SI9300438A - Indole and indoline derivates, process for their preparation and use thereof in the treatment - Google Patents

Abstract

Compounds of formula (I) or a salt thereof wherein: P represents a quinoline or isoquinoline residue, or a 5- or 6-membered aromatic heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur; R1 is hydrogen or C1-6 alkyl; R2, R3, R10 and R11 are independently hydrogen or C1-6 alkyl, or R10 and R11 together form a bond, or R2 and R10 or R3 and R11 together form a C2-6 alkylene chain; R4 is hydrogen, C1-6 alkyl, halogen, NR8R9 or OR12, where R8, R9 and R12 are independently hydrogen or C1-6 alkyl; R5 is hydrogen or C1-6 alkyl; R7 is hydrogen, C1-6 alkyl, OR12 or halogen, where R12 is hydrogen or C1-6 alkyl; n is 2 or 3; and the groups R13 and R14 are independently hydrogen or C1-6 alkyl, are 5HT2C/5HT2B receptor antagonists and are of potential use in the treatment of CNS disorders such as anxiety.

Description

(57) The following compounds are disclosed:

Sl 9300438 A

in which P is a quinoline or isoquinoline residue or

A 5- or 6-membered aromatic heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulfur; R ¹ is hydrogen or C 1-6 alkyl; R ² , R ³ , R ¹⁰ and R ¹¹ are independently hydrogen or C 1-6 alkyl, or form R ¹⁰ and R ¹¹ together or form a R ² and R ¹⁰ or R ³ and R ¹¹ together a C 2-6 alkylene chain; R ⁴ is hydrogen, C 1-6 alkyl, halogen, NR ⁸ R ⁹ or OR ¹² , wherein R ⁸ , R ⁹ and R ^{12 are} independently hydrogen or C 1-6 alkyl; R ⁵ is hydrogen or C 1-6 alkyl; R ⁷ is hydrogen, C 1-6 alkyl, OR ¹² or halogen, where R ^{12 is} hydrogen or C 1-6 alkyl; and n is 2 or 3; and R ¹³ and R ^{14 are} independently hydrogen or C 1-6 alkyl, processes for their preparation and use as medicaments.

SMITHKLINE BEECHAM pic

NEW COMPOUNDS

The present invention relates to compounds having pharmacological activity, to a process for their preparation, to preparations containing them, and to their use in the treatment of mammals.

P. Fludzinski et. al., J. Med. Chem. 1986 29 2415-1418 describes N- (1,2-dimethyl-3-ethylH-indol-5-yl) -N '- (3-trifluoromethylphenyl) urea showing selectivity for the rat serotonin receptor of the rat.

WO 92/05170 describes certain urea derivatives that have been described to have 5HT _1C receptor antagonist activity. The 5HT _1C receptor was recently re-classified as the 5HT _2C receptor [P. Hartig et al., Trends in Pharmacological Sciences (TIPS) 1993],

But now we have discovered a structurally distinct class of compounds that have been found to have 5HT _2C receptor antagonist activity. Certain compounds of the invention also exhibit the activity of the 5HT _2B receptor antagonist, the 5HT _2B receptor being hitherto known as the fundus receptor [P. Hartig et al., Trends in Pharmacological Sciences (TIPS) 1993]. The 5HT _2C / 5HT _2B receptor antagonists are thought to be potentially useful in the treatment of CNS disorders such as anxiety, depression, obsessive compulsive disorder, migraine, anorexia, Alzheimer's disease, sleep disorders, bulimia, panic attacks, abuse disorders drugs such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia and also disorders related to spinal injuries and / or head injuries such as hydrocephalus.

Accordingly, in the first aspect, the present invention provides a compound of formula (I) or a salt thereof:

in which

P represents a quinoline or isoquinoline moiety or a 5- or 6-membered aromatic heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulfur; R ¹ is hydrogen or C 1-6 alkyl;

R ² , R ³ , R ¹⁰ and R ¹¹ are independently hydrogen or C 1-4 alkyl, or form R ¹⁰ and R ¹¹ together or form a R ² and R ¹⁰ or R ³ and R ¹¹ together a C 2-6 alkylene chain;

R ⁴ is hydrogen, C 1-6 alkyl, halogen, NR ⁸ R ⁹ or OR ¹² , wherein R ⁸ , R ⁹ and R ^{12 are} independently hydrogen or C 1-6 alkyl;

R ⁵ is hydrogen or C ₁₄ -alkyl;

R ⁷ is hydrogen, C 1-6 alkyl, OR ¹² or halogen, where R ^{12 is} hydrogen or C 1-6 alkyl; and n is 2 or 3; and R ¹³ and R ^{14 are} independently hydrogen or C 1-6 alkyl.

The C 1-6 alkyl moieties may be unbranched or branched and are preferably C _1-3 alkyl, such as methyl, ethyl, n- and iso-propyl.

Suitable halogens R ⁴ and R ⁷ include chloro and bromo.

R ^{1 is} hydrogen or C 1-6 alkyl, such as methyl, ethyl or propyl. Preferably R ^{1 is} methyl or ethyl.

Suitably R ² , R ³ , R ¹⁰ and R ^{11 are} independently hydrogen or C 1-6 alkyl, or R ¹⁰ and R ¹¹ form a bond together, or R ² and R ¹⁰ or R ³ and R ¹¹ together form a C _2-6 alkylene chain. Preferably R ^{2 is} hydrogen or methyl. Preferably R ^{3 is} hydrogen.

In the indoline structure, R ¹⁰ and R ^{11 are} preferably hydrogen. Most preferably R ¹⁰ and R ^{11 form a} bond to form an indole structure.

Suitably, R ⁴ is hydrogen, C ^ -alkyl, halogen, NR ⁸ R ⁹ or OR ^12, wherein R ^8, R ⁹ and R ¹² are independently hydrogen or C _M alkyl. Preferably R ^{4 is} hydrogen or methyl.

R ^{5 is} hydrogen or C 1-6 alkyl. Preferably R ^{5 is} hydrogen.

Suitably R ^{7 is} hydrogen, C 1-6 alkyl, OR ¹² or halogen, where R ^{12 is} hydrogen or C 1-6 alkyl. The R ⁷ group may be attached to any unoccupied position in the phenyl portion of the indole or indoline ring, i.e., the position of the 4, 6 or 7 indole or indoline ring. Preferably R ^{7 is} hydrogen.

Suitably P represents a quinoline or isoquinoline moiety or a 5- or 6-membered aromatic heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulfur. If ring P is a 5-membered aromatic heterocyclic ring, suitable moieties include e.g. isothiazolyl, isoxazolyl, thiadiazolyl and triazolyl. If ring P is a 6-membered aromatic heterocyclic ring, suitable moieties include e.g. pyridyl, pyrimidyl or pyrazinyl. If P is a quinoline or isoquinoline moiety, the urea moiety may be bound in any position of the ring, preferably in position 4.

Preferably P is 4-quinoline or 3-pyridyl common.

The urea moiety may be attached to a carbon atom or any available nitrogen atom of ring P, preferably bonded to a carbon atom.

Suitably the group is - (CR ¹³ R ¹⁴ ) an n-ethylene or propylene group, each of which may be substituted by C 1-6 alkyl. The group - (CR ¹³ R ¹⁴ ) n- may be attached to the 4 or 6 position of the indole or indoline ring, preferably attached to the 6 position. Preferably, the group is - (CR ¹³ R ¹⁴ ) _n - ethylene.

Particularly preferred compounds of formula (I) include:

5-methyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole,

6-methyl-3- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole,

5,7-dimethyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole, 1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole,

6-methyl-3- (4-pyridylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole,

6-methyl-3- (2-pyridylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole,

5-methyl-1- (2-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole,

5-methyl-1- (4-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole,

5-methyl-1- (3-pyridylcarbamoyl) -2,3,6,7-tetrahydropyrrolo [2,3-f] indole,

5-ethyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole,

5- n-propyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole,

5.6-dimethyl 4- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole,

6.7-dimethyl-3- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole, 1-methyl-N- (3-pyridyl) -5,6,7,8-tetrahydro-1H- pyrrolo [2,3-g] quinoline-5-carboxamide,

3-methyl-N ~ (3-pyridyl) -6,7,8,9-tetrahydro4H-pyrrolo [2,3-f] quinoline-6-carboxamide,

6- methyl-3- (2-methyl-4-quinolinylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole,

6-methyl-3- (5-quinolinylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole,

6-methyl-3- (3-quinolinylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole,

5-methyl4- (2-methyl-4-quinolinylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole,

6.8-dimethyl-3- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole,

6-methyl-3- (3-pyridylcarbamoyl) -2,3,7,8-tetrahydropyrrolo [3,2-e] indole,

5-methyl-1- (2-pyrazinylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole,

2.3-dihydro-5-methyl-1- (3-methyl-5-isothiazolylcarbamoyl) -1H-pyrrolo [3,2-e] indole,

2.3-dihydro-5-methyl4- (3-methyl-5-isothiazolylcarbamoyl) 4H-pyrrolo [2,3-f] indole,

2,3-dihydro-5-methyl4- (5-quinolylcarbamoyl) 4H-pyrrolo [2,3-f] indole,

2,3-dihydro-5-methyl-1- (3-methyl-5-isoxazolylcarbamoyl) -1H-pyrrolo [2,3-f] indole, N- (5-isoquinolyl) -5-methyl-2,3-dihydropyrrolo [ 2,3-fluoro-indole-4-carboxamide, N- (6-quinolyl) -5-methyl-2,3-dihydropyrrolo [2,3-f] indole-1-carboxamide, or pharmaceutically acceptable salts thereof.

The compounds of formula (I) may form acid addition salts with acids such as conventional pharmaceutically acceptable acids, e.g. maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, milky, almond, tartaric or methanesulfonic.

The compounds of formula (I) may also form N-oxides or solvates as hydrates, and the invention also encompasses these forms. When referring to a compound of formula (I), it is meant that the expression includes those forms.

If R ¹ (in indole) and / or R ^{5 is} hydrogen or if R ^{4 is} hydroxy or NR ⁸ R ⁹ and at least one of R ⁸ and R ^{9 is} hydrogen, compounds of formula (I) may be tautomically in more than one form. The invention also encompasses these and any other tautomeric forms or mixtures thereof.

Certain compounds of formula (I) are capable of existing in stereoisomeric forms, including enantiomers, and the invention also covers each of these stereoisomeric forms and mixtures thereof, including racemates. Different stereoisomeric forms can be separated from one another by conventional methods, or any given isomer can be obtained by stereospecific or asymmetric synthesis.

The present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that (a) the compound of formula (II) is attached

4 '

R

-tPt (II) to a compound of formula (III)

13 '14 ·

(III) wherein A and R ⁶ contain the appropriate functional group (s) required (to be required) to form, if attached, a -NR ⁵ CO moiety, wherein R ⁵ 'and R ^{5 are} defined as in formula (I), or a group which can be converted thereto,

N is defined as in formula (I) and the variables R ¹ ', R ² ', R ³ ', R ¹⁰ ', R ¹¹ ', R ¹³ ', R ¹⁴ ', R ⁴ ', R ⁵ ', and R ⁷ 'are R ¹ , R ² , R ³ , R ¹⁰ , R ¹¹ , R ¹³ , R ¹⁴ , R ⁴ oz. R ⁷ as defined in formula (I), or groups which can be converted thereto, and then in any case and if necessary and in any appropriate order, convert any of the variables R ¹ ', R ² ', R ³ ', R ¹⁰ ', R ¹¹ ', R ¹³ ', R ¹⁴ ', R ⁴ ', R ⁵ 'and R ⁷ ' if different from R ¹ , R ² , R ³ , R ¹⁰ , R ¹¹ , R ¹³ , R ¹⁴ , R ⁴ , R ⁵ oz. R ⁷ , to R ¹ , R ² , R ³ , R ¹⁰ , R ¹¹ , R ¹³ , R ¹⁴ , R ⁴ , R ⁵ and R ⁷ , convert R ¹ , R ² , R ³ , R ¹⁰ , R ¹¹ , R ¹³ , R ¹⁴ , R ⁴ , R ⁵ and R ⁷ to each other, and form a pharmaceutically acceptable salt thereof; or (b) cyclize a compound of formula (IV)

where R ⁴ ', R ⁵ ', R ⁷ 'R ¹³ ' and R ¹⁴ 'are defined as in formulas (II) and (III), defined as in formula (I) and C and D contain the corresponding functional group (corresponding to functional groups) necessary to form an indole or indoline ring substituted with R ¹ ', R ² ', R ³ ', R ¹⁰ ' and R ¹¹ ', as defined in formula (III), and then, where appropriate, and if necessary and in any order convert any of the variables R ¹ ', R ² ', R ³ ', R ¹⁰ ', R ¹¹ ', R ¹³ ', R ¹⁴ ', R ⁴ ', R ⁵ 'and R ⁷ ', if different from R ¹ , R ² , R ³ , R ¹⁰ , R ¹¹ , R ¹³ , R ¹⁴ , R ⁴ , R ⁵ and R ⁷ , in R ¹ , R ² , R ³ , R ¹⁰ , R ¹¹ , R ¹³ , R ¹⁴ , R ⁴ , R ⁵ and R ⁷ , convert R ¹ , R ² , R ³ , R ¹⁰ , R ¹¹ , R ¹³ , R ¹⁴ , R ⁴ , R ⁵ and R ⁷ into each other and form a pharmaceutically acceptable salt.

Suitable examples of groups A and R ⁶ include:

(i) A is -N = C = O and R ⁶ is -H, (ii) A is -NR ⁵ 'COL and R ⁶ is -H, (iii) A is -NHR ⁵ ' and R ⁶ is COL, or (iv) A is halogen and R ⁶ is -CONHR ⁵ , where R ⁵ 'is defined as above and L is a leaving group. Suitable exemplary leaving groups L include imidazole, halogen, such as chloro or bromo, or phenoxy or phenylthio, which is optionally substituted e.g. with halogen.

If A is -N = C = O and R ^{6 is} H, the reaction is suitably carried out in an inert solvent, e.g. dichloromethane or toluene at room temperature.

If A is -NR ⁵ COL and R ^{6 is} H or if A is -NHR ⁵ 'and R ^{6 is} COL, a reaction suitable in an inert solvent such as dichloromethane is carried out at room temperature, optionally in the presence of a base, such as triethylamine , or in dimethylformamide at room or elevated temperature.

If A is halogen and R ^{6 is} CONHR ⁵ ', the reaction is suitably carried out in an inert solvent, such as toluene, at elevated temperature, optionally in the presence of a base.

Cyclization of a compound of formula (IV) for the preparation of indoles (R ¹⁰ and R ¹¹ are bonds) can be performed using a standard methodology as described in Comprehensive Heterocyclic Chemistry 1984 4, 313 et seq., Or J. Het. Chem. 1988 25, p. 1 onwards.

Examples of more important possible pathways include Leimgruber synthesis, Fischer synthesis, Japp-Klingemann variant, Madelung synthesis, and Nordlander synthesis.

Examples of groups C and D in the preparation of indoles include:

(v) C is NO ₂ and D is CH = CH-NZ ₂ , wherein each Z is independently C _1-6 alkyl or together are C _2-7 alkylene;

(vi) C is NR ¹ '-N = C (R ² ') -CR ₂ R ³ 'and D is H;

(vii) C is NH-N = C (CO ₂ X) -CH ₂ R ³ 'and D is H, where XC is _16- alkyl;

(viii) C is NR ^r COR ² and D is CH ₂ R ³ ';

(ix) C is NHCH ₂ CR ³ '(OR) ₂ and D is H, where RC _{1 is a 6-} alkyl group.

Indoline can also be prepared by reducing the indoles obtained according to the above variants (vi) to (ix), e.g. with NaCNBH ₃ .

In the metabolism variant (v) (Leimgrube synthesis), a compound of formula (IV) is prepared from 2-methylnitrophenylurea by treatment with dialkylformamide OHCNZ ₂ under heating and the product of formula (IV) is cyclized by hydrogenation on a suitable catalyst such as palladium and charcoal a given example under pressure to give a compound of formula (I) wherein R 1 is RM 4 H.

In the metabolism variant (vi) (Fischer synthesis), a compound of formula (IV) is prepared from hydrazinophenylurea by dehydration, preferably by heating, with a suitable ketone R ^ COCF ^ R ³ and the product of formula (IV) is cyclized by heating with an acid catalyst, such as hydrochloric or sulfuric acid.

In the metabolite variant (vii) (Jepp-Klingemann synthesis), a compound of formula (IV) is prepared from an aminophenyl urea by diazotization followed by treatment of e.g. with CH ₃ COCH (CO ₂ X) -CH ₂ R ³ ', where X is C 1-6 -alkyl, under basic conditions in aqueous alcohol as a solvent.

The product of formula (IV) can then be cyclized as in the Fischer synthesis above.

In variant (viii) of the metabolite (Madelung synthesis), the compound of formula (IV) is cyclized with the base in an inert solvent, optionally when heated.

In the metabolite variant (ix) (Nordlande synthesis), the compound of formula (IV) is cyclized by heating in a trifluoroacetic acid / trifluoroacetic acid anhydride mixture.

It will be appreciated that if D is hydrogen, either of the indole isomers or both may be formed during the cyclization process.

Suitable Examples for R ² ', R ³ ', R ⁴ ', and R ⁷ ' Groups Convertible to R ² , R ³ , R ^4, or R ^{4 '} or alkyl groups, respectively. R ⁷ includes acyl groups which are introduced in the usual way and which can be converted to the corresponding alkyl group by conventional reduction, such as by using sodium borohydride in an inert solvent, followed by hydrogenolysis in an inert solvent. Hydrogen substituents can be obtained from alkoxycarbonyl groups which can be converted to hydrogen by hydrolysis and decarboxylation. If R ^{4 is} hydroxy, it is preferably protected in a compound of formula (II), such as e.g. benzyl which is removed by hydrogenation.

Suitable examples for the R ¹ group which can be converted to R ¹ include typical N protecting groups such as alkoxycarbonyl, in particular t-butyloxycarbonyl, acetyl, trifluoroacetyl, benzyl and para-methoxybenzyl, which are converted to R ¹ using normal conditions.

Suitable examples of the group R ⁵ 'which can be converted to R ⁵ include alkoxycarbonyl and benzyl or para-methoxybenzyl, which are converted to hydrogen R ⁵ using standard conditions.

The interconversions between R ¹ , R ² , R ³ , R ¹⁰ , R ¹¹ , R ¹³ , R ¹⁴ , R ⁴ , R ⁵ and R ^{7 are} carried out in the usual manner.

For example, if R ¹ , R ² and R ^{3 are} C 1-6 alkyl and R ^{5 is} hydrogen, a 6 alkyl group in the R ⁵ position can be introduced by conventional alkylation using 1 mole equivalent of C 16 alkyl halide and 1 mole equivalent of a suitable base in an inert solvent. The C ₁₆ alkyl groups of R ¹ can also be introduced by conventional alkylation, e.g. using C _1-6 alkylhalide and a base such as sodium hydride, or by reducing C 1-6 acyl.

Halo R ⁴ and halo R ⁷ can be introduced by selective halogenation of the ring P or. indole / indoline ring using normal conditions.

It should be borne in mind that it may be necessary to protect any variable R ¹ to R ¹² as hydrogen which does not have to be converted to each other.

Protection, especially for hydrogen R ¹ ', may also be required between coupling reaction (a) and reaction of ring formation (b) above.

Suitable protecting groups and methods for their introduction and removal are common in the art of organic chemistry, such as those described in Greene T.W. Protective groups in organic synthesis New York, Wiley (1981).

However, it is preferable that the groups R ¹ to R ^{12 are} introduced and converted into another before being attached to the compounds of formulas (II) and (III) or before cyclizing the compound of formula (IV).

Compounds of formula (I) which are substituted indoles and their corresponding derivatives can be converted to the corresponding indolines and vice versa by conventional methods, e.g. by reduction with NaCNBH ₃ in acetic acid and oxidation using MnO ₂ in an inert solvent.

Compounds of formula (II) in which A is NHR ⁵ 'are known compounds or can be prepared analogously to known compounds, see e.g. WO 92/05170.

Compounds of formula (II) in which A is -N = C = O can be prepared by treating a compound of formula (II) in which

i) A amino, with phosgene or phosgene equivalent in the presence of an excess of base in an inert solvent.

ii) A acylazide (i.e. CON ₃ ) via nitrene by thermal displacement using normal conditions (see LS Trifonov et al. Helv. Chim. Acta 1987 70 262).

iii) A CONH ₂ , via a nitrene intermediate using standard conditions.

A compound of formula (II) in which A is -NR ⁵ COL can be prepared by metabolizing a compound of formula (II) in which A is -NHR ⁵ ', with phosgene or phosgene equivalent, in an inert solvent at low temperature if is required in the presence of one base equivalent, such as triethylamine.

The compounds of formula (III) can be prepared:

(a) by cyclization of compounds of formula (V), followed, if necessary, by reduction to amine

where Q is CR ¹³ R ¹⁴ L, CR ¹³ O or CO ₂ R, where L is a leaving group, R ¹³ and R ¹⁴ are as defined in formula (I), m is 1 or 2, R ¹ ', R ² ', R ³ ', R ⁷ ', R ¹⁰ ', R ¹¹ ', R ¹³ 'and R ¹⁴ ' are defined as in formula (III) above, R ⁶ 'is a group R ⁶ as defined in formula (III). and R is aryl or

A C ₁₆ -alkyl group, or (b) by cyclization of compounds of formula (VI)

13 '14' [CR R) _n

R wherein R ⁶ ', R ⁷ ', R ¹³ ', R ¹⁴ ' and n are defined as in formula (V) and C and D are defined as in formula (IV) above.

The cyclization of a compound of formula (V) may conveniently be carried out in an inert solvent at room or elevated temperature, optionally in the presence of a base. Reduction can be performed using conventional reduction techniques. The cyclization of a compound of formula (VI) can conveniently be carried out using the methods of operation described above for cyclization of a compound of formula (IV).

Compounds of formula (II) in which A is halogen and R ⁴ 'is hydrogen are commercially available.

Also, new intermediates of formulas (III) and (IV) form part of the invention.

Pharmaceutically acceptable salts may be prepared in a conventional manner by metabolism with a suitable acid or acid derivative.

N-oxides can be formed in the usual way by metabolism with hydrogen peroxide or percarboxylic acids.

The compounds of formula (I) and their pharmaceutically acceptable salts have 5HT _2C receptor antagonist activity and certain compounds exhibit 5HT ₂₀ antagonist activity. The compounds of formula (I) are therefore considered to be potentially useful in the treatment or prophylaxis of anxiety, depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's, sleep disorders, bulimia, panic attacks, disorders of drug abuse, schizophrenia, and also disorders related to spinal cord injury and / or head injury such as hydrocephalus.

Therefore, the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a therapeutic substance, especially in the treatment or prophylaxis of the above disorders.

The invention further provides a method for the treatment or prophylaxis of the above disorders comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of the above disorders.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The pharmaceutical composition of the invention which can be prepared by mixing, suitable at room temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules , lozenges, re-assembled powders, solutions or suspensions for injection or infusion or suppositories. Generally oral preparations are preferred.

Tablets and capsules for oral administration may be in unit dosage form and may contain conventional excipients such as binders, fillers, tablet lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid preparations may be e.g. in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they may be in the form of a dry product which can be re-assembled with water or another suitable carrier before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifiers, non-aqueous vehicles (which may include edible oils), preservatives and, if desired, conventional flavoring or flavoring agents or colorants.

For parenteral administration, liquid dosage unit formulations are prepared using the compound of the invention or a pharmaceutically acceptable salt and sterile carrier thereof. Depending on the carrier used and the concentration, the compound in the carrier may be suspended or dissolved. In the preparation of solutions, the compound for injection can be dissolved and sterilized by filtration, before being filled into a suitable vial or ampoule and sealed. It is advantageously dissolved in the excipient carrier such as topical anesthetic, preservatives and buffering agents. To improve durability, the preparation may be frozen after filling into a vial and the water removed under vacuum. Parenteral suspensions are prepared in essentially the same way except that the compound is suspended in the vehicle instead of dissolved and sterilization cannot be performed by filtration. The compound can be sterilized by exposing it to ethylene oxide before suspending it in a sterile vehicle. Preferably, a surfactant or wetting agent is incorporated into the preparation to facilitate even distribution of the compound.

The preparation may contain depending on the route of administration of 0.1 wt. % to 99 wt. %, preferably from 10 to 60 wt. % of active substance.

The dose of the compound used in the treatment of the disorders mentioned above will vary in the usual way depending on the severity of the disorder, the weight of the patient, and other similar factors. However, as a general guideline, dosage units of 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, e.g. 0.2 to 5 mg, and such dosage units can be administered more than once daily, e.g. two or three daily so that the total daily dose is in the range of about 0.01 to 100 mg, and such treatment may last for weeks or months.

When administered in accordance with the invention, no unacceptable toxicological effects are expected from the compounds of the invention.

The following examples explain the preparation of pharmacologically active compounds of the invention. The following descriptions explain the preparation of intermediates for the compounds of the present invention.

Description 1 l-acetyl-5-aminoindoline (D1) 1-acetyl-5-nitroindoline (12.77 g, 62 mmol), cyclohexene (62 ml, 610 mmol) and 5% palladium-on-charcoal (2.34 g) was stirred at reflux under nitrogen for 18 h. A further portion of the catalyst (0.5 g) was then added and reflux continued for 3 h. The mixture was cooled, filtered through diatomite and evaporated to give the title compound (9.33 g, 85%) as an orange-yellow solid.

NMR (D ₆ -DMSO) δ: 2.05 (3H, s), 3.0 (2H, t, J 8), 3.97 (2H, t, J 8), 4.97 (2H, bs) , 6.33 (1H, dd, J 7.1), 6.46 (1H, d, J1), 7.72 (1H, d, J 7).

Description 2

N- (1-acetyl-5-indolinyl) -2,2-diethoxyethylamine (D2) 1-acetyl-5-aminoindoline (D1) (9.33 g, 53 mmol), bromoacetaldehyde diethyl acetal (6.0 ml, 40 mmol) and sodium hydrogen carbonate (4.58 g, 54 mmol) were stirred at reflux under nitrogen for 64 h. Further acetal (2.0 mL, 13 mmol) was then added and reflux continued for 24 h. The mixture was cooled, filtered and evaporated to near dryness. Silica gel chromatography using ethyl acetate / petroleum ether (boiling point 60-80 ° C) (50100% ethyl acetate) gave the title compound (6.59 g) as a yellow-brown solid, in addition to the recovered starting amine (3.09 g). Product yield was 63% based on consumed starting material.

NMR (CDCl ₃ ) δ: 1.25 (6H, t, J 7), 2.2 (3H, s), 3.13 (2H, t, J 8), 3.22 (2H, d, J 5) ), 3.53.65 (2H, m), 3.65-3.8 (2H, m), 4.01 (2H, t, J 8), 4.68 (1H, t, J 5), 6.5 (2H, m), 8.03 (1H, d, J 7).

Alternative mode of operation 1-acetyl-5-aminoindoline (D1) was reductively alkylated with glyoxal monomethyl acetal in ethanol at 45 ° C using 10% palladium on carbon and 3.5 bar hydrogen. Removal of the catalyst by filtration followed by evaporation of the solvent gave the corresponding dimethyl acetal, which was used directly in Description 3 instead of diethyl acetal.

Description of 3 1-acetyl-5-trifluoroacetyl-2,3-dihydropyrrolo [2,3-f] indole (D3)

N- (1-acetyl-5-indolinyl) -2,2-diethoxyethylamine (D2) (6.51 g, 22 mmol) was added to an ice-cold mixture of trifluoroacetic acid (25 ml) and trifluoroacetic anhydride (25 ml) while stirring. ). The mixture was stirred at 0 ° C under nitrogen for 0.5 h and then further trifluoroacetic acid (40 ml) was added. The mixture was then refluxed for 64 h, cooled and evaporated to dryness. Chromatography on silica gel using ethyl acetate / chloroform (0-60% ethyl acetate) then afforded the title compound (6.28 g, 89%) as a light yellowish solid, which turned slightly dark on condition.

NMR (CDCl ₃ ) δ: 2.33 (3H, s), 3.37 (2H, t, J 8), 4.17 (2H, t, J 7), 6.76 (1H, d, J 3) ), 7.45 (1H, m), 8.27 (1H, s), 8.44 (1H, s).

Description 4 1-Acetyl-2,3-dihydropyrrolo [2,3-f] indole (D4) 1-acetyl-5-trifluoroacetyl-2,3-dihydropyrrolo [2,3-f] indole (D3) (2.80 g, 9.4 mmol) was suspended in methanol (100 ml) while stirring and anhydrous potassium carbonate (1.96 g, 14.2 mmol) was added. The mixture was stirred for 0.5 h, evaporated to near dryness and partitioned between ethyl acetate and water. After separation, the aqueous portion was extracted with 5% methanol / chloroform and the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and evaporated to give the title compound (1.53 g, 80%) as a yellowish solid.

NMR (D ₆ -DMSO) δ: 2.15 (3H, s), 3.18 (2H, t, J 8), 4.08 (2H, t, J 8), 6.33 (IH, bs) , 7.2 (2H, m), 8.22 (1H, s), 10.9 (1H, bs).

Description of 5 1-acetyl-5-methyl-2,3-dihydropyrrolo [2.3-flindole (D5)

Sodium hydride (80% en, 0.25 g, 8.3 mmol) was stirred under nitrogen in dry Ν, dimethylformamide (DMF) (5 ml) and l-acetyl-2,3-dihydropyrrolo was added with effervescence [2, 3-f] indole (D4) (1.52 g, 7.6 mmol) in DMF (20 ml). The mixture was stirred for 0.5 h and then iodomethane (0.52 mL, 8.3 mmol) in DMF (5 mL) was added. After stirring for another 1 h, the excess sodium hydride was decomposed by the addition of water (1 ml) and the mixture was partitioned between ethyl acetate and water and separated. The organic portion was washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. Chromatography on silica gel using ethyl acetate / chloroform (0-50% ethyl acetate) then gave the title compound (0.80 g, 49%) as a pale yellow solid.

NMR (CDC1 ₃ mixture of rotamers about 5: 1 δ:

2.26 (majority rotamer, 3H, s), 2.51 (minority rotamer, 3H, s), 3.16 (minority rotamer, 2H, t, J 8), 3.3 (majority rotamer, 2H, s, J 8), 3.74 (majority rotamer, 3H, s), 3.77 (minority rotamer, 3H, s), 4.1 (majority rotamer, 2H, t, J 8), 4.19 (minority rotamer, 2H, t, J 8), 6.44 (both, IH, d, J 2), 6.98 (majority rotamer, IH, d, J 2), 7.0 (minority rotamer, m), 7.09 (majority rotamer, IH, s), 7.18 (minority rotamer, IH, s), 7.31 (minority rotamer, IH, s), 8.48 (majority rotamer, IH, s).

Description 6

5-methyl-2,3-dihydropyrrolo [2,3-flindol (D6) 1-acetyl-5-methyl-2,3-dihydropyrrolo [2,3-f] indole (D5), (0.70 g, 3 , 3 mmol) was stirred at reflux under nitrogen in 10% sodium hydroxide solution (50 ml) for 4 h. The mixture was cooled, diluted with water (200 ml) and extracted with ethyl acetate. The extract was dried (Na 2 OJ and evaporated to give the title compound (0.58 g) as a light brown resin, which still contained about 20% starting amide (NMR). This material was used without purification in the next step.

NMR (CDCl ₃ ) δ: 3.12 (2H, t, J 9), 3.33 (1H, bs), 3.56 (2H, t, J 9), 3.7 (3H, s), 6 , 27 (1H, d, J 3), 6.85 (1H, s), 6.9 (1H, d, J 3), 7.08 (1H, s).

Description 7 (1-methyl-5-nitro-4-indolyl) acetonitrile (D7) 1-methyl-5-nitroindole (0.77 g, 4.4 mmol) and (4-chlorophenoxy) acetonitrile (0.88 g, 5.2 mmol) was stirred in dry DMF (10 ml) at 0 ° C and potassium t-butoxide (1.47 g, 13.1 mmol) in dry DMF (10 ml) was added. The mixture was stirred at 0 ° C for 15 min, poured into 1 M hydrochloric acid (200 ml) and stirred until the precipitate had boiled. The solid was then filtered off and dried. Chromatography on silica gel using chloroform then gave the title compound (0.48 g, 51%) as a yellow solid.

NMR (CDCl ₃ ) δ: 3.9 (3H, s,), 4.37 (2H, s), 6.78 (1H, d, J 3), 7.31 (1H, d, J 3). 7.38 (1H, d, J 8), 8.12 (1H, d, J 8).

Description 8

2- (1-methyl-5-nitro-4-indolyl) ethanol

1-Methyl-5-nitro-4-indolyl) acetonitrile (D7) (3.36 g, 15.6 mmol) was stirred in dry tetrahydrofuran (THF) (100 ml) under nitrogen and diisobutylaluminum hydride (1.5 M was added) in toluene, 21 ml, 31.5 mmol). The mixture was stirred for 6 h and methanol (25 ml) was added. After a further 5 min, it was diluted with water (500 ml), acidified with 5 M hydrochloric acid and extracted with chloroform. The extract was dried (Na ₂ SO ₄ ), evaporated to a magnesium resin and suspended in ethanol (100 ml). Sodium borohydride (0.88 g, 23.1 mmol) was added and the mixture was stirred for 0.5 h when another similar portion of sodium borohydride was added. After a further 0.5 h, the mixture was diluted with water (500 ml), acidified with 5 M hydrochloric acid and extracted with chloroform. The extract was washed twice with brine, dried (Na ₂ SO ₄ ) and evaporated to a brown gum. Silica gel chromatography using ethyl acetate / petroleum ether (60-80 ° C) (20-60% ethyl acetate) gave the title compound (0.50 g, 15%) as an oil.

NMR (CDCl ₃ ) δ: 3.47 (2H, t, J 7), 3.78 (3H, s), 4.02 (2H, t, J 7), 6.73 (1H, d, J 3) ), 7.2 (2H, m), 7.89 (1H, d, J = 8).

Description 9

2- (1-methyl-5-nitro-4-indolyl) ethyl methanesulfonate (D9)

2- (1-methyl-5-nitro-4-indolyl) ethanol (D8) (0.50 g, 2.3 mmol) and triethylamine (0.38 ml, 2.7 mmol) were stirred in dichloromethane (10 ml ) and methanesulfonyl chloride (0.21 ml, 2.7 mmol) was added. The mixture was stirred for 10 min, water (10 ml) was added and then vigorously stirred for another 10 min. After acidification with 5 M hydrochloric acid, the layers were separated and the organic portion was dried (Na ₂ SO ₄ ) and evaporated to give a dark oil. Chromatography on silica gel using chloroform and then dichloromethane gave the title compound (0.54 g, 79%) as an orange solid.

NMR (CDCl ₃ ) δ: 2.44 (3H, s), 3.68 (2H, t, J 7), 3.85 (3H, s), 4.63 (2H, t, J 7), 6 , 81 (1H, d, J 3), 7.25 (1H, d, J 3), 7.3 (1H, d, J 8), 8.0 (1H, d, J 8).

Description 10

6-methyl-2,3-dihydropyrrolo [3.2-eindole (D10)

2- (1-methyl-5-nitro-4-indolyl) ethyl methanesulfonate (D9) (0.38 g, 1.3 mmol) was hydrogenated over 5% palladium on charcoal (0.23 g) in dry DMF (20 ml) at 5.6 bar Hj for 2 h, diluted with ethanol (80 ml), filtered through diatomite and evaporated to a brown gum. The title compound can be purified by preparing a salt with HCl to give 6-methyl-2,3-dihydropyrrolo [3,2-e] indolehydrochloride.

Description 11

N- (1-acetyl-5-indolinyl) -2-chloroallylamine (Dll) 1-acetyl-5-aminoindoline (D1) (4.36 g, 24.8 mmol), anhydrous potassium carbonate (5.1 g, 37 mmol) and 2,3-dichloro-1-propene (4.5 ml, 48.9 mmol) were stirred in dry DMF (50 ml) at 70 ° C for 16 h. The mixture was then diluted with water (500 ml) and stirred for 10 min. Filtration and air drying then gave the title compound (5.71 g, 92%) as a dark olive solid.

NMR (CDCl ₃ ) δ: 2.19 (3H, s), 3.13 (2H, t, J 8), 3.9-4.2 (5H, m), 5.32 (1H, m). 5.41 (1H, m), 6.4-6.6 (2H, m), 8.05 (1H, d, J 9).

Description 12

N- (1-acetyl-5-indolinyl) -2-chloro-N-trifluoroacetylallylamine (D12) 1- (1-acetyl-5-indolinyl) -2-chloroallylamine (Dll) (5.71 g, 24.8 mmol ) and triethylamine (3.8 ml, 27.3 mmol) were stirred in chloroform (100 ml) and trifluoroacetic acid anhydride (3.8 ml, 27.3 mmol) was added dropwise over 1 min. The mixture was stirred for 1 h and water (100 ml) was added. This mixture was stirred vigorously for 20 min, acidified with 5 M hydrochloric acid and separated. The organic portion was dried (Na ₂ SO ₄ ) and evaporated to give the title compound as a dark oil (7.49 g, 95%) which solidified on condition.

NMR (CDCL) δ: 2.25 (3H, s), 3.24 (2H, t, J 8), 4.16 (2H, t, J 8), 4.52 (2H, s), 5. 23 (1H, s), 5.36 (1H, s), 7.1 (2H, m), 8.23 (1H, d, J 8).

Description 13 1-Acetyl-7-methyl-5-trifluoroacetyl-2,3-dihydropyrrolo [2,3-flindole (D13)

N- (1-acetyl-5-indolinyl) -2-chloro-N-trifluoroacetylallylamine (D12) (7.63 g, 22 mmol) was stirred in polyphosphoric acid (38 g) at 140 ° C for 1.5 h. The mixture was cooled, dispersed in water (200 ml) and extracted with ethyl acetate. The extract was filtered through diatomite, dried (Na ₂ SO ₄ ) and evaporated to give a dark resin (about 3 g). Chromatography on silica gel eluting with 0-20% ethyl acetate in chloroform gave the title compound (0.49 g, 7%) as a pale yellow solid.

NMR (CDCl ₆ ) δ: 2.28 (3H, s), 2.33 (3H, s), 3.36 (2H, t, J 8), 4.18 (2H, t, J 8), 7 , 19 (1H, s), 8.24 (1H, s), 8.36 (1H, s).

Description 14 1-Acetyl-7-methyl-2,3-dihydropyrrolo [2,3-f] indole (D14)

It is prepared from 1-acetyl-7-methyl-5-trifluoroacetyl-2,3-dihydropyrrolo [2,3-f] indole (D13) (0.49 g, 1.58 mmol) according to the method described in Description 4, only that we have processed by dilution with water. The title compound (0.31 g, 91%) was then isolated by filtration and dried as a yellow solid.

NMR (D ₆ -DMSO) δ: 2.15 (3H, s), 2.18 (3H, s), 3.17 (2H, t, J 8), 4.09 (2H, t, J 8) , 7.00 (1H, s), 7.14 (1H, s), 8.16 (1H, s), 10.55 (1H, bs).

Description 15 1-Acetyl-5,7-dimethyl-2,3-dihydropyrrolo [2,3-f] indole (D15)

It was prepared from 1-acetyl-7-methyl-2,3-dihydropyrrolo [2,3-f] indole (D14) (0.31 g, 1.46 mmol) according to the method of Example 5, except that it was processed by dilution with water. The title compound (0.26 g, 79%) was then isolated by filtration and dried as an orange-yellow solid.

NMR (CDC1 ₃ ) mixture of rotamers about 5: 1, δ:

2.27 and 2.30 (majority, 3H, s + both, 3H, s), 2.53 (minority, 3H, s), 3.15 (minority, 2H, t, J 8), 3.30 ( majority, 2H, t, J 8), 3.68 (majority, 3H, s), 3.70 (minority, 3H, s), 4.10 (majority, 2H, t, J 8), 4.20 ( minority, 2H, t, J 8), 6.76 (majority, 1H, s), 6.80 (minority, 1H, s), 7.05 (majority, 1H, s), 7.13 (minority, 1H , s), 7.19 (minority, 1H, s), 8.42 (majority, 1H, s).

Description 16

5,7-Dimethyl-2,3-dihydropyrrolo [2.3-f] indole (D16)

It was prepared from 1-acetyl-5,7-dimethyl-2,3-dihydropyrrolo [2,3-f] indole (D15) (0.44 g, 1.93 mmol) according to the method of Example 6, wherein was used as solvent as a mixture of 10% sodium hydroxide / ethanol 5: 1 solution. NMR after a reaction time of 7 h showed about 60% metabolism, but this material (0.30 g) was used in the next step without separation of the starting material.

Description 17 1-acetyl-5-ethyl-2,3-dihydropyrrolo [2,3-flindole (D17)

The title compound was prepared from 1-acetyl-2,3-dihydropyrrolo [2,3-f] indole (D4), sodium hydride and ethyl iodide in 90% yield using a method similar to that for D5.

NMR (CDC1 ₃ ) (mixture of rotamers) δ main signals:

1.44 (3H, t, J 8), 2.23 (3H, s), 3.29 (2H, t, J 10), 4.0-4.25 (4H, m), 6.43 ( 1H, d, J 3), 7.03 (1H, d, J 3), 7.10 (1H, s), 8.48 (1H, s).

Description 18

5-ethyl-2,3-dihydropyrrolo [2,3-f] indole (D18)

The title compound was prepared from 1-acetyl-2,3-dihydropyrrolo [2,3-f] indole (D17) in 100% yield using a method similar to that for D6.

NMR (CDCl3) δ: 1.41 (3H, t, J 8), 3.12 (2H, t, J 10), 3.58 (2H, t, J 10), 4.08 (2H, q.

J 8), 6.26 (1H, d, J 3), 6.84 (1H, s), 6.97 (1H, d, J 3), 7.12 (1H, s).

Description 19 1-Acetyl-5-n-propyl-2,3-dihydropyrrolo [2,3-f | indole (D19)

Prepared as described in Description 5 using sodium hydride (80% en, 0.08 g, 2.8 mmol), 1-acetyl-2,3-dihydropyrrolo [2,3-f] indole (D4) (0.4 g, 2 mmol) and 1-iodopropane (0.27 ml, 2.8 mmol). The mixture was partitioned between ether / H ₂ O and the organic layer was separated, dried and evaporated to give the title compound (0.48 g, 99%) as a yellow solid.

NMR (CDC1 ₃ ) mixture of rotamers (about 4: 1) δ:

0.92 (t, 3H, J = 8.4 Hz), 1.84 (m, 2H, J = 8.4 Hz), 2.25 (majority, s, 3H), 2.50 (minority, s , 3H), 3.14 (minority, t, 2H, J = 8.4 Hz), 3.29 (majority, t, 2H, J = 8.4 Hz), 4.02 (t, 2H, J = 8.4Hz), 4.09 (majority, t, 2H, J = 8.4Hz), 4.19 (minority, t, 2H, J = 8.4Hz), 6.4 (d, 1H, J = 5Hz) ), 7.02 (d, 1H, J = 5Hz), 7.10 (s, 1H), 8.46 (s, 1H).

Description 20

5-n-propyl-2,3-dihydropyrrolo [2,3-f | indole (D20)

Prepared as described in Example 6 using 1-acetyl-5-propyl-2,3-dihydropyrrolo [2,3-f] indole (D19) (0.48 g, 1.9 mmol) in ethanol (30 ml) and 10 % NaOH solution (5 ml). Silica gel chromatography eluting with 3% MeOH / CH ₂ Cl ₂ gave the title compound (0.23 g, 60%).

NMR (CDCl ₃ ) δ: 0.93 (t, 3H, J = 8.4 Hz), 1.86 (m, 2H, J = 8.4 Hz), 3.12 (t, 2H, J = 8. 4Hz), 3.56 (t, 2H, J = 8.4Hz), 4.01 (t, 2H, J = 8.4Hz), 6.27 (d, 1H, J = 5Hz), 6.87 ( s, 1H), 6.97 (d, 1H, J = 5Hz), 7.02 (s, 1H).

Description 21

N- (1-acetyl-5-indolinyl) -2-chloro-N-methylallylamine (D21)

Formaldehyde (40% aqueous solution, 2.8 ml, 36 mmol) and 3 M sulfuric acid (5 ml, 15 mmol) were stirred on ice. A suspension of sodium borohydride (1.66 g, 44 mmol) and N- (1-acetyl-5-indolinyl) -2-chloroallylamine (Dll) (3.08 g, 12.2 mmol) in tetrahydrofuran (60 ml) was added to this by meal. ), maintaining the temperature below 20 ° C. The mixture was stirred at room temperature for 0.25 h and basified with excess solid sodium hydroxide. The supernatant was decanted and the solid was dissolved in water (150 ml) and extracted with ethyl acetate. The combined organic extracts were dried (Na ₂ SO ₄ ) and evaporated to brown tar, which was dissolved in chloroform, dried again (Na ₂ SO ₄ ), filtered and evaporated to give the title compound (3.80 g> 100% ) as a brown solid. We used this without cleaning.

NMR (CDCl ₃ ) 5: 2.20 (3H, s), 3.00 (3H, s), 3.16 (2H, t, J 7), 3.95-4.20 (4H, m). 5.22 (1H, m), 5.30 (1H, m), 6.56 (2H, m), 8.08 (1H, d, J 8).

Description 22 1-Acetyl-5,6-dimethyl-2,3-dihydropyrrolo [2,3-fluoroindole and 1-acetyl-6,7-dimethyl-2,3-dihydropyrrolol 3.2-e] indole (D22)

N- (1-acetyl-5-indolinyl) -2-chloro-N-methylallylamine (D21) (2.1 g, 7.9 mmol) was stirred in polyphosphoric acid (44 g) at 140 ° C for 24 h, cooled , dispersed in water (200 ml) and extracted with ethyl acetate. The extract was washed with brine, dried (Na ₂ SO ₄ ) and evaporated to give a pink solid. Chromatography on silica gel eluting with 0-20% ethyl acetate in dichloromethane gave:

1) faster eluting material, linear [2,3-f] indole (0.21 g, 11.6%) as a white solid; NMR showed a mixture of rotamers in an approximate ratio of 5: 1

NMR (CDCl ₃ ) δ: 2.25 (3H, majority, s), 2.39 (3H, majority, s), 2.41 (3H, minority, s), 2.50 (3H, minority, s) , 3.15 (2H, minority, t, J 7), 3.29 (2H, majority, t, J 7), 3.62 (3H, majority, s), 3.64 (3H, minority, s) , 4.10 (2H, majority, t, J 7), 4.19 (2H, minority, t, J 7), 6.22 (1H, both, s), 7.03 (1H, majority, s) , 7.11 (1H, minority, s), 7.21 (1H, minority, s), 8.38 (1H, majority, s);

2) slower-eluting material, angulam [3,2-e] indole (0.10 g, 5.5%) as a white solid; NMR showed a mixture of rotamers in an approximate ratio of 8: 1

NMR (CDCl ₃ ) δ: 2.25 (3H, majority, s), 2.4-2.5 (3H, minority + 3H, both: m), 3.18 (2H, minority, t, J 8) , 3.33 (2H, majority, t, J 8), 3.56 (3H, both, s), 4.15 (2H, majority, t, J 8), 4.26 (2H, minority, t, J 8), 6.1 (1H, both, m), 7.0-7.15 (1H, both +)

IH minority), 8.20 (1H, majority, d, J 8).

Description 23

5.6-dimethyl-2,3-dihydropyrrolo [2,3-f] indole (D23)

It was prepared from 1-acetyl-5,6-dimethyl-2,2-dihydropyrrolo [2,3-f] indole (D22) (0.42 g, 1.84 mmol) according to the method of operation for D6. This gave the title compound (0.30 g) as a brown resin. NMR showed about 60% conversion to the desired material. We used it without cleaning.

NMR (CDCl ₃ ) δ: 2.36 (3H, s), 3.12 (2H, t, J 7), 3.56 (2H, t, J 7), 3.58 (3H, s), 6 , 06 (1H, s), 6.78 (1H, s), 7.03 (1H, s).

Description 24

6.7- Dimethyl-2,3-dihydropyrrolol 3,2-eindole (D24)

It was prepared from 1-acetyl-6,7-dimethyl-2,3-dihydropyrrolo [3,2-e] indole (D22) (0.156 g, 0.68 mmol) according to the method of operation for D6. This gave the title compound (0.124 g, 97%) as a dark oil.

NMR (CDCl ₃ ) δ: 2.38 (3H, s), 3.16 (2H, t, J 7), 3.6 (5H, m), 6.04 (1H, s), 6.63 ( 1H, d, J 8), 6.95 (1H, d, J 8).

Description 25

N- (6-quinolyl) trifluoroacetamide (D25)

6-aminoquinoline (5.75 g, 40 mmol) and triethylamine (6.7 ml, 48 mmol) were stirred in chloroform (100 ml) and trifluoroacetic acid anhydride (6.7 ml, 48 mmol) was added over 2 min. The mixture was stirred for 1 h and water (100 ml) was added. After stirring for 5 min, the resin precipitate was filtered off, washed with chloroform and water and dried in vacuo at 50 ° C. This gave the title compound (7.68 g, 80%) as a semi-solid straw colored substance containing residual triethylamine (NMR).

NMR (CDCl ₃ ) δ: 7.57 (1H, dd, J 9, 4), 7.97 (1H, dd, J 9.2), 8.08 (1H, d, J 9), 8.4 (2H,

m), 8.90 (1H, dd, J = 5.2), 11.63 (1H, s).

Description 26

N- (1,2,3,4-tetrahydro-6-quinolyl) trifluoroacetamide (D26)

N- (6-quinolyl) trifluoroacetamide (D25) (6.84 g, 28.5 mmol) and nickel chloride hexahydrate (1.36 g, 5.71 mmol) were stirred in methanol (100 ml) and sodium borohydride was added ( 4.3 g, 113 mmol) in portions over 0.5 h. After stirring for another 0.5 h, another portion of sodium borohydride (1.0 g, 26 mmol) was added. After a further 0.5 h, the mixture was evaporated to dryness, partitioned between 5 M hydrochloric acid (25 ml) and ethyl acetate (100 ml) and stirred until clarified. The mixture was neutralized with excess sodium hydrogen carbonate and separated. The aqueous portion was extracted with further ethyl acetate and the combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and evaporated. Chromatography on silica gel eluting with 0-30% ethyl acetate / chloroform gave the title compound (5.07 g, 73%) as a light greenish solid.

NMR (CDCl ₃ ) δ: 1.44 (2H, m), 2.75 (2H, t, J 6), 3.31 (2H, t, J 6), 3.92 (1H, bs), 6 , 45 (1H, d, J 9), 7.09 (1H, dd, J 9, 2), 7.16 (1H, d, J 2), 7.65 (1H, bs).

Description 27

N- (1-acetyl-1,2,3,4-tetrahydro-6-quinolyl) trifluoroacetamide (D27)

N- (1,2,3,4-tetrahydro-6-quinolyl) trifluoroacetamide (D26) (5.64 g, 23.1 mmol) and acetyl chloride (2.0 ml, 28 mmol) were stirred in dichloromethane (100 ml) and pyridine (2.25 ml, 28 mmol) was added. The mixture was stirred for 0.5 h and water (100 ml) was added. After 0.25 h of vigorous stirring, it was acidified with 5 M hydrochloric acid and separated. The organic portion was washed with brine, dried (Na ₂ SO ₄ ) and evaporated to give the title compound (5.24 g, 79%) as a yellowish solid.

NMR (CDCl ₃ ) δ: 1.99 (2H, m), 2.25 (3H, s), 2.57 (2H, t, J 6), 3.78 (2H, t, J 6), 7 , 3 (b), 7.52 (1H, bs), 8.08 (1H, bs).

Description 28 1-acetyl-6-amino-1,2,3,4-tetrahydroquinoline (D28)

N- (1-acetyl-1,2,3,4-tetrahydro-6-quinolyl) trifluoroacetamide (D27) (1.85 g, 6.5 mmol) was stirred in ethanol (15 ml) and sodium hydroxy (0 was added) , 52 g, 13.0 mmol) in water (3 ml). The mixture was stirred at room temperature for 0.5 h and then heated to reflux for 0.25 h. After 0.5 h at reflux, the mixture was cooled, acidified with 5 M hydrochloric acid, basified with solid sodium carbonate, diluted with water (100 ml) and extracted with chloroform. The extract was dried (Na ₂ SO ₄ ) and evaporated to give the title compound (1.38 g> 100%) as a brown oil containing the remaining chloroform (NMR).

NMR (CDCl ₃ ) δ: 1.92 (2H, m), 2.27 (3H, s), 2.60 (2H, m), 3.67 (2H, b, s), 3.79 (2H , bm), 6.5 (2H, m), 6.87 (1H, bd, J 6).

Description 29 l-Acetyl-6- (2,2-diethoxyethyl) amino-l, 2,3 ₁ 4-tetrahydroquinoline (D29) l-Acetyl-6-amino-l, 2,3,4-tetrahydroquinoline (D28) ( 2.35 g, 12.4 mmol) and N, N-diisopropylethylamine (2.7 ml, 15.5 mmol) were stirred in 1,2-dichloroethane (50 ml) under Ar. For 5 min, 2,2-diethoxyethyl trifluoromethanesulfonate (3.78 g, purity about 90%, about 13 mmol) was added dropwise. The mixture was then stirred at reflux for 0.5 h, cooled, washed with water, dried (Na ₂ SO ₄ ) and evaporated to give a black oil. This material was combined with the material obtained in the same manner using 1.40 g of amino-quinoline reagent and chromatographed on silica gel using 0-100% ethyl acetate / chloroform. This gave the title compound (3.72 g, 61%) as an amber oil, which was contaminated with a little dialkylated material (NMR).

NMR (CDCl ₃ ) δ: 1.25 (6H, t, J 7), 1.92 (2H, m), 2.20 (3H, s), 2.63 (2H, b, m), 3. 25 (2H, t, J 5), 3.5-3.9 (7H, m), 4.69 (1H, t, J 6), 6.45 (2H, m), 6.89 (1H, bd, J 6).

Description 30

5-acetyl-1-trifluoroacetyl-5,6,7,8-tetrahydro-1H-pyrrolo [2,3-glyquinoline (D30) 1-acetyl-6- (2,2-diethoxyethyl) amino-1,2,3,4 -tetrahydroquinoline (D29) (3.72 g, 12.2 mmol) was stirred at 0 ° C under Ar in a mixture of trifluoroacetic acid (20 ml) and trifluoroacetic anhydride (20 ml) for 0.5 h. Further trifluoroacetic acid (30 ml) was added and the solution was then stirred at reflux for 90 h, cooled and evaporated to give a black resin. Silica gel chromatography eluting with 0-60% ethyl acetate / chloroform gave the title compound (2.77 g, 73%) as an amber oil.

NMR (CDCl ₃ / D ₆ -DMSO) δ: 2.03 (2H, m), 2.25 (3H, s), 2.87 (2H, t, J 6), 3.80 (2H, t, J 7), 6.83 (1H, d, J 4), 7.51 (2H, m), 8.25 (1H, s).

Description 31

5-acetyl-5,6,7,8-tetrahydro-1H-pyrrolo [2,3-g] quinoline (D31)

5-acetyl-1-trifluoroacetyl-5,6,7,8-tetrahydro-1H-pyrrolo [2,3-g] quinoline (D30) (2.76 g, 8.9 mmol) and anhydrous potassium carbonate (3, 7 g, 27 mmol) was stirred in methanol (50 ml) for 1 h. The mixture was then concentrated in vacuo, diluted with water (100 ml) and extracted with chloroform. The extract was dried (Na ₂ SO ₄ ) and evaporated to give the title compound (1.40 g, 73%) as an orange-brown solid. NMR showed a mixture of rotamers in an approximate ratio of 9: 1.

NMR (CDCl ₃ ) δ: 1.97 (2H, majority, m), 2.07 (2H, minority, m), 2.22 (3H, both, s), 2.73 (2H, majority, t). J 6), 3.01 (2H, minority, t, J 6), 3.86 (2H, both, t, J 7), 6.52 (1H, both, m), 7.20 (2H, both , m), 7.34 (1H, majority, s), 8.33 (1H, both, b).

Description 32

5-acetyl-1-methyl-5,6,7,8-tetrahydro-1H-pyrrolo [2,3-glyquinoline (D32)

5-Acetyl-5,6,7,8-tetrahydro-1H-pyrrolo [2,3-g] quinoline (D31) (1.39 g, 6.5 mmol) in dry dimethylformamide (DMF) (20 mL) was added while stirring under Ar to a suspension of sodium hydride (80% in mineral oil, 0.25 g, 8.3 mmol) in DMF (5 ml). After stirring for 20 min, iodomethane (0.61 ml, 9.8 mmol) was added. The resulting suspension was stirred for 1 h, diluted with water (100 ml) and extracted with ethyl acetate. The extract was washed with water and brine, dried (Na ^ C ^) and evaporated to give a resin. Silica gel chromatography eluting with 0-100% ethyl acetate / chloroform gave the title compound (0.97 g, 65%) as a light straw color that solidified on condition.

NMR showed a mixture of rotamers in an approximate ratio of 6: 1.

NMR (CDCl ₃ ) δ: 1.97 (2H, both, m), 2.20 (3H, both, s), 2.75 (2H, majority, t, J 6), 2.98 (2H, minority) , t, J 6), 3.78 (3H, both, s), 3.84 (2H, both, t, J 7), 6.45 (1H, both, d, J 3), 7.04 ( 1H, both, d, J 3), 7.12 (1H, both s), 7.31 (1H, both s).

Description 33

1- Methyl-5,6,7,8-tetrahydro-1H-pyrroloi2,3-glyquinoline (D33)

5-acetyl-1-methyl-5,6,7,8-tetrahydro-1H-pyrrolo [2,3-g] quinoline (D32) (0.96 g, 4.2 mmol) was dissolved in ethanol (10 ml ) and 2.5 M sodium hydroxide (90 ml) was added. This mixture was stirred at reflux under Ar for 23 h, cooled, diluted with water (200 ml) and extracted with ethyl acetate. The extract was dried (Na ₂ SO ₄ ) and evaporated to give the title compound (0.64 g, 81%) as a light brown resin.

NMR (CDCl ₃ ) δ: 2.00 (2H, m), 2.95 (2H, t, J 6), 3.0 (1H, b), 3.30 (2H, t, J 5.5) , 3.68 (3H, s), 6.20 (1H, d, J 3), 6.72 (1H, s), 6.87 (1H, d, J 3), 6.92 (1H, s) ).

Description 34

3- (1-methyl-5-nitro-4-indolyl) propionitrile (D34)

2- (1-methyl-5-nitro-4-indolyl) ethane methanesulfonate (D9) (1.60 g, 5.4 mmol) and sodium cyanide (0.53 g, 10.8 mmol) were stirred in dry dimethyl sulfoxide (15 ml) at 100 ° C under Ar for 5 h. After cooling, the mixture was diluted with ethyl acetate (150 ml), washed with water, dried (Na ₂ SO ₄ ) and evaporated to give the title compound (1.16 g, 94%) as a brown solid.

NMR (CDCl ₃ ) δ: 2.93 (2H, t, J 7), 3.60 (2H, t, J 7), 3.87 (3H, s), 6.80 (1H, d, J 3) ), 7.3 (2H, m), 8.05 (1H, d, J 8).

Description 35

3- (1-Methyl-5-nitro-4-indolyl) propanoic acid (D35)

3- (1-methyl-5-nitro-4-indolyl) propionitrile (D34) (1.16 g, 5.1 mmol) was stirred at reflux in concentrated hydrochloric acid (150 ml) for 7.5 h. After cooling, the dark mixture was extracted with ethyl acetate, the extract dried (Na ₂ SO ₄ ) and evaporated to give the title compound (0.74 g, 59%) as a brown solid.

NMR (CDCl ₃ ) δ: 2.88 (2H, t, J 7), 3.55 (2H, t, J 7), 3.84 (3H, s), 6.76 (1H, d, J 3) ), 7.21 (1H, d, J 3), 7.25 (1H, d, J 8), 7.98 (1H, d, J 8).

Description 36

Methyl 3- (1-methyl-5-nitro-4-indolyl) propanoate (D36)

3- (1-Methyl-5-nitro-4-indolyl) propanoic acid (D35) (0.94 g, 3.8 mmol) was stirred in methanol (10 ml) and thionyl chloride (1 ml) was added dropwise. The mixture was then stirred at reflux for 2 h and evaporated to a dark oil. Chromatography on silica gel eluting with dichloromethane gave the title compound (0.58 g, 58%) as a pale yellow solid.

NMR (CDCl ₃ ) δ: 2.81 (2H, t, J 7), 3.55 (2H, t, J 7), 3.70 (3H, s), 3.84 (3H, s), 6 , 73 (1H, d, J 3), 7.20 (1H, d, J 3), 7.24 (1H, d, J 8), 7.97 (1H, d, J 8).

Description 37

3- (1-methyl-5-nitro-4-indolyl) -1-propanol (D37)

Methyl-3- (1-methyl-5-nitro-4-indolyl) propanoate (D36) (0.46 g, 1.8 mmol) was stirred under Ar in tetrahydrofuran (25 ml) when lithium aluminum was added in portions. hydride (0.10 g, 2.6 mmol). After 3 h, water (0.5 ml), 2.5 M sodium hydroxide solution (0.75 ml) and water (1.5 ml) were added sequentially. The mixture was then dried (Na ₂ SO ₄ ) and evaporated to a brown oil. Silica gel chromatography eluting with 0-20% ethyl acetate in dichloromethane then gave the title compound (0.39 g, 95%) as an orange solid.

NMR (CDCl ₃ ) δ: 2.05 (2H, m), 3.34 (2H, t, J 7), 3.78 (2H, q, J 6), 3.85 (4H, m), 6 , 77 (1H, d, J 3), 7.18 (1H, d, J 3), 7.22 (1H, d, J 8), 7.96 (1H, d, J 8).

Description 38

3- (1-methyl-5-nitro-4-indolyl) -1-propyl methanesulfonate (D38)

It was prepared from 3- (1-methyl-5-nitro-4-indolyl) -1-propanol (D37) (0.39 g, 1.7 mmol) according to the procedure described in Description 8. This gave the title compound ( 0.54 g> 100%) as a brown oil that was used without purification.

NMR (CDCl ₃ ) δ: 2.25 (2H, m), 3.05 (3H, s), 3.36 (2H, t, J 7), 3.84 (3H, s), 4.37 ( 2H, t, J 7), 6.73 (1H, d, J 3), 7.21 (1H, d, J 3), 7.25 (1H, d, J 8), 7.98 (1H, d, J 8).

Description 39

3-methyl-6,7,8,9-tetrahydro-3H-pyrrolo [3,2-flquinoline (D39)

It was prepared from 3- (1-methyl-5-nitro-4-indolyl) -1-propyl methanesulfonate (D38) (0.54 g, 1.7 mmol) according to the method of operation described in 10. Neutralization with sodium hydrogen carbonate solution gave the title compound (0.21 g, 65%) as a brown oil.

NMR (CDCl ₃ ) δ: 2.05 (2H, m), 2.95 (2H, t, J 6), 3.32 (2H, t, J 6), 3.63 (1H, b), 3 , 73 (3H, s), 6.70 (1H, d, J 3), 6.86 (1H, d, J 8), 6.96 (1H, d, J 3), 7.00 (1H, d, J 8).

Description 40

6-methyl-8- (N-dimethylaminomethyl) -3- (3-pyridyl-carbamoyl) -2,3-dihydropyrrolo [3,2-elindole (D40)

6-methyl-3- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole (D2) (0.65 g, 0.0022 mol), suspended in 1,4-dioxane (10 ml ), while stirring at 5 ° C, 37% aqueous formaldehyde (0.2 ml) and 33% dimethylamine in ethanol (0.46 ml) in a mixture of 1,4-dioxane (3.5 ml) were added. ) and glacial acetic acid (3.5 ml). The mixture was stirred at room temperature for 20 h and then diluted with water (80 ml) and basified with 10% aqueous sodium hydroxide. Filtration gave the title compound (D40) (0.66 g, 85%) as a gray-white solid.

NMR (D ₆ -DMSO) δ: 2.17 (6H, s), 3.41 (2H, s), 3.50 (2H, t, J = 8 Hz), 3.71 (3H, s),

4.19 (2Η, t, J = 8Hz), 7.11-7.17 (1H, m), 7.26-7.34 (1H, m), 7.88 (1H, d, J = 8Hz) ), 7.95-8.01 (1H, m), 8.16-8.22 (1H, m), 8.58 (1H, s), 8.74 (1H, d, J = 4Hz).

Description 41

2,3-Dihydro-1- (1-imidazolylcarbonyl) -5-methyl-1H-pyrroloF2,3-f | indole (D41)

To a solution of carbonyldimidazole (0.71 g, 4.4 mmol) in DMF (25 ml) was added dihydropyrroloindole (D6) (0.69 g, 4 mmol) in DMF (5 ml). The mixture was stirred for 1 h at 110-140 ° C, then cooled and poured into water. After allowing the precipitate to form, the solid material was filtered off, washed with water and dried. The crude product was recrystallized from dichloromethane / gasoline to give the title compound (0.45 g, 42%), m.p. 178-180 ° C.

NMR (D ₆ -DMSO) δ: 3.22 (2H, t, J = 8), 3.77 (3H, s), 4.24 (3H, t, J = 8), 6.40 (IH, d, J = 4), 7.08 (1H, s), 7.28 (1H, d, J = 4), 7.38 (1H, s), 7.69 (1H, s), 7.83 (1H, broad s), 8.24 (1H, s).

Description 42

1- Acetyl-2-methylindoline (D42

2-methylindoline (5.0 g, 0.037 mol) acetic anhydride (40 ml) and pyridine (2 ml) were heated under argon at reflux for 4 h. The mixture was cooled, poured into water (100 ml), allowed to stand for 30 min, extracted (EtOAc, 2 x 250 ml), the combined organic solution washed (K 2 CO ₄ solution and dried (Na ₂ SO ₄ ). The solution was filtered. evaporated to dryness under reduced pressure and purified by column chromatography (SiO ₂ , Et ₂ O) to give the product as a yellow oil (6.57 g, 96%) which crystallized on condition.

NMR (CDCl3 δ: 1.30 (3H, d), 2.30 (3H, s), 2.68 (1H, d), 3.41 (1H, dd), 4.49 (1H, m), 7.04 (1H, t), 7.24 (2H, m), 8.18 (1H, d).

Description 43 1-acetyl-2-methyl-5-nitroindoline (D43) 1-acetyl-2-methylindoline (D42) (6.57 g, 37.5 mmol) was dissolved in AcOH (56 ml) and a conc. HNO ₃ (16 ml) and AcOH (8 ml). The blue solution was heated to 50 ° C below Ar, after which the solution was red-brown and began to emit brown vapor. After stirring at 50 ° C for 2 h, the solution was poured into water (500 ml), extracted with EtOAc (300 ml), washed with saturated aqueous Na ₂ CO 2 (200 ml), dried (Na ₂ SO ₄ ) and evaporated under reduced pressure. the pressure to get the orange oil. This was purified by column chromatography (SiO ₂ ) to give an orange oil (7.82 g, 95%) which solidified on condition.

NMR (CDCl ₃ ) δ: 1.3 (3H, d), 2.30 (3H, s), 2.72 (1H, d), 3.41 (1H, dd), 4.58 (1H, m ), 8.10 (2H, m).

Description 44 1-acetyl-5-amino-2-methylindoline (D44) 1-acetyl-2-methyl-5-nitroindoline (D43), (16 g, 0.073 mol) was dissolved in EtOH (180 ml), 10% was added Pd-C (0.3 g) and the suspension were hydrogenated at 50 ° C and 3.5 bar in a Parr shaker for 6 h. The mixture was filtered through Celite and evaporated to dryness to give product (D44) (14.0 g, 100%) as a red oil.

NMR (CDCl ₃ ) δ: 1.30 (3H, d), 2.24 (3H, s), 2.58 (1H, d), 3.38 (1H, dd), 4.41 (1H, m ), 6.58 (2H, m), 7.98 (1H, d).

Description 45 1-acetyl-5-i (2,2-dimethoxyethyl) -amino] -2-methylindoline (D45) 1-acetyl-5-amino-2-methylindoline (D44), (5.0 g, 0.027 mol) was dissolved in EtOH (100 ml), 10% Pd-C (0.5 g) was added followed by glycolaldehyde dimethylacetal (5.53 g of a 60% solution in water, 1.2 eq.). The mixture was hydrogenated at room temperature and pressure while stirring overnight, filtered through Celite, evaporated to near dryness, taken up in EtOAc (200 ml), washed (H ₂ O, brine), dried (Na ₂ SO ₄ ) and evaporated to dryness under reduced pressure to give product (D45) as a brown oil (7.69 g, 95%).

NMR (CDCl ₃ ) δ: 1.30 (3H, d), 2.24 (3H, s), 2.58 (1H, d), 3.23 (2H, d), 3.33 (1H, dd) ), 3.41 (6H, s), 4.41 (1H, m), 4.58 (1H, t), 6.51 (2H, m), 7.98 (1H, d).

Description 46 1-acetyl-2-methyl-2,3-dihydropyrrolo [2,3-f] indole (D46)

1-acetyl-5 - [(2,2-dimethoxyethyl) amino] -2-methylindoline (D45) (7.5 g, 0.027 mol) was dissolved in TFA (32 ml) and cooled to 0 ° C under Ar. TFAA (30 ml) was added and the brown solution was stirred at 0 ° C for 30 min. TFA (50 ml) was added and the mixture was refluxed for 6 days, evaporated to dryness and purified by column chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH 0.5-0.75%) to give the product as light pink solid (4.84 g, 58%). 2.84 g (9.2 mmol) was dissolved in MeOH (70 ml) and anhydrous K2 COg (1.90 g, 1.5 equiv) was added. The mixture was stirred vigorously for 1 h, briefly warmed to 40 ° C, cooled, evaporated to dryness and partitioned between water and CHC1 ₃ . The organic layer was dried (Na ₂ SO ₄ ) and evaporated to dryness under reduced pressure to give product (D46) (1.89 g, 96%) as a light brown solid.

NMR (CDCl ₃ ) 5: 0.72 (3H, d), 2.17 (1H, d), 2.52 (3H, s), 2.91 (1H, m), 3.98 (1H, m) ), 5.80 (1H, s), 6.58 (1H, s), 6.68 (1H, s), 7.70 (1H, s), 9.95 (1H, s, NH).

Description 47

2-methyl-2,3-dihydropyrrolo [2,3-flindol (D47) 1-acetyl-2-methyl-2,3-dihydropyrrolo [2,3-f] indole (D46) (2.55 g, 0. 0119 mol) in EtOH (30 ml) and 10% NaOH (120 ml) was heated at reflux under Ar overnight. The mixture was extracted with EtOAc (2 x 200 ml), the organic solution was dried (Na ₂ SO ₄ ), evaporated to dryness and purified by column chromatography (SiO ₂ , Et ₂ O / MeOH 1%) to give the product (D47) (1.4 g, 68%).

NMR (CDC1 ₃₎ δ: 1.32 (3H, d), 2.71 (IH, dd), 3.19 (IH, dd), 3.98 (IH, m), 6.38 (IH, s ), 6.83 (1H, s), 7.07 (1H, s), 7.12 (1H, s), 7.92 (1H, bs, NH).

Description 48 1-Acetyl-2 ₁ 5-dimethyl-2,3-dihydro-pyrrolo [2 ₁ 3-phenyl (D48)

As in description 5 using 1-acetyl-2-methyl-2,3-dihydropyrrolo [2,3-f] indole (D46) (1.35 g, 6.3 mmol) in dry DMF (10 ml), NaH (265 mg 80% suspension in oil) v

DMF (10 ml) and MeJ (0.55 ml, 1.4 equiv). After the digestion was complete, the mixture was evaporated to dryness, partitioned between saturated aqueous NaHCO 3 (100 mL) and CH ₂ Cl ₂ (3 x 100 mL), the organic solutions were dried, combined and evaporated to dryness and then purified by column chromatography ( SiO ₂ , Et ₂ O / MeOH 2-20%) to give product (D48) as a pale yellow solid (1.16 g, 81%).

NMR (CDCl ₃ ) δ: 1.30 (3H, d), 2.32 (3H, s), 2.40 (1H, d), 2.75 (1H, dd), 3.76 (3H, s) , NMe), 4.50 (1H, m), 6.47 (1H, s), 7.00 (1H, s), 7.12 (1H, s), 8.41 (1H, s).

Description 49

2,5-dimethyl-2,3-dihydropyrrolo (2,3-f] indole (D49) 1-acetyl-2,5-dimethyl-2,3-dihydropyrrolo [2,3-f] indole (D48) (1 , 1 g, 4.82 mmol) in EtOH (40 ml) and 10% NaOH (3.45 ml, 1.8 equiv) with solid NaOH (1.93, 10 equiv) were heated under reflux under Ar atmosphere (Fireston valve) for 6 h, partitioned between H ₂ O and CH ₂ C1 ₂ , the organic solutions were dried (Ni ^ SO *), evaporated to dryness and purified by column chromatography (SiO ₂ , CHCl ₃ / MeOH 10%), to give the product as an oil (370 mg, 37%).

NMR (CDCl ₃ ) δ: 1.30 (3H, d), 2.72 (1H, dd), 3.22 (1H, dd), 3.78 (3H, s, NMe), 4.00 (1H , m), 6.28 (1H, d), 6.89 (1H, d), 6.80 (1H, s), 7.08 (1H, s).

Example 1

5-methyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-phenyl] (EI)

Nicotinoyl azide (0.56 g, 3.8 mmol) was stirred at reflux under nitrogen in dry toluene (20 ml) for 0.75 h and cooled to room temperature. While stirring, 5-methyl-2,3-dihydropyrrolo [2,3-f] indole (D6) (0.59 g, nominally 3.4 mmol) in dichloromethane (20 ml) was added with immediate precipitation. The suspension was stirred for 2.5 h and then the solid was filtered off, washed with dichloromethane / toluene 1: 2 and dried thoroughly. This gave the title compound (0.60 g, 60%) as a light gray powder.

NMR (D ₆ -DMSO) S: 3.28 (2H, t, J 8), 3.73 (3H, s), 4.17 (2H, t, J 8), 6.81 (1H, d. J 3), 7.1-7.35 (3H, m), 8.0 (1H, m), 8.03 (1H, s), 8.21 (1H, m), 8.63 (1H, s), 8.76 (1H, d, J

2).

Found: C 70.1; H, 5.6; N 18,8%

C ₁₇ H ₁₆ N ₄ O requires C 69.8; H, 5.5; N 19.2% Found: M ⁺ 292, C _1? H ₁₆ N ₄ O requires 292

Example 2

6-methyl-3- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole (E2)

2- (1-methyl-5-nitro-4-indolyl) ethyl methanesulfonate (D9) (0.38 g, 1.3 mmol) was hydrogenated over 5% palladium on charcoal (0.23 g) in dry DMF (20 ml) at 5.6 bar H _{2 for} 2 h, diluted with ethanol (80 ml), filtered through diatomite and evaporated to a brown gum. This was dissolved in dichloromethane (10 ml) and digested with 3-pyridyl isocyanate obtained by pyrolysis of nicotinoyl azide (0.20 g, 2.35 mmol) as described in Example 1, except that before the crude mesylate salt was added isocyanate triethylamine (0.18 g, 1.3 mmol). After a reaction time of 16 h, filtration, washing and drying as before gave the title compound (0.16 g, 44%) as a light green powder.

NMR (D ₆ -DMSO) δ: 3.33 (2H, t, J 8), 3.77 (3H, s), 4.22 (2H, t, J 8), 6.28 (1H, d. J 3), 7.23 (1H, d, J 8), 7.3 (2H, m), 7.89 (1H, d, J 8), 8.0 (1H, d, J 8), 8 , 2 (1H, d, J 5), 8.61 (1H, s), 8.75 (1H, d, J 2).

Found: C 66.1; H, 5.4; N 17,8%

C ₁₇ H ₁₆ N ₄ OH ₂ O requires C 65.8; H, 5.8; N 18,0%

Found: M ⁺ 292, C _1? H ₁₆ N ₄ O requires 292

Example 3

5,7-dimethyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-flindole (E3)

It was prepared from 5,7-dimethyl-2,3-dihydropyrrolo [2,3-f] indole (D16) (0.30 g, nominally 1.6 mmol) according to the method of Example 1. This gave the title compound (0.19 g, 42% of (D 15)) as a white solid which still contained traces of toluene (NMR).

NMR (D ₆ -DMSO) 5: 2.19 (3H, s), 3.27 (2H, t, J 8), 3.67 (3H, s), 4.18 (2H, t, J 8) , 6.96 (1H, s), 7.21 (1H, s), 7.32 (1H, dd, J 7, 4), 8.00 (1H, s), 8.02 (1H, dd, J 7, 2), 8.22 (1H, dd, J 4.2), 8.62 (1H, s), 8.77 (1H, s).

Found: C, 70.6; H, 6.0% C, H, _{lg lg} N ₄ O requires C, 70.6; H 5.9% Found: M ⁺ .: 306 C _lg H ₁₈ N ₄ O requires 306

Example 4 1- (3-Pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole (E4)

This material was isolated by chromatography on silica gel eluting with 0-5% methanol in chloroform as impurity in a sample of 5-methyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole (El) . Recrystallization from ethanol / petroleum ether (boiling point 60-80 ° C) gave the compound as fine gray needles, m.p. 207-208 ° C (decomposition), which still contained crystallization ethanol. It can also be prepared by hydrolyzing D4 and then coupling to 3-pyridylisocyanate.

NMR (D ₆ -DMSO) δ: 1.15 (t, J 7; EtOH), 3.34 (2H, t, J 8), 3.55 (quintet, J 7; EtOH), 4.26 (2H , t, J 8), 4.48 (t, J 6; EtOH), 6.42 (1H, s, 7.31 (2H, s), 7.42 (1H, dd, J 7, 4), 8.05-8.2 (2H, m), 8.31 (1H, d, J 4), 8.72 (1H, s), 8.86 (1H, s), 10.95 (1H, s) ).

Found: C, 67.2; H, 6.1; N 17,6%

C ₁₆ H ₁₄ N ₄ O.0,75 (C ₂ H ₆ O) requires C 67.2; H, 6.0; N 17,9%

Found: M ⁺ 278, C ₁₆ H ₁₄ N ₄ O requires 278

Example 5

6-methyl-3- (4-pyridylcarbamoyl) -2,3-dihydropyrrolo [3,2-elindole (E5)

The title compound was prepared from 4-aminopyridine, l, l'-carbonyldiimidazole, 6-methyl- (2,3-dihydropyrrolo [3,2-e] indole) hydrochloride (D10) and triethylamine in methylene chloride / dimethylformamide. The reaction mixture was poured onto water to give the title compound in 98% yield, m.p. > 230 ° C.

NMR (D ₆ -DMSO) δ: 3.30 (2H, t, J 7), 3.75 (3H, s), 4.25 (2H, t, J 7), 6.30 (1H, d. J 4),

7.21 (1H, d, J 10), 7.30 (1H, d, J 4), 7.58 (1H, s), 7.62 (1H, s), 7.90 (1H, d. J 10), 8.31 (1H, s), 8.36 (1H, s), 8.75 (1H, s).

Found: C, 69.5; H, 5.6; N 19.1% C _1? H ₁₆ N ₄ O requires C 69.8; H, 5.5; N 19.1%

Found: M ⁺ 292, C ₁₇ H ₁₆ N ₄ O requires 292.

Example 6

6-methyl-3- (2-pyridylcarbamoyl) -2,3-dihydropyrrolo [3,2-eneindole (E6)

The title compound was prepared from 2-aminopyridine, Ι, Γ-carbonyldiimidazole, 6methyl- (2,3-dihydropyrrolo [3,2-e] indole) hydrochloride (D10) and triethylamine using a method of operation detailed for that described for Example 5, with a 39% yield, m.p. Mp 143-144 ° C.

NMR (D ₆ -DMSO) δ: 3.35 (2H, t, J 7), 3.85 (3H, s), 4.38 (2H, t, J 7), 6.40 (1H, d. J 4), 7.08-7.15 (1H, m), 7.33 (1H, d, J 7), 7.41 (1H, d, J 4), 7.79-7.89 (1H , m), 7.95-8.05 (2H, m), 8.39 (1H, d, J 4), 9.00 (1H, s).

Found: C, 69.6; H, 5.6; N 19.1% C _1? H ₁₆ N ₄ O requires C 69.8; H, 5.5; N 19,2%

Found: M ⁺ 292, C _1? H ₁₆ N ₄ O requires 292.

Example 7

5-methyl-1- (2-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-flindole (E7)

The title compound was prepared from 2-aminopyridine, Ι, Γ-carbonyldiimidazole and 5-methyl- (2,3-dihydropyrrolo [2,3-f] indole (D7) using a method similar to that described for Example 5, at 75% yield, mp 137-138 ° C.

NMR (D ₆ -DMSO) δ: 3.25 (2H, t, J 7), 3.75 (3H, s), 4.21 (2H, t, J 7), 6.31 (1H, d. J 4), 7.03 (1H, t, J 4), 7.20 (1H, s), 7.30 (1H, s), 7.75 (1H, t, J 7), 7.95 ( 1H, d, J 7), 8.04 (1H, s), 8.30 (1H, d, J 4), 8.95 (1H, s).

Found: C 66.0; H, 5.6; N, 18.0% C ^ H ^ O.I ^ O requires C, 65.8; H, 5.8; N 18,0%

Found: M ⁺ 292, C _1? H ₁₆ N ₄ O requires 292.

Example 8

5-methyl-1- (4-pyridylcarbamoyl-2,3-dihydropyrrolo [2,3-flindole (E8))

The title compound was prepared from 4-aminopyridine, Ι, Γ-carbonyldiimidazole and 5-methyl- (2,3-dihydropyrrolo [2,3-f] indole (D7) using a method similar to that described for Example 5, with 84% yield, mp 251-253 ° C.

NMR (D ₆ -DMSO) δ: 3.25 (2H, t, J 7), 3.72 (3H, s), 4.18 (2H, t, J 7), 6.32 (1H, d. J 4), 7.18 (1H, d, J 4), 7.27 (1H, s), 7.62 (2H, d, J 7), 8.05 (1H, s), 8.35 ( 2H, d, J 7), 8.85 (1H, s).

Found: C, 69.2; H, 5.7; N 19.0% C _1? H ₁₆ N ₄ O requires C 69.8; H, 5.5; N 19,2%

Found: M ⁺ 292, C _1? H ₁₆ N ₄ O requires 292.

Example 9

5-methyl-1- (3-pyridylcarbamoyl) -2,3,6,7-tetrahydropyrrolo [2,3-f] indole (E9)

5-methyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole (El) (0.8 g, 2.7 mmol) was treated with sodium cyanoborohydride (0.86 g, 13.7 mmol) in glacial acetic acid (20 ml) at room temperature for 4 h. Water (100 ml) was added and the mixture basified with 10% aqueous sodium hydroxide. Extraction with dichloromethane, followed by drying (Na ₂ SO ₄ ) and evaporation to dryness, gave a solid. Recrystallization from methanol / 60-80 gasoline gave the title compound (E9) (0.43 g, 53%) as a white crystalline solid from the ground. Mp 153-155 ° C.

NMR (D ₆ -DMSO) δ: 2.62 (3H, s), 2.80 (2H, t, J 8), 3.05 (2H, t, J 8), 3.17 (2H, t. J 8), 4.10 (2H, t, J 8), 6.40 (1H, s), 7.30 (1H, q, J 4), 7.65 (1H, s), 7.91- 7.98 (1H, m), 8.19 (1H, d, J 4), 8.55 (1H, s), 8.72 (1H, d, J 4).

Found: C 68.7; H, 6.2; N 18.9% C ₁₇ H _lg N ₄ O requires C 69.4; H, 6.2; N 19.0% Found: M ⁺ 294, C ₁₇ H _-1 N ₄ O requires 294.

Example 10

5-ethyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole (E101

The title compound was prepared from 5-ethyl-2,3-dihydropyrrolo [2,3-f] indole (D18) and

Of 3-pyridylisocyanate (prepared in situ from nicotinoyl azide) in 58% yield using a method similar to that for El, m.p. 202-203 ° C.

NMR (D ₆ -DMSO) δ: 1.33 (3H, t, J 8), 3.28 (2H, t, J 10), 4.16 (4H, m), 6.31 (1H, d.

J 3), 7.24 (1H, d, J 3), 7.30 (1H, s), 7.32 (1H, m), 8.00 (1H, m), 8.03 (1H, s) ), 8.22 (1H, m), 8.65 (1H, s), 8.77 (1H, s).

Found: C 70.70; H, 6.01; N 18.46% C _lg H ₁₈ N ₄ O requires C, 70.57; H, 5.92; N 18.29% Found: M ⁺ 306, _{Cg Hg Ng 4} O requires 306.

Example 11

5-n-propyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole (Eli)

Prepared as in Example 1 using nicotinoyl azide (0.19 g, 1.4 mmol) and 5-propyl-2,3-dihydropyrrolo [2,3-f] indole (0.23 g, 1.2 mol). Silica gel chromatography eluting with 5% MeOH / CH ₂ Cl ₂ gave the title compound (0.27 g, 70%) as a light green powder.

NMR (CDC1 ₃₎ δ: 0.93 (t, 3H, J = 8.4 Hz), 1.87 (m, 2H, J = 8.4 Hz), 3.31 (t, 2H, J = 8.4 Hz ), 4.05 (t, 2H, J = 8.4Hz), 4.28 (t, 2H, J = 8.4Hz), 6.45 (d, 1H, J = 2.8Hz), 6.77 (br s, 1H), 7.06 (d, 1H, J = 2.8Hz), 7.18 (s, 1H), 7.29 (m, 1H), 7.92 (s, 1H), 7 , 85 (m, 1H), 8.30 (dd, 1H, J = 2.8Hz), 8.51 (s, 1H).

Found: C, 70.54; H, 6.34; N 17.39% ^C i9 ^H 20 ^N 4 ° - ^1/6 Πζ ^{0 c 70} >⁵⁸; ^H, 6.39; ^{N 17} > ^33%

Found: M ⁺ 320, C ^ H ^^ O requires 320.

Example 12

5,6-dimethyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole (E12)

It was prepared from 5,6-dimethyl-2,3-dihydropyrrolo [2,3-f] indole (D23) (0.30 g, nominally 1.61 mmol) according to the method of Example 1. This gave the title compound (0.219 g, 39% of D22) as a brown-yellow powder containing residual CH ₂ C1 ₂ (NMR) and decomposing at about 225 ° C.

NMR (D ₆ -DMSO) δ: 2.36 (3H, s), 3.26 (2H, t, J 8), 3.60 (3H, s), 4.17 (2H, t, J 8) , 6.11 (1H, s), 7.21 (1H, s), 7.32 (1H, dd, J 7, 4), 7.93 (1H, s), 8.00 (1H, d. J 7), 8.21 (1H, d, J 4), 8.63 (1H, s), 8.75 (1H, d, J 2).

Found: C, 69.2; H, 5.9; N, 17.6%,

C ₁₈ H ₁₈ N ₄ O. (0.08 CT ^ CLj) requires C 69.3; H, 5.8; N 17,9%

Found: M ⁺ 306, C _lg H _lg N ₄ O requires 306.

Example 13

6,7-dimethyl-3- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole (E13)

It was prepared from 6,7-dimethyl-2,3-dihydropyrrolo [3,2-e] indole (D24) (0.124 g, 0.67 mmol) according to the method of Example 1. This gave the title compound (0.128 g , 62%) as a light brown powder containing residual CH ₂ C1 ₂ (NMR), m.p. 216-218 ° C (dec.).

NMR (D ₆ -DMSO) δ: 2.45 (3H, s), 3.33 (2H, t, J 8), 3.70 (3H, s), 4.28 (2H, t, J 8) , 6.15 (1H, s), 7.21 (1H, d, J 9), 7.37 (1H, dd, J 8, 5), 7.86 (1H, d, J 9), 8. 06 (1H, dm, J 9), 8.26 (1H, d, J 5), 8.67 (1H, s), 8.81 (1H, d, J 2).

Found: C, 69.4; H, 5.9; N, 17.7%,

C _lg H _lg N ₄ O. (0.08 CH ₂ C1 ₂ ) requires C 69.3; H, 5.8; N 17,9%

Found: M ⁺ 306, C _lg H _lg N ₄ O requires 306.

Example 14 1-Methyl-N- (3-pyridyl) -5,6,7,8-tetrahydro-1H-pyrrolo [2,3-g] quinoline-5-carboxamide (E14)

This material was prepared from 1-methyl-5,6,7,8-tetrahydro-1H-pyrrolo [2,3-g] quinoline (D33) (0.64 g, 3.4 mmol) according to the method of Example 1 This gave a pale orange solid (0.64 g, 60%). Recrystallization from ethanol / petroleum ether (boiling point 60-80 ° C) gave glossy bright orange tiles (0.56 g), m.p. 154.5-155.5 ° C.

NMR (D ₆ -DMSO) δ: 1.93 (2H, m), 2.80 (2H, t, J 7), 3.72 (2H, t, J 7), 3.77 (3H, s) , 6.34 (1H, d, J 3), 7.25 (3H, m), 7.49 (1H, s), 7.89 (1H, dt, J 8.2), 8.25 (1H , dd, J 4.2, 8.65 (2H, m).

Found: C, 70.2; H, 5.4; N 18.0%, C ₁₈ H ₁₈ N ₄ O requires C 70.6; H, 5.9; N 18,3%

Found: M ⁺ 306, C ₁₈ H ₁₈ N ₄ O requires 306.

Example 15

3-methyl-N- (3-pyridyl) -6,7,8,9-tetrahydro-3H-pyrrolo [2,3-f] quinoline-6-carboxamide (E15)

It was prepared from 3-methyl-6,7,8,9-tetrahydro-3H-pyrrolo [3,2-f] quinoline (D39) (0.21 g, 1.1 mmol) according to the method of Example 1. The reaction mixture was evaporated to give a brown oil which was chromatographed on silica gel eluting with 0 to 10% methanol / dichloromethane. Finally, recrystallization from ethanol / petroleum ether (60-80 ° C) gave the title compound (0.26 g, 75%) as a yellowish solid, m.p. 174-175 ° C, which contained residual ethanol (NMR).

NMR (D ₆ -DMSO) δ: 1.98 (2H, m), 2.94 (2H, t, J 7), 3.75 (5H, m), 6.41 (1H, d, J 3) , 7.13 (1H, d, J 8), 7.23 (1H, d, J 8), 7.25-7.30 (2H, m), 7.89 (1H, m), 8.15 (1H, d, J 3), 8.64 (1H, m), 8.77 (1H, s).

Found: C, 70.2; H, 6.1; N, 17.8%,

C _lg H ₁₈ N ₄ O (0.14 C ₂ H ₆ O) requires C, 70.2; H, 6.1; N 17,9%

Found: M ⁺ 306, C _lg H _lg N ₄ O requires 306.

Example 16

6-Methyl-3- (2-methyl-4-quinolinylcarbamoin-2,3-dihydro-pyrrolo [2,3-elindole] (E16)

The title compound was prepared from 2-methyl-4-aminoquinoline, Ι, Γ-carbonyl diimidazole, 6-methyl- (2,3-dihydropyrrolo [3,2-e] indole) hydrochloride (D10) and triethylamine with 76% by profit, m.p. > 230 ° C.

NMR (D ₆ -DMSO) δ: 2.60 (3H, s), 3.34 (2H, t, J 7), 3.75 (3H, s), 4.42 (2H, t, J 7) , 6.31 (1H, d, J 3), 7.25 (1H, d, J 8), 7.35 (1H, d, J 3), 7.52 (1H, t, J 7), 7 , 70 (1H, t, J 7), 7.80 (1H, s), 7.88 (1H, s), 7.92 (1H, s), 8.17 (1H, d, J 7). 8.70 (1H, s).

Found: C, 73.3; H, 5.8; N, 15.5%,

C ^ H ^ OJA H ₂ O requires C 73.3; H, 5.7; N 15,5%

Found: M ⁺ 356, C ₂₂ H ₂₀ N ₄ O requires 356.

Example 17

6-Methyl-3- (5-quinolinylcarbamoyl) -2,3-dihydro-pyrrolo [3,2-elindole (E17)

The title compound was prepared from 5-aminoquinoline, N, N-carbonyldiimidazole, 6-methyl- (2,3-dihydropyrrolo [3,2-e] indole) hydrochloride (D10) and triethylamine in 42% yield, m.p. > 240 ° C.

NMR (D ₆ -DMSO) δ: 3.35 (2H, t, J 7), 3.75 (3H, s), 4.38 (2H, t, J 7), 6.30 (1H, d. J 4), 7.19 (1H, d, J 8), 7.30 (1H, d, J 4), 7.50-7.58 (1H, m), 7.62 (1H, d, J 7), 7.75 (1H, t, J 7), 7.83-7.93 (2H, m), 8.45 (1H, d, J 7), 8.70 (1H, s), 8 , 92 (1H, d, J 4).

Found: C, 73.6; H, 5.50; N 16,3%

C ₂₁ H ₁₈ N ₄ O requires C 73.7; H, 5.3; N 16,4%

Found .: M ⁺ 342, C ₂₁ H _lg N ₄ O requires 342nd

Example 18

6-Methyl-3- (3-quinolinylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole (E18)

The title compound was prepared from 3-aminoquinoline, Ι, Γ-carbonyl diimidazole, 6-methyl- (2,3-dihydropyrrolo [3,2-e] indole) hydrochloride (D10) and triethylamine in 53% yield, m.p. 222-224 ° C.

NMR (D ₆ -DMSO) δ: 3.35 (2H, d, J 7), 3.78 (3H, s), 4.32 (2H, d, J 7), 6.30 (1H, d. J 4), 7.25 (1H, d, J 8), 7.32 (1H, d, J 4), 7.50-7.68 (2H, m), 7.83-8.00 (3H , m), 8.54 (1H, d, J 4), 8.82 (1H, s), 9.05 (1H, s).

Found: C, 72.9; H, 5.5; N 16,2%

C ₂₁ H ₁₈ N ₄ O. 'A II ₂ O requires C 72.7; H, 5.3; N 16.2% Found .: M ⁺ 342, C ₂₁ H _lg N ₄ O requires 342nd

Example 19

5-Methyl-1- (2-methyl-4-quinolinylcarbamoyl) -2,3-dihydropyrrolo [2,3-flindole (E19)

The title compound was prepared from 2-methyl-4-aminoquinoline, Ι, Γ-carbonyl diimidazole, and 5-methyl- (2,3-dihydropyrrolo [2,3-f] indole (D6) in 57% yield, m.p. > 240 ° C.

NMR (D ₆ -DMSO) S: 2.64 (3H, s), 3.30 (2H, t, J 7), 3.72 (3H, s), 4.38 (2H, t, J 7) , 6.3 (1H, d, J 4), 7.20 (1H, d, J 4), 7.30 (1H, s), 7.53 (1H, t, J 7), 7.70 ( 1H, t, J 7), 7.78 (1H, s), 7.90 (1H, d, J 7), 8.08 (1H, s), 8.15 (1H, d, J 7). 8.73 (1H, s).

Example 20

6,8-dimethyl-3- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole (E20)

6- methyl-8- (N, N-dimethylaminomethyl) -3- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [3,2-eindol (D40) (0.5 g, 0.0014 mol) was hydrogenated at STP in ethanol (50 ml) over 10% palladium on charcoal as catalyst (0.5 g) for 24 h and then at 3.5 bar for 4 h. Filtration through diatomite followed by evaporation to dryness gave the crude product. Flash chromatography on silica gel eluting with 0-5% methanol / dichloromethane followed by recrystallization from ethyl acetate / methanol gave the title compound (E20) (0.174 g, 40%) as white crystals of m.p. Mp 228-230 ° C.

NMR (D ₆ -DMSO) δ: 2.32 (3H, s), 3.55 (2H, t, J = 8 Hz), 3.65 (3H, s), 4.21 (2H, t, J = 8Hz), 7.00 (1H, s,), 7.10 (1H, d, J = 8Hz), 7.24-7.33 (1H, m), 7.83 (1H, d, J = 8Hz) ), 7.94-8.03 (1H, m), 8.19 (1H, d, J = 4Hz), 8.57 (1H, s), 8.73 (1H, d, J = 3Hz).

Found: C, 69.77; H, 6.00; N, 18.08%,

C _lg H ₁₈ N ₄ 0.1 / 5 H ₂ O requires C, 69.77; H, 5.94; N 18.09%

Found: M ⁺ 306, C _lg H _lg N ₄ O requires 306.

Example 21

6-methyl-3- (3-pyridylcarbamoyl) -2,3,7,8-tetrahydropyrrolo [3,2-e] indole (E21)

6-Methyl-3- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole (E2) (1.0 g, 0.0034 mol) was dissolved in glacial acetic acid (25 ml) and was treated at room temperature with sodium cyanoborohydride (1.0 g, 0.016 mol). The mixture was stirred for 4 h and then diluted with water (100 ml). The mixture was basified with 10% aqueous sodium hydroxide and the product extracted into dichloromethane and dried with sodium sulfate. Evaporation of the solvent, followed by flash chromatography on silica gel eluting with 0-5% methanol / dichloromethane, gave a white solid residue. Recrystallization from ethyl acetate / gasoline (60-80 ° C) gave the title compound (E21) as white crystals (0.68 g, 67%), m.p. 201-203 ° C.

NMR (D ₆ -DMSO) S: 2.75 (3H, s), 2.89 (2H, t, J = 8 Hz), 3.15 (2H, t, J = 8 Hz), 3.31 (2H. t, J = 8Hz), 4.22 (2H, t, J = 8Hz), 6.40 (1H, d, J = 7Hz), 7.33-7.45 (1H, m), 7.70 ( 1H, d, J = 7Hz), 8.03-8.12 (1H, m), 8.30 (1H, d, J = 4Hz), 8.65 (1H, s), 8.85 (1H, d, J = 4Hz).

Found: C, 69.07; H, 6.29; N, 18.90%,

C ₁₇ H _lg N ₄ O requires C, 69.37; H, 6.16; N 19.03%

Found: M ⁺ 294, C ₁₇ H _-1 N ₄ O requires 294.

Example 22

5-Methyl-1- (2-pyrazinylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole (E22)

The title compound was prepared from 2-aminopyrazine anion (prepared using sodium hydride), 1,1'-carbonyldiimidazole and 5-methyl-2,3dihydropyrrolo [2,3-f] indole in dimethylformamide using a method similar to that which described for Example 5, at 75% yield, m.p. 196-198 ° C.

NMR (D ₆ -DMSO) δ: 3.26 (2H, t, J = 10), 3.76 (3H, s), 4.25 (2H, t, J = 10), 6.33 (IH, d, J = 3), 7.20 (1H, d, J = 3), 7.28 (1H, s), 8.07 (1H, s), 8.28 (1H, d, J = 2) , 8.37 (1H, d, J = 2), 9.19 (1H, m), 9.38 (1H, s).

Found: C, 65.55; H, 5.36; N, 23.54%,

C ₁₆ H ₁₅ N ₅ O requires C 65.52; H, 5.15; N, 23.88%

Found: M ⁺ 293, C ₁₆ H ₁₅ N ₅ O requires 293.

Example 23

2,3-Dihydro-5-methyl-1- (3-methyl-5-isothiazolylcarbamoyl) -1H-pyrrolo [3,2-e] indole (E23)

A solution of 5-amino-3-methylisothiazole hydrochloride (0.38 g, 2.5 mmol) and triethylamine (0, respectively) was added to an ice-cooled solution of carbonyldiimidazole (DCI) (0.445 g, 2.75 mmol) in dichloromethane (15 ml). 35 ml, 2.5 mmol) in dichloromethane (15 ml). The mixture was stirred for 1 h at 0 ° C and then evaporated to dryness. The residue was dissolved in dimethyl formamide (DMF) (15 ml) and dihydropyrroloindole hydrochloride (D10) (0.52 g, 2.5 mmol) and triethylamine (0.35 ml) in DMF (2.5 ml) were added to this solution. The mixture was heated under stirring for 1 h at about 130 ° C, then cooled and poured into water. The solid was filtered off, washed with water and dried, then triturated with dichloromethane / methanol. The trituration of the pellet was concentrated with the addition of gasoline to obtain a precipitate which was filtered off and combined with the residue from the trituration. Drying in vacuo gave the title compound (0.42 g, 54%), m.p. > 250 ° C.

NMR (D ₆ -DMSO) S: 2.29 (3H, s), 3.33 (2H, t, J = 7), 3.75 (3H, s), 4.20 (2H, t, J = 7), 6.29 (1H, d, J = 4), 6.74 (1H, s), 7.25 (1H, d, J = 9), 7.32 (1H, d, J = 4) , 7.90 (1H, d, J = 9), 10.41 (1H, s).

Found: C, 61.13; H, 5.16; N, 17.84%,

C ₁₆ H ₁₆ N ₄ OS requires C 61.52; H, 5.16; N, 17.93%

Example 24

2,3-Dihydro-5-methyl-1- (3-methyl-5-isothiazolylcarbamoyl) -1H-pyrrolo [2,3-f] indole (E24)

The title compound was prepared by the method of E23 using 5-amino-3methylisothiazole hydrochloride (0.60 g, 4 mmol), CDI (0.71 g, 4.4 mmol), triethylamine (0.56 ml, 4 mmol) and dihydropyrroloindole (D6) (0.69 g, 4 mmol). Triethylamine was only added with isothiazole hydrochloride.

After the final mixture was poured into water and the product filtered off, the crude material was recrystallized from dichloromethane / methanol / gasoline to give the title compound (0.76 g, 61%), m.p. 254-255 ° C.

NMR (D ₆ -DMSO) δ: 2.30 (3H, s), 3.30 (2H, t, J = 7), 3.74 (3H, s), 4.14 (2H, t, J = 7), 6.35 (1H, d, J = 4), 6.76 (1H, s), 7.20 (1H, d, J = 4), 7.29 (1H, s), 8.08 (1H, s), 10.48 (1H, s).

Found: C, 61.31; H, 5.24; N, 17.74%,

C ₁₆ H ₁₆ N ₄ OS requires C 61.52; H, 5.15; N, 17.93%

Example 25

2,3-Dihydro-5-methyl-1- (5-quinolylcarbamoyl) -1H-pyrrolo [2,3-f] indole (E25)

The title compound was prepared by the method of E23 using 5-aminoquinoline (0.58 g, 4 mmol), CDI (0.71 g, 4.4 mmol) and dihydropyrroindole (D6) (0.69 g, 4 mmol) . Triethylamine was not used and the initial reaction mixture was stirred for 1 h at 0 ° C and 0.5 h at room temperature.

After the final mixture was poured into water and the product filtered off, the crude material was recrystallized from dichloromethane / methane / gasoline to give the title compound (0.48 g, 35%), m.p. 240-243 ° C.

NMR (D ₆ -DMSO) δ: 3.43 (2H, t, J = 8), 3.84 (3H, s), 4.42 (2H, t, J = 8), 6.37 (IH, d, J = 4), 7.27 (1H, d, J = 4), 7.38 (1H, s), 7.63 (1H, dd, J = 8.5), 7.72 (1H, d, J = 8), 7.87 (1H, t, J = 8), 7.99 (1H, d, J = 8), 8.08 (1H, s), 8.55 (1H, d. J = 8), 8.84 (1H, s), 9.00 (1H, d, J = 5).

Found: C, 72.85; H, 5.45; N, 16.36%,

C ₂₁ H ₁₈ N ₄ O requires C 73.67; H, 5.30; N, 16.36%.

Example 26

2,3-Dihydro-5-methyl-1- (3-methyl-5-isoxazolylcarbamoyl) -1H-pyrrolo [2,3-f] indole (E261

To a suspension of sodium hydride (80% in oil, 40 mg, 1.33 mmol) in dry DMF (10 ml) was added 5-amino-3-methylisoxazole (0.12 g, 1.24 mmol) and the mixture was stirred 20 min at 0 ° C. Imidazolylcarbamoyl pyrroloindole (D41) (0.32 g, 1.20 mmol) was then added and the mixture was stirred for 1.5 h at 100-130 ° C, then cooled and poured into water. The precipitate was filtered off, washed with water and dried to give the title compound (0.17 g, 48%), m.p. Mp 212-215 ° C.

NMR (D ₆ -DMSO) δ: 2.19 (3H, s), 3.24 (2H, t, J = 7), 3.73 (3H, s), 4.14 (2H, t, J = 7), 6.07 (1H, s), 6.33 (1H, d, J = 4), 7.20 (1H, d, J = 4), 7.28 (1H, s), 8.05 (1H, s), 10.20 (1H, s).

Found: C, 64.83; H, 5.51; N, 18.83%,

C ₁₆ H ₁₆ N ₄ O ₂ requires: C 64.85; H, 5.44; N, 18.91%.

Example 27

N- (5-isoquinolyl) -5-methyl-2,3-dihydropyrrolo [2,3-f] indole-1-carboxamide (E27)

The title compound was prepared from 5-aminoisoquinoline, carbonyl diimidazole and 1-amino-5-methyl-2,3-dihydropyrrolo [2,3-f] indole using a method similar to that described for Example 25, with 15% with the profit, m.p. 245-250 ° C.

NMR (D ₆ -DMSO) δ: 3.48 (2H, t, J = 6), 3.86 (3H, s), 4.42 (2H, t, J = 6), 6.38 (IH, d, J = 2), 7.28 (1H, d, J = 2), 7.40 (1H, s), 7.80 (1H, t, J = 6), 7.91 (1H, d. J = 6), 7.99 (1H, d, J = 6), 8.08 (2H, d, J = 6), 8.60 (1H, d, J = 6), 8.79 (1H, s), 9.42 (1H, s).

Found .: M ⁺ 342.40, C ₂₁ H _lg N ₄ O requires: 342.40.

Example 28

N- (6-quinolyl) -5-methyl-2,3-dihydro-pyrrolo [2,3-f] indole-1-carboxamide (E28)

The title compound was prepared from 6-aminoquinoline, carbonyl diimidazole and 1-amino-5-methyl-2,3-dihydro-pyrrolo [2,3-f] indole using a method similar to that described for Example 25, with 12% profit, m.p. 217-220 ° C.

NMR (D ₆ -DMSO) δ: 3.30 (2H, t, J = 6), 3.74 (3H, s), 4.23 (2H, t, J = 6), 6.32 (IH, d,

J = 2), 7.20 (1H, d, J = 2), 7.29 (1H, s), 7.42-7.49 (1H, m), 7.94 (2H, s), 8 , 09 (1H, s),

8.27 (2H, m), 8.74-8.79 (2H, m).

Found .: M ⁺ 342.40, C ₂₁ H _lg N ₄ O requires: 342.40.

Example 29

2-methyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole (E29)

Nicotinoyl azide (0.142 g, 0.96 mmol) was stirred at reflux under Ar in dry toluene (40 ml) for 1 h, allowed to cool and 2-methyl-2,3-dihydropyrrolo [2,3-f] indole (D47) was added. ) (0.15 g, 0.87 mmol) in dry toluene (10 ml). The solution was stirred for 1 h, the resulting precipitate was filtered off, washed with a small amount of Et ₂ O and dried thoroughly to give the title compound (E29) (70 mg, 28%).

NMR (D ₆ -DMSO) δ: 1.25 (3H, d), 2.75 (IH, d), 3.46 (IH, dd), 4.82 (IH, m), 6.32 (IH, s), 7.20 (1H, s), 7.33 (1H, dd), 8.01 (1H, m), 8.01 (1H, s), 8.21 (1H, d), 8. 68 (1H, s), 8.78 (1H, d), 10.83 (1H, bs, NH).

Found: C, 69.69; H, 5.71; N 19.16%

C ₁₇ H ₁₆ N ₄ O requires C 69.85; H, 5.52; N 19.16%

Found: M ⁺ 292, C ₁₇ H ₁₆ N ₄ O requires: 292.

Example 30

2,5-dimethyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-flindole (E30)

Nicotinoyl azide (28.7 mg, 1.1 eq) was stirred at reflux under Ar in dry toluene (40 ml) for 1 h, allowed to cool and 2.5-dimethyl-2,3-dihydropyrrolo [2,3- f] indole (D49) (0.37 g, 1.76 mmol) in dry toluene (10 ml). The solution was stirred for 1 h, evaporated to dryness and purified by column chromatography (SiO ₂ , CHCl ₃ / MeOH 9: 1) to give the product as a light yellow oil, which was triturated with Et ₂ O to give a light yellow solid (170 mg).

NMR (CDCl ₃ ) δ: 1.33 (3H, d) 2.89 (1H, d), 3.62 (1H, dd), 3.84 (3H, s, NMe), 4.96 (1H. m), 6.42 (1H, d), 7.30 (1H, d), 7.39 (1H, s), 7.42 (1H, dd), 8.08 (1H, s), 8. 13 (1H, s), 8.32 (1H, d), 8.80 (1H, s), 8.85 (1H, s, NH).

Found: C, 69.98; H, 6.11; N, 17.72%

C ₁₈ H ₁₈ N ₄ Ol / 6 H ₂ O requires C 69.90; H, 6.04; N 18.10% Found: M ⁺ 306, _{Cg Hg Ng 4} O requires: 306.

Example 31

5-ethyl-1- (3-pyridylcarbamoyl) -2,3,6,7-tetrahydropyrrolo [2,3-f] indole (E31)

5-ethyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-findol (E10) (0.7 g, 0.0023 mol) was dissolved in glacial acetic acid (15 ml) and treated with sodium cyanoborohydride (0.72 g, 0.0114 mol) at room temperature with stirring. The mixture was stirred for 1 h, then diluted with water (100 ml), basified with 10% aqueous sodium hydroxide and extracted with dichloromethane (2 x 100 ml). The organic solution was dried (Na ₂ SO ₄ ), filtered and evaporated to dryness. Flash chromatography on silica gel eluting with 2-5% methanol / dichloromethane followed by recrystallization of the resulting ethyl acetate / gasoline solid by boiling. 40-60 ° C gave the title compound (E31) as a white crystalline solid (0.45 g, 64%), m.p. Mp 151-153 ° C.

NMR (D ₆ -DMSO) 5: 1.10 (3H, t, J 7) 2.81 (2H, t, J 7), 2.98-3.11 (4H, m), 3.21 (2H , t, J 7), 4.07 (2H, t, J 7), 6.41 (1H, s), 7.29 (1H, q, J 5), 7.62 (1H, s), 7 , 93-7.96 (1H, m), 8.19 (1H, d, J 2), 8.51 (1H, s), 8.70 (1H, s).

Found: C, 69.56; H 6.50; N 18.04% (^ Η ^ Ο.Ι / δ H ₂ O requires: C 69.58; H 6.57; N 18.03%

Found .: M ⁺ 308 C _lg H ₂₀ N ₄ O requires:. 308

Example 32

5-methyl-1- (2-methyl-4-quinolinylcarbamoyl) -2,3,6,7-tetrahydropyrrolo [2,3-f] indole (E32)

5-Methyl-1- (2-methyl-4-quinolinylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole (E19) (0.7 g, 0.002 mol) in glacial acetic acid (15 ml) was treated with sodium cyanoborohydride (0.58 g, 0.009 mol) as in the method of Example 9 to give the title compound (E32) as light yellow crystals (0.44 g, 63%), m.p. 242-244 ° C.

NMR (D ₆ -DMSO) δ: 2.61 (3H, s), 2.69 (3H, s), 2.80 (2H, t, J 7), 3.10 to 3.22 (4H, m ), 4.29 (2H, t, J 7), 6.45 (1H, s), 7.45-7.53 (1H, m), 7.64-7.77 (3H, m), 7 , 88 (1H, d, J 8), 8.12 (1H, d, J 8), 8.54 (1H, s).

Found: C, 72.69; H, 6.37; N, 15.36%

C ^ EL ^ Ol / ⁴ H ₂ O requires: C 72.83; H, 6.21; N, 15.45%

Found: M ⁺ 358, C ₂₂ H ₂₂ N ₄ O requires: 358.

Example 33

5-Methyl-1- (2-methyl-4-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-flindole (E33)

The title compound was prepared from 2-methyl-4-aminopyridine anion (prepared using sodium hydride), Ι, Γ-carbonyldiimidazole and 5-methyl-2,3dihydropyrrolo [2,3-f] indole in dimethylformamide using a similar mode of operation to the one described in Example 5, with a 45% gain.

NMR (D ₆ -DMSO) δ: 2.40 (3H, s), 3.27 (2H, t, J 7), 3.72 (3H, s), 4.18 (2H, t, J 7) , 6.32 (1H, d, J 3), 7.19 (1H, d, J 3), 7.26 (1H, s), 7.43 (1H, d, J 8), 7.50 ( 1H, s), 8.05 (1H, s), 8.22 (1H, d, J 8), 8.74 (1H, s).

Found .: M ⁺ 306, C H _{lg lg} N ₄ O requires: 306th

Example 34

Pharmaceutical preparations for oral administration can be prepared by combining the following:

1) A solid dosage preparation

a compound of formula I % wt / wt 10% magnesium stearate 0.5% starch 2.0% HPM cellulose 1.0% microcrystalline cellulose 86.5%

The mixture can be compressed into tablets or filled into hard gelatin capsules.

The tablet may be coated by applying a suspension of a film maker (e.g., HPM cellulose), a pigment (e.g. titanium dioxide) and a plasticizer (e.g. diethyl phthalate) and the film is dried by solvent evaporation. The film coating may comprise 2.0% to 6.0% by weight of the tablet, preferably about 3.0%.

2) Capsule Compound of Formula 1 Polyethylene Glycol% w / w 20%

80%

The drug compound is dispersed or dissolved in a liquid carrier with the addition of a thickener, if necessary. The preparation is then sealed with a suitable technology into a soft gelatin capsule.

Example 35

The pharmaceutical preparation for parenteral administration can be prepared by combining the following:

A preferred amount of the compounds of Formula 1 is saline

1.0% 99.0%

The solution is sterilized and sealed in sterile containers.

Pharmacological information

Binding of iH]-mesulergin to rat or human 5-HT _2C clones expressed in 293 cells in vitro

Evidence from the literature suggests that 5-HT _2C antagonists could have multiple therapeutic inclusions, including treatment for anxiety, migraine, depression, eating disorders, and obsessive compulsive disorders (Curzon and Kennett, 1990; Fozard and Gray, 1989) in AIzheimer's Disease (Lawlor, 1989, J. Arch. Gen. Psychiat. Vol. 46, p. 542).

The affinity of test drugs for the 5-HT _2C binding site can be determined by determining their ability to displace [ ³ H]-mesulergin from 5-HT _2C clones expressed in 293 cells (Julius et al., 1988). The method used was similar to the method of Pazosa et al., 1984.

The cell suspension (400 ml) was incubated with [ ³ H]-mesulergin (0.5 nM) in Tris HCl buffer (pH 7.4) at 37 ° C for 30 min. Non-specific binding was measured in the presence of myanserin (ΙΟ ^ Μ). In a volume of 50 ml, 10 concentrations of test drug (3 x 10 ' ⁹ to a final concentration of 10 ⁴ M) were added. The total volume of the analysis was 500 ml. Incubation was terminated by rapid filtration using a Brandel cell collector and radioactivity was measured using a scintillation counter. IC ₅₀ values were determined using a 4-parameter logistic program (DeLean 1978) and pK (negative logarithm of the inhibition constant) was calculated from the Cheng Prusoff equation, where:

+ C Kd

K = inhibition constant.

C = concentration of [ ³ H] -mesulergin

Kd = affinity of mesulergin for the 5-HT _2C binding sites

Curzon, G.A. and Kennett, G.A. (1990). TIPS, Vol. 11,181-182. Fozard, J. R., & Gray, J. A. (1989). TIPS, Vol. 10, 307-309. Pazos, A. et al. (1984). Eur. J. Pharmacol., 106, 531-538.

Julius et al. (1988) Science 241,558-564.

DeLean A, Munson P.J., Rodbaud D (1978) Am. J. Physiol 235, E97 – E102.

Results: The compounds of Examples 1 to 11 have pK values. from 6.04 to 9.29.

Reversion to mCPP-induced hypolocomotion

Administration of m- (chlorophenyl) piperazine (mCPP) triggers hypolocomotion in rats (Kennett and Curzon 1988; Luckie et al. 1989), as demonstrated by the related drug 1- (m-trifluoromethylphenyl) piperazine (TFMPP) (Lučki and Frazer 1982; Kennett and Curzon 1988). This effect was blocked by non-specific 5-HT _2C / 5-HT _2A receptor antagonists myanserin, ciproheptadine and metergoline and possibly mesulergin. However, it was not blocked by either the 5-HT4 receptor antagonist ketanserin and ritanserin at appropriate doses (Kennett and Curzon 1991), nor the 5-HT _1A , 5-HT _1B , 5-HT ₃ a ₂ receptor or dopamine D ₂ receptor antagonists. Therefore, they are thought to mediate the effect of m- (chlorophenyl) -piperazine 5-HT _2c receptors (Kennett and Curzon 1988), as confirmed by later studies (Lučki et al. 1989). Because it causes mCPP hypolocomotion when infused into the brain ventricles, this effect is likely to be mediated centrally (Kennett and Curzon 1988).

Hypolocal induced mCPP was measured in automated locomotion cages 56 cm long, 16.5 cm wide and 25 cm high, made of black Perspex. The cages crossed two light rays at both ends of the ground at a height. The successive interruptions of these beams made it possible to measure the number of transitions through the cage.

Male Sprague Dawley rats (200-250 g) (Charles River) were housed in groups after 6.1 h before the test, given oral medication, and 40 min later, mCPP (7 mg / kg ip). red light in the adjacent space into individual automated cages in groups of four. After 10 min, the test was completed. The reversal of mCPP-induced hypolocomotion was considered to be evidence of the central anatagonist properties of 5-HT _2C receptors in vivo.

Kennett, G. A., Curzon, G., (1991). Brit. J. Pharmacol. 103,2016-2020.

Lučki, I., Frazer, A., (1982). Am. Soc. Neurosci. 8 (abstr.), 101.

Lučki, I., Ward, H.R., Frazer, A., (1989). J. Pharmacol. Exp. Therap. 249,155-164.

Results: The compounds of Examples 1, 2 and 4 had ID ₅₀ values from 5.5 to 22.3 mg / kg

p.o.

Social interaction test

Potential anxiolytic properties were determined using a social interaction test based on the test described by File (1980 J. Neurosci. Meth., 2, 219). Active social interaction between male rats is usually quantified by counting interactive behaviors such as monitoring, nurturing, wrapping, climbing over and under, biting, bouncing, and scrolling. This behavior is suppressed when the rats meet each other in an environment that is new and highly illuminated. In these circumstances, an anxiolytic drug will improve the level of social interaction.

The rats were housed in groups of 8 for 8 days in a holding room adjacent to the experimental chamber. 3 days before the experiment day, we individually housed them in the same room. On the day of the experiment, rats were injected p.o. 1 h before the test. steam carrier or drug at 15 min intervals starting at 10.00 in the morning. 60 min later, we put them together with an equally difficult male (whom they met for the first time) in a crate for social interaction in a separate room. The box was made of white Perspex with dimensions 54 x 37 x 26 cm and was without cover. The bottom was divided into 24 equal squares and the cage was heavily lit. Active social interaction was recorded over the next 15 min with remote video control to obtain the total number of interactions. We also recorded the number of squares crossed by each rat and summed the numbers. After each test, the box was carefully wiped with a damp cloth. Unlike anxiolytic drugs, drugs that enhance social interaction through stimulating action will also increase locomotion. Sedative drugs reduce locomotion.

The compounds of Example 2 showed a significant increase in social interaction at doses of 10 mg / kg.

Geller-Seifter process

Potential anxiolytic properties are determined using the Geller-Seifter procedure based on that originally described by Geller and Seifter, (1960) Psychopharmacologia, 1, 482-492. This process has proven to be selective for drugs with anxiolytic properties (Cook and Sepinwall, (1975) Mechanism of Ac54 tion of Benzodiazepines ed. Costa, E. and Greengard, P., Raven Press, New York, pp. 1-28) .

Rats are trained in a 30-second variable interval scheme (VI30) to push the lever to receive a food reward. The 5-minute VI30 lessons are alternated with 2-5 minutes of the FR5, followed by every five pressures on the lever of food ball, which is combined with a 0.5 second slight gust in the taco. The whole learning takes 30 min. Rats typically respond with a high leverage rate in Scheme VI30 and a low response rate in the FR5 conflict lesson. Anxiolytic drugs increase the repressed responses of rats in a conflict lesson.

The drugs were administered 30 min before testing intraperitoneally or orally to groups of 3 to 8 rats. The results are expressed as the percentage increase in the square root of the total number of leverage pressures in the conflicting FR5 lesson. Conversion to square root is necessary to normalize the data for statistical analysis using parametric methods.

The compound of Example 2 showed a significant increase in response in the conflict lesson at dose levels in the range of 5 mg / kg p.o.

For

SMITHKLINE BEECHAM pic:

FATENT WRITER

Claims (10)

in which P represents a quinoline or isoquinoline moiety or a 5- or 6-membered aromatic heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulfur; R ¹ is hydrogen or C 1-6 alkyl; R ² , R ³ , R ¹⁰ and R ¹¹ are independently hydrogen or C 1-6 alkyl, or form R ¹⁰ and R ¹¹ together or form a R ² and R ¹⁰ or R ³ and R ¹¹ together a C ₂₆ alkylene chain; R ⁴ is hydrogen, C 1-6 alkyl, halogen, NR ⁸ R ⁹ or OR ¹² , wherein R ⁸ , R ⁹ and R ^{12 are} independently hydrogen or C 1-6 alkyl; R ⁵ is hydrogen or C _1-6 alkyl; R ⁷ is hydrogen, C ₁₄ -alkyl, OR ¹² or halogen, where R ^{12 is} hydrogen or C 1-6 alkyl; and n is 2 or 3; and R ¹³ and R ^{14 are} independently hydrogen or C 1-6 alkyl. A compound according to claim 1 wherein R ^{1 is} methyl or ethyl. Compound according to claim 2, characterized in that R ² and R ^{3 are} hydrogen and R ¹⁰ and R ¹¹ together form a bond. A compound according to claim 3, wherein R ^{4 is} hydrogen or methyl. A compound according to claim 4, wherein R ⁵ and R ^{7 are} hydrogen. Compound according to claim 5, characterized in that (CHR ¹³ ) is an _n ethylene group. A compound according to claim 1, selected from 5-methyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole, 6-methyl-3- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole, 5,7-dimethyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole, 1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole, 6-methyl-3- (4 ~ pyridylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole, 6-methyl-3- (2-pyridylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole, 5-methyl-1- (2-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole, 5-methyl-1- (4-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole, 5-methyl-1- (3-pyridylcarbamoyl) -2,3,6,7-tetrahydropyrrolo [2,3-f] indole, 5-ethyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole, 5- n-propyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole, 5.6-dimethyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole, 6.7-dimethyl-3- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole, 1-methyl-N- (3-pyridyl) -5,6,7,8-tetrahydro-1H- pyrrolo [2,3-g] quinoline-5-carboxamide, 3-methyl-N- (3-pyridyl) -6,7,8,9-tetrahydro-1H-pyrrolo [2,3-f] quinoline-6-carboxamide, 6-methyl-3- (2-methyl-4-quinolinylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole, 6-methyl-3- (5-quinolinylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole, 6-methyl-3- (3-quinolinylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole, 5-methyl-1- (2-methyl-4-quinolinylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole, 6.8-dimethyl-3- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [3,2-e] indole, 6-methyl-3- (3-pyridylcarbamoyl) -2,3,7,8-tetrahydropyrrolo [3,2-e] indole, 5-methyl-1- (2-pyrazinylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole, 2.3-dihydro-5-methyl-1- (3-methyl-5-isothiazolylcarbamoyl) -1H-pyrrolo [3,2-e] indole, 2,3-dihydro-5-methyl-1- (3-methyl-5-isothiazolylcarbamoyl) -1H-pyrrolo [2,3-f] indole, 2,3-dihydro-5-methyl-1- (5-quinolylcarbamoyl) -1H-pyrrolo [2,3-f] indole, 2,3-dihydro-5-methyl-1- (3-methyl-5-isoxazolylcarbamoyl) -1H-pyrrolo [2,3-f] indole, N- (5-isoquinolyl) -5-methyl-2,3-dihydropyrrolo [ 2,3-f] indole-1-carboxamide, N- (6-quinolyl) -5-methyl-2,3-dihydropyrrolo [2,3-findol-1-carboxamide, or pharmaceutically acceptable salts thereof. A compound according to any one of claims 1 to 7 for use in therapy. A pharmaceutical composition comprising a compound according to any one of claims 1-7 and a pharmaceutically acceptable carrier or excipient. A process for the preparation of a compound of formula (I) or a salt thereof, characterized in that (a) the compound of formula (II) is attached to a compound of formula (III) 4 ' R A (||) (lil) where A and R ⁶ contain the functional group (s) required (required) to form, if attached, the -NR ⁵ 'CO moiety where R ^s 'and R ⁵ defined as in formula (I), or a group which can be converted thereto, N is defined as in formula (I) and the variables R ¹ ', R ² ', R ³ ', R ¹⁰ ', R ¹¹ ', R ¹³ ', R ¹⁴ ', R ⁴ ', R ⁵ ', and R ⁷ ' are R ¹ , R ² , R ³ , R ¹⁰ , R ⁿ , R ¹³ , R ¹⁴ , R ⁴ oz. R ⁷ as defined in formula (I), or groups which can be converted thereto, and then in any case and if necessary and in any appropriate order, convert any of the variables R ¹ ', R ² ', R ³ ', R ¹⁰ ', R ¹¹ ', R ¹³ ', R ¹⁴ ', R ⁴ ', R ⁵ 'and R ⁷ ' if different from R ¹ , R ² , R ³ , R ¹⁰ , R ¹¹ , R ¹³ , R ¹⁴ , R ⁴ , R ⁵ oz. R ⁷ , to R ¹ , R ² , R ³ , R ¹⁰ , R ¹¹ , R ¹³ , R ¹⁴ , R ⁴ , R ⁵ and R ⁷ , convert R ¹ , R ² , R ³ , R ¹⁰ , R ¹¹ , R ¹³ , R ¹⁴ , R ⁴ , R ⁵ and R ⁷ to each other, and form a pharmaceutically acceptable salt thereof; or (b) cyclize a compound of formula (IV) (IV) wherein R ⁴ ', R ⁵ ', R ⁷ 'R ¹³ ' and R ¹⁴ 'are defined as in formulas (II) and (III), n is defined as in formula (I) and C and D contain the corresponding functional group (s) required to form an indole or indoline ring substituted with R ¹ ', R ² ', R ³ ', R ¹⁰ ' and R ¹¹ ', as defined in formula (III), and then in any case and if necessary and in any order, convert any of the variables R ¹ ', R ² ', R ³ ', R ¹⁰ ', R ^ir , R ¹³ ', R ¹⁴ ', R ⁴ *, R ⁵ ' and R ⁷ 'if different from R ¹ , R ² , R ³ , R ¹⁰ , R ¹¹ , R ¹³ , R ¹⁴ , R ⁴ , R ⁵ and R ⁷ , in R ¹ , R ² , R ³ , R ¹⁰ , R ¹¹ , R ¹³ , R ¹⁴ , R ⁴ , R ⁵ and R ⁷ , convert R ¹ , R ² , R ³ , Rio, R ⁴⁴ , R ¹³ , R ¹⁴ , R ⁴ , RS and R ^{7 to each} other to form a pharmaceutically acceptable salt. For SMITHKLINE BEECHAM pic: HTERTHA RISARKA LJUBLJANA/ " 23000-VIII-93-KA SUMMARY New compounds Compounds of formula (I) are disclosed in which P represents a quinoline or isoquinoline moiety or a 5- or 6-membered aromatic heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulfur; R ¹ is hydrogen or C 1-6 alkyl; R ^2, R ^3, R ¹⁰ and R ¹¹ are independently hydrogen or C ^ -alkyl, or form, R ¹⁰ and R ¹¹ together form a bond, or R ² and R ¹⁰ or R ³ and R ¹¹ together C ₂ ^ alkylene chain; R ⁴ is hydrogen, C 1-6 alkyl, halogen, NR ⁸ R ⁹ or OR ¹² , wherein R ⁸ , R ⁹ and R ^{12 are} independently hydrogen or C 1-6 alkyl; R ⁵ is hydrogen or C 1-6 alkyl; R ⁷ is hydrogen, C 1-6 alkyl, OR ¹² or halogen, where R ^{12 is} hydrogen or C 1-6 alkyl; and n is 2 or 3; and R ¹³ and R ^{14 are} independently hydrogen or C 1-6 alkyl, processes for their preparation and use as medicaments.