DK150143B - ANALOGY PROCEDURE FOR THE PREPARATION OF INCIDENTAL DERIVATIVES - Google Patents

Description

150143

The present invention relates to an analogous process for the preparation of novel indole derivatives (derivatives of imidazo / I, 2-a-indoles, pyrimido / I, 2-a7 indoles and diazepino / I, 2-a / indoles) of the general formula 2 1501 A3-w where R is hydroxyl, alkoxy of not more than 6 carbon atoms, phenyl-alkoxy of not more than 6 carbon atoms in the alkoxy group, tetrahydropyryloxy or acyloxy of not more than 6 carbon atoms, R4 is a phenyl or naphthyl group optionally substituted once or twice by halogen, alkyl of not more than 6 carbon atoms, alkoxy of not more than 6 carbon atoms, or trifluoromethyl, or R 2 carbon atoms, alkynyl of not more than 6 carbon atoms or aminoalkyl of not more than 26 carbon atoms in the alkyl group, R and R are the same or different and each represents hydrogen, hydroxyl, alkyl of not more than 6 carbon atoms, alkoxy of not more than 6 carbon atoms r, trifluoromethyl, halogen, amino or mono- or dialkylamino, wherein the alkyl group contains at most 6 carbon atoms, R and R are the same or different and each independently means hydrogen or alkyl of not more than 6 carbon atoms, 3 4 or R means hydrogen and R is hydroxy, n is 0, 1 or 2, the dotted line represents a possible bond in the indicated

C

position and R present only when the optional bond represented by the dotted line does not exist means hydrogen or phenalkyl of not more than 6 carbon atoms in the alkyl group, alkyl of not more than 6 carbon atoms, alkenyl of not more than 6 carbon atoms, alkynyl of not more than 6 carbon atoms, aminoalkyl of not more than 6 carbon atoms in the alkyl group or acyl of not more than 6 carbon atoms, or pharmaceutically acceptable acid addition salts or quaternary ammonium salts thereof.

3 4

Obviously, R and R may be attached to the same or different carbon atoms, but it is preferred that they be attached to the same carbon atom, for example at the 3-position of the pyrimido [1,2-a] indoles or in 2 position (or 3 position) in the imidazo [1,2-a] indoles. The term aminoalkyl used in conjunction with the group R ^ means unsubstituted aminoalkyl or mono- or disubstituted aminoalkyl such as alkylaminoalkyl, dialkylaminoalkyl or heterocycloalkyl.

150143 3

Since the compounds of the present invention may contain one or more asymmetric carbon atoms, there is the possibility of the occurrence of optical enantiomorphic forms, and the compounds of the invention may be the pure enantiomorphic forms or mixtures of such enantiomorphic forms, e.g. racemates.

Examples of R are hydroxyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, benzyloxy, phenethoxy, acetoxy, propionoxy and butyryloxy. Examples of R1 are optionally substituted phenyl and naphthyl, thienyl and pyridyl. Suitable substituents are halogen, e.g. fluorine, chlorine or bromine, alkyl, for example methyl, ethyl, propyl or butyl, alkoxy, for example methoxy, ethoxy, propoxy or butoxy, and haloalkyl, for example trifluoromethyl. Examples of phenalkyl groups R 2 are benzyl and phenethyl, each of which may be substituted by the substituents listed above for the aryl groups R 1. Alkyl groups R 1 can be methyl, ethyl, propyl or butyl, the alkenyl groups can be straight or branched and are, for example, allyl or dimethyl allyl, the alkynyl groups can be straight or branched and are, for example, propargyl. Aminoalkyl groups may be, for example, dimethylaminoethyl, dimethylaminopropyl, diethylaminopropyl, diethylaminoethyl, methylaminoethyl, methylaminopropyl, morpholinopropyl and piperidinopropyl. Examples of R and R include alkyl, for example, methyl, ethyl, propyl and butyl, or alkoxy, for example, methoxy, ethoxy, propoxy and butoxy. For example, haloalkyl may be trifluoromethyl, and halogen may be chlorine and bromine, for example. Examples of alkyl groups R and 4 R are methyl, ethyl, propyl and butyl.

Examples of phenalkyl groups R ° are benzyl and phenethyl, each of which may be substituted by the substituents listed above in compound * L g with the aryl groups R. Alkyl groups R may be straight or branched and include e.g. methyl, ethyl, propyl and butyl, the alkenyl groups may be straight or branched and may e.g. be alkyl or dimethylallyl, the alkynyl groups may be straight or branched and may e.g. be propargyl. Amino-alkyl groups may e.g. be dimethylaminoethyl, dimethylaminopropyl, diethylaminopropyl, diethylaminoethyl, methylaminoethyl, methylaminopropyl, morpholinopropyl and piperidinopropyl. Acyl groups R be formyl, acetyl, propionyl and butyryl.

4 150143

The preferred compounds are those of formula (I), wherein R, R, R and R are hydrogen atoms, R is hydroxyl, and R R is a phenyl, halogenophenyl or alkylphenyl group and the dotted line represents a bond.

A preferred group of compounds of formula (i) are the tetrahydropyrimido / ϊ, 2-α7indoles of the general formula (Ia) R2 © © ® K3 φ -N ^ O> <© © 1,4 (ia) R5 ® R R1 or acid addition salts or quaternary ammonium salts thereof, in which formulas R and R 1 have the above-mentioned compounds of formula (i)

2 R

ne means R and Br may be the same or different and represent hydrogen, hydroxyl, lower alkyl, lower alkoxy, halo-lower alkyl X 2l or halogen, and Br and R, which may be the same or different, represent hydrogen or lower alkyl . The ring system in the pyrimido / 1,2-α / indoles is numbered as described in the general formula (Ia).

Particularly valuable compounds of formula (Ia) are the following: 2,3, 4,10-Tetrahydro-10-phenylpyrimido / 1,2-a-indol-10-ol 10-m (-chlorophenyl) -2,3,4,10- tetrahydropyrimido / 1,2-a / indol-10-ol 2,3,4,10-Tetrahydro-10- (p-chlorophenyl) pyrimido / 1,2-a / indol-10-ol 2,3,4,10-Tetrahydro-10- (2- thienyl) pyrimido [2,2-a] indol-10-ol 10- (m-Fluorophenyl) -2,3,4,10-tetrahydropyrimidine [1,2-a] indol-10-ol 10- (3,4-dichlorophenyl) ) -2,3,4,10-Tetrahydropyrimido [1,2-a] indol-10-ol 10- (m-Chlorophenyl) -2,3,4,10-tetrahydro-3,3-dimethylpyrimido / X, 2-a7indole - -10-ol 2,3,4,10-Tetrahydro-10-phenyl-3,3-dimethylpyrimido [1,2-a] indol-10-ol (+) - 2,3,4,10-Tetrahydro-10 (m-chlorophenyl) pyrimido [1,2-a] indol-10-ol and (-) - 2,3,4,10-Tetrahydro-10- (m-chlorophenyl) -pyrimido [1,2-a] indol-10-ol .

In the process of the invention, tetrahydropyrimido / 1,2-a-indoles other than those of the general formula (Ia) are prepared.

For example, compounds of the general formula (Ib) r 2 I X H (Ib) r 5 R R1 5010143 or acid addition salts or quaternary ammonium salts thereof are prepared, in which formula R, R, R and R have the above compounds of formula (I) ) stated meanings.

Another group of compounds which fall within the scope of formula (i) are the hexahydropyrimido / ϊ, 2-α / indoles, e.g. compounds of the general formula (Ie) R5 R1 H16 and acid addition salts and quaternary ammonium salts thereof, in which Formula R, R1 and R4 have the meanings set forth above in connection with Formula (I), and 2, Br, R and Br have the meanings given above for formula (Ia).

Another type of compounds falling within the scope of the general formula (I) are those compounds where n is 0 or 2, ie. the imida-zo / I, 2-a / indoles and the diazepino / I, 2-a7 indoles. A particular group of imidazo [1,2-a] indoles are those of the general formula (Id) - R 5 R 1, as well as their acid addition salts and quaternary ammonium salts, in which formulas R and R 1 have the above-mentioned compounds of formula (I) 45, and R, R, R and R have the meanings given above in connection with formula (Ia).

Indole derivatives of the general formula (I) are prepared by the process according to the invention, characterized in that a ketone of the general formula

(ID

r5 II

ISLAND

Wherein R, R, R, R and n have the above meanings, reacted with a Grignard reagent of the formula R 2 MgY, where Y means halogen and R 1 has the meaning given above, or with a 1 '1' aryllithium of the general formula R Li wherein R is phenyl or naphthyl optionally substituted with one or two of the substituents defined above under R 1, thienyl, or pyridyl or with sodium or potassium acetylide, and optionally (a) alkylated or the acylated compound of formula I is formed, wherein R is a hydroxyl group and the dotted line is a bond and R, R, R, R, R and n have the above meanings to form a corresponding compound wherein R is alkoxy, phenylalkoxy, tetrahydropyranyloxy or acyl-oxy, as defined in connection with formula (I), and optionally (b) is converted to the compound of general formula I wherein the dotted line represents a bond and R, R, R , R, 4,5, R, R and n have the above-mentioned bets (c) the compound of formula I wherein the dotted line represents a bond and R, R 1, R 2, R 3, R 4, R 5 and n have the meanings set forth above, are reduced to an acid addition salt or quaternary ammonium salt thereof. or a quaternary ammonium salt thereof to form a compound of formula I wherein the bond represented by the dotted line is not present, R, r \ R2, R3, R4 and R5 and n have the

C

and R is hydrogen and optionally (d) the compound of formula I formed is converted in which the bond represented by the dotted line is not to denote R, R, R, R, R, R and n. have the meanings given above first, and R is hydrogen, to an acid addition salt or quaternary ammonium salt thereof, and optionally.

(e) alkylating or acylating a compound of formula I wherein the bond represented by the dotted line is not present, R is hydrogen and R, R, R, R, R, R and means to form a corresponding compound wherein R is phenalkyl, alkyl, alkenyl, alkynyl, aminoalkyl or acyl as defined in formula (I).

150143 7

In the above method, the organometallic compound is preferably selected from (a) Grignard reagents of the formula R 1 MgY, where Y is halogen and R 1 has the meaning given above, and (b) alkali metal compounds such as arylllthium compounds of the formula R 1 Li, e.g. sodium and potassium acetylide. When n is 0, the organometallic compound is preferably an aryl lithium. The reaction with the organometal compound is usually carried out in an inert organic solvent, e.g. ether or tetrahydrofuran using known standard conditions for the reaction in question.

As already mentioned, the compound wherein R represents a hydroxyl group and the dotted line represents a bond at the indicated position may be optionally alkylated or aeylated to introduce a lower alkoxy, aryl lower alkoxy, tetrahydropyranyloxy or acyl oxy residue R. Such alkylation or aeylation reactions are carried out by known standard methods. The hydroxy compound may e.g. "is converted to its alkali metal derivative, especially the sodium derivative, and then treated with the appropriate alkylating or aeylating agent. Examples of alkylating agents are lower alkyl or aryl lower alkyl halides such as the chlorides, bromides or iodides, while examples of acylating agents are acid halides, the chlorides, or acid anhydrides of the aliphatic carboxylic acids.

The compounds of general formula (I) in which the bond represented by the dotted line is not present, has the general "formula (VI) H UH2 V B? R4 (VI) R5 R R1 | β where R, R1, R ^, R ^, R4, R ^, R ^ and n have the meanings given above in connection with formula (I) can be prepared by reducing, f. Ex. a hydride transfer agent such as a complex metal hydride, a compound of the general formula (VII) 8, or a quaternary ammonium salt thereof, wherein the cation has the formula (VIII) 5CH2] n r3 L \ 1 3 4 (VIII) r5 R- ^ R1 16, 1 p -5 11 k • where R, R, R, Rr, R, Rv and n have the meanings immediately above, and R alkyl, lower alkyl, lower alkenyl, lower alkynyl or amino-lower alkyl, and optionally one group R and / or R 2 and / or R 2 and / or R 2 and / or R 2 is converted to another group R and / or R and / or R 2 and / or R 2 and / or R 2 having the above meanings for R, R 1, R 2 and R 2, or optionally a free base is converted to an acid addition salt or a quaternary ammonium salt thereof.

For example, when it is desirable to prepare a compound of the general formula (Ie) wherein R, R 1, R 2, R 2 and R 2 have the meanings given above in compound of formula (VI) and R 2 is hydrogen, 4, a compound of the general formula (Ia) in which R, R, R, R, R and R 2 have the meanings given above in connection with formula (VI) is reduced in known manner. Hydride transfer agent, especially a complex metal hydride such as sodium borohydride or lithium aluminum borohydride The reaction is carried out using known standard conditions for the specifically used reducing agent.

When it is desired to prepare a compound of the general formula (Ie) wherein R 1, R 1, R 2, R 2 and R 2 have the meanings given above in connection with Formula (VI) and R 1 is aryl-lower-alkyl , lower alkyl, alkenyl, alkynyl or amino-lower alkyl, a quaternary compound is reduced, where the cation has the general formula 9 wherein R, R1, R2, Tp, R meanings, as described above.

Once a compound has been prepared with the general one. and formula (I) wherein R, R, R, R, R, R · and R have the meanings given above in connection with formula (I), one group R and / or R 2 and / or R 2 and / or R? and / or R 2 and / or R 2 and / or R 2, if present, optionally converted to another group R and / or R 2 2 4 4 cg and / or R and / or Jr and / or R and / or R p and / or R, each having in particular the meanings set forth above for R, R, R, R ', R, R ·, and 6 2 * 5 R. When R and / or Jr means a hydrogen atom, this may e.g. is converted into a halogen atom or a nitro group in known manner, especially in the 8-position of the pyrimido / 1,2-a-indoles. When the chlorine compound is desired to be prepared, this can be done by treating with N-chlorosuccinimide. Furthermore, when R and / or R 2 is a lower alkoxy group, especially a methoxy group, it can be deetherified in known manner to form 2 of the corresponding hydroxyl group R and / or R, or conversely, a hydroxyl group R and / or R in a known manner to form a lower alkoxy group R and / or R. When R is an alkynyl group, it can be reduced to an alkenyl group R A dimethylaminoalkyl group R 1 - can monodeme thyler s to form the corresponding methylamino alkyl group. Optionally, a hydroxyl function R can be alkylated or acylated by the previously described methods to form a lower alkoxy, aryl lower alkoxy or acyl group R.

When R 1 represents a hydrogen atom, the compound may be alkylated or acylated in known manner to introduce a group R 2 other than hydrogen. If necessary, any reactive group of a compound may be protected in known manner before carrying out any of the above-described reactions, after which the protecting group may be removed in known manner after the reaction.

The ketone starting materials of the general formula (II) can be prepared by cyclizing a ketone of the general formula (III) 150143 or IT (III)

c II N

Wherein R, R, R, Hr and n have the meanings given above for formula (II) and X is halogen and optionally one group and / or R second group R and / or R in known manner.

The ketone of the general formula (III) can be cyclized by a modified Ullmann reaction. The ketone can e.g. is treated with a metallic agent, for example, copper or a salt thereof, especially cuprioxide or cuprous chloride. The reaction is usually carried out in the presence of a base such as an alkali metal carbonate, e.g. potassium carbonate, triethylamine or N-ethylmorpholine and preferably in a solvent, e.g. dimethylacetamide, pyridine, hexamethylphosphoric triamide or preferably dimethylformamide.

The group X preferably represents bromine and in the ketone of the general formula (IV), R and R 1 are preferably hydrogen or electron-attracting groups such as halogen.

The ketones of general formula (III) can be prepared by oxidation of the corresponding hydroxy compounds of general formula (IX) p2 -7 \ X H (CHp)

x '2> "K

Γ Jf ϊ (ix)

/ H X0H

2 3 4 5 wherein R, R, R, R, n and X have the above meanings. Preferably, the oxidation is carried out with a mild oxidizing agent such as manganese dioxide (e.g., in solvents such as dichloromethane, chloroform, benzene, acetone or aqueous acetone) or lead tetraacetate (e.g.

in pyridine). The compound of formula (IX) wherein R 1 is hydrogen, 4 and R is hydroxy can be selectively oxidized to the compound of general formula (III) wherein R 1 and R have the same meanings, using suitable mild oxidizing agents such as precipitated manganese dioxide.

The compounds of the general formula (IX) are described in the literature or may be prepared from known compounds in known manner. For example, they can prepared by that of Neilscn et al. in J. Chem.

Soc. (C), 1968, 1855, method described.

110143 11

The ketone starting materials of general formula (II) / where n is 1 may be prepared by an alternative method comprising hydrolysis of the corresponding compound of general formula (X) R5 ||

Z

wherein Z represents an alkylene ketal residue or a di-alkoxy residue.

The hydrolysis can be carried out in a manner known per se, e.g. by heating with acid, e.g. dilute mineral acid such as hydrochloric acid. The yield of the ketone (II), which in this method is usually isolated as the mineral acid salt, is only of the order of $ 50. In a preferred hydrolysis method, the compound is treated with concentrated sulfuric acid at room temperature. In this method, the ketone (II) is usually isolated as the free base in yields of the order of $ 90.

In a preferred method of preparing the compounds of formula X, a substituted isatin of the general formula (IV) R

-N - 0Ho - C - CN

[I ί R * (IV) r5 z 2 wherein Z has the meaning given immediately above and R, R · ^, R ^ and R ^ have the meanings specified in formula (i). The hydrogen ring is usually conducted in the presence of a nickel, palladium or platinum catalyst at elevated temperature and pressure.

When using temperatures in the range of 100 ° C, the tricyclic compound usually gives directly. In some cases and even when somewhat lower temperatures are used, the isolated product 12 consists of a mixture of the desired tricyclic compound and an intermediate amine of formula (V) - N - CH

Cn 1 (v) R3 ^ V "° z

The amine can be dehydrated to form the desired tri-cyclic compound by winding the mixture azeotropic distillation with a solvent such as benzene, xylene or toluene. The compounds of formulas IV and V are known or can be prepared in known manner.

The compounds of formula (I) can form acid addition salts with acids, especially pharmaceutically acceptable acids, and in the process of the invention such salts are also prepared. The salts can be isolated directly by the method described above or can be prepared by dissolving the specific compound of formula (I) in base form in a suitable organic solvent and treating with a solution of the selected acid in accordance with the prior art in the preparation of acid addition salts. from base compounds. Examples of acids include hydrochloric, hydrobromic, tartaric, phosphoric, maleic, citric, acetic and benzoic.

The compounds of general formula (i) may also form quaternary ammonium salts, and such salts are also prepared by the process of the invention. The quaternary salts can be prepared by treating the compound in base form in the presence or absence of a solvent with an aryl-lower-alkyl halide, a lower-alkyl halide, an alkenyl halide, an alkynyl halide or an amino-lower-lower alkyl halide. Examples of such halides are methyl iodide and benzyl chloride as well as benzyl bromide.

The optical isomers of the compounds of formula (I) can be prepared by various methods. Preferably, a racemic mixture of a compound of the general formula (i) is resolved by known standard methods. The racemate can be prepared by any of the methods outlined above. It is to be understood that the resolution may be carried out on the racemic mixture of the desired final product or on a racemate 1501 A3 13 of one of the compounds of general formula (I), after which the optical isomers may be subjected to post-treatments such as alkylation, acylation, hydrolysis, hydrogenolysis and reduction to form the desired product of formula (i).

Optionally, an optically active isomer of a compound of the general formula (I) can be prepared by any of the methods described above using an optically active starting material, or resolution can be made at any stage before forming the compound of the general formula (IN). Optionally, the optically active isomer thus prepared can be subjected to reactions such as alkylation, acylation, hydrolysis, hydrogenolysis or reduction to form the desired product.

A resolution is preferably carried out on a novel mixture of a basic compound of the general formula (i) in a known manner, e.g. using an optically active acid. For example, a solution of the racemate in a suitable solvent such as an alcohol is treated with a solution of an optically active acid to produce crystallization of the salt of one particular enantiomorph. The second enantiomorph can often be recovered from the mother liquor or, if necessary, by treatment with a base and then with the second optical isomer of the optically active acid, or optionally a fresh solution of the racemate can be treated with a solution of the second enantiomorph of the optically active acid. . The current solvent and the current optically active acid to be used in each case can be determined by routine experimentation. The best combination is one which allows the lightest isolation of the salt in high purity, ie. without content of the second enantiomer, and in crystalline form.

It has been found that D (-) and L (+) - tartaric acid are particularly suitable for resolving some of the compounds of formula (I).

The compounds of general formula (I) exhibit pharmacological action. In particular, many of the compounds possess one or more of the effects listed below, as demonstrated by standard experiments with warm-blooded animals. These effects are antidepressant, anti-inflammatory, antihistamine, cardiocascular, dietary and hypoglycaemic. Many of the compounds of general formula (I) in which n is 1, i. The pyrimido / I, 2-a / indoles, are particularly important as antidepressants, evaluated by e.g. their antireserpine effects in vivo according to that of Beryl M. Askew in Life 150143 14

Sciences, 1, 725-730 (1963), cf. the results of this particular test set out in the table below are carried out on the compounds prepared by the process of the invention (i.e., a number of representative compounds prepared according to the examples given below). Some compounds, e.g., 10 - (m-chlorophenyl) -2,3,4,10-tetrahydropyrimido [1,2-a] indol-10-ol exhibit many of the antidepressant properties of conventional tricyclic antidepressants, but exhibit minor anti-cholinergic side effects in pharmacological testing. Therefore, it is appropriate according to the invention that 10- (m-chlorophenyl) -2,3,4,10-tetrahydropyrimido [1,2-a] indol-10-ol be prepared. Some of the pyrimido [1,2-a] indoles have been shown to have antihistamine properties when tested by H.O. Shield in Brit. J. Pharmacol., 2, 189-206 (1947).

1501 A3 15

Antidepressant Activity Measured by Temperature Change after Reser-Pin-Induced Hypothermia According to Beryl M. Askew, Life Sciences, 1963, 1, 725-730

Compound Temperature rise Dose prepared (° C) (mg / kg per ounce) according to Example no.

4,5,6 5.3 8 7.3 16 9.6 32 7 4.4 4 2.9 8 6.2 16 7.8 32 9 2.9 5 4.7 10 4.0 20 12 4.4 3 8.5 9 9.6 27 16 7 , 5 29 9.3 40 17 6.3 20 6.4 40 10.2 50 18 4.0 5 4.2 50 19 5.1 10 6.0 20 8.4 40 20 7.6 10 7.5 20 9.0 40 10.9 50 150143 16

Compound Temperature increase Dose prepared ° C (mg / kg per ounce) according to Example No. 21 7.4 10 10.5 15 9.0 20 24 6 20 25 5.5 5 6.9 10 9.8 20 26 4, 6 5 7.5 10 9.8 20 28 5.2 5 8.5 10 9.5 20 30 4.9 5 7.2 10 10.9 20 31 2.8 5 4.9 10 9.4 20 36 4.3 10 3.4 20 39 7.9 16 6.5 32 4Q 6.2 8 5.6 10 6.6 15 41 8.8 8 9.9 10 12.0 15 150143 17

Compound Temperature increase Dose prepared ° C (mg) kg per US) according to Ex.

50 4.9 40 52 7.0 3 8.7 9 10.2 20 12.5 80 53 4.4 2.5 8.9 5 9.3 10 11.7 20 150143 18

The process of the invention is further illustrated in the following examples.

Example 1 5 * -Dihydrospiro / 1,5-dioxolane-2,10 '(2H, 10H) pyrimido / 1,2-a-indole7.

57 g of 21-oxospiro / Ϊ, 5-dioxolane-2, 51 -indolin7-11 -propionitrile 2 are reduced at an initial pressure of 84.4 kg / cm and a final temperature of 100 ° C in 200 ml of ethanol which is half saturated with ammonia,! presence of 6 g of Raneynickel for 5 hours. After cooling, the catalyst is filtered off and the solvent removed under reduced pressure to give a viscous oil. The oil is dissolved in 200 ml of xylene and heated under reflux with stirring for 26 hours in an apparatus fitted with a water separator. The xylene is removed under reduced pressure. The dark oil is dissolved in hot ethyl acetate and treated with decolorizing coal. 29.5 g of colorless needles are obtained with m.p. ll4-115 ° C.

Analysis for c12 H20 N2 O2:

Cfo E% W °

Calculated 67.8 6.1 12.2

Found 68.0 5.9 12.2

Example 2 5,4-Dihydropyrimido / 1,2-a-indole-10 / 2H7-one 12.2 gy 2 '- dihydrospiro' / 1 '-dioxolanyl' 10 '(2H, 10H) pyrimido- (1,2-a) indol7 is suspended in 50 ml of water and 50 ml of concentrated hydrochloric acid is added with stirring. The mixture is heated to 85 ° C for 5 hours. The mixture is evaporated to a red oil under reduced pressure, dissolved in 100 ml of absolute ethanol and evaporated to 50 ml. On cooling, 1.9 g of high-red needle-shaped product with m.p. 215-225 ° C (dec.).

Analysis for C11H10N2O: Q / fo Ufo

Calculated 59.5 5.0 12.6

Found 59.0 5.0 12.5 · 150143 19

Example 3 5 Λ-Dihydropyrimido [1,2-a] indol-10 / 2H7-one 10 g of finely powdered 3,4,4'-dihydrospiro // 1,3-dioxolane-2,10 '- (2H, 10H) pyrimido- (1 2-a) -indole 7 is added portionwise to 50 ml of stirred concentrated sulfuric acid which is maintained at 25 ° C by cooling with an ice bath. After the addition is complete, the mixture is stirred at room temperature overnight, poured into ice and neutralized with aqueous concentrated ammonia, keeping the temperature below 30UC. The mixture is extracted with chloroform and dried over anhydrous magnesium sulfate. After evaporation, the product is crystallized by a mixture of benzene and light petroleum (boiling range 60-80 ° C) to give 7 * 3 g of strong red crystal needles with m.p. 121-122 ° C.

Analysis for O-qH ^ q ^ O: C% H% W °

Calculated 70.95 5 * 4 15> 05

Found 71 # 0 5Λ 14.7

Example 4 2.5 Λ, 10-Tetrahydro-10-phenylpyrimido [1,2-a] indol-10-ol 5.82 g of finely pulverized 3β-dihydropyrimido / 1,2-a7 indole-10 / 2I | 7-one Hydrochloride is added portionwise to phenylmagnesium bromide prepared from 12.9 g of magnesium and 8.2 g of bromobenzene in 100 ml of ether. Upon completion of the addition, the reaction mixture is heated under reflux overnight. over, cool and pour into a mixture of ice and 10 g of ammonium chloride. The separated yellow solid is filtered off and washed with water and ether to give 3 * 67 g of almost white powder with m.p. 246-247 ° C.

The base is recrystallized from ethanol in the form of colorless rhombus with m.p. 247-248 ° C.

Analysis for 0ι7Ηι6Ν20: G% E% Wo

Calculated 77 * 5 6.1 10.6

Found 77 * 6.2 6.2 10.5

The hydrochloride of the base is prepared by dissolving in hot absolute ethanol and adding a solution of hydrogen chloride gas in dry ether. A product in the form of colorless needles with m.p. 264-270 ° C (dec.).

Analysis for C17 H16 N2 O:

Efo N fo

Calculated .67.85 5 * 7 9 * 5

Found 68.2 5 * 7 9 * 2 20.

150143

Example 5 2.3.4.10- Tetrahydro-10-phenylpyrimido / 1,2-a7indol-10-ol 0.05 mole of phenyllithium in ether is added dropwise to a stirred suspension of 2.2 g of pyrimido / I, 2-a7indole-10 / The 5H7-on hydrochloride of Example 2 in 1 liter of dry ether under a stream of nitrogen. The colorless solution formed is left at room temperature overnight and decomposed by the addition of 35 ml of water and 15 ml of 2N hydrochloric acid. The solid formed is filtered off, washed with water and dried to give 1.59 S of the intended compound, m.p. 220-225 ° C. After recrystallization from ethanol, the melting point rises to 246-247 ° C.

Example 6 2.3.4.10- Tetrahydro-10-phenylpyrimido / 1,2-a7indol-10-ol 5.58 g of 3,4-dihydropyrimido / 1,2-a7indol-10-one in dry tetrahydrofuran is added dropwise with stirring to 0.05 mole of phenylmagnesium bromide in 200 ml of dry ether. The reaction mixture is heated under reflux with stirring for 3 hours. The reaction mixture is cleaved by pouring into a mixture of ice and ammonium chloride to give 6.38 g of pink powder with m.p. 230-235 ° C (dec.). After recrystallization of ethanol, the melting point rises to 246-248 ° C (dec.).

Example 7 2.3.4.10- Tetrahydro-10- (p-ehlorophenyl) pyrimido [1,2-a] indol-10-ol 6.5 g, 0.03 mol, finely powdered 3,4-dihydropyrimido / I, 2-a indole-10 / 2g7-one hydrochloride is reacted with 0.2 mole of p-chlorophenylmagnesium bromide in 700 ml of dry ether in the manner described in Example 4. Processing with ice and ammonium chloride gives the base with m.p. 185-191 ° C (dec.).

Analysis for C ^H ^NgClO: C% Ef E% Cl fo

Calculated 60.4 5.35 7.8 10.1

Found 60.3 5.3 7.6 9.9.

A total of 2.6 g of the hydrochloride with solution in ethanol is obtained and heating with a solution of hydrogen chloride in dry ether, m.p. 275-279 ° C (dec.).

Analysis for C ^H, NpCl10.HCl.l / 2 C „IL OH: C% E% N for Cl

Calculated 60.4 5.35 7.8 10.1

Found 60.3 5.3 7.6 9.9 150143 21

EXAMPLE 8 2,3 µl, 10-Tefcrahydro-10- (o-tolyl) pyrimido [1,2-a] nyl] Chol-10-ol 6.66 g, 0.03 mol, 3,4-Dihydropyrimido / 1,2 Hydrochloride is reacted with 0.1 mole of o-tolylmagnesium bromide in 1 liter of ether in the manner described in Example 4. When working up, 4.1 g of the base are obtained with m.p. 205-207 ° C (dec.).

Analysis for C ^ gHH gNNO: G% E% Nf0

Calculated 77 * 7 6.5 10.1

Pound 77 * 5 6.7 9 * 9

When treating the base in isopropanol with dry hydrogen chloride 1 ether, the hydrochloride is obtained in the form of colorless fine needles in an amount of 4.4 g, m.p. 30O-302 ° C (dec.).

Analysis for C- gHH ^GNgO.HCl: C% E% N $

Calcd 68.7 6.1 8.9

Found 68.7 6.25 8 * 8

Example 9 2,5,4,10-Tetrahydro-10- (p-tolyl) pyrimido [1,2-a] indol-10-ol

Analogous to the procedure described in Example 4, 6.6 g of 5 * 4-dihydropyrimido / 1,2-a-indole-10 / 2H7-one hydrochloride and 0.15 nil of p-tolylmagnesium bromide are reacted in 1500 ml of dry ether to give 1, 28 g of the hydrochloride of the above compound in the form of colorless needles, m.p. 265-267 ° C (dec.).

Analysis for C- gHH gNNO.HCl:

Cfo E% N fo

Calcd 68.7 6.1 8.9

Found 68.9 6.5 8.9

Example 10 2, 3,4,10-Tetrahydro-10-methylpyrimido [1,2-a] indol-10-ol

Analogous to the procedure described in Example 6, 5 * 72 g of 3β-dihydropyrimido / 1,2-a-indole-10- / 2H7-one and 0.06 mol of methyl magnesium iodide are reacted in 500 ml of ether. After refluxing for 4 hours and standing overnight, the reaction mixture is poured into ice and ammonium chloride, the ether layer is isolated and the aqueous layer is extracted with chloroform. The chloroform extracts are dried over anhydrous magnesium sulfate and evaporated to a solid which is recrystallized from isopropa 22 TSO143 nol to give 2.1 g of light brown rhombs with m.p. l89-191 ° C.

Analysis for c 12 ^ 14¾0: C <fo Hfo W °

Calculated 71.5 7.0 15.85

Found 71.6 7.1 15.9

By dissolving this solid in isopropanol and treating with anhydrous hydrogen peroxide in ether, 2.0 g of the hydrochloride is obtained with m.p. 210-212 ° C.

Analysis for C, ρΗΊ 2, Np0: HCl: C% H% N%

Calculated 60.4 6.5 11.7

Found 60.8 6.5 11.7

Example 11 10-Benzyl-2,5Λ, 10-tetrahydropyrimido / 1,2-a-indol-10-ol

Analogous to the procedure described in Example 6, 5.72 g of 5.72 g of 5,4-dihydropyrimidoi / 1,2-a-indole-10 / 2I ^ 7-one is added dropwise to a stirred solution of 0.04 mole of benzylmagnesium chloride in 50 ether. The reaction mixture is heated at reflux for 4 hours, left overnight and cleaved by pouring on ice and ammonium chloride to give 4.5 g of the desired base, m.p. 225-250 ° C (dec.).

When treated with an isopropanol solution with hydrogen chloride in dry ether, the hydrochloride is obtained in the form of colorless fine needles with m.p.

241-245 ° C (dec.).

Analysis for C ^ gH ^ gNNO.HCl: C% H₂O N fo fo

Calcd 68.7 6.1 8.9

Found 68.9 6.2 9.1

Example 12 10- (m-Chlorophenyl) -2,5,4,10-tetrahydropyrimido [1,2-a] indol-10-ol

Analogous to the procedure described in Example 6, 3.72 g of 5,4-dihydropyrimido [1,2-a] indol-10 / 2H7-one is reacted with 0.04 mole of m-chlorophenylmagnesium bromide in 500 ml of dry ether. The reaction mixture is heated under reflux for 6 hours and then left overnight. The mixture is poured into ice and ammonium chloride and the filtered product gives 4.1 g of white powder with m.p. 195-195 ° C (dec.). After conversion to the hydrochloride, 4.79 g of fine needles are obtained, m.p. 275-280 ° C (dec.).

Analysis for 0.HC1: 2 Cfo Efo Nfo

Calculated 60.9 4.7 8.4

Found 6L, 0 4.9 8.5

Example 13 8 '-Chloro-31,4-dihydrospiro // 1,3 -dioxolane-2.10' (2H, 10H) pyrimido (1,2-a) -indole7,3,3 g3 ', 4, -dihydrospiro // 1,3 'dioxolane-2.10, (2H, 10H) pyrimido - (1,2-a) -indole7 is heated under reflux and stirring in 50 ml of carbon tetrachloride with 1.43 g of N-chlorosuccinimide for 16 hours. hours. After cooling, the carbon tetrachloride is washed with 2 N sodium hydrogen carbonate solution. The organic layer is then washed with 2N hydrochloric acid. The acid extracts are made basic with concentrated aqueous ammonia water and the white solid is extracted with ether. After drying with anhydrous magnesium sulfate, the solvent is removed to give an oil crystallizing from light petroleum (boiling range 100-120 ° C) containing a few drops of benzene. 0.73 g of product is obtained in the form of colorless needles with m.p. 112-114 ° C. Analysis for C- HH ^ClNgOg: Cf Efo N fo

Calculated 59.0 4.95 10.6

Pound 58.95 5.0 10.3

Example 14 31,4'-Dihydrospiro [3,3-dioxolane-3 ', 3'-dimethyl-2,101 (2H, 10H) pyrimido- (1,2-a) indole7 (a) 7.35 g isatin, 11 , 2 ml of ethylene glycol and 2 g of toluene-p-sulphonic acid in 300 ml of benzene are heated under reflux in an apparatus equipped with a water separator for 5 hours, during which 2.1 ml of water is collected in the water separator and the reaction is stirred in the mixture colorless. The reaction mixture is cooled, washed with sodium bicarbonate solution and water. After drying over magnesium sulfate, benzene is removed under reduced pressure and the residue is crystallized by methanol to give 9.9 g of 2'-oxospiro / 1,3-dioxolane-2,3'-indoline / in the form of pale pink needles, m.p. 131-132 ° C.

Analysis for C10H9N3O3:

Cfo H # - H #

Calculated. 62.8 4.8 7.2 'Pound 62.72 4.8 7.2 (b) 42.0 g of t-butyl cyanide is heated at 60 ° C with stirring in a mixture of 26 ml of bromine and 1 liter of carbon tetrachloride for 7 hours. days, while simultaneously irradiating with an ultraviolet lamp at moderate pressure. The carbon tetrachloride is removed under reduced pressure and the residual oil is dissolved in dichloromethane and washed with sodium hydrogen carbonate solution and then with water. After drying over anhydrous magnesium sulfate, the solvent is removed and by distillation 26 g of product consisting of 3-hromo-2,2-dimethylpropionitrile in the form of a colorless with kp are obtained. 77-82 ° C / 12 it Hg.

24 150143

Analysis for C ^ HHgBrN: 0% Uf> Ntf

Calculated 37.1 5.0 8.65

Pound 38.1 4.8 7> 3 (c) 3.8 g of 2, -oxospiro / 1J3-dioxolane-2,3'-indole is added portionwise to a stirred suspension of 0.84 g of sodium amide in 30 ml of dry hexamethylphosphoric triamide under reduced pressure. a stream of nitrogen. The reaction mixture is heated to 40 ° C for 2 hours, cooled to 10 ° C and 3.24 g of 3-bromo-2,2-dimethylpropionitrile are added at once. The reaction mixture is stirred at room temperature for 2 days. The reaction mixture is poured into water and extracted with benzene. The benzene extracts are washed with dilute hydrochloric acid, dried over anhydrous magnesium sulfate and evaporated to a dark oil. Crystallization from absolute ethanol gives 3.05 g of 2'-oxo-spiro / 1,3-dioxolane-2,3'-indolin7-l1 - [%. 2-dimethylpropionitrile / in the form of colorless rhombs with m.p. 112-113 ° C.

Analysis for C ^H ^ gN₂O-: C fo UfOf> Ufo

Calculated 66.2 5.9 10.3

Found 66.5 6.2 10.3 (d) 2.7 g of the product prepared under (c) is reduced in ethanolic ammonia in the presence of Raneynickel in the manner described in Example 1. After working up, the product is refluxed with toluene for 24 hours. Removal of the toluene and recrystallization of benzene give 1.23 g of the intended compound in the form of colorless rhombus with m.p. 109-110 ° C.

Analysis for C- HH ^ gNNO:

Cfo Ufo Nf>

Calculated 69.7 7.0 10.85

Found 70.0 7.2 11.1

Example 15 8-Chloro-2,3,4,10-tetrahydropyrimido [1,2-a] indol-10 / 2H7-one 8.0 g of 8'-chloro-3 ', 4,4-dihydro-spiro / I, 3- dioxolane-2.10 '(2H, 10H) -pyrimido (1,2-a) indole7 is finely powdered and added to 50 ml of concentrated sulfuric acid in the manner described in Example 3. Analogously to the procedure of Example 3, the benzene is worked up and recrystallized to give 5.8 g of red plate crystals with m.p. 163-165 ° C (dec.).

Analysis for C- HH ^CIN₂O:

Cfo Ufo Ufo

Calculated 59.9 4.1 12.7

Found 60.2 3.9 12.8 25 1501 A3

Example 16 8-Chloro-2,3,4,10-tetrahydro-10-phenylpyrimido [1 H] -indole-10-ol

Analogous to the procedure described in Example 6, 8-chloro-2,5 µl-tetrahydropyrimido [1,2-a] indol-10-one in 60 ml of tetrahydrofuran is added to a solution of 0.026 mol of phenylmagnesium bromide in 50 ml of ether. The mixture is heated under reflux and stirring for 5 hours and after standing overnight, the mixture is poured into a mixture of ice and ammonium chloride. The solid formed is filtered off and washed with water and ether to give 2.74 g of light brown powder with snip. 240-250 ° C (dec.).

Analysis for C ^H ^ClNgO: C fH fo NNf

Calculated 68.9 5.6 9.4

Found 67.6 5.3 8.9

The powder is suspended in warm absolute ethanol and treated with a solution of dry hydrogen chloride gas in dry ether to give 1.89 g of fine needles, m.p. 279-282 ° C (dec.).

Analysis for C- HH-jClNgO.HCl:

Cf Hf Nf

Calculated 60.9 4.8 8.1

Found 61.25 4.8 8.5

Example 17 8-Chloro-2,3,4,10-tetrahydro-10- (m-chlorophenyl) -pyrimido / 1,2-a-indol-10-ol Analogously to the procedure described in Example 6, 2.8 g of 8- chloro-2,5,4,10-tetrahydropyrimido / (1,2-a-indol-10-one in 60 ml of dry tetrahydrofuran to 0.03 mole of m-chlorophenylmagnesium bromide in 60 ml of ether. The reaction mixture is refluxed for 4 hours.

After standing overnight, the reaction mixture is poured into ice and ammonium chloride. The organic layer is isolated and the aqueous layer is extracted with methylene dichloride. The organic layer is extracted with 2N hydrochloric acid, the acidic layer is made basic, extracted with methylene dichloride, and after drying over magnesium sulfate, the solvent is removed and the residue is dissolved in absolute ethanol and treated with a solution of hydrogen chloride in dry ether. 1, 6l g of pink rhombs are obtained with m.p. 279 ° C (dec.).

Analysis for C ^ yHHClgNgO.HCl:

Cf Hf Nf

Calculated 55.2 4.1 7.6

Found 54.8 4.15 7.3 26.150143

Example 18 10- (m-Anlsyl) -2,5,4,10-tetrahydropyrmido [1,2-a] indol-10-ol

Analogous to the procedure described in Example 6, 3.72 g of 2,3,4i10-tetrahydropyrimido [1,2-a] indol-10-one in 50 ml of dry tetrahydrofuran is added to 0.04 mole of m-anisylmagnesium bromide in 50 ml of ether. Reflux and stir for 5 hours, then leave overnight and pour on ice and ammonium chloride. After acid-base extraction, 2.16 g of base are obtained with m.p. 255 ° C (dec.). The solid is converted to the hydrochloride by dissolving in ethanol and adding hydrogen chloride in dry kether to give 2.2 g of colorless rhombus with m.p. 260-262 ° C (dec.).

Analysis for C ^ gHH gNNO ^-HCl: <# E% N $

Calculated 65.5 5 * 8 8.5

Found 65.5 6.0 8.5

Example 19 2.5.4.10- Tetrahydro-10- (m-tolyl) pyrimido / 1,2-a-indol-10-ol Analogous to the procedure described in Example 6, 2.5.4.10-tetrahydropyrimido / 1,2-a / 7indole-10 is added. -one in 50 ml of tetrahydrofuran to 0.05 mole of m-1olylmagnesium bromide in 200 ml of ether. After the addition is complete, the mixture is heated under reflux for 5 hours. After standing overnight, the reaction mixture is poured into a mixture of ice and ammonium chloride. The organic layer is isolated and the aqueous layer is extracted with chloroform. After drying, chloroform is removed to give a red oil. Trituration with ether gives a white solid. The solid is recrystallized from a mixture of benzene and ether to give 1.36 g of pale yellow rhombus with m.p. 179-L80 ° C.

Analysis for C ^ gH ^ gNGO: Q.% Efo Efo

Calculated 77.7 6.5 10.1

Found 77.4 6.7 9.8

Example 20 2,5,4,10-Tetrahydro-10 (2-thienyl) pyrimido [1,2-a] indol-10-ol 3.72 g of 2,3,4,10-tetrahydropyrimido [1,2-a] indol-10-one in 150 ml of dry tetrahydrofuran is added to 0.05 mole of 2-thienylmagnesium bromide in the manner described in Example 19. After the addition is complete, the reaction mixture is stirred under reflux for 4 hours. The reaction mixture is poured onto ice and ammonium chloride and filtered to give 4.38 g of gray powder. The powder is suspended in absolute ethanol and treated with a solution of hydrogen ether in dry ether, the mixture is boiled and then treated with charcoal and filtered. By dilution with ether, 3 * 68 g of the intended compound is obtained in the form of colorless needles with m.p. 226-228 ° C (dec.).

Analysis for C ^^ HH - ^^ NNgOS.HCl: C% E% N $

Calculated 58 * 7 4.9 9 * 1

Tied 58.6 5 * 0 9 * 9

Example 21 10- (m-Fluorophenyl) -2,5,4 * 10-tetrahydropyrmido / 1,2-a-indindol-10-ol 5 * 72 g 3 * - dihydropyrimido / l * 2-a7indole-10 // 2 H7 in 100 ml dry tetrahydrofuran is added dropwise to a stirred solution of 0 * 05 mol of m-fluorophenylmagnesium bromide in dry ether. The reaction mixture is heated to reflux for 4 hours, cooled and decomposed by pouring on a mixture of ice and ammonium chloride. The organic layer is isolated and the aqueous layer is extracted with chloroform. The combined organic extracts are washed with water and dried over anhydrous magnesium sulfate.

After removal of the solvent, the residue is triturated with ether to give 5 * 5 g of light brown solid. The solid is suspended in boiling absolute ethanol, a solution of hydrogen chloride gas in dry ether * is added, and the resulting solution is treated with charcoal and filtered. After cooling the filtrate, the desired compound crystallizes in the form of the hydrochloride and gives 3 * 5 g of needle-shaped product with m.p. 280-290 ° C (dec.).

Analysis for C

Calculated 64.05 5 * 1 8.9

Found 64 * 0 5 * 1 8 * 9

Example 22 10- (1-Naphthyl) -2,3,4,10-tetrahydropyrimido [1,2-a] indol-10-ol

Analogous to the procedure described in Example 21, 2 * 86 g of 3 * 4-dihydropyrimido [1,2-a] indol-10 (2H) -one in 100 ml of dry tetrahydrofuran is added to 0.05 mole of 1-naphthylmagnesium bromide. After working up and removing the solvent, the base is obtained in the form of an oil which is converted into the hydrochloride in the usual manner. 5 * 8 g of product with m.p. 270-274 ° C (dec.).

Analysis for C2] H18 N2 O.HCl.1 / 4H2 O: C ^Η% N₂O

Calculated 71 * 25 5 * 5 7 * 9

Found 71 * 0 5 * 5 7 * 7 28 150143

Example 25 10- (o-Chlorophenyl) -2,3,4'10-tetrahydropyrimido [1,2-a] indol-10-ol

Analogous to the procedure described in Example 21, 2.8 g of 5,4-dihydropyrimido [1,2-indole-10/227-one] sulfur is added to a solution of 0.05 mole of o-chlorophenylmagnesium bromide in 100 ml of dry tetrahydrofuran.

After pouring the reaction mixture on ice and ammonium chloride solution, the solid formed is filtered off and washed with water and ether. The hydrochloride is prepared in the usual manner in colorless rhombus and 5.47 g of product are obtained, m.p. 287-290 ° C (dec.).

Analysis for C ^^ ClClNgO.HCl.llCgH ^OH:

Gfo W ° N #

Calculated 60.55 5.9 7.7

Found 60.1 5.8 7.7

Example 24 2,3,4,10-Tetrahydro-10- (m-trifluoromethylphenyl) pyrimido [1,2-a] indol-10-ol Analogous to the procedure described in Example 21 is added.

To a solution of 0.05 mole of m-trifluoromethylphenylmagnesium bromide. After pouring on ice and ammonium chloride solution, the precipitate is removed and the organic layer is worked up and evaporated An additional amount of base is obtained The base is converted to the hydrochloride in the usual manner to give 5.95 g of the desired compound in the form of the hydrochloride, mp 291-292 ° C

(Decomposition).

Analysis for C ^ gH ^F ^NgO.HCl: C% H

Calculated 58.6 4.4 7.6

Found 58.6 5.5 7.5

Example 25 10- (5,4-Diohlorophenyl) -2,5,4,10-tetrahydropyrimido [1,2-a] indol-10-ol

Analogous to the procedure described in Example 21, 2.7 g of 5,4-dihydropyrimido / 1,2-a / indol-10 / 2H7-one is reacted with 0.05 mole of 5β-dichlorophenylmagnesium bromide. After working up, the organic layer is isolated and the aqueous layer is extracted with chloroform. The combined organic extracts are treated with 2N hydrochloric acid and the precipitated hydrochloride is filtered off and dried. Recrystallization of a mixture of methanol and ether gives 5.4 g of colorless needles with m.p. 287-290 ° C (dec.).

Analysis for 0η "H, lClpW" 0.HCl: C for H for Wo

Calculated 55.2 4.1 7.6

Found 54.9 4.1 7.5 29

Example 26 10- (p-Fluorophenyl) -2,3,4,10-tetrahydropyrimido [1,2-a] indol-10-ol

Analogous to the procedure described in Example 21, 2.5 g of 3,4-dihydropyrimido / 1,2-a-indol-10 / 2H7-one is reacted with 0.05 mole of p-fluoro-phenylmagnesium bromide. The hydrochloride is prepared in the usual manner and 2.4 g of cream colored needles are obtained with m.p. 270-272 ° C.

Analysis for C-H H ENN₂O.HCl:

Qfo Efo

Calculated 64.0 5.1 8.8

Found 63.9 4.9 8.6

Example 27 2,3,4,10-Tetrahydro-10- (o-trifluorophenyl) pyrimido [1,2-a] indol-10-ol According to the procedure described in Example 21, 2.79 g of 3,4-dihydropyrimido (/ I, 2-aiindole-10 / 2g7-one with 0.05 mole of o-trifluoromethylphenylroagnesium bromide The hydrochloride is obtained in an amount of 3.72 g and in the form of fine needles, mp 255-257 ° C (decomposition).

Analysis for C- gHH FF- ^NgO.HCl.1 / GGgH ^ OH: C% Efo

Calculated 58.2 4.9 7.15

Found 58.4 4.9 7.3

Example 28 10- (2,5-Dichlorophenyl) -2,3,4,10-tetrahydropyrimido [1,2-a] indol-10-ol

Analogous to the procedure described in Example 21, 1.86 g of 3,4-dihydropyrimido ([1,2-a] indol-10 / 2H7-one is reacted with 0.025 moles of 2,3-dichlorophenylmagnesium bromide. After working up the base is obtained in the form of oil giving 1.95 g of the hydrochloride, mp 292-294 ° C (dec.).

Analysis for C - HH HClgNgO.HCl.HgO:

Cfo Hfo 0

Calculated 52.7 4.4 7.2

Found 52.7 4.1 7.5

Example 29 3,4-Dihydro-5,5-dimethylpyrimido / 1,2-a-indol-10 / 2H7-one 8.5. g of 3, 1, - dihydrospiro, 1,3-dioxolane-3,5,5-dimethylbyl-2,10, - (2H, 10H) pyrimido [1,2-a] indole is added portionwise to 100 ml of concentrated sulfuric acid, the temperature is kept below 30 ° C and the rate of addition is adjusted so that all the ketal is dissolved before the next batch is added. Stir overnight at room temperature and stirring, then pour the mixture on ice and neutralize with concentrated aqueous ammonia, keeping the temperature below 30 ° C 30 ° C. The red oil is extracted with methylene dihydrochloride, dried over anhydrous magnesium sulfate, evaporated to a red foam which gives 598 g red rhombs with m.p. 125-126 ° C after crystallization in a mixture of benzene and light petroleum (boiling range 40-60 ° C).

Analysis for C 15 H 14 N 2 O: C% H

Calculated 72.9 6.6 13.1

Pound 73.3 6.7 13.0

Example 30 10- (m-Chlorophenyl) -2,3,4,10-tetrahydro-3,3-dimethylpyrimido [1,2-a] indole -__-IQ-ol

Analogous to the procedure described in Example 21, 2.4 g of 3,4-dihydropyrimido-3,3-dimethyl / 1,2-a / indole-10 / SH7-one is added to a solution of 0.05 mole of m-chlorophenylmagnesium bromide. After working up, the base is filtered and converted to the hydrochloride in the usual manner to give 2.0 g of the desired hydrochloride with m.p. 271-273 ° C (dec.).

Analysis for C- HH ^CIN ^O · HCl:

Cfo Efo Efo

Calculated 62.8 5.55 7.7

Pound 62.8 5.5 7.6

Example 31; 2,3,4,10-Tetrahydro-10-phenyl-3,5-dimethylpyrimido / I.2-a7indol-10-ol

Analogous to the procedure described in Example 21, 3 g of 3,4-dihydro-3,3-dimethylpyrimido [1,2-a] indol-10 / 5g7-one is reacted with 0.05 mole of phenylmagnesium bromide. After working up, 2.4 g of the hydrochloride is obtained with m.p. 260-261 ° C (dec.).

Analysis for C ^ HHg ^ igOOCl:

Cfa Efo Efo

Calculated 69.4 6.4 8.5

Pound 69.0 6.75 8.3

Example 32 3,4-Dihydro-8-methoxypyrimido [1,2-a] indole-10 (2H) -one.

a) 5-Methoxy-2,3-dioxoindoline-1-propionitrile 20.28 g of 5-methoxyisatin and 5 ml of 4 O $ aqueous benzyltrimethylammonium hydroxide solution are heated to reflux in 500 ml of absolute ethanol and 19 ml of acrylonitrile are added dropwise. The mixture is heated at reflux for 30 minutes, cooled and the purple red crystals are filtered off to give 17.39 g of the desired compound. The product is recrystallized from aqueous dimethylformamide for characterization, m.p. 182-185 ° C.

Analysis for c12 H10 N2 ° 3: C% E% Wo

Calculated 62.5 4.4 12.2

Found 62.5 4.5 12.2 b) 2 * -Oxospiro / 1,2-dioxolane-2,5 * - / 5-methoxyindolin77-1'-propionitrile 12 ml Ethane-1,2-diol, 16.4 g of 5-Roethoxy-2,3-dioxoindoline-1-propionitrile, 500 ml of benzene and 0.5 g of toluene-p-sulfonic acid are heated together under reflux in an apparatus equipped with a water separator. After 12 hours, the theoretical amount of water is separated. The mixture is washed with water and then with sodium bicarbonate solution and the organic phase is dried over anhydrous magnesium sulfate. After removal of the solvent and recrystallization of propan-2-ol, 13.6 g of product are obtained with m.p. 110-111 ° C.

Analysis for

C% E% W

Calculated 61.2 5.1 10.2

Found 61.5 A 10 * 2 c) 3 ', 4, -Dihydrospiro / 1,3-dioxolane-2.10' (2H, 10H) -8, -methoxypyrimido-1,2-a-indole7 13 g of the product prepared under (b) is reduced o at an initial hydrogen pressure of 77.4 kg / cm and a temperature of 40 ° C in 400 ml of absolute ethanol, which is semi-saturated with ammonia, in the presence of 2.0 g of W7 Raney nickel in a period of 4 hours. The reaction's mixture is cooled, the catalyst is filtered off and the ethanol is removed under reduced pressure. The product is dissolved in toluene and heated under reflux with 10 drops of phosphorus oxychloride for 12 hours. The insoluble material is filtered off and the toluene is removed under reduced pressure to give an oil which spontaneously crystallizes. The oil is converted to the hydrochloride and recrystallized from propan-2-ol to give 5.65 g of product, decomposed at 300-360 ° C.

Analysis for C ^H ^ ^NNOO - HCl: C C E E% Wo

Calculated 56.65 5.8 9.4

Found 56.53 5.7 9.15 32 154343 d) 4.6 g of the product prepared above under (c) is added with stirring to 50 ml of concentrated sulfuric acid, keeping the temperature below 20 ° C. The mixture is stirred for 30 minutes and then poured on ice. After neutralization with ammonia, the purple product is extracted with chloroform, dried over magnesium sulfate and recrystallized after removal of the solvent from benzene to give 2.7 g of purple rhombus with m.p. 150-151 ° C.

Analysis for c12 H12 N2 ° 2:

Cfo Efo E%

Calculated 66.7 5 * 6 13.0

Pound 66.9 5 * 7 12.7

Example 33 10- (m-Chlorophenyl) -2,3,4,10-tetrahydropyrimido [1,2-a] indol-10-ol

Analogous to the procedure described in Example 21, 1.45 g of 3β-dihydro-8-methoxypyrimido / 1, 2-a-indole-10 (2H) -one and 0.025 mole of m-chlorophenylmagnesium bromide are reacted. On working up, 1.36 g of the hydrochloride is obtained with m.p. 282-283 ° C (dec.).

Analysis for C- HH ^ClNgOg. HC1: C # Hfo N #

Calculated 59.1 5.0 7.6

Pound 39 # 2 5A 7> 6

Example 34 2.3.4.10- Tetrahydro-8-methoxy-10-phenylpyrimido [1,2-a] indol-10-ol Analogous to the process described in Example 21, 1.45 g of 3,4-dihydro-8-methoxypyrimidine / I are reacted, 2-a-indole-10 (2H) -one with 0.025 mole of phenylmagnesium bromide. At work-up, 1.29 S of the hydrochloride are obtained with m.p. 285-288 ° C (dec.).

Analysis for C ^ gH- ^GNgOg.HCl: C fo.. Efo Ef>

Calculated 65.25 5.8 8.45

Pound 64.1 5 * 8 8.4

Example 35 2.3.4.10- Tetrahydro-8-nitropyrimido / 1,2-a-indole-10 (2H) -one 6.92 g of finely powdered 3 ', 4'-dihydrospiro / 1,3-dioxolane-2.10' - (2H 10 H) -pyrimido (1,2-a) indole is added to 30 ml of concentrated sulfuric acid. When the addition is complete, the mixture is stirred at room temperature for 2 hours, cooled to -10 ° C and 2 ml of nitric acid are added dropwise. The reaction mixture is allowed to reach room temperature, then stirred for 30 minutes. The mixture is poured onto ice and neutralized with concentrated ammonia water at a temperature below 3 ° Ο0. The precipitate is filtered off and extracted with hot benzene. The yellow residue weighs 5.95 S and decomposes without melting between 300 and 360 ° C.

Analysis for C ^ HH ^N OO-: C CF E? 0

Calculated 57.1 5.9 18.2

Pound 57.2 4.05 18.3

Example 36 10- (o-Fluorophenyl) -2,3,4,10-tetrahydropyrimido [1,2-a] indol-10-ol 1.86 g of 3 * 4-dihydropyrimido [1,2-a] indole-10 (2H) -one in 80 ml of dry tetrahydrofuran is added to a solution of 0.02 mole of o-fluorophenyl lithium in 50 ml of ether at -60 ° C. After the addition is complete, the colorless reaction mixture is stirred at -60 ° C for 2 hours, then bubbled on ice and ammonium chloride solution. When the mixture has reached room temperature, the base is filtered off. The hydrochloride is prepared in the usual manner to give 2.8 g of product with m.p. 269-270 ° C (dec.)

Analysis for C ^H- ^FNgO.HCl: 0% Efo0

Calculated 64.05 5.1 8.6

Found 63.6 5 * 0 8.6

Example 37 2,3,4,10-Tetrahydro-10- (2,6-dimethylphenyl) pyrimido [1,2-a] indol-10-ol 1.86 g of 3,4-dihydropyrimido [1,2-a] indole-10 (2H) -one in tetrahydrofuran is added to 0.02 moles of 2,6-dimethylphenylmagnesium bromide prepared by the so-called admixture method. The reaction mixture is worked up as described in Example 1 and 1.35 g of the hydrochloride is obtained in the form of colorless needles, m.p. 274-27β ° 0 (decomposition).

Analysis for C ^^ HHgQNgO.HCl: C fo HH foO 00

Calculated 69.0 6.4 8.5

Found 69.5 6.55 8 * 4

Example 38 10-Ethynyl-2,3 * 4,10-tetrahydropyrimido / 1,2-a-indol-10-ol 7.4 g of 3 * 4-dihydropyrimido / 1,2-a-indindol-10- (2H) -one in tetrahydrofuran react with 0.15 moles of ethynylmagnesium bromide by analogy to the procedure described in Example 21. When working up, 5 * 8 g of the base are obtained with m.p. 224-226 ° C (dec.). The hydrochloride has m.p. 210-215 ° C (dec.).

150143 34

Analysis for C ^inninnNpOfHCl; 0 0 0

Calculated 62.8 5 * 3 11 * 3

Found 62.5 λ H * 0

Example 39 2,5, 4,10-Tetrahydro-10- (m-chlorophenyl) pyrimido [1,2-a] indol-10-ol-acetate 3 g 2,3,4,10-tetrahydro-10- (m-chlorophenyl) ) pyrimidoi / l, 2-É £ 7indol - ΙΟ-ol is dissolved in 100 ml of acetic anhydride and left at room temperature for 48 hours. The acetic anhydride is removed under reduced pressure and the residue is re-evaporated with 50 ml of toluene. The residue is dissolved in as little ethanol as possible and treated with a solution of hydrogen chloride in dry ether. 5.24 g of the hydrochloride is obtained in the form of colorless rhombus with m.p. 213-216 ° C (dec.).

Analysis for σΐ9% γΝ2 ^ 2 * 5 Øo Øo Øo

Calculated 60.5 4.8 7.4

Found 60.4 4.8 7.3

Example 40 (+) - 2,5,4,10-Tetrahydro-10- (m-chlorophenyl) pyrimido [1,2-a] indol-10-ol 6.6 g 2,3,4,10-tetrahydro-10 (m-chlorophenyl) pyrimido / 1,2-a-indole-10-ol is dissolved in warm absolute ethanol and 3 * 3 g of L (+) (natural) tartaric acid is added. The mixture is heated to complete dissolution.

Crystallization gives 2.23 g of the L (+) tartrate salt. By recrystallization three times and evaporation of the mother liquor, a total of 2.1 g of product is obtained with Zs7 | 4 + 70.9 ° (c = 1 in methanol), m.p. 18 ° C (dec.).

Analysis for C ^H ^ClNNO. (CHOH.C00H) 2: C fo Ø N $

Calculated 56.2 4.7 6.2

Found 55 * 7 5 * 0 6.2

Example 4L (-) - 2,5,4,10-Tetrahydro-10- (m-chlorophenyl) pyrimido [1,2-a] indol-10-ol

The mother liquor of Example 40 containing the (-) isomer is evaporated to dryness and converted to 3 * 84 g of the base. The base is dissolved in hot ethanol and treated with D (-) (non-natural) tartaric acid. After working up as in Example 40, 2.0 g of the levobase is obtained as the D (-) tartrate salt. 177 -71 ° 4 ° (c = 1 in methanol), m.p. 18 ° C (dec.).

150143 35

Example 42 2,3,4,10-Tetrahydro-1Q- (2-pyridyl) pyrimido [1,2-a] indol-10-ol 4.0 g of 3,4-dihydropyrimido [1,2-a] indole-10 - (2H) -one in 10 ml of dry tetrahydrofuran is added to a solution of 0.04 mol of 2-pyridyllithium at -40 ° C. The reaction mixture is allowed to reach room temperature over 2 hours, after which it is cleaved by the addition of ice and ammonium chloride. The organic layer is isolated and the aqueous layer is extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent is removed and 2.73 g of base is obtained in the form of a light brown powder. The hydrochloride is formed in the usual way and 3.0 g with m.p. 268-270 ° C.

Analysis for c16 H15 N3 ° * 2HCl1 / 4H2O: C% H% N $

Calculated 56.1 5.0 12.3

Found 56.0 5.2 12.4

Example 43 10- (m-Chlorophenyl) -2,3,4,10-tetrahydro-10-hydroxy-1-methylpyrimido-β-1,2-aindolinium iodide 2.94 g of 10- (m-chlorophenyl) -2,3 , 4,10-Tetrahydropyrimido / 1,2-a-7in-dol-10-ol is dissolved in 50 ml of hot propanol and 2 ml of methyl iodide is added. Reflux for 30 minutes. After cooling, the indolinium iodide is separated and 4.03 g of product are obtained which decompose without melting at 250-254 ° C.

Analysis for C ^ HH g gClNgO: C% N $

Calculated 49.1 4.1 6.35

Found 49.3 4.3 6.6

EXAMPLE 44 '10- (m-Chlorophenyl) -1,2,3,4'10 O10-hexahydro-1-methylpyrimido [1,2-a] in-dole-10-ol 2.5 g of the above in Example 43 prepared quaternary salt is added portionwise to a stirred suspension of 1.8 g of lithium aluminum hydride in 100 ml of dry tetrahydrofuran. The reaction mixture is stirred at reflux for 5 hours, cooled and decomposed by the addition of 5 ml of water. The precipitated organic material is filtered off, the filtrate is dried over anhydrous magnesium sulfate and evaporated to give an oil which crystallizes from a mixture of benzene and light petroleum (boiling range 60-80 ° C) to give 9 µm of product with m.p. 135-137 ° C.

36 15QU3

Analysis for C ^ HH₂ Cl ClNgO: 0 0 0

Calculated 68.7 6.1 7 * 8

Pound 68.2 6.8 7 * 8

Example 45 1,2,3,4,10,1Oa-Hexahydro-10-phenylpyrimido [2,2-a] indol-10-ol 1.9 g 1,2,3,4-tetrahydro-10-phenylpyrimidoZI, 2- α / indol-10-ol is added in the form of a slurry in dry tetrahydrofuran to a suspension of 0.6 g of lithium aluminum hydride in 20 ml of dry tetrahydrofuran. The reaction mixture is stirred under reflux for 3 hours, cooled and digested with water. After separating the organic material and removing the solvent, a yellow oil is obtained which solidifies by trituration with ether to give 1.0 g of product with m.p. L47 ° C.

Analysis for 017ΗηοΝρ0: C% H% Øo

Calculated 76.7 6.8 10.5

Pound 76.25 7.0 10.4

The fumarate is prepared from 2-propanol, m.p. 157 ° ·

Analysis for Z 2 H 7 N 2 O 2 72, C 4 H 4 ° 4: C

Calculated 70.35 6.2 8.6

Found 70.3 6.2 8.4

Example 46 1,2,3,4,10,10a-HexahydrospiroZl, 3-dioxolane-2,10'Z3 *, 3-dimethyl-7-pyrimido [1,2-a7indole] 17 g of 2'-oxospiroZl, 3-dioxolane -2.31-indoline / -1 '- / 2,2-dimethyl-

ISLAND

propionitrile7 is reduced at an initial pressure of 105.5 kg / cm and at 100 ° C for 5 hours in 200 ml of ethanol semi-saturated with ammonia in the presence of 8 g of Raneynickel W7 · The catalyst is removed and the ethanol is removed under reduced pressure. The residual oil is crystallized by benzene to give .12.09 g of product, m.p. 93-96 ° C.

Analysis for C 15 H 20 N 2 ° 2:

Cfo 0 0

Calculated 69.2 7.7 10.8

Found 69.7 7.7 10.8

Example 47 3,4-Dihydropyrimido [1,2-a] indol-10 / 2H7-one A 10 -Bromophenyl (1,4,5,6-tetrahydro-2-pyrimidyl) ketone (a) A solution of 20 g of ao-bromophenyl - (1,4,5,6-tetrahydro-2-pyrimidyl) methanol in 1000 ml of Diehlormethane is stirred with 150 g of precipitated manganese dioxide at room temperature for 48 hours. After filtration, the manganese dioxide is stirred with 400 ml of fresh dichloromethane for an additional 1 hour, then filtered and the combined filtrate is dried over magnesium sulfate. Removal of the solvent under reduced pressure and crystallization of the residue from light petroleum (boiling range 60-80 ° C) yields 12.1 g of product in the form of colorless needles, m.p. 100-101 ° C.

Analysis for cnHiiBrN2®: C% H% N #

Calculated 49.45 4.15 10.5

Found 49.45 4.15 10.45 (b) A solution of 2.69 g, 0.01 mol, ao-bromophenyl- (1,4,5,6-tetrahydro-2-pyrimidyl) methanol and 5 35 g, 0.012 mole of lead tetraacetate in 40 ml of dry pyridine is stirred at room temperature for 60 hours. After removing the pyridine under reduced pressure, the residue is diluted with water and extracted with chloroform. The combined extracts are washed with water, dried over MgSO 4 and the solvent removed to give a brown residue. Crystallization of petroleum ether (bp 60-80 ° C), after treatment with charcoal, leads to the product.

B_5,4-dihydropyrimido / l, 2-a7indol-10 / 2H7-one

A mixture of 0.67 g, 0.0025 mol, o-bromophenyl (1,4,5,6-tetrahydro-2-pyrimidyl) ketone, 0.345 g, 0.0025 mol, potassium carbonate and 0.025 g of cuprioxide in 5 ml of dry dimethylformamide is stirred under nitrogen at 90 ° C for 2 hours. The mixture is diluted with 100 ml of benzene, filtered, the filtrate washed with 4 x 50 ml and dried over MgSO 4. Upon removal of the solvent and crystallization of the residue from benzeneyclohexane, after treatment with charcoal, 0.088 g of product in the form of orange needles with m.p. ll8-121 ° C.

Example 48 2,3-Dihydro-2,2 (or 5,3) -dimethylimidazo [1,2-a7-indole- / 9H7-9-one (a) A solution of 29.4 g, 0.1 mole, Ethyl o-bromandelimidate hydrochloride and 8.8 g, 0.1 mol, 1,2-diamino-2-methylpropane in 150 ml of absolute ethanol are heated under reflux for 5 hours. By removing the solvent and crystallizing the residue from a mixture of isopropanol and ether, 23.4 g of crude hydrochloride are obtained. An aqueous solution of the crude hydrochloride is made basic with NaOH while simultaneously scrubbing on the flask to give 16.2 g of crystalline α- (o-bromophenyl) -4,4 (or 5.5) -dimethyl-2-imidazoline methanol in the form of the free base with m.p. 128-130 ° C.

Optionally, the free base can be extracted with chloroform, the extracts dried over MgSO4 and the residue triturated with light petroleum (boiling range 60-80 ° C) after removal of the solvent.

150143 38

An analytical sample of the hydrochloride is prepared by acidifying a solution of the free base in isopropanol with ethereal hydrochloric acid, m.p. 213-217 ° C.

Analysis for c12 H15 N2 BrN2 ° * HCl: C% H% N $

Calculated 45.1 5.05 8.75

Pound 45.35 5.05 8.6 (b) A solution of 15.8 g of α- (o-bromophenyl) -4,4 (or 5.5) dimethyl-2-imidazoline methanol in 750 ml of dichloromethane is stirred. with 150 g of precipitated manganese dioxide at room temperature for 40 hours. The manganese dioxide is filtered off and stirred with an additional 400 ml of dichloromethane for 1 hour. After filtration, the combined filtrates are dried over MgSO 4, the solvent removed and the residue recrystallized from petroleum (boiling range 60-80 ° C) to give 11.01 g of o-bromophenyl-4.4 (or 5.5) -dimethyl-2 -, -imidazolinyl ketone, m.p. 107-108 ° C.

Analysis for C ^H- ^ BrNgO: C% H% N%

Calculated 51.25 4.65 9.95

Pound 51.25 4.85 10.05.

(c) A solution of 0.7 g, 0.0025 mol, o-bromophenyl-4.4 (or 5.5) -dimethyl-2-imidazolinyl ketone in 5 ml dry dimethylformamide is stirred with 0.545 g, 0.0025 mol , anhydrous potassium carbonate and 0.030 g of euprioxide under dry nitrogen at 125 ° C for 1 1/2 hours. The reaction mixture is diluted with 100 ml of benzene, filtered, the filtrate washed with 4 x 50 ml of water and dried over MgSO 4. Removal of the solvent under reduced pressure and crystallization of the residue from cyclohexane gives 0.244 g of the desired compound in the form of bright red needles, m.p. 136-138 ° C.

Analysis for C, pH, NpO: C% H% N $

Calculated 72.0 6.05 14.0

Found 71.7 6.1 13.9

The hydrochloride crystallizes as orange prisms from a mixture of ethanol and ethereal hydrochloric acid and decomposes at a temperature above ca. 230 ° C Analysis for Ο-, ρΗ-, ρΝρΟ.ΗΟΙ: Η% N%

Calculated 56.6 5.95 11.0

Found 56.8 6.2 10.95 39 .150143

Example 49 2,3-Dihydro-2,2 (or 3,3) -dimethylimidazo [1,2-a7-indole-9H7-9-one 0.59 g, 0.0025 mol of o-chlorophenyl-4.4 (or 5.5) -dimethyl-2-imidazolinyl ketone, prepared as described in Example 48 (a) and (b) for the corresponding o-bromophenyl compound, in 5 ml of dry dimethylformamide is stirred with 0.345 g, 0.0025 mol , anhydrous potassium carbonate and 0.030 g of cuprous chloride under dry nitrogen at 125 ° C for 3 hours. The reaction mixture is worked up as described in Example 48 (c) to give 0.255 g of product with m.p. 136-138 ° C.

Example 50 9- (m-Chlorophenyl) -2,3-dihydro-2,2 (or 3,3) -dimethylimidazo [1,2-a] nine-dol-9 / 57-9-01

To a stirred solution of m-chlorophenyllithium prepared from 9.6 g, 0.05 mole, m-bromochlorobenzene and 27 ml, 0.045 mole, of a 1.67 M solution of n-butyllithium in pentane, 25 ml of dry ether under nitrogen at 0 ° C are added 3.0 g, 0.015 mole, 2,3-dihydro-2,2 (or 3,3) -dimethylimidazo [1,2-a] indol-927-9-one 50 ml of dry tetrahydrofuran over 5 minutes. The dark green solution is stirred for 30 minutes at 0 ° C, poured into a mixture of ice and ammonium chloride solution and extracted with chloroform. The combined extracts are washed with water, dried over MgSO 4, the solvent removed and the residue triturated with petroleum (boiling range 60-80 ° C) to give 4.01 g of white crystalline product.

3.5 g of the crude base are dissolved in a small amount of ethanol, acidified with ethereal hydrochloric acid, diluted with a large volume of ether and the hydrochloride is allowed to crystallize, yield 3.72 g, decomposing at a temperature above ca. 205 ° C.

Analysis for C- HH- ^ClNgO.HCl: C% H for N $

Calculated 61.9 5.2 8.0

Pound 61.9 5.3 8.0

By reaction of p-chlorophenyl lithium and phenyl-lithium with 2,3-dihydro-2,2 (or 3,3) -dimethylimidazo [1,2-a] indole - Z927-9 -one, respectively, are prepared in an analogous manner to 9 "( p-chlorophenyl) -2,3-dihydro-2,2 (or 3,3) -dimethylimidazolo [2,2-a] indole-9 / H7-9-0I, which decomposes at a temperature above ca. 215 ° C and 2,3-dihydro-2,2 (or 3,3-dimethyl-9-phenylimidazo [1,2-a] indole-9β-S7 “9-ol) which decompose at a temperature above ca. 240 ° C.

40 1501A3

Example 51 2,5-Dihydroimidazo / 1,2-a7indole- / 9H7-9-one (a) A solution of 16.0 g of α- (o-bromophenyl) -2-imidazoline methanol in 160 ml of acetone is stirred for 2 hours with 100 g of precipitated manganese dioxide, previously deactivated by stirring with water. After filtration and washing of the manganese dioxide with acetone, the solution is evaporated to a small volume under reduced pressure, diluted with water and extracted with chloroform. The combined extracts are dried over the MgSO 4 solvent, and the residue is allowed to crystallize from a small volume of ether to give 11.5 g of crude o-bromophenyl-2-imidazolinyl ketone. A sample recrystallized from a mixture of benzene and petroleum (boiling range 60-80 ° C) has m.p. l49-151 ° C.

Analysis for C ]oH9N₂BrO: C $ H% N $

Calculated 4-7 * 5 5.6 11 * 1

Pound 47 * 9 5.7 11.1 (b) A solution of 0.65 g * 0.0025 mol * o-bromophenyl-2-imidazolinyl ketone in 5 ml dry dimethylformamide is stirred with 0 * 55 g * 0.0025 mole, potassium carbonate and 0.050 g of cuprioxide under dry nitrogen at 140 C for 1/2 hour. The mixture is diluted with 100 ml of benzene, filtered and the filtrate washed with 4 x 50 ml of water. Removal of the solvent and crystallization of the residue from cyclohexane yields 0.151 g of product in the form of red needles * which decompose at a temperature above ca. 100 C.

Analysis for C10HgN2O: G% Έ.% N%

Calculated 69.8 4 * 7 16.5

Found 70 * 2 4.7 16 * 45

Example 52 11- (m-Chlorophenyl) -2,4,5,11-tetrahydro-3H-1,3-diazepino [1,2-a] -indol-11-ol-ol (a) o-Bromophenyl-4,5 , 6,7-tetrahydro-lH-l, 3-diazepino - 2-methanol hydrochloride.

8.8 g of 1,4-diaminobutane in 10 ml of absolute ethanol are added dropwise to a stirred ice-cooled solution of 29.5 g of ethyl-o-bromandelimidate hydrochloride in 200 ml of absolute ethanol. After the addition is complete, the mixture is stirred for an additional 1 hour with cooling with an ice bath, and the mixture is heated under reflux for 20 hours. After cooling, the solution is concentrated under reduced pressure and ether is added to give 24.15 g of white crystalline product with m.p.

213-216 ° C (dec.). Recrystallization from a mixture of ethanol and ether gives an analytical sample with m.p. 213-216 ° C (dec.).

Analysis for C ^H ^Br ^O.HCl: C% H% N «

Calculated 45.1 5.05 8.75

Found 45.2 5.2 9.0.

(b) o-Bromophenyl-4,5,6,7-tetrahydro-1H-1,3-diazepino-2-yl-ketone.

A suspension of 6.0 g of o-bromophenyl-4,5,6,7-tetrahydro-1H-1,3-diazepino-2-methanol hydrochloride in 300 ml of dry benzene is stirred with 50 g of active manganese dioxide at room temperature for 60 minutes. hours. After filtration through diatomaceous earth, the solvent is removed and 2.227 g of residue are obtained with m.p. 57-60 ° C which crystallized from a light petroleum fraction at a boiling range of 60-80 ° C after treatment with charcoal. Recrystallization from the light petroleum fraction gives an analytical sample with m.p. 62-63 ° C.

Analysis for C12 H13 BrN2 O: C% H% N%

Calculated 51.25 4.65 9.95

Found 51.55 4.8 10.0 (c) 2,3,4,5-Tetrahydro-1,3-diazepino [1,2-a] indol-11-one A solution of 0.7 g of o-bromophenyl -4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl ketone in 5 ml of dry dimethylformamide is stirred with 0.35 g of potassium carbonate and 0.030 g of cuprioxide at 90 ° C for 2 hours under nitrogen . The mixture is diluted with 100 ml of benzene, filtered, washed with 3 x 50 ml of water and dried over magnesium sulfate. After removing the solvent under reduced pressure, the residue is extracted with ca. 150 ml of warm cyclohexane. From the extracts, a slow crystallization of 0.179 g of 2,3,4,5-tetrahydro-1,3-diazepino [1,2-a] indol-11-one is obtained in the form of reddish-brown needles, m.p. 137-139 ° C (dec.). An analytical sample is recrystallized from toluene, m.p. 140-141 ° C (dec.).

Analysis for C ^H - ^^O: C% H% N%

Calculated 72.0 6.05 14.0

Found 72.0 6.2 13.75.

(D) 2,4,5,11-Tetrahydro-11-phenyl-3H-1,3-diazepino- [1,2-a] indol-11-ol.

By reacting 2,3,4,5-tetrahydro-1,3-diazepino- [1,2-a] indol-11-one with phenylmagnesium bromide analogous to the procedure described in Example 6, the hydrochloride of the title compound is obtained. mp. 266-270 ° C (dec.).

Example 53

Spiro [1,3-dioxolane-2.31] -7-methylindolin-2-one

A mixture of 53.6 g of 7-methylisatin, 40 ml of ethylene glycol and 0.5 g of toluene-p-sulfonic acid is heated under reflux with stirring in 1.5 liters of chloroform in an apparatus fitted with a water separator. After 24 hours 7.5 ml of water (theoretical amount of 6 ml) have been collected. The reaction mixture is cooled, washed with water and dried over magnesium sulfate. The solvent is removed to give a light orange solid which is recrystallized from isopropanol to give 64.3 g of crystalline product, m.p. 184-185 ° C.

Analysis for C11 HHNO3: C% H% N%

Calculated 64.4 5.14 6.8

Found 64.7 5.4 6.9.

7'-Methyl-2'-oxospiro [1,3-dioxolan-2,3'-indoline] -11-propionitrile 60 g of spiro [1,3-dioxolan-2,3r] -7-methylindolin-2-one dissolve in boiling isopropanol, and to the refluxing solution which is kept stirring is added dropwise a 40% aqueous solution of 7.5 ml of Triton B "L® (tetramethylammonium hydroxide) and 3.5 ml of acrylonitrile. The reaction mixture is heated at reflux for 1 hour and then cooled. The crystalline product is filtered off and washed with isopropanol to give 37 g of product, m.p. 122-123 ° C.

Analysis for c14H24N2 ° 3i C% H% N%

Calculated 65.1 5.5 10.9

Found 65.1 5.5 10.9 31 4'-Dihydro-e-methylspiro [1,3-dioxolen-2.10 '(2Ή) pyrimido (1,2-a) indole] 10 g of 7'-methyl 2'-oxospiro [1,3-dioxolane-2,3'-indoline] -1 '- propionitrile is reduced by 105.5 atm in ethanol, which is half saturated with 150 ml of ammonia in the presence of Raney nickel (W7) for 4 hours at 100 ° C. After cooling, the catalyst is removed, the solvent is removed under reduced pressure and the product is recrystallized from ethyl acetate to give 5.2 g of m.p. 166-167 ° C.

150143 43

Analysis for ci4HigN2O2! C% H% N%

Calcd 68.8 6.6 11.5

Found 69.3 6.7 11.5.

2.3.4.10- Tetrahydro-6-methylpyrimido [1,2-a] indol-10-one 2 g 3,4,4-dihydro-6-methylspiro [1,3-dioxolane-2,10 '(2, H) -Pyrimido [1,2-a] indole] is slowly added to 15 ml of stirred concentrated sulfuric acid, keeping the temperature below 30 ° C on cooling.

After stirring for 1 hour, the reaction mixture is poured into ice and neutralized at a temperature below 30 ° C with concentrated ammonia water. By extraction with dichloromethane the ketone is obtained which is recrystallized from benzene to give a red solid with m.p. 142-144 ° C.

2.3.4.10- Tetrahydro-6-methylpyrimido [1,2-a] indol-10-ol 1.75 g crude 2,3,4,10-tetrahydro-6-methylpyrimido [1,2-a] indole-10 -one in 17 ml of dry tetrahydrofuran is added to a stirred solution of 0.022 mol of phenylmagnesium bromide in 35 ml of dry tetrahydrofuran. The reaction mixture is heated at reflux for 2 hours, then stirred overnight at room temperature. The complex is decomposed with ice and ammonium chloride and extracted with chloroform. After drying over magnesium sulfate, the solvent is removed to give a red oil which, upon trituration with ether, gives 1.86 g of pink solid. The solid is dissolved in ethanol and treated with a solution of hydrogen chloride in dry ether to give the desired compound in the form of the hydrochloride in an amount of 1.68 g, m.p. 258-259 ° C (dec.).

Analysis for C 18 H 18 N 2 ° HCl: C% H% N%

Calcd 68.7 6.1 8.9

Found 68.7 6.2 8.8.

Claims (2)

150-143 Patent Claims. An analogous process for the preparation of indole derivatives of the general formula R 2 n R 3 R 3 R 6 where R is hydroxyl, alkoxy of not more than 6 carbon atoms, phenyl-alkoxy of not more than 6 carbon atoms in the alkoxy group, tetrahydropyryloxy or acyloxy of not more than 6 carbon atoms, R3- means a phenyl or naphthyl group optionally substituted once or twice by halogen, alkyl of not more than 6 carbon atoms, alkoxy of not more than 6 carbon atoms or trifluoromethyl, or R3- means thienyl, pyridyl, phenalkyl of not more than 6 carbon atoms. the alkyl group, alkyl of not more than 6 carbon atoms, alkenyl of not more than 6 carbon atoms, alkynyl of not more than 6 carbon atoms or aminoalkyl of not more than 26 carbon atoms in the alkyl group, R and R are the same or different and each represents hydrogen, hydroxyl, alkyl of not more than 6 carbon atoms, alkoxy with not more than 6 carbon atoms, trifluoromethyl, halogen, amino or mono- or dialkylamino, wherein the alkyl group contains at most 6 carbon atoms, R and R are the same or different and each represents hydrogen or alkyl of not more than 6 carbon atoms, 34 or R represents hydrogen, and R. means hydroxy, n is 0, 1 or 2, the dashed line represents any bond at the indicated r position, and R present only when the optional bond represented by the dotted line does not exist means hydrogen or phenalkyl of not more than 6 carbon atoms in the alkyl group, alkyl of not more than 6 carbon atoms, alkenyl of not more than 6 carbon atoms, alkynyl of not more than 6 carbon atoms, aminoalkyl with not more than 6 carbon atoms in alkyl group or acyl with not more than 6 carbon atoms, or pharmaceutically acceptable acid addition salts or quaternary ammonium salts thereof, characterized in that a ketone of the general formula iSDoOfe - R3 0 150143 wherein R, R, R, R and n has the above meanings, reacted with a Grignard reagent of the formula R R MgY, where Y is halogen and R R1 has the meaning given above, or with an arylithium having the general formula R Li, wherein R is phenyl or naphthyl, optionally substituted with one or two of the substituents defined above under 1R, thienyl or pyridyl or with sodium or potassium acetylide, and optionally (a) alkylating or acylating the compound of formula Wherein R is a hydroxyl group and the dotted line is a bond and R, R, R, R, R and n have the meanings given above to form a corresponding compound wherein R is alkoxy, phenylalkoxy , tetrahydropyranyloxy or acyl-oxy, as defined in connection with formula (I), and optionally (b) converting the compound of general formula I wherein the dotted line represents a bond and R, R, R, R, 4,5 R, R and n have the meanings given above for a pharmaceutical acid addition salt or a quaternary ammonium salt thereof, and optionally (c) the compound of formula I wherein the dashed line represents a bond is reduced; and R, R, R, R, R, R and n have the meanings given above, or a quaternary ammonium salt thereof to form a compound of formula I wherein the bond represented by the dotted line is not present. , R, R, R, R, R and R and n have the above g meanings and R is hydrogen, and optionally (d) the compound of formula I formed is converted in which the bond represented by the dotted line is not supported. 1 2 3 4 5 de> R, R, R, R, R, R and n have the above meanings, and R is hydrogen, to a pharmaceutically acceptable acid addition salt or quaternary ammonium salt thereof, and optionally (e) ) alkylates or acylates a compound of formula I wherein the bond represented by the dotted line is not present, R is hydrogen and R, R, R, R, R, R and n have the meanings given above. , to form a corresponding g compound wherein R is phenalkyl, alkyl, alkene yl, alkynyl, aminoalkyl or acyl as defined in formula (I).