP> R15 <SEP> prefix // suffix
 <tb> <SEP> 143 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> CH3 <SEP> n-C3H7 <SEP> CH2CO <SEP> CH3 <SEP> 10-methyl-1-propyl // acetic acid,
 <tb> <SEP> Smp.

   <SEP> 146-148 "C
 <tb> <SEP> 144 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> C2H5 <SEP> CH3 <SEP> CH2CH2CO <SEP> CH3 <SEP> 10-ethyl-1-methyl //
 <tb> <SEP> propionic acid
 <tb>
Example 155 N, 1,10-Trimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indole-1-acetamide
6 g of triethylamine and 5 g of ethyl chloroformate are added to a solution, cooled to -5 C, of 10 g of 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3a] indole-1-acetic acid, as in Example 138 described, added in 150 ml of tetrahydrofuran. After the suspension has been stirred for two hours at 10 ° C., it is further cooled to about -10 ° C., treated with 66 ml of methylamine (40% water solution) and stirred for a further hour at the given temperature.

  Most of the tetrahydrofuran is evaporated and the residue is divided between ether and water.



  The ethereal solution is washed with water, dried over magnesium sulfate and concentrated to a solid. This is recrystallized from ethyl acetate and gives the title compound with a melting point of 131 "to 133" C.



  If you work in the same way, replace the 40% aqueous methylamine solution with an equivalent amount of the amines of the formula HNR3R9, concentrated ammonium hydroxide, 30% aqueous dimethylamine solution, 20% aqueous n-hexylamine solution, 30% aqueous diethylamine solution, 40% % strength aqueous isopropylamine solution, 70% strength aqueous ethylamine solution, 50% strength aqueous pyrrolidine solution, piperidine, morpholine, N-methylpiperazine replaced, 1, 10-dimethyl-3,4-dihydro-1H-1,4-oxazino [4 , 3-a] indole-l-acetamide, melting point 156 to 157 C Nuclear magnetic resonance spectrum (CDC1s) 8 1.69 (3H), 2.33 (3H), N, N,

   1,1 O-Tetramethyl-3,4-dihydro-1 Hl, 4-oxazino [4,3-a] indole-1-acetamide, nuclear magnetic resonance spectrum (CDECl3) 8 1.78 (3H), 2.33 (3H) , 2.95 (6H), 1,1 O-dimethyl-N-hexyl-3,4-dihydro-1 H-1,4-oxazino [4, 3-a] indole-1-acetamide, N, N- Diethyl 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indole-1-acetamide, 1,1 0-dimethyl-N -isopropyl-3, 4-dihydro-1H -1, 4-oxazino [4,3-a] indole-1-acetamide, 1,1 O-dimethyl-N -ethyl-3,4-dihydro-1 H-1,4-oxazino [4,3-a ] indole-1-acetamide,

   Melting point 114 to 116 C,
1 - [(1,10-Dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indol-4-yl) acetyl] pyrrolidine,
10-dimethyl-3,4-dighydro-1H-1,4-oxazino [4,3-a] indol-1-yl) acetyl] piperidine, 10-dimethyl-3,4-dihydro-1H-1,4- oxazino [4,3-a] indol-1-yl) acetyl] morpholine and 1-methyl-4 - [(1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3 - a] indole-1-yl] acetyl] piperazine.



   Following the procedure of the present example, but using an equivalent amount of one of the acid compounds of formula IV, as described in Examples 139 to 144, as starting material instead of 1,10-dimethyl -3,4-dihydro-1H-1,4 -oxazino [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, the corresponding amide compounds of the formula IV are obtained. Examples of such amides are as products in the tables XVII, XVIII, XIX and XX are listed along with the appropriate starting material and amine used to make the amide. In each case the starting material is given the number of the example in which it was produced.



   TABLE XVII Example No. of Example in which Amine Product: [(Prefix) -3,4-Dihydro-1H-1,4-oxazino [4,3-a]
Starting material produced is indole-1- (suffix)]
Prefix // suffix
146 139 CH3NH2 N, 1,10-trimethyl // orppionamide, m.p. 147-149 C
147 139 NHs 1,10-dimethyl // propionamide, m.p. 97-98 C
148 139 (CH3) 2NH N, N, 1,10-tetramethyl // propionamide, NMR (CDC13) 8 1.64 (3H), 2.33 (3H), 2.88 (6H)
149 139 C2H5NH2 1,10-dimethyl-N-ethyl // propionamide, m.p. 104-106 C
150 139 (C2H 5) 2NH N, N-diethyl-1,10-dimethyl // propionamide
VmaxCHCl3 1660 cm-1
151 140 CHaNHs N, 10-dimethyl-1-propyl // acetamide, m.p. 96-98 C
152 140 (CH3) 2NH 1-propyl-N, N, 10-trimethyl // acetamide, m.p.

   84-86 C
153 140 (C3Hs) aNH N, N-diethyl-10-methyl-1-propyl // acetamide,
VmaxCHCl3 1680 cm-1
154 140 C2H5NH2 N-ethyl-1 0-methyl-1-propyl // acetamide,
VmaxCHCl3 1680 cm-1
155 141 CH3NH2 N, 1-dimethyl-10-ethyl // propionamide, m.p. 138-139 C
156 142 CH3NH2 N, 1,10-trimethyl // butyramide, m.p. 164-166 C
157 142 (CH3) 2NH N, N, 1,10-tetramethyl // butyramide, VmaxCHCl3 1680 cm-1
TABLE XVIII Example No. of the example in which amine product:

   [(Prefix) -3,4-dihydro-1H-1,4-oxazino [4,3-a] -
Starting material produced is indole-1- (suffix)]
Prefix // suffix
158 139 pyrrolidine 1 - [(1,10-dimethyl // propionyl)] pyrrolidine
159 139 piperidine 1 - [(1,10-dimethyl // propionyl)] - piperidine
160 139 morpholine 4 - [(1,10-dimethyl // propionyl)] - morpholine,
M.p. 160-162 C
161 139 N-methylpiperazine 1-methyl-4 - [(1,10-dimethyl // propionyl)] piperazine
TABLE XIX Example No. of Example in Which Amine Product: [(Prefix) -3,4-Dihydro-1H-1,4-thiazino [4,3-a]
The starting material is indole-1- (suffix)] pretix // stsmx
162 143 CH3NH2 N, 10-dimethyl-1-propyl // acetamide
163 144 (CH3) 2N 10-ethyl-N, N, 1-trimethyl // propionamide
TABLE XX Example No. of the example in which amine product:

   [(Prefix) -3,4-dihydro-1H-1,4-thiazino [4,3-a]
Starting material produced is indole-1- (suffix)] prefix // suffix
164 143 piperidine 1 - [(10-methyl-1-propyl // acetyl)] piperidine
165 144 Morpholine 1 - [(10-ethyl-1-methyl // propionyl)] morpholine
Example 166 1,10-Dimethyl-1- [2- (methylamino) ethyl] -3,4-dihydro-iH-
1,4-oxazino- [4,3-a] indole
11.0 g of the amide N, 1,10-trimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indole-1-acetamide, as described in Example 145, in 200 ml of tetrahydrofuran are added dropwise to a stirred mixture of 6.3 g of lithium aluminum hydride in 200 ml of tetrahydrofuran. The reaction mixture is heated under reflux for 2 hours and cooled.



  The excess hydride is destroyed with water.



  The mixture is filtered and the filtrate is evaporated.



  The residue is taken up in ether, washed with water and the solution is evaporated to give the title compound, nuclear magnetic resonance spectrum (CDCl3) # 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, 1,4oxazino- [4,3-a] indole hydrobromide, has a melting point of 249 to 251 ° C , after recrystallization from isopropanol.



   If one works in the same way, but replaces the lithium aluminum hydride with an equivalent amount of lithium aluminum hydride / aluminum chloride, aluminum hydride / aluminum chloride, diborane or sodium borohydride / aluminum chloride, the title compound is also obtained.



   In the same way, but replacing the N, 1,10-trimethyl3,4-dihydro-1H-1,4-oxazino [4,3-a] indole-1-acetamide with an equivalent amount of the following amides described in Example 145 .



  1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indole-1 acetamide, N, N, 1,10-tetramethyl-3,4-dihydro-1H-1 , 4-oxazino [4,3-a] indole-1-acetamide, 1, 10-dimethyl-N-hexyl-3, dihydro-1H-1, oxazino [4,3-a] indole-1-acetamide, N , N-diethyl-1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indole-1-acetamide, 1,10-dimethyl-N-isopropyl-3,4 Dihydro-1H-1,4-oxazino [4,3-a] indole-1-acetamide, 1,1O-dimethyl-N-ethyl-3,4-dihydro-1H-1,4-o-xazino (4 , 3-a] indole-1-acetamide, 1 - [(1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indol-1-yl) acetyl] pyrrolidine , 1 - [(1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indol-1-yl) acetyl] piperidine,

   4 - [(1,10-Dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indol-1-Yl) acetyl] morpholine and 1-methyl-4 - [(1, 10-dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indol-1-yl) acetyl] piperazine, the following compounds are obtained: 1- (2-Ammoethyl] -1, 10 -dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indole, nuclear magnetic resonance spectrum (CDC13) 8 1.62 (3H),
2.34 (3H) 1,10-dimethyl-1 - [(2-dimethylamino) ethyl] -3,4-dihydro-1H-1,4 oxazino [4,3-a] indole, Nuclear Magnetic Resonance Spectrum (CDC13) s 1 , 60 (3H), 2.30 (3H), the corresponding hydrochloric acid addition salt (hydrochloride) has a melting point of 237 to 239 C after reconditioning from methanol / ether,

   1,10-dimethyl-1- [2- (hexylamino) ethyl] -3,4-dihydro-1H-1,4 oxazino- [3,4-a] indole, 1- [2- (diethylamino) ethyl] - 1, 10-dimethyi-3,4-dhydro-1H-1,4 oxazino [4,3-a] indole, nuclear magnetic resonance spectrum (CDCl3) s 1.60 (3H), 2.30 (3H), the corresponding hydrobromic acid addition salt ( Hydrobromide) has a melting point of 191 to 193 C after recrystallization from isopropanol / ether, 1,10-dimethyl-1- [2- (isopropylamino) ethyl] -3,4-dihydro
1H-1,4-oxazino [4,3-a] indole, 1,10-dimethyl-1- [2- (ethylamino) ethyl] -3,4-dihydro-1H-1,4 oxazino- [4,3 -a] indole, nuclear magnetic resonance spectrum CD Cl 3) 8 1.58 (3H), 2.32 (3H), the corresponding hydrobromic acid addition salt has a melting point of 196 to
198 C after recrystallization from isopropanol ether,

   1,10-dimethyl-1- [2- (1-pyrrolidinyl) ethyl] -3,4-dihydro-1H-1,4 oxazino [4,3-a] indole, nuclear magnetic resonance spectrum (CDCl3)
8 1.60 (3H), 2.30 (311), the corresponding hydrochloric acid addition salt has a melting point of 223 to 225 ° C
Recrystallization from isopropanol ether, 1, 10-dimethyl-1- (2-piperidinoethyl) -3,4-dihydro-1H-1,4-oxazino [4,3-a] indole, nuclear magnetic resonance spectrum (CDC13) 8 1.61 (3H), 2.33 (3H), the corresponding hydrobromic acid addition salt has a melting point of 253 to
255 C after recrystallization from methanol, 1,10-dimethyl-1- (2-morpholinoethyl) -3,4-dihydro-1H-1,4-oxazino (4,3-a] indole,

   Nuclear magnetic resonance spectrum (CDCl3) 8 1.60 (3H), 2.31 (3H), the corresponding hydrochloric acid addition salt has a melting point of 234 to 236 C after recrystallization from isopropanol ether, and 1,10-dimethyl-1- [2- (4-methyl-1-piperazinyl) ethyl] -3,4-dihydro
1H-1,4-oxazino [4,3-a] indole, Nuclear Magnetic Resonance Spectrum (CDC1-3) s 1.62 (s, 311), 2.32 (s, 3H), the corresponding
Maleic acid addition salt (dimalic acid ester) has one
Melting point of 196 to 198 C after recrystallization from methanol.



   Following the procedure of the present example, but using an equivalent amount of one of the amide compounds of the formula IV, as described in Examples 156 to 165, instead of N, 1.10 trimethyl-3,4-dihydro-1H as starting material -1, 4-oxazino [4,3-a] indole-1-acetamide, the corresponding compounds of the formula I are obtained. Examples of such compounds of the formula I are listed as products in Tables XXI and XXII together with the appropriate starting material cited. In each case the starting material is given the number of the example according to which it was manufactured.



   TABLE XXI Example No. of Example, Product: (Prefix) -3,4-Dihydro.



   in which 1H-1,4-oxazino [4,3-a] indole
Starting material is produced
167 146 1,10-Dimethyl-1- [3- (dimethylamino) propyl], NMR (CDCl3) s 1.62 (3H), 2.32 (3H).



   corresponding hydrochloric acid
The addition salt has a melting point of 193-195 ° C. after recrystallization
Isopropanol ether 168 147 1- (3-aminopropyl) -1,10-dimethyl, NMR (CDC13) ô 1.58 (3H), 1.90 (2H), the corresponding hydrochloric acid addition salt has m.p. 204-206 C, after recrystallization from methanol ether 169 148 1,10-dimethyl-1- [3- (dimethylamino) propyl], NMR (CDC13) 8 1.64 (3H), 2.33 (3H), 2.35 (4H), corresponding hydrochloric acid
The addition salt has m.p. 200-2010C, after recrystallization
Methanol ether 170 149 1,10-dimethyl-1- [3- (ethylamino) propyl], NMR (CDCl3) 8 1.61 (3H), 2.33 (3H), corresponding hydrochloric acid
Addition salt has m.p.

   220-2220C, after recrystallization
Ethanol ether 171 150 1- [3- (diethylamino) propyl] -1,10 dimethyl, NMR (CDCls)
8 0.94 (t, 6H) 1.58 (s, 3H), the corresponding hydrobromic acid addition salt
M.p. 174-176 C, after
Recrystallization from isopropanol 172 151 10-methyl-1- [2- (methylamino) ethyl] -l-propyl, NMR (CDCl3) 8 0.84 (t, 3H), 2.30 (s, 3H),
4.03 (m, 4H), equivalent
Has hydrochloride addition salt
M.p. 229-230 C
TABLE XXI (continued) Example No. of Example, Product:

   (Prefix) -3,4-dihydro- in which 1H-1,4-oxazino [4,3-a] -indole
Starting material is produced
173 152 1 - [2- (dimethylamino) ethyl) -1 0-methyl-1-propyl, NMR (CDCls) 8 1.64 (3H), 2.34 (3H), the corresponding hydrobromic acid addition salt
196-1970C, after
Recrystallization from isopropanol
174 153 1 - [2- (diethylamino) ethyl) -10- methyl-1-propyl, NMR (CDCls) 8 1.62 (3H), 2.33 (3H), the corresponding hydrobromic acid addition salt
M.p. 165-167 C, after
Recrystallization from isopropanol
175 154 1 - [2- (ethylamino) ethyl] -1 0-methyl-1-propyl, NMR (CDCl3) 8 0.84 (t, 3H), 1.26 (t, 3H),
2.30 (s, 3H), 4.03 (m, 3H), corresponding hydrochloric acid
Addition salt has m.p.

   212-214 C
176 155 10-ethyl-1-methyl-1- [3- (methy-1 amino) propyl], NMR (CDCla) 8 1.22 (t, 3H), 1.62 (s, 3H),
3.98 (m, 4H), equivalent
Hydrochloric acid addition salt
M.p. 157-159 C
177 156 1,10-dimethyl-1- [4- (methylamino) butyl], NMR (CDCl3) 8 1.54 (s, 3H), 2.28 (s, 311), 4.00 (m, 4H) , corresponding
Has hydrochloride addition salt
M.p. 166-168 C
178 157 1,10-dimethyl-1- [4- (dimethylamino) butyl], NMR (CDCl3) 8 1.59 (s, 3H), 2.28 (s, 3H),
3.98 (m, 4H), equivalent
Hydrochloride addition salt has m.p.

   194-196 C
179 158 1,10-Dimethyl-1- [3- (1-pyrrolidinyl) propyl], NMR (CDCl3) 8 1.61 (s, 3H), 4.03 (4H), the corresponding hydrobromic acid addition salt
M.p. 154-156 C, after
Recrystallization from isopropanol
180 159 1,10-dimethyl-1- (3-piperidino propyl), NMR (CDCl3) 8 1.60 (s, 3H), 2.29 (s, 3H), the corresponding hydrobromic acid addition salt
M.p. 205-207 C, after
Recrystallization from isopropanol
181 160 1, 10-dimethyl-1- (3-morpholinopropyl), NMR (CDCl3) 8 1.60 (s, 3H), 4.02 (4H), corresponding hydrochloric acid
The addition salt has a melting point of 210-212 ° C. after recrystallization
Isopropanol
TABLE XXI (continued) Example No. of Example, Product:

   (Prefix) -3,4-dihydro in which 1H-1,4-oxazino [3,4-a] -indole
Starting material is produced
182 161 1,10-Dimethyl-1- [3- (4methyl-1-piperazinyl) propyl], NMR (CDC13) 8 1.63 (s, 3H), 2.31 (3H), corresponding hydrobromic acid addition salt ( Dihydrobromide)
M.p. 260-262 C, after
Recrystallization from methanol
TABLE XXII Example No. of Example, Product:

  : (Prefix) -3, SDihydro- in which 1H-1, sthiazino [4,3-a] -indole
Starting material is produced
183 168 (10. Methyl-1- [2- (methylamino) ethyl] -1-propyl
184 169 1- [(3-diethylamino) propyl) -10-ethyl-1-methyl
185 170 1-10-methyl-1-propyl-1- (2- piperidinoethyl)
186 171 10-ethyl-1-methyl-1- (3 morpholinopropyl)
Example 187 1,10-Dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indole-1-acetamide
Following the procedure of Example 139 (B) using an equivalent amount of acetacetamide in place of levulinic acid, the title compound, which is identical to the product of the same name described in Example 151, is obtained.



   In the same way, but using an equivalent amount of the suitable starting material of the formula I1 instead of 3-methylindole-1-ethanol together with the suitable α-, β-, Y- or 8-ketamide, those in Example 145 and in the tables XVII, XVIII, XIX and XX listed products.



   Example 188
1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indole-1 propanol
A. 10.4 g of the acid intermediate of formula V, 1.10 dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indole-1-propionic acid, which is described in Example 139, in 100 ml of tetrahydrofuran are slowly added to a stirred mixture of 2 g of lithium aluminum hydride in 100 ml of tetrahydrofuran. The reaction mixture is kept at 0 ° C. by means of an ice water bath. After the acid has been added, the excess hydride is destroyed with water and the precipitate is collected on a filter. The filtrate is evaporated, the residue is taken up in ether, the ether phase is washed with water, dried over sodium sulphate and evaporated to an oil under reduced pressure.

  After chromatography of the oil on silica gel using a mixture of ethyl acetate-chloroform in a ratio of 1: 1, the title compound is obtained, VCzXCl3 = 3610, 3450, 1080 cm¯l.



   B. On the other hand, the title compound can also be obtained by following the procedure of Example 139 (A) if the ethyl levulinate is replaced by an equivalent amount of the lower alkyl keto alcohol ester, 5-acetoxypentan-2-one. It should be noted that the procedure of the example mentioned includes the hydrolysis of the ester obtained as an intermediate.



   Example 189 1,10-Dimethyl-1- [3- (methylamino) propy0-3,4dEhydro-1H-
1,4-oxazino- [4,3-a] indole
9.5 g of the 1,10-dinsethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indole-1-propanol described in Example 188 are dissolved in 20 ml of dry pyridine. 7.4 g of p-toluenesulfonyl chloride are added in portions to the vigorously stirred and cooled solution. The mixture is stirred for a further hour at 0 C, ice and water are then introduced and the aqueous mixture is extracted with ether. The combined ether extracts are washed with 10% ice-cold hydrochloric acid, water, 5% sodium bicarbonate solution and dried over sodium sulfate.



  After concentrating the extracts, 1,10-dimethyl-3, dihydro-1H-1,4-oxazino [4,3-a] indole-1-propyl tosylate is obtained, vC3Hcí3 = 1600, 1370, 1190 and 1170 cm-1.



   12.3 g of the latter tosylate are dissolved in 100 ml of dry acetone and the resulting solution is treated with 15 g of sodium iodide. The mixture is stirred at room temperature for 24 hours. Most of the acetone is removed under reduced pressure, water and ice are added and the brown solution obtained is extracted with ether. The combined ether extracts are washed with 10% strength thiosulphate solution and water and then dried over sodium sulphate. The solvent is evaporated under reduced pressure A yellow oil is obtained, which is chromatographed on silica gel and eluted with benzene.

  After concentrating the eluate, 1, 10-dimethyl-1- (3-iodopropyl) -3,4-dihydro-1,4oxazino [4,3-a] indole, nuclear magnetic resonance spectrum (CDC13) 8 1.59 (3H), 3.13 (2H).



   10.2 g of a mixture of the latter compound in 100 ml of tetrahydrofuran and 199 ml of 40% strength aqueous methylamine are stirred for 6 hours at room temperature. Most of the tetrahydrofuran is removed under reduced pressure, the milky aqueous solution extracted with ether and washed with water until the water is neutral.

 

  The extract is dried over sodium sulfate and evaporated to give the title compound, which is identical to the product of Example 167.



   Following the procedure of Example 188 and the present example in sequence, but using an equivalent amount of the appropriate ester intermediate of Formula IV as starting material in Example 188 (A) or a suitable starting material of Formula II and a suitable keto alcohol lower alkyl ester of Formula m, as above described (in the case of B) and with subsequent use of a suitable amine of the formula UNR6R7, e.g. the amines described in Example 156 in the procedure of the present example, the corresponding compounds of formula I are obtained, e.g. those described in Examples 166-186.



   Following the procedure of Example 188 (A), replacing 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino [4,3-a] indole-1-propionic acid with 1,10-dimethyl-3 , 4-dihydro-lH-1,4oxazino [4,3-a] indole-1-butyric acid, as described in Example 142, gives l, 10-dimethyl-3,4-dihydro lH-l, 4- oxazino [4,3-a] indole-1-butanol, VCaHCl3 = 3600 and 3460 cnsl, then the latter compound is converted into its corresponding tosylate, VCaHyCl3 = 1600, 1370, 1190, 1170 cm- '.



  which in turn is treated with sodium iodide and 1, 10-dimethyl-1 - (4-iodbutyl) -3, dihydro-1 H-1,4oxazino [4,3-a] indole, melting point 60 to 62 "C. The 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, nuclear magnetic resonance spectrum (CDC13 ) 61.54 (s, 3H), 2.25 (s, 3H), 3.98 (m, 4H), the corresponding hydrochloric acid addition salt of which has a melting point of 1440 to 146 "C.



   Example 190
1,10-dimethyl-1- [3- (ethylamino) propyl] -3,4-dihydro-1H-1,4 oxazino [4,3-a] indole
A mixture of 4.2 g of 3-methylindole-1-ethanol and 3.7 g of N- (4-oxopentyl) acetamide as described by L.P. Kuhn et al., J. Am. Chem. Soc. 89, 3858 (1967) is described, in 300 ml of dry benzene is stirred and heated to reflux temperature. The water is collected in a Dean-Stark water separator. After the water has been removed, 5 drops of boron trifluoride etherate are added and the mixture is heated to the reflux temperature for 30 minutes using the water separator repeatedly. 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 concentrated sodium chloride solution. The chloroform solution is dried over magnesium sulfate, filtered and converted to 1- [3- (Aceta mido) -pro-pyl] -l, 10-dimethyl3, 4-dihydro-1 H-1,4-oxazine o 14,3-a] indole evaporated, VmaHXCl3 = 1650 cm-l.



   2.6 g of the latter compound in 80 ml of dry tetrahydrofuran are added to a suspension of lithium aluminum hydride in 200 ml of tetrahydrofuran. The resulting slurry is stirred and refluxed and cooled for 2 hours. 2.4 g of lithium aluminum hydride are then added. The mixture is heated to reflux for 16 hours and then decomposed with 22.4 ml of water, which is added dropwise over 3 hours while stirring and cooling the mixture. The precipitate is separated off by filtration. The filtrate is dried over magnesium sulfate. After removal of the solvent, the title compound, which is identical to the product of Example 170, is obtained.



   Following the procedure of the present example, but using as starting material an equivalent amount of the appropriate starting material of formula II, e.g. those described in Examples 136-144, and an equivalent amount of a suitable ketoamide of the formula
EMI26.1
 as described above, used, then one obtains the corresponding secondary amine compounds of the formula I.



   Example 191
1,10-dimethyl-1- [3- (methylamino) propyQ-3.4-dEhydro-1H-
1,4-oxazino [4,3-a] indole To a solution of 2.28 g of p-toluenesulfonic acid in 40 ml of toluene, 1.6 g of the starting material of the formula II,
3-methylindole-1-ethanol, and 1.3 g of the aminoketone
5- (methylamino) -2-pentanone added. The mixture is evaporated under reduced pressure and the residue is stirred for 45 minutes under nitrogen at 130 ° C. (bath temperature). 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 phase, which contains a dark, heavy oil, is combined with the aqueous washing liquids.



  Conc. NH40H (10 ml) is added and the mixture is extracted once with 10 ml and twice with 5 ml of toluene each time.



  The combined toluene solution is washed twice with 5 ml of water each time, dried over sodium sulfate, treated with activated charcoal and evaporated under reduced pressure to give the title compound, which is identical to the product of Example 167.



   The title compound is also obtained in the same way, but by replacing 3-methylindole-1-ethanol with an equivalent amount of sodium or potassium 3-methylindole-1-ethylthlosulfate.



   Following the procedure of the present example but using an equivalent amount of the appropriate starting material of formula II, e.g. those as described in Examples 136 to 144, and an equivalent amount of the suitable aminoketone of the formula RlCO-Alk-NR6R7, in which R1, Alk, R6 and R7 have the meanings given in the first case, are the corresponding oxazinoindoles of the formula I received.



   Example 192 Indene-3-ethanethiol
17 g of 3- (2-bromoethyl) indene, prepared from inden-3-ethanol according to a method analogous to Example 137 (B), are treated for 3 hours with a solution of 13.3 g of sodium thiosulfate in 109 ml of water and 2000 ml of ethanol heated under reflux. The solvents are removed under reduced pressure and give the corresponding sodium indenethylthiosulfate derivative (2, B = B3, R2, R3, R4, R3 and R18 = H and Y = -S-SO3Na). The latter derivative is dissolved in a solution of 15 g of NaOH in 100 ml of water. 300 ml of ethanol are added. The solution is heated under reflux for 2 hours, allowed to cool and extracted with three portions of ether.

  The combined extracts are washed with saturated sodium chloride solution and concentrated. The residue is passed through a column filled with silica gel and eluted with benzene-hexane (1: 3). Bis- [69- (3-indenyl) ethyl] disulphide is obtained, nuclear magnetic resonance spectrum (CDCl3) 8 3.02 (s, 8H), 3.33 (m, 4H), 6.25 (m, 2H), 7, 30 (m, 8H) as an oil. 12 g of the latter compound in anhydrous ether are added dropwise with vigorous stirring to a suspension of 2.5 g of lithium aluminum hydride in 200 ml of ether. The reaction mixture is stirred overnight at room temperature, decomposed with 10 ml of water and the precipitate is collected on a filter.

  The filtrate is dried over magnesium sulphate, and after evaporation of the solution the title compound, nuclear magnetic resonance spectrum (CDCl3) 8 1.48 (t, 1H), 2.83 (m, 4H), 3.32 (m, 2H), 6 is obtained , 25 (m, 1H), 7.30 (m, 4H).



   On the other hand, the sodium indenethylthiosulfate derivative described above can be treated with hydrochloric or phosphoric acid in a manner analogous to the acid treatment of the sodium indolylethylthiosulfate derivative in Example 137 (B) and then gives the title compound directly.



   Following the procedure of this example, other starting materials of the formula II (B = B3 and Y = SH) are prepared by suitable choice of the appropriately substituted 3- (2-bromoethyl) indene derivative, which is derived from its corresponding starting material of the formula II (B = B3 and Y = OH) is produced by treatment with phosphorus tribromide in carbon tetrachloride.



   If you e.g. Replacing 3- (2-bromoethyl) -indene by an equivalent amount of 3- (2-bromoethyl) -5-methoxyindene in the procedure of this example gives 5-methoxyindene-3-ethanethiol. In the same way, when 3- (2-bromoethyl) indene is replaced by 3- (2-bromo-1-methylpropyl) indene, α, β-dimethyl indene-3-ethanethiol can be obtained.



   Example 193 I-Methyz-1,3,4,9-tetrahyduoindeno 2, l-clpyran-I-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 about 2 g of hydrated alkali aluminum silicate (molecular sieves No. 4), 1 ml of boron trifluoride etherate is added and the mixture is stirred for 4 hours at room temperature. 1 further ml of boron trifluoride etherate is introduced, the reaction mixture is stirred at room temperature overnight and then heated at reflux temperature for 1 hour. The hydrated alkali aluminum silicate is collected and the filtrate washed with 10% sodium bicarbonate solution and water.

  After drying over magnesium sulfate, the benzene is removed under reduced pressure, and 1-methyl-1,3,4,9-tetrahydroindeno [2, 1-c] pyran-1-acetic acid methyl ester, d = 1724 cm- 'is obtained.



   The 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. The residue is diluted with water. The aqueous solution is extracted repeatedly with ether and acidified with 6N hydrochloric acid. The precipitate obtained is extracted with ether. The ether extract is dried over magnesium sulfate, filtered and concentrated. The residue is crystallized from benzene and gives the title compound, melting point 179 to 1800C, nuclear magnetic resonance spectrum (CDCla) 8 1.45 (s, 3H), 2.51 (m, 2E5), 2.73 (s, 2H), 3, 25 (t, 2H), 4.02 (t, 2H) 7.26 (m, 4H), 9.80 (broad, 1H).



   An equivalent amount of ethyl acetoacetate can replace methyl acetoacetate in the process of this example. In this case, 1-methyl-1,3,4,9-tetrahydroindeno [3,1-c] pyran-1acetic acid ethyl ester is obtained.



   An equivalent amount of propyl acetoacetate can be substituted for methyl acetoacetate in the procedure of this example.



  In this case, 1-methyl-1,3,4,9-tetrahydroindeno [2,1-c] pyran-1-acetic acid propyl ester is obtained.



   Example 194
1-methyl-1,3,4,9-tetrahydroindeno [2,1-c] 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 sieves no. 4) is stirred for 2 hours at room temperature.



   The reaction mixture is filtered, the filtrate is washed three times with Sn-NaOH, the combined aqueous phase is washed twice with ether and then with cold dilute
Acidified with hydrochloric acid. The aqueous layer is with
Chloroform extracted, the chloroform extract dried over sodium sulfate and evaporated to dryness. The residue is crystallized from ether-hexane and gives the title compound, melting point 970 to 99 -C, vCaHcla = 1700 cm-1,
Nuclear Magnetic Resonance Spectrum (CDCli) 8 1.4 (s, 3H), 2.2 (m, 4H),
2.5 (m, 2H), 3.25 (t, 2H).



   Example 195
1-methyl-1,3,4,9-tetrahydroindeno [2,1-c] pyran-1-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 for 5 hours at reflux temperature using a water separator. After cooling, the reaction mixture is washed with 10% strength sodium bicarbonate solution 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] thiopyran-1-acetic acid methyl ester, vmH: '3 = 1730 cm-1.



   The latter ester is dissolved in 200 ml of methanol, and
100 ml of 1.25N NaOH are added. After three hours of stirring under reflux, the methanol is removed by evaporation and the aqueous residue is extracted with ether.



  The aqueous layer is acidified with 6N hydrochloric acid and extracted with ether. The ether extract is over
Magnesium sulfate dried, filtered and evaporated to dryness. The residue is crystallized from ether and gives the title compound, melting point 119 to 121 ° C., vmaHXCl3 = 3000, 1700 cm 1.



   The procedure of Example 193 is followed and other compounds of the formula IV are prepared in which A = A3, as stated in the first case, R1, R2, R3, R4, R5 and X have the meanings given in the first case, and Z = COOR19 and AlKÚ0COOR19 is where R19 and Alk 'have the meaning given above. Examples of such compounds of the formula IV are listed in Tables XXtII and XXIV together with the required starting materials of the formulas II and III. It should be noted that in each of these examples, the ester obtained before hydrolysis is the corresponding ester of the product obtained therein.

 

   Similarly, the procedure of Example 194 can be used to prepare the products listed in Tables XXIII and XXIV. In this case, an equivalent amount of the corresponding keto acid is used in place of the keto ester of formula II TABLE XXIII
EMI28.1


 <tb> example <SEP> source material <SEP> the <SEP> formula <SEP> II <SEP> ketoester <SEP> the <SEP> formula <SEP> III <SEP> product: <SEP> (Preix) -1,3,4,9
 <tb> <SEP> tB <SEP> = <SEP> B3 <SEP> and <SEP> Y <SEP> = <SEP> OH) <SEP> O <SEP> tetrahydroindeno- [2,1-c]
 <tb> <SEP> pyran-1- (suffix)
 <tb> <SEP> Rl-C-Alkl-CO-ORlD
 <tb> <SEP> R3 <SEP> R3 <SEP> R4 <SEP> R5 <SEP> R15 <SEP> R1 <SEP> Alkl-CO <SEP> R15 <SEP> prefix // suffix
 <tb> <SEP> 196 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> CH3 <SEP> CO <SEP> C3H3 <SEP> 1-methyl // carboxylic acid,
 <tb> <SEP> Smp.

   <SEP> 141-143 "C
 <tb> <SEP> 197 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> n-C3H7 <SEP> CH2CO <SEP> C3H5 <SEP> 1-propyl // acetic acid,
 <tb> <SEP> Smp. <SEP> 131-1330C
 <tb> TABLE XXIV
EMI28.2


 <tb> example <SEP> source material <SEP> the <SEP> formula <SEP> II <SEP> ketoester <SEP> the <SEP> formula <SEP> III <SEP> product:

   <SEP> (prenx) -1,3,4,9
 <tb> <SEP> (B. <SEP> = <SEP> B3 <SEP> and <SEP> Y <SEP> = <SEP> OH) <SEP> O <SEP> tetrahydroindeno- [2,1-c]
 <tb> <SEP> II <SEP> thiopyran-1- (suffix)
 <tb> <SEP> Rl-C-Alkl-CO-ORl
 <tb> <SEP> R5 <SEP> R3 <SEP> R4 <SEP> Rs <SEP> R13 <SEP> R1 <SEP> Alkl-CO <SEP> R15 <SEP> prefix // suffix
 <tb> <SEP> 198 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> CH3 <SEP> CO <SEP> CsH3 <SEP> 1-methyl // carboxylic acid
 <tb> <SEP> 199 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> CH5 <SEP> CH2CO <SEP> CsHs <SEP> 1-ethyl // acetic acid
 <tb>
Example 200
N, N, 1-trimethyl-1,3,4,9-tetrahydroindeno [2,1-c] pyran-1 acetamide
12.0 g of triethylamine and then 13 g of ethyl chloroformate in 50 ml of tetrahydrofuran are added to a solution, cooled to -5 C, of 97 g of 1-methyl-1,3,4,9-tetrahydroindeno [2,1-c] -1- acetic acid, which is described in Example 193,

   added in 150 ml of tetrahydrofuran. After the mixture has been stirred for 90 minutes, it is cooled further to about -10 ° C., treated with 230 ml of a 40% strength aqueous dimethylamine solution and stirred at -10 ° C. for a further 30 minutes. Most of the tetrahydrofuran is evaporated and the residue is partitioned between chloroform and water.



  The chloroform layer is washed with water, dried over magnesium sulfate and concentrated. The title compound is obtained as an oil, vCaHcl3 = 1625, 1400, 1075 cm nuclear magnetic resonance spectrum (CDCl3) 8 1.55 (s, 311), 3.07, 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).



   If you proceed in the same way, but replace the 40% aqueous dimethylamine solution with an equivalent amount of the amines of the formula HNRR7, ammonium hydroxide (concentrated) or a 40% aqueous methylamine solution, l-methyl-1,3 is obtained, 4,9-tetrahydroindeno [2,1-c] pyranacetamide, melting point 87 to 88 ° C., VCaHXCl3 = 3460, 3340, 1670 cm- ', and N, 1-dimethyl-1,3,4,9-tetrahydroindeno [ 2,1-c] pyran-1-acetamide, melting point 90 to 91 ° C, vmaHCl3 = 3460, 3395, 1665 cm-1.



   Example 201
N, N, 1-trimethyl-1,3,4,9-tetrahydroindeno [2,1-c] thiopyran-1-acetamide
4.0 1-Methyl-1,3,4,9-tetrahydroindeno [2,1-c] thiopyran-1-acetic acid, prepared according to Example 195, are dissolved in 60 ml of anhydrous tetrahydrofuran. This solution is treated with 4.7 g of ethyl amine at -5.degree. 5.0 g of ethyl chloroformate in 30 ml of tetrahydrofuran are added dropwise to the solution and the resulting mixture is stirred at -5 ° C. for 90 minutes. 60 ml of a 40% aqueous dimethylamine solution are introduced and stirring is carried out
Continued for 30 minutes at room temperature. The solvent is removed under reduced pressure and the remaining suspension is partitioned between chloroform and water.

  The organic phase is separated off, washed with water, dried over magnesium sulfate and concentrated.



  It provides the title compound as a solid,
Nuclear Magnetic Resonance Spectrum (CDCl3) 8 1.75 (s, 3H), 2.95 (broad m, 1211), 3.50 (t, 2H), 7.26 (m, 4H).



   If you work in the same way, but replace the 40% aqueous dimethylamine solution with an equivalent amount of the amines of the formula HNR6R7, ammonium hydroxide (concentrated) or with a 40% aqueous methylamine solution, l-methyl-1 is obtained, 3,4,9-tetrahydroindeno [2,1-c] thiopyran-1-acetamide and N, 1-dimethyl 1,3,4,9-tetrahydroindeno [2,1-c] thiopyrano-1-acetamide.



   Following the procedure of Example 200 or this example but adding as starting material an equivalent amount of one of the acid compounds of formula IV (A = A3), e.g.



  those described in Examples 194-199 in place of 1-methyl-1,3,4,9-tetrahydroindeno [2,1-c] pyran-1-acetic acid or its thio analog and an equivalent amount of a suitable amine, e.g. Ammonia or a primary or secondary amine, as described in Example 200, is used, the corresponding amide compound of the formula IV is obtained.



   Examples of such amides are listed as products in Tables XXV and XXVI along with the appropriate starting material of Formula II with the amine used to make the amide. In each case the starting material is identified by the number of the example in which it was prepared.



   TABLE XXV Example No. of Example in which Amine Product: [(Prefix) -1,3,4,9-Tetrahydroindeno [1,1-c]
The starting material produced is pyran-1- (suffix)] prefix // suffix
202 194 (CH3) 2 NH N, N, 1-trimethyl // propionamide, NMR (CDCl3) # 1.40 (3H), 2.14 (4H), 2.47 (2H), 2.85 and 2, 89 (6H), 3.30 (2H),
3.95 (2H), 7.25 (4H)
203 196 (CH3) 2NH N, N, 1-trimethyl // carboxamide, NMR (CDCls) 8 1.68 (s, 3H), 2.65 (m, 211), 3.12 (s, 6H), 3 .54 (m, 2H),
4.08 (m, 2H), 7.28 (m, 4H)
TABLE XXVI Example No. of Example in which Amine Product:

   [(Prefix) -1,3,4,9-tetrahydroindeno [2,1-c] -
Starting material produced is thiopyran-l- (Sumx)] prefix // suffix
204 198 NH3 l-methyl // carboxamide
205 199 NHa l-ethyl // acetamide
Example 206
N, N, 1-trimethyl-1,3,4,9-tetrahydroindeno [2.1-c] pyran-1-ethylamine
6.0 g of the amide described in Example 200, N, N, 1-trimethyl-1,3,4,9-tetrahydroindeno [2,1-c] pyran-1-acetamide, in 50 ml of dry tetrahydrofuran are added dropwise to a stirred mixture of 3.0 lithium aluminum hydride in 50 ml of ether added. The reaction mixture is stirred for 90 minutes at room temperature.



  The excess hydride is decomposed with 24 ml of water.



   100 ml of tetrahydrofuran are introduced, the mixture is filtered, the filtrate is dried over magnesium sulfate and filtered and the filtrate is evaporated. The residue is evaporated and gives the title compound, nuclear magnetic resonance spectrum (CDCl3) # 1.42 (s, 3H), 1.70 to 2.80 (611), 2.22 (s, 6H),
3.30 (t, 2E1), 3.97 (t, 211), 7.30 (m, 4H).



   The corresponding hydrochloric acid addition salt, N, N, 1-trimethyl-1,3,4,9-tetrahydroindeno [2.1-c] ethylamine hydrochloride, has a melting point of 266 to 268 C after recrystallization from ethanol.



   In the same way, but by replacing lithium aluminum hydride with an equivalent amount of lithium aluminum hydride-aluminum chloride, aluminum hydride-aluminum chloride, diborane or sodium borohydride-aluminum chloride, the title compound is also obtained.



   In the same manner but by replacing N, N, 1-trimethyl1,3,4,9-tetrahydroindeno [2.1-c] pyran-1-acetamide by an equivalent amount of the following in Example 200
Amides, 1-methyl-1,3,4,9-tetrahydroindeno [2.1-c] pyranl-1-acetamide or N, 1-dimethyl-1,3,4,9-tetrahydroindeno [2.1-c] pyran-1-acetamide replaced, 1-methyl-1,3,4,9-tetrahydroindeno [1,1-c] pyran-1-ethylamine or N, 1-dimethyl1,3,4,9-tetrahydroindeno [2.1-c] pyran-1 is obtained ethylamine.



   Example 207
N, N, 1-trimethyl-1,3,4,9-tetrahydroindeno [2.1-c] thiopyran-1-ethylamine
2.7 g of the amide described in Example 201, N, N, 1-trimethyl-1,3,4,9-tetrahydroindeno [2,1-c] thiopyran-1-acetamide in 200 ml of anhydrous ether are stirred dropwise to a Suspension of 1.0 g of lithium aluminum hydride in 100 ml of anhydrous ether was added. The mixture is stirred at room temperature for 30 minutes.



  Excess hydride is decomposed with 4 ml of water.



  The mixture is filtered, the filtrate is dried over magnesium sulfate and concentrated to the title compound, nuclear magnetic resonance spectrum (CDC13) 6 1.45 (s, 3H), 3.50 (m, 2H), 7.32 (m, 4H).



   The corresponding hydrochloric acid addition salt, N, N, 1-trimethyl-1, 3,4,94etrahydroindeno [2, 1-c] thiopyran-1-ethylamine hydrochloride, has a melting point of 2650 to 267 ° C. after recrystallization from ethanol.



   In the same manner, but using an equivalent amount of lithium aluminum hydride-aluminum chloride, aluminum hydride-aluminum chloride, diborane or sodium borohydride-aluminum chloride instead of lithium aluminum hydride, the title compound is also obtained.

 

   In the same way, but by using an equivalent amount of the suitable amide described in Example 201 instead of N, N, 1-trimethyl-l, 3,4,9-tetrahydroindeno [2, 1-c] thlopyran-l-acetamide, the following corresponding identhiopyran-alkylamines are obtained: 1-methyl-1, 3,4,9-tetrahydroindeno [2, 1 -c] thlopyran-1-ethylamine and N, 1-dimethyl-1,3,4,9-tetrahydroindeno [2.1-c] tbiopyran-1-ethylamine.



   If, in the procedure of Example 206 or this example, an equivalent amount of one of the amide compounds of formula IV, e.g. those which are described in Examples 202 to 205, used instead of N, N, 1-trimethyl-1,3,4,9-tetrahydroindeno [2.1-c] pyran-1-acetamide or its thio analogue, the corresponding compounds of the Formula I. Examples of such compounds of the formula I are listed as products in Tables XXVII and XXVIII together with the appropriate starting material. In each case the starting material is given the number of the example in which it was produced.



   TABLE XXI Example No. of Example, Product: [(pretix) -l 3,4,9- in which tetrahydroindeno [2,1-c]
Starting material thiopyran-l- (Sufflx)] produced is Präíix // Suffix
208 202 N, N, l-trimethyl // propylamine,
NMR (CDCl3) # 1.42 (s, 3H),
3.30 (m, 2H), 3.94 (t, 2EI), corresponding hydrochloric acid
Addition salt has m.p. 210-2120C, according to
Recrystallization from isopropanol
209 203 N, N, 1-trimethyl // methylamine,
NMR (CDC13) 61.45 (s, 3H),
3.35 (m, 4H), 3.94 (m, 2H);

   corresponding hydrochloric acid
Addition salt has m.p. 250-251 "C, according to
Recrystallization from isopropanol
TABLE XXVIII Example No. of Example, Product: [(Prefix) -1,3,4,9- in which tetrahydroindeno [2,1-c]
Starting material thiopyran-l- (suffix)] is made prefix // suffix
210 204 1-methyl // methylamine
211 205 1-ethyl // ethylamine
Example 212 N, N, 1-Trimethyl-1,3,4,9-tetrakydroindeno [2,1-c] pyran-1-carboxamide
A mixture of 500 mg indene-3-ethanol, 580 mg N, N-dimethylpyruvic acid amide, as described in the on 28.

  US Pat. No. 2,429,877, published October 1947, describes -1.7 g of phosphorus pentoxide, 0.5 g of diatomaceous earth (Celite) in 75 ml of benzene is stirred for 15 minutes at room temperature and then for 1 1/2 hours at 705 C. The reaction mixture it is filtered, the filtrate is washed with water, dried over magnesium sulphate and evaporated.



  The title compound, which is identical to the product of Example 203, is obtained.



   In the same way, if instead of indene-3-ethanol, an equivalent amount of the suitable starting material of the formula II is used together with the suitable a-, ss-, y- or b-ketoamide, which are shown in Tables XXV and XXVI and in the Examples 200 and 206 listed products.



   Example 213
1-methyl-1,3,4,9-tetrahydroindeno [2.1-c] pyran-1-methanol
A. 10.4 g of the acid intermediate of the formula IV, 1-methyl-1,3,4,9-tetrahydroindeno [2.1-c] pyran-1-carboxylic acid, as described in Example 196, in 100 ml of tetrahydrofuran are slow added to a stirred mixture of 2 grams of lithium aluminum hydride in 100 ml of tetrahydrofuran.



  The reaction mixture is kept at 0 ° C. by means of an ice water bath. After the acid has been added, the excess hydride is destroyed with water and the precipitate is collected on a filter. The filtrate is evaporated, the residue is taken up in ether, the ether phase is washed with water, dried over sodium sulfate and evaporated under reduced pressure. An oil is obtained which, after chromatography on silica gel using chloroform, gives the title compound, vmC3iax3 = 3580, 3440, 1470, 1120, 1095, 1075, 1050 cm, nuclear magnetic resonance spectrum (CDC13) 8 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 ).



   B. On the other hand, the title compound can also be prepared according to the procedure of Example 193 by using an equivalent amount of the lower alkyl keto alcohol ester, acetoxyacetone, instead of methyl acetoacetate.



  It should be emphasized that the procedure of said example includes the hydrolysis of the ester obtained as an intermediate.



   Example 214 N, N, I-Dimethyl-1,3,4,9-tetvahyduoindeno [2,1-c] pyran-1-methylamine
9.0 g of the 1-methyl-1,3,4,9 tetrahydroindeno [2,1-c] pyran-1-methanol described in Example 213 are dissolved in 20 ml of dry pyridine. 7.4 g of p-toluenesulfonyl chloride are added to the vigorously stirred and cooled solution.



  The mixture is stirred for a further hour at 0 C, then ice and water are introduced and the aqueous mixture is extracted with ether. The combined ether extracts are washed with 10% ice-cold hydrochloric acid, water, 5% sodium bicarbonate solution and dried over sodium sulfate. After concentrating the extracts, 1-methyl-1,3,4,9-tetrahydroindeno [2.1-c] pyran-1-methyl tosylate is obtained.



   11.7 g of the latter tosylate are dissolved in 100 ml of dry acetone and the solution obtained is treated with 15 g of sodium iodide. The mixture is stirred at room temperature for 24 hours. Most of the acetone is removed under reduced pressure, water and ice are added and the brown solution obtained is extracted with ether. The combined ether extracts are washed with 10% strength sodium thiosulfate solution and water and dried over sodium sulfate. The solvent is evaporated under reduced pressure and a yellow oil is obtained. Chromatograph on silica gel and elute with benzene. After concentrating the eluate, 1- (3-iodomethyl) -1-methyl-1, 3,4,9-tetrahydroindeno [2, 1-c] pyran is obtained.

 

   A mixture of 11.7 g of the latter compound in 100 ml of tetrahydrofuran and 199 ml of 40% strength aqueous dimethylamine is stirred for 6 hours at room temperature. Most of the tetrahydrofuran is removed under reduced pressure, the milky aqueous solution extracted with ether and washed with water until the water is neutral. The extract is dried over sodium sulfate and evaporated. The title compound, which is identical to the product of Example 209, is obtained.



   If one works in succession according to the procedure of Example 213 and this example, as starting material in Example 213, however, an equivalent amount of the suitable ester intermediate of formula IV (in the case of procedure A) or a suitable starting material of formula II and the suitable keto alcohol lower alkyl ester of the formula m as described above (in the case of procedure B) and a suitable amine of the formula HNR6R7, e.g. those described in Example 200, used in the procedure of the present example, the corresponding compounds of formula I are obtained, for example.



  those described in Examples 206-212.



   Example 215
1-methyl-1- (3-nitropropyl) -1,3,4,9-tetrahydroindeno [2,1-c] pyran
5 drops of boron trifluoride etherate and 3 drops of trifluoroacetic acid are added to a solution of 352 mg indene-3-ethanol and 273 mg of the nitro ketone, 5-nitro-2-pentanone, H. Shechter et al., Op. Cit., In 100 ml benzene. The reaction mixture is stirred and heated at reflux temperature under a water separator for 18 hours. The benzene solution is cooled, washed with 10% strength sodium bicarbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate, the solvent is removed and the residue is chromatographed on silica gel. After eluting with chloroform, the title compound is obtained, vC = 3 = 1550 cm −1.



   If the latter compound is reduced with lithium aluminum hydride, 1-methyl-1,3,4,9-tetrahydroindeno [2,1-c] pyran-1-propylamine, nuclear magnetic resonance spectrum (CDCl3) 8 1.51 (see 3H) , 3.32 (m, 2H), 7.28 (m, 4H).



   If one works according to the process of the present example and also carries out the reduction, however, as starting material an equivalent amount of the suitable starting material of formula II, e.g. those described in Examples 193-199 and an equivalent amount of a suitable nitroketone of the formula
0
II Rl-C-AlkNO2, as described above, used, the corresponding primary amine compounds of the formula I are obtained.



   Example 216 N, N, 1-Trimethyl-1,3,4,9-tetrakydroindeno [2,1-c] pyran-1-ethylamine
1.3 g of p-toluenesulphonic acid are added to a solution of 1.0 g of 1-dimethylamino-3-butanone dissolved in 10 ml of toluene. The suspension is stirred for 10 minutes. Then 1.0 g of indene-3-ethanol in 5 ml of toluene are added to the suspension and the resulting solution is stirred for 2 hours. Then 0.25 ml of boron fluoride etherate are added together with about 0.5 g of hydrated alkali aluminum silicate. The mixture is heated at 80 ° C. for 30 minutes, then 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 diluted with conc. NH4OH made alkaline and extracted with toluene. The latter extract is treated with activated charcoal and then concentrated. The title compound is obtained, which is identical to the compound of the same name described in Example 206.

 

   If the procedure of the present example is followed but an equivalent amount of the appropriate starting material of formula II, e.g. those described in Examples 193 to 199, and using an equivalent amount of the suitable aminoketone of the formula R'CO-Alk-NR6R7, in which R1, Alk, R6 and R7 have the meanings given above, the corresponding indenopyran and indenochropyranaLkylamines are obtained of formula I.

 

Claims (1)

PATENT CLAIM Process for the preparation of a compound of formula I. EMI31.1 wherein RÚ alkyl of 1 to 6 carbon atoms; R2, R3, R4 and R5 are identical or different and are hydrogen or alkyl having 1 to 6 carbon atoms; R5 and R7 are the same or different and are hydrogen or alkyl of 1 to 6 carbon atoms or R6 and R7 together with the nitrogen atom to which they are attached form a heterocyclic ring; Alk CR8R9, CR8R9CRloRll, CR8R9CR'0R "CR12R'3 or CR8R9CR10R11CR12R13CR14R15, wherein R8, R9, R10, R11, R'2, R13, R14 and R15 represent hydrogen or alkyl having 1 to 6 carbon atoms; X oxygen or sulfur; and A is a divalent radical of the formula EMI31.2 wherein R16 is hydrogen or alkyl having 1 to 6 carbon atoms, R13 is alkyl having 1 to 6 carbon atoms and R18 is hydrogen, alkyl having 1 to 6 carbon atoms, hydroxyl, alkoxy having 1 to 4 carbon atoms, alkanoyloxy having 2 to 6 carbon atoms or halogen, characterized in that a compound of the formula II B-CR4R5CRêR Y (II), where B is a monovalent radical of the formula EMI32.1 and Y represents hydroxy, mercapto, -S-SO3Na or -S-SO3-K, with a compound of formula m RÚCO-Z (III), wherein Z a) Alk-NR6R7; b) CONR6R7 or AlkÚ-CONR6R7, where Alk 'CR8R9 Represents CR10R11 or CR8R9CR10R11CR12R13; or c) Alk NR6COR21, in which R21 is hydrogen or alkyl having 1 to 5 carbon atoms, in the presence of an acid catalyst to give a corresponding compound of the formula IV EMI32.2 converts, and if a compound of the formula m has been used in which Z has the meaning given under (b) or (c), the compound of the formula IV is reduced. SUBClaim Process according to claim, characterized in that a compound of the formula I is prepared in which the Group -NR6R7 is a 1-pyrrolidinyl, piperidino, morpholino, piperazino, 4-lower alkyl-1-piperazinyl or 4- (Hydroxy-lower alkyl) -1-piperazinyl radical means.