FR2619817A1 - NOVEL 3-SUBSTITUTED BETA CARBOLINES, PROCESS AND PREPARATION INTERMEDIATES, MEDICAMENT APPLICATION AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME - Google Patents

Abstract

The invention relates to novel 3-substituted beta-carbolines corresponding to the formula: (CF DRAWING IN BOPI) in which R represents a cycloalkyl group containing from 3 to 6 carbon atoms as well as their addition salts with acids, their preparation process their application as medicaments and the compositions containing them.

Description

I

  The present invention relates to novel beta-carboLins 3-

  substituted, the process of preparation and the application as a

  drugs of these new products.

  European patent applications published under Nu 31254, 545U7 and 128415 describe a number of beta-carbolines substituted by

  position 3 by various groups. None of these requests describes any

  carbolines substituted in the 3-position by a cycloalkylcarbonyl. It has just been found that these products have properties quite

  surprising at the level of benzodiazepine receptors.

  The present application thus relates to new beta-carbolines.

  substitutes corresponding to formula II

'N (1)

  In which R represents a cycloalkyl group containing from 3 to 6

  carbon atoms, as well as their addition salts with acids.

  In general formula I and in the following, cycloalkyl group containing from 3 to 6 carbon atoms is preferably understood to mean

  a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical.

  Among the addition salts with acids, mention may be made of those formed with mineral acids, such as hydrochloric, hydrobromic, sulfuric or phosphoric acids or with organic acids such as formic acid, acetic acid, propionic acid, benzoic acid and maleic acid, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulfonic such as methane or ethanesulphonic, arylsulphonic acids such as

  benzene or para-toluenesulfonic acids.

  Among the products of the invention, the products corresponding to formula I as defined above, in which

  R represents a cyclopropyl, cyclobutyl or cyclopentyl radical.

  Among the latter, the following products are particularly selected: - Cbeta-carbolin-3-yl) cyclopropylmethanone, - (beta-carbolin-3-yl) cyclobutylmethanone, - (beta-carbolin-3- yl) Cyclopentylmethanone and their addition salts

with acids.

  The invention also relates to a process for the preparation of beta

  3-substituted carbolines corresponding to formula I as defined

2 2 6 12619817

  above, in which R has the meaning already indicated characterized in that a product of formula

NNJW (IV)

  Wherein A represents a suitable protecting group such as a trimethylsilyl radical, with the organometallic derivative of the formula

M-R (V)

  wherein M represents an alkali metal atom such as lithium or a -Mg-lial group in which Hal represents a chlorine, bromine or iodine atom and R is defined previously to obtain a product of formula C

R CIII)

  and then releases the protecting group A to obtain a product of formula: O H

I

  in which R has the meaning already indicated, then oxidizes the product of formula II to obtain the product of formula I:

THIS)

  thus sought in which R has the meaning already indicated, that, if

desired one salifies.

  Under preferential conditions for carrying out the invent ion, the preparation process as defined above is characterized in that: a) the reaction of the product of formula IV with the organometallic of formula V is carried out in anhydrous conditions preferably in an organic solvent such as rahydrofuran head. b) The deprotection of the group A is carried out by means of a weakly acidic aqueous alkaline solution or by means of a source of fluoride ions such as tetrabutylammonium fluoride within the

and rahydrofuran.

  c) The oxidation of the compound of formula II is carried out with manganese dioxide, nitric acid, ferric chloride or chromium oxide, in the presence of pyridine, or by the method of Oppenauer or finally by

  dehydrogenation in the presence of a copper catalyst.

  According to a variant of the preparation process as defined above, the novel 3-substituted beta-carbolines corresponding to formula I as defined above, may be prepared by a process characterized in that the reaction is carried out a product of formula ## STR2 ## (VII) wherein B represents a suitable protecting group such as a para-toluenesulfonyl radical, Ra represents an alkyl group containing from 1 to 3 carbon atoms, Rb represents an alkyl group containing from 1 to 3 carbon atoms or an alkoxy radical containing of 1 to 3 carbon atoms, with the organometallic derivative of formula

M-R (V)

  in which M and R are defined as above to obtain a product of formula

NOT

R C (V I)

  in which U and R have the meaning already indicated, then releases the protective group E, to obtain the product of formula I

(.1)

  H thus sought, in which R has the meaning already indicated, that if

desired, we salify.

  Under preferred conditions of implementation of the invention, the method of preparation as defined above is characterized in that: a) the reaction of the product of formula VII with the organometallic of formula V is carried out under conditions anhydrous, preferably within

  an organic solvent such as tetrahydrofuran.

  b) The release of the protective group B is effected by means of

  an alkaline solution such as potassium hydroxide solution.

  The products of formula IV can be prepared by reaction of the product of formula C

N (V I I I

  with a suitable reagent capable of introducing the protective group A such as, for example, trimethylsilyl chloride. Advantageously carried out

  the reaction by mixing under an inert gas a solution of beta-carboline3-

  carboxaldehyde in hexamethylphosphoramide with sodium hydride

  then adding trimethylsilyl chloride.

  Beta-carboline-3-carboxaldehyde can be prepared especially horn

  reported in J.I'ed (1982) 25 (9) 1081.

  The products of formula VII may be prepared by reacting a product of formula: ## STR2 ##

H

  in which Alk represents an alkyl radical containing from 1 to 3 carbon atoms with a reagent capable of introducing a protective group B, to obtain a product of formula C _C CK I '

O N S K (XII)

  1U wherein B is defined as above, saponifies the product of formula XII thus obtained, to obtain a product of formula C 'li NS t _ "(XI) N in which B has the meaning already indicated, reacts the latter with carbonyl-diimiazole, to obtain a product of formula

C

  In which B has the meaning already indicated and then reacts the latter with a compound of formula X Ra H-i - (X) Rb in which Ra and Rb are defined as above, to obtain the

product of formula VII sought.

  The reagent capable of introducing a protective group into the product of formula XIII is, for example, para-toluenesulfonyl chloride,

  and the reaction is carried out in the presence of an amine such as 4-

  dimethylaminopyridine or triethylamine in an anhydrous organic solvent such as dichloromethane. The reaction of the product of formula XI with carbonyl diimidazole is carried out in an organic solvent such as

dimethylformamide.

6 2619817

  The compounds of formula XIII may be prepared as indicated in

J.rled.Chem. (1982) 25 (9) 1U81.

  The products of formula (I) have a basic character.

  The addition salts of the products of formula CI) can advantageously be prepared by reacting, in substantially stoichiometric proportions, an inorganic or organic acid with the said products of formula (I). Salts

  can be prepared without isolating the corresponding bases.

  The products which are the subject of the present invention possess very interesting pharmacological properties; they are endowed notably with remarkable affinities for the benzodiazepine receptors. Some products exhibit inverse agonist and antagonist properties of

  benzodiazepines, have, in addition, tranquilizing properties.

  These properties are illustrated further in the experimental section.

  These properties justify the use of the novel 3-substituted beta carbolines of formula (I) as well as their pharmaceutically acceptable salts.

  acceptable as drugs.

  The subject of the present invention is also the application as medicaments of the novel 3-substituted beta carbolines as defined by the general formula (I) as well as their addition salts with

  2U pharmaceutically acceptable acids.

  Among the medicinal products which are the subject of the invention, the medicaments characterized in that they consist of the novel 3-substituted beta carbolines corresponding to formula I in which R represents a cyclopropyl, cyclobutyl or cyclopentyl radical, as well as their salts

  addition with pharmaceutically acceptable acids.

  Among the preferred medicaments of the invention, all the following are particularly: - (beta-carbolin-3-yl) cyclopropylmethanone, - (beta-acarbolin-3-yl) cyclobutylmethanone, - (beta-carbolin-3- yl) cyclopentylmethanone and their addition salts

  with pharmaceutically acceptable acids.

  These drugs find, for example, their use in the treatment of memory disorders, particularly in geriatrics, disorders of cerebral senescence. Some products can also be used in the treatment of obesity as well as as a minor tranquilizer in the

  treatment of certain agents or irritants.

  The usual dose that varies according to the product used, the subject treated and the affection in question may be, for example, from 0.1 mg to 20 mg per day, per

oral route in adults.

  Advantageously, the compositions may be formulated in unit dose form, each unit being designed to deliver a given dose of active substance. Unit doses suitable for administration to adults contain from 0.1 to 100 mg, preferably from 0.1 to 20 mg, of

active substance.

  The subject of the invention is also the pharmaceutical compositions which contain at least one abovementioned derivative or one of its addition salts with the

  pharmaceutically acceptable acids as the active ingredient.

  As medicaments, the derivatives corresponding to formula (I) and their addition salts with pharmaceutically acceptable acids may be incorporated into pharmaceutical compositions intended for the route.

digestive or parenteral.

  These pharmaceutical compositions can be, for example, solid or liquid and be in the pharmaceutical forms commonly used in human medicine, such as, for example, tablets, single or coated tablets, capsules, granules, suppositories, preparations injectable; they are prepared according to the usual methods. The active ingredient (s) may be incorporated therein in excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or the like. no, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents,

  dispersants or emulsifiers, preservatives.

  The invention finally has as its object, as new products and in particular intermediates necessary for the preparation of the products of formula (I): - The products of formula II: OH 0

'(II)

I-

  in which R has the meaning already indicated.

  The products of formula VII: O (VII)

B

  in which B, Rb have the meaning already indicated, - The products of formula (VI): (VI) B

  in which B and R have the meaning already indicated.

  The following examples illustrate the invention without limiting it.

  Exemplary 1: (beta-carbotin-3-yl) cyclopropyl-mithanone.

  Stage A: (beta-carbolin-3-yl) cyclopropylmethanol.

  15 g of betacarboline-3-carboxaldehyde in 10 cm 3 of hexamethylphospharamide are stirred at 20 ° C. for 15 minutes under nitrogen flow with 0.31 g of sodium hydride (as a dispersion at 80% in oil). ). 2.5 cm 3 of trimethylsilyl chloride are added and the mixture is stirred for 10 minutes at 20 mC. A solution of cyclopropylmagnesium bromide prepared with 1.6 g of magnesium, 7.2 g of cyclopropyl bromide in 15 cm3 of t-rahydrofuran is added slowly while cooling. It is stirred for 18 hours at room temperature and then decomposed by addition of a saturated solution of ammonium chloride. We filter the principal; dissolved in dry chloroform over magnesium sulphate and evaporated to dryness in vacuo, 1.58 g

  expected product F = 205n-207uC (recrystallized from ethanol).

  IR spectrum (Kbr): 3420, 3150, 1632, 1501, 1469, 1337, 1251 cm -1 R11 N: (CDCl3 / CD3O) S 8.71 (s); 8.12 (d); 8.07 (s); 7.50 (m, 2H); 7.28 (m);

  4.23 (d, CH-O); 1.30 (m, 1H, cyclopropyl); 0.60 (m, 4H, cyctopropyl).

  Stage B: (beta-carboline-3-yl) cyclopropylmethanol.

  Refluxed for 3 hours, 1.47 g of (beta-carbotin-3-yl) cyclopropylmethanol dissolved in 500 cm3 of chloroform and with 5.5 g of manganese dioxide. After filtering hot and then evaporating under reduced pressure, 1.3 g of the expected product, F = 225 nm-227 ° C., are obtained.

the hate.

Analysis for C15H12N2O.

  % calculated c = 76.25 H = 5.12 N = 11.86 X found c = 76.28 H = 5.17 N = 11.76 IR spectrum (KBr): 3240, 1660, 1591, 1386, 1248 cm -1 NMR: (CD30D) δ 8. 91 (s); 8.80 (s); 8.24 (d); 7.51 (m, 21H); 7.31 (m);

  3.58 (m, COCH); 1.15 (m, 4H, cyclopropyt).

  Example 2: (α-carbolin-3-yl) cyclohexylmethylate.

  Step A: methyl 9- (p-toluenesulphonyl) -beta-carboline-3-carboxylate.

  12.5 g of methyl beta-carboline-3-carboxylate in solution in 70 cm 3 of methylene chloride, 19.3 cm 3 of triethylamine and 2.02 g of dimethyl amino pyridine are refluxed for 2 hours 30 minutes. The solution is cooled. then washed with dilute hydrochloric acid, then with water and evaporated under reduced pressure. The residue is chromatographed on silica eluting with chloroform. 18.4 g of expected product are obtained, isolated from the ether.

F1 76m-179nC.

  IR (KBr): 1720, 1383, 1294, 1176, 980 cm -1 RIN: (CDCl3) δ 9.74 (d); 8.71 (d); 8.39 (d.d); 8.06 (d.d); 7.76 (d, 2H, tosyl); 7.69 (m); 7.48 (m); 7.15 (d, 2H, tosyl);

  4.06 (s, 3H, omre); 2.27 (s, 3H, tosylMe).

  Stage B: 9- (p-toluenesulphonyl-beta-carboline-3-carboxylic acid.

  To a solution of 18.4 g of product obtained in Stage A in 750 cm3 of acetone was added 203 cm3 of a 0.25 M sodium hydroxide solution and stirred for 2 hours at room temperature. Then acidified to pH = 3 with dilute hydrochloric acid, or washed with water and dried under pressure

  reduced, 17 g of expected product is obtained F = 228m-232nC.

  IR spectrum (KBr): 32UU-2400 (br), 1770-1680 (br), 1450, 1380, 1257, 1175 cm1

  Stage C: N, N-dimethyl-9- (p-toluenesulphonyl) -beta-carboline-3-carboxamide.

  To a solution of 17 g of product obtained in Stage B in 400 cm3 of dimethylformamide is added 15 g of carbonyl diimidazole. It is stirred for 2 hours at room temperature and then saturated for 5 minutes with dimethylamine gas and stirred for another hour. The solution is diluted with acetate

  of ethyl, washed with water, dried, filtered and evaporated to dryness under reduced pressure.

  The residue is crystallized with ether containing a little ethyl acetate,

  16.1 g of expected product are obtained F = 184m-185uC.

  IR spectrum (KBr): 1640, 1443, 1388, 1178, 980 cm -1 RrN: (CDCl3) δ 9.58 (d); 8.38 (d.d); 8.25 (d); 8.00 (d.d); 7.73 (d, 2H);

  7.68 (m); 7.46 (m); 7.15 (d, 2H); 3.18 (s, 6H, NMe2); 2.28 (s, 3H).

  Stage D: cyclohexyl (9- (p-toluenesulphonyl) beta-carbolin-3-yl) methanone.

  To a stirred solution of 2 g of the product obtained in Stage C in 150 ml of tetrahydrofuran at OnC is added over 30 minutes 47 cm 3 of a 0.44 M solution in THF of cyclohexyl magnesium bromide. It is stirred at OnC for 1 hour. It is poured into a dilute solution of ammonium chloride and extracted with ethyl acetate. The residue is evaporated under reduced pressure and the residue is chromatographed on silica with methylene chloride. We

  crystallized from ether and 1.6 g of expected product is obtained F = 181U184aC.

  IR spectrum (KBr): 2930, 1688, 1448, 1380, 1175, 979 cm -1.

  1H NMR: (CDCL3) S9.67 (d); 8.61 (d); 8.37 (d.d); 8.05 (d.d); 7.79 (d, 2H); 7. 68 (m); 7.46 (m); 7.17 (d, 2H); 4.O (J (br.m, 1H, COCH);

  2.30 (s, 3H); 1.15-2.U5 (br.m, 1UH, cyclohexyl).

  Stage E: (beta-carbolin-3-yl) cyclohexylmethanone.

  To a suspension of 1.6 g of the product obtained in Stage D in 80 cm3 of methanol, 623 mg of potassium hydroxide are added and the mixture is heated at 60 ° C. for 1 hour 30 minutes. Cool, drain, wash with ether and dry. 9110 mg is obtained

expected product F = 227m-230nC.

Analysis for C18H18N2O.

  1U X calculated C = 77.67 H = 6.52 N 10.06% t ruvous C = 77.58 H = 6.61 N = 10.02 IR spectrum (KBr): 3250, 2930, 1660, 1625, 1590 1200 cm -1 RMiN: (D <SO-d6) S 9.01 (d); 8.83 (d); 8.40 (d.d); 7.63 (m, 2H); 7.32 (m);

  4.02 (br.m); 1.2-1.9 (br.m, 10H, cyclohexyl).

Alternative preparation:

  Cyclohexyl / 9- (p-toluene sulfonyl) -beta carboline was prepared

  3-yl / methanone from methyl N-methyl 9- (p-toluene sulfonyl) -beta

  carbolin-3-carbohydroxamate by a process similar to that described in stage D.

  Preparation of N-methyl 9- (p-toluene sulfonyl) -beta-carboline-3-

  Carbohydroxamate: From the acid, in a manner similar to the process described in

  stage C using 2 equivalents of N-methyl-O-hydrochloride

  methylhydroxylamine instead of dimethylamine. the product is purified by chromatography on silica eluting chloroform and crystallized from ether. We

  obtains 7U8 mg of expected product F = 148m-15UmC.

  IR spectrum (KBr): 1641, 1618, 1148, 1375, 1175, 980 cm-1 RN: (CDCl3) δ9.22 (d); 8.38 (d); 8.30 (d); 8.02 (d); 7.75 (d, 2H); 7.68 (m); 7.4o (m); 7.16 (d, 2H); 3.84 (s, 3H, OMe); 3.50 (s, 3H, NMFe);

2.30 (s, 311, osylryl).

Analysis for C14H13N302.

  % calculated C = 65.87 H = 5.13 N = 16.46% found C = 65.79 H = 5.23 N = 16.34

  Exempt 3-: (beta-carbotin-3-yl) cyclobutylthanone.

  By operating as described in Steps D and E of Example 2 but using cyclobutyl magnesium bromide, the product is obtained.

expected F = 218m-2200C.

Analysis for C16H14N20-

  % calculated C = 76.78 H = 5.64 N = 11.19% found C = 76.73 H = 5.81 N = 11.09

2 6 1 9 8 1 7

  IR spectrum (KBr): 3270, 1665, 1625, 1590, 1375, 1255 cm -1 RM4: (DMSO-d6) δ 8.96 (d); G.55 (d); 8.41 (m); 7.68 (m); 7.61 (m);

  7.32 (m); 4.58 (m); 2.28 (m, 2H); 2.07 (m); 1.84 (br.m, 6H).

  Example 4: (b-ta-carbolin-3-yl) cyclopentylmethanone

  By operating as in stages D and E of Example 2 but using

  cyclopentyl magnesium bromide, the expected product is obtained F = 219U220mC.

Analysis for C17H16N2O.

  X calculated C = 77.25 H = 6.10 N = 10.6% t rived C = 77.02 H = 6.20 N = 10.51 1U IR spectrum (KBr): 3270, 1663, 1625, 1590, 1374, 1251 cm -1 NMR: (DMSO-d 6) S 9.00 (d); 8.86 (d); 8.41 (m); 7.68 (m); 7.62 (m);

  7.33 (m); 4.39 (br.m); 1.94 (br.m, 2H); 1.75 (br.m, 6H).

Example 5

  Tablets having the following formula - Compound of Example 1 ................................. 20 mg - Excipient qs a tablet finished at .................... 150 mg

  (Details of the excipient: lactose, starch, talc and magnesium stearate).

Example 6

  Tablets having the following formula 2U - Compound of Example 3 ................................ 20 mg - Excipient qs a tablet finished at .................... 150 mg

  (Details of the excipient: lactose, starch, talc and magnesium stearate).

PHAMCOLOGICAL ACTIVITY

  The products of formula CI) is an interaction on the benzodiazepine receptors of the brain and some of them can be used as light tranquilizers, as well as for the treatment of obesity or

disturbances of knowledge.

  3U Screening for benzodiazepine receptor binding (FRB) was performed by the method described in UKIC Patent Application No. 2,128,989 A. The values given in Table I are expressed in terms of

/ (IC 50) in nanomoles /.

  The affinity of the compounds for the benzodiazepine receptors was evaluated using a radioligand / 3H! flunitrazepam and the method of

  Squires and Braestrup (Nature, 1977, 266, 732) modified.

  The values shown in Table II below are the nanomolar concentrations of the test product which inhibit in a proportion of 50 X the specific binding of 0.6 nanomoles of / 3H / flunitrazepam in rat brain membrane preparations. IC50)

12 2619817

in nanomoles /.

TABLE I

III Composed of I FRB III example

I 1 "0.7

2 1O0O

3 4.0

4 7.9

I I I

  The inverse agonist properties of the benzodiazepines are indicated by the following tests: a) The ability of the compounds to induce contractions in the Hyoidat muscle of rats was studied according to the method of V.W. James and R.C. Gardner

  (EUR J. Pharmacol (1985), 113, 233).

TABLE II

I I I

  Hy-Contraction Conmposed Example | in mg / kg

I, 1 I

  I 1 1-10 i.p. ++ I I 1 i.v. +++ 3 | I.v. (ant) + I 4 I 20 i.p. (Ant)

I I _ _ _ _ _ _ _ I

  (ant) means that the product is antagonistic.

  b) Potentiation of convulsions induced by subcutaneous injection of

Leptazol to CD1 mice.

  A dose of Leptazol was chosen which produced 10-20 X convulsions in 4U untreated CD1l mice. The active products increase the percentage of convulsions and the ED50 is calculated by Lichfield's method and

  Wilcoxon (J. Pharmacol Exp Ther (1949) 96, 99).

  - Compound of Example 1: DE50 T 0.45 mg / kg IP

(30 minutes before the test).

2: DE50> 100 mg / kg i.p.

3: DE50> 100 mg / kg i.p.

4: DE50> 100 mg / kg i.p.

Claims (10)

  1) Novel 3-substituted beta-carbolines corresponding to the formula: 0   (I) II in which R represents a cycloalkyl group containing from 3 to 6   carbon atoms, as well as their addition salts with acids.   2) Products according to formula I of claim 1, wherein R   represents a cyclopropyl, cyclobutyl and cyclopentyl radical.   3) - (beta-carbolin-3-yl) cyclopropylmethanone and its addition salts with acids.   4) - (beta-carbolin-3-yl) cyclobutylmethanone and its addition salts with acids.   ) - (beta-carbolin-3-yl) cyclopentylmethanone and its addition salts with acids.   6. A process for the preparation of the novel substituted B-Carbolines-3 corresponding to the formula I of claim I wherein R has the meaning already indicated characterized in that a product of the formula: t / cH (IV) is reacted A 3U wherein A represents a suitable protecting group such as a trimethylsilyl radical, with the organometallic derivative of formula M-R (V)   wherein M represents a metal alkali metal such as lithium or a group -.Ig-Hal in which Hal represents a chlorine, bromine or iodine atom and R is defined previously to obtain a product of formula: oe then releases the protective group A to obtain a product of formula: OFH I year, Hue (II) A R I   in which R has the meaning already indicated, then oxidizes the product of formula II to obtain the product of formula I: OI.t. 1-   thus sought in which R has the meaning already indicated, that, if desired one salifies.   7) Process according to claim 6, characterized in that: a) the reaction of the product of formula IV with the organometallic of formula V is carried out under anhydrous conditions preferably within   an organic solvent such as tetrahydrofuran.   b) The deprotection of the group A is carried out by means of an alkaline solution such as a weakly acidic aqueous solution or by means of a fluoride ion source such as tert-butylammonium fluoride at within tetrhydrofuran.   c) The oxidation of the compound of formula II is carried out with manganese dioxide, nitric acid, ferric chloride or chromium oxide, in the presence of pyridine, or by the method of Oppenauer or finally by   dehydrogenation in the presence of a copper catalyst.   8) Variant of the process for the preparation of new Betacarbolin derivatives   3-yl corresponding to the formula I of claim 1 wherein R has the meaning already indicated, characterized in that a product of formula: * 2619817 o R c (VII) IF E   B in which B represents a suitable protecting group such as a para-toluenesulfonyl radical, Ra represents an alkyl group containing from 1 to 3 carbon atoms, Rb represents an alkyl group containing from 1 to 1 carbon atoms or an alkoxy radical containing from 1b 3 carbon atoms, with the organometallic derivative of formula: M-R (V)   in which M and R are defined as above to obtain a product of formula: 1   in which B and R have the meaning already indicated, then releases the protective group B, to obtain the product of formula I: ## STR2 ## H   thus sought, in which R has the meaning already indicated, which one salify, if desired.   9) Process according to claim 8, characterized in that: a) the reaction of the product of formula VII with the organometallic of formula V is carried out under anhydrous conditions, preferably within   an organic solvent such as tetrahydrofuran.   b) The release of the protective group B is effected by means of   an alkaline solution such as potassium hydroxide solution.   ) Medicaments, characterized in that they consist of the new beta-carbolin-3-yl derivatives as defined by formula I of the claim 1.   11) Medicaments, characterized in that they are constituted by the new beta-Carbolin-3-yL derivatives as defined in any one of claims 2, 3, 4, or 5.   12) Pharmaceutical compositions, characterized in that they contain as active ingredient, at least one of the drugs, as defined, to   any one of claims 10 or 11.   13) As intermediates necessary for the preparation of the products of formula I as defined in claim 1, 1U - The products of formula II: o Ij 0I I   in which R has the meaning already indicated.   - The products of formula VII: in which B, Rb have the meaning already indicated, - The products of formula VI N. N N (VI) B   in which Bet R ot the meaning dj indicates.   in which B and R have the meaning already indicated.