SK398A3 - Pyrrolopyrimidines and processes for the preparation thereof - Google Patents

Abstract

Described are 7H-pyrrolo[2,3-d]pyrimidine derivatives of formula (I) wherein the symbols are as defined in claim 1. Those compounds inhibit tyrosine protein kinase and can be used in the treatment of hyperproliferative diseases, for example tumour diseases.

Description

The present invention relates to 7H-pyrrolo [2,3-d] pyrimidine derivatives, to processes for their preparation, to novel intermediates in their preparation, to pharmaceutical compositions containing such derivatives, and to the use of these derivatives as medicaments.

SUMMARY OF THE INVENTION

The invention relates to 7H-pyrrolo [2,3-d] pyrimidine derivatives of the general formula I

O) wherein q is 0 or 1, n is 1 to 3 when q is 0, or n is 0 to 3 when q is 1,

R is halogen, lower alkyl, hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, amino, lower alkanoylamino lower alkylamino, N, N-di- (lower alkyl) amino, or trifluoromethyl, wherein when the molecules contain several R radicals, the radicals may be the same; or different,

a) R ^x and R "are independently from each other

a) phenyl substituted by carbamoyl-methoxy, carboxy-methoxy, benzyloxycarbonylmethoxy, lower alkoxycarbonylmethoxy, phenyl, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino , hydroxyl, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, or nitro;

β) a hydrogen atom;

t) a pyridyl group unsubstituted or substituted by a halogen atom or a lower alkyl group;

δ) N-benzyl-pyridinium-2-yl; a naphthyl group; cyano; a carboxyl group; a lower alkoxycarbonyl group; a carbamoyl group; N- (lower alkyl) carbamoyl; N, N-di- (lower alkyl) carbamoyl; N-benzylcarbamoyl; a formyl group; a lower alkanoyl group; a lower alkenyl group; a lower alkenyloxy group; or

e) a lower alkyl group substituted by e, a) a halogen atom, an amino group, a lower alkylamino group, a piperazine group, a di- (lower alkyl) amino group, ε, β) a phenylamino group which is unsubstituted or substituted by a halogen atom in the phenyl moiety; lower alkyl, hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano , amine test, lower alkanoylamino, lower alkylamino, N, N-di (lower alkyl) amino or trifluoromethyl, e, t) hydroxyl, lower alkoxy, cyano, carboxyl, lower alkoxycarbonyl, carbamoyl N- (lower alkyl) carbamoyl, N, N- (n lower alkyl) -carbamoyl, mercapto, or e, δ) a radical of formula R ² -S (O) _m - in which R ² is a lower alkyl group and _m is 0, 1 or 2, or

(b) when q is 0, one of the radicals R ³ and R ² is an unsubstituted lower alkyl group or an unsubstituted phenyl group and the other of the radicals R ¹ and R ² has one of the meanings given in (a) above, except for a hydrogen atom or

c) R ¹ and R ² together are a 1,4-alkadienylene group having 4 to 10 carbon atoms, substituted with an amino group, a lower alkanoylamino group, a lower alkylamino group, a N, N-di- (lower alkyl) amino group, a nitro group, an atom halogen, hydroxyl, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl or cyano, or are aza-1 A 4-alkadienylene group containing up to 9 carbon atoms, or

d) when q is 1, the radicals R ¹ and R ² are independently unsubstituted lower alkyl or unsubstituted phenyl or have one of the meanings mentioned under a), and

R is hydrogen, lower alkyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl or N, N-di- (lower alkyl) -carbamoyl, and salts thereof, with the exception of the formula I wherein: n is 0, q is 1, R and R are hydrogen and R ² is methyl.

The term lower as used herein means a radical containing up to 7 (inclusive), especially up to 4 (inclusive), and in particular 1 or 2 carbon atoms.

Preferably n is 2 or especially 1. When there is only one R substituent in the molecule, this substituent is preferably in the 3-position on the phenyl ring. If two R substituents are present, these substituents are preferably in the 3 and 4 positions.

The halogen atom R is preferably a bromine or iodine atom, in particular a fluorine or chlorine atom. When n is 1, the radical R is preferably a chlorine atom.

Lower alkyl is, for example, methyl.

A lower alkanoyloxy group is, for example, an acetoxyl group.

A lower alkoxy group is, for example, a methoxy group.

Lower alkoxycarbonyl is, for example, methoxycarbonyl.

N- (lower alkyl) -carbamoyl is, for example, N-methylcarbamoyl, N- (n-butyl) -carbamoyl or N- (3-methyl-but-1-yl) -carbamoyl.

N, N-Di- (lower alkyl) -carbamoyl is, for example, N, N-dimethyl-carbamoyl.

Lower alkanoylamino is, for example, acetylamino.

A lower alkylamino group is, for example, a methylamino group.

N, N-Di- (lower alkyl) amino is, for example, dimethylamino.

Lower alkoxycarbonylmethoxy is, for example, methoxycarbonylmethoxy.

A substituted phenyl R or R group may carry one or more, but preferably no more than three, substituents, which may be the same or different. The substituted phenyl group R or R preferably carries only one substituent, which may be in the ortho position, in the meta position or preferably in the para position.

The phenyl group substituted with the phenyl group R ¹ or R ² can be, for example, a biphenyl group, preferably a 4-biphenyl group.

A pyridyl group is, for example, a 2-pyridyl group.

Ί 9

The halogen atom in the radical R or R is a fluorine atom, a bromine atom, an iodine atom or preferably a chlorine atom.

Naphthyl is, for example, 2-naphthyl.

Lower alkenyl is, for example, vinyl, prop-1-enyl or prop-2-enyl (allyl).

Lower alkenyloxy is, for example, vinyloxy, prop-1-enyloxy or prop-2-enyloxy (allyloxy).

A substituted lower alkyl group R ¹ or R ² may carry one or more, but preferably no more than three, substituents, which may be the same or different. The substituted lower alkyl group R ¹ or R ² preferably carries only one substituent.

A lower alkyl group R ¹ or R ² substituted by a phenylamino group which is unsubstituted or substituted by a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkanoyloxy group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino, or trifluoromethyl, in particular methyl, which is substituted in this way, for example anilino-methyl or 4-methoxy-anilino-methyl.

The 1,4-Alkadienylene group having 4 to 10 carbon atoms is a divalent buta-1,3-diene radical in which each of the terminal atoms ######. 1 and no. 4 has free valency, and that can be. substituted by lower alkyl, but the radical as a whole contains no more than 10 carbon atoms, for example buta-1,3-dien-1,4-ylene.

The aza-1,4-alkadienylene group having up to 9 carbon atoms is a 1,4-alkadienylene group having 4 to 10 carbon atoms as defined above in which at least one carbon atom, preferably a carbon atom in the butadiene chain, in particular a terminal atom in the butadiene chain has been replaced by nitrogen, for example a 1-aza-1,4-alkadienylene group, in particular a 1-aza-buta-1,3-dien-1,4-ylene group. The aza-1,4-alkadienylene group preferably contains 1 to 3 nitrogen atoms, most preferably only one. A 1-Aza-1,4-alkadienylene group with only one nitrogen atom is preferably attached via this nitrogen atom to the carbon atom C6 in the 7H-pyrrolo [2,3-d] pyrimidine cyclic system.

Salts of the compounds of formula I are in particular addition salts with organic or inorganic acids, in particular pharmaceutically acceptable non-toxic salts. Suitable inorganic acids are, for example, carbonic acid (preferably in the form of carbonates or acidic carbonates); hydrohalic acids such as hydrochloric acid; sulfuric acid; or phosphoric acid. Suitable organic acids are, for example, carboxylic acids, phosphonic acids, sulfonic acids or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, glucosomonocarboxylic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, glucuric acid, galactaric acid, amino acids such as glutamic acid, aspartic acid, N-methylglycine, acetylaminoacetic acid, N -acetylasparagine or N-acetylcystine, pyruvic acid, acetacetic acid, phosphoserine, 2- or 3-glycerophosphoric acid, glucose-6-phosphoric acid, glucose-1-phosphoric acid, fructose-1,6-bis-phosphoric acid, maleic acid , k hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 1-hydroxynaphthyl-2-carboxylic acid, 3-hydroxynaphthyl-2-carboxylic acid, 3,4,5-trimethoxybenzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, nicotinic acid, isonicotinic acid, glucuronic acid, galacturonic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid 2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenesulfonic acid, 2-, 3- or 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methylsulfamic acid , N-ethylsulfamic acid, Np ropylsulfamic or other organic protic acids such as ascorbic acid.

Compounds of formula I having at least one free carboxyl group may form inner salts, metal salts or ammonium salts such as alkali metal or alkaline earth metal salts, for example sodium salts, potassium salts, magnesium salts or calcium salts, or ammonium salts with ammonia or suitable organic amines such as tertiary monoamines, for example triethylamine or tri (2-hydroxyethyl) amine, or heterocyclic bases, for example N-ethylpiperidine or N, N'-dimethylpiperazine.

Pharmaceutically unacceptable salts, for example picrates or perchlorates, may also be used for isolation or purification purposes. However, only pharmaceutically acceptable and non-toxic (at appropriate doses) salts are used therapeutically, and such salts are therefore preferred.

There is a close relationship between the free form of the novel compounds of the invention and the form of their salts, including salts used as intermediates in their purification and identification, and therefore throughout the application, any reference to the free compound of the invention also relates to the corresponding salts of this compound.

The compounds of formula I have valuable pharmacologically useful properties. In particular, they exhibit specific inhibitory activities of pharmacological interest. They are particularly effective as tyrosine protein kinase inhibitors or (in addition) as serine / threonine protein kinase inhibitors; for example, they strongly inhibit the epidermal growth factor (EGF) receptor tyrosine kinase activity and c-erbB2 kinase activity. These receptor-specific enzymatic activities play a key role in signal transduction in many mammalian cells, including human cells, especially epithelial cells, immune system cells, and central and peripheral nervous system cells. For example, EGF-induced receptor-associated tyrosine protein kinase (EGF-R-TPK) is a prerequisite for cell division and also for the proliferation of their population in different cell types. Thus, an increase in the number of EGF receptor-specific tyrosine kinase inhibitors prevents cell proliferation. The same applies analogously to the other protein kinases disclosed in this patent application.

In addition to or instead of inhibiting the EGF-receptor specific tyrosine protein kinase, the compounds of formula I also inhibit, to varying degrees, other tyrosine protein kinases involved in trophic-mediated signal transduction, such as abl kinase, especially v-abl-kinase, src- kinase family kinases. kinases, in particular c-src-kinase, lck, fyn; other EGF family kinases such as c-erbB2-kinase (HER-2), c-erbB3-kinase, c-erbB4-kinase; members of the PDGF-receptor tyrosine protein kinase family, for example PDGF-receptor kinase, CSF-1 receptor-kinase, Kit-receptor kinase, VEGF-receptor kinase (e.g. KDR and Flt-1) and FGF-receptor kinase; insulin-like growth factor receptor kinase (IGF-1-kinase) and serine-threonine kinases, for example protein kinase C or cdc-kinases, all of which play a role in growth regulation and in mammalian cell transformations, including human cells.

Inhibition of EGF-receptor-specific tyrosine protein kinase (EGF-R-TPK) can be demonstrated by known methods, for example using the recombinant intracellular domain of the EGF-receptor (EGF-R ICD; see, e.g., E. McGlynn et al., Europe. Biochem. 207: 265-275 (1992)). Compared to the non-inhibitor control, the compounds of formula I inhibit the enzyme activity by 50% (IC 50), for example at a concentration of from 0.0005 to 1 μΜ, in particular from 0.001 to 0.1 μΜ.

The effect of compounds of formula I on EGF-stimulated cellular phosphorylation of tyrosine at the EGF receptor can be determined on human epithelial cancer cells of line A431 by the ELISA method described (U. Trinks et al., J. Med. Chem. 37: 7, 1015 -1027 (1994)). In this assay (EGFR-ELISA), compounds of Formula I exhibit an IC 50 of about 0.001 to 1 µΜ.

Quiescent stimulation. of BALB / c3T3 cells by EGF rapidly induces expression of c-fos mRNA. When cells are treated with compounds of Formula I prior to EGF stimulation, an IC _{50 of} c-fos expression is observed from approximately 0.001 to 0.1 μΜ. U. Trinks et al. (J. Med. Chem. 37: 7, 1015-1027 (1994)).

Also in the micromolar region, compounds of formula I inhibit, for example, the growth of EGF-dependent cell lines, for example the murine epidermoid BALB / c keratinocyte cell line (see Weissmann, BA and Aaronson, SA, Cell 32, 599 (1983)) or A431 cell line. a recognized standard source of EGF-dependent epithelial cells (see Carpenter, G. and Zendegni, J. Anal. Biochem. 153, 279-282 (1985). A known method for testing inhibitory activity of compounds of formula I (see Meyer et al. Int. J). Briefly, Cancer 43, 851 (1989)): BALB / MK cells (10,000 cells per well of microtiter plate) are transferred to a 96-well microtiter plate Test compounds (dissolved in DMSO) are added at various concentrations (dilution). series) so that the final DMSO concentration is not greater than 1% (v / v) After addition, the plates are incubated for three days during which time control cultures without test compounds are run The growth of MK cells is measured by methylene blue staining: after incubation, the cells are fixed with glutaraldehyde, washed with water and stained with a 0.05% methylene blue solution. After washing, the dye is leached with 3% HCl and the optical density at 665 nm is measured for the corresponding wells using a Titertek Multiskan instrument. IC 50 values were obtained using a computer using the formula

IC ₅₀ = [(OD _test - OD _start ) / (OD _controls - 0D _start >) x 100.

The IC ₅₀ value in these experiments is given as the concentration of test compound at which the number of cells is 50% lower than the number of cells in the control without inhibitor. The inhibitory activity of the compounds of formula I is in the micromolar range, for example the IC ₅₀ is in the range of 0.1 to 1 μΜ.

The compounds of formula I also inhibit tumor cell growth in vivo, as shown, for example, in the assay below. This assay is based on inhibiting the growth of A431 human epidermoid carcinoma (ATCC No. CRL 1555; American Type Culture Collection, Rockville, Maryland, USA; see Santon, JB et al. Cancer Research 46, 4701-4705 (1986) and Ozawa, S. et al., Int. J. Cancer (1990), 706-710, which is transplanted into female BALB / c nude mice (Bomholtgard, Denmark). The growth of this cancer corresponds to the extent of EGF receptor expression. In the assay, in vivo cultured tumors of about 1 cm ³ in size are surgically harvested under sterile conditions. Tumors are comminuted and suspended in 10 volumes (w / v) of phosphate buffered saline. The suspension is injected subcutaneously into the animals in the left flank (0.2 ml / mouse in phosphate buffered saline). Alternatively, 1 x 10 6 cells from in vitro culture in 0.2 ml phosphate buffered saline may also be injected. Test compounds of formula I are started 5 to 7 days after transplantation when the tumors are 4-5 mm in diameter. The test compound is administered (at different doses for different groups of animals) once a day for 15 days. Tumor growth is determined by measuring the average of the three perpendicular axes, and the volume was calculated using the known formula px L x D ^2/6 (see Evans, BD, et al., Brit. J. Cancer 45, 466-8 (1982 )). Results are reported in percent test / control (T / C x 100 = T / C%). A clear inhibition of tumor growth was found at a dose of active compound of 3 to 50 mg / kg. For example, T / C values of less than 10 were found, indicating a strong inhibition of tumor growth.

In addition to or instead of inhibiting the EGF-receptor tyrosine protein kinase, the compounds of formula I also inhibit other tyrosine protein kinases involved in the transmission of a signal mediated by trophic factors, such as abl-kinase, such as especially v-abl-kinase (IC ₅₀ e.g. 5 μΜ), kinases of the src-kinase family, such as in particular c-src-kinase (IC ₅ q for example from 0.1 to 10 μΜ) and c-erbB2-kinase (HER-2), and serine / threonine kinases, for example, protein kinase C, all of which are involved in the regulation of growth and transformation in mammalian cells, including human cells.

The above-mentioned inhibition of v-abl-tyrosine kinase is determined by the methods of N. Lydon et al. (Oncogene Research 5, 161-173 (1990)) and JF Geissler et al. (Cancer Research 52: 4492-4498 (1992)). These methods use [Val ⁵ ] -angiotensin II and [t- ³² P] -ATP as substrates.

Inhibition of c-erbB2-tyrosine kinase (HER-2) can be determined, for example, analogously to the method used for EGF-R-TPK (see C. House et al., Evrop, J. Biochem. 140, 363-367 (1984)) . The c-erbB2 kinase can be isolated and determined by known methods, such as described by T. Akiyama et al. (Science 232: 1644 (1986)).

Compounds of formula I that inhibit the epidermal growth factor (EGF) receptor tyrosine kinase activity or the activity of the other mentioned tyrosine protein kinases are therefore useful, for example, in the treatment of benign or malignant tumors. They are able to cause tumor regression and prevent the formation of its metastases and the growth of micrometastases. They can be used especially in cases of epidermal hyperproliferation (psoriasis), in the treatment of epithelial neoplasms, such as breast cancers and leukemia. In addition, the compounds of formula I (particularly novel compounds) may also be used in the treatment of immune system disorders in which several tyrosine protein kinases (or, in particular, individual tyrosine protein kinases) or (hereinafter) serine / threonine protein kinases are involved; these compounds of formula I may also be used in the treatment of disorders of the central or peripheral nervous system in which several, or especially one, tyrosine protein kinase or (hereinafter) serine / threonine protein kinase (s) are involved in signal transduction.

In general, this invention relates to the use of compounds of formula I in inhibiting said protein kinases.

The compounds of the invention may be used as such or in combination with other pharmacologically active substances, for example together with polyamine synthesis enzyme inhibitors, protein kinase C inhibitors, other tyrosine kinase inhibitors, cytokines, negative growth regulators, for example TGF-β or

IFN-β, aromatase inhibitors, antiestrogens or cytostatic drugs.

Where appropriate and expedient, for the preferred subject of the invention, the general definitions may be replaced by more precise specifications given at the outset.

Preferred are compounds of formula I wherein q is 0 or 1, n is 1 to 3 when q is 0, or n is 0 to 3 when q is 1,

R is halogen, lower alkyl, hydroxyl, lower alkanoyloxy, lower alkoxy carboxyl, lower alkoxycarbonyl, N- (lower alkyl) -carbamoyl alkyl) -carbamoyl, cyano-lower alkanoylamino, lower alkylamino, Ν, Ν, -di (lower alkyl) amino, or trifluoromethyl, wherein when the molecule contains several R radicals, the radicals may be the same or different, a group, a group, a carbamoyl group, a N, N-di- (lower pin, amine group,

a) R ¹ and R ² independently of each other are phenyl substituted by carbamoyl-methoxy, carboxy-methoxy, benzyloxycarbonyl-methoxy, lower alkoxycarbonyl-methoxy, phenyl, amino, lower alkanoylamino, lower alkylamino, N , N-di- (lower alkyl) amino, hydroxyl, lower alkanoyloxy, lower alkoxycarbonyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, or nitro; a hydrogen atom; pyridyl, unsubstituted or substituted by halogen or lower alkyl; N-benzyl-pyridinium-2-yl; naphthyl, cyano; a carboxyl group; lower alkoxycarbonyl, carboxyl, carbamoyl; a carbamoyl group; N- (lower alkyl) carbamoyl; N, N-di- (lower alkyl) carbamoyl; N-benzylcarbamoyl; a formyl group; a lower alkanoyl group; a lower alkenyl group; a lower alkenyloxy group; or a lower alkyl group substituted with a halogen atom, an amino group, a lower alkylamino group, a piperazine group, a di- (lower alkyl) amino group, a hydroxyl group, a lower alkoxy group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, N- (lower) alkyl) -carbamoyl, N, N-di (lower alkyl) -carbamoyl, mercapto or a radical of the formula R -S (O) _m - in which R is a lower alkyl group and _m is 0, 1 or 2, or

-i n

(b) when q is 0, one of the radicals R and R is an unsubstituted lower alkyl group or an unsubstituted phenyl group and the other of the radicals R and R has one of the meanings given in (a) above, or

c) R ¹ and R ² together are a 1,4-alkadienylene group having 4 to 10 carbon atoms, substituted with an amino group, a lower alkanoylamino group, a lower alkylamino group, a N, N-di- (lower alkyl) amino group, a nitro group, an atom halogen, hydroxyl, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl or cyano, or are aza-1 A 4-alkadienylene group containing up to 9 carbon atoms, or

d) when q is 1, the radicals R ¹ and R ² are independently unsubstituted lower alkyl or unsubstituted phenyl or have the meaning given in a), and R® is H, lower alkyl, lower alkoxycarbonyl, carbamoyl, a group, N- (lower alkyl) -carbamoyl or N, N-di (lower alkyl) -carbamoyl, and salts thereof, with the exception of the compound of formula I wherein N is 0, qjel, R a are hydrogen and R ² is a methyl group .

Also preferred are compounds of formula I wherein q is 0 or 1, n is 1 to 3 when q is 0, or n is 0 to 3 when q is 1,

R is halogen, lower alkyl, hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino, or trifluoromethyl, wherein when the molecule contains several R radicals these radicals may be. same or different,

a) R ¹ is hydrogen and R ² is phenyl substituted by carbamoyl-methoxy, carboxy-methoxy, benzyloxycarbonyl-methoxy, lower alkoxycarbonylmethoxy, phenyl, amino, lower alkanoylamino, lower alkylamino, N, N -di- (lower alkyl) amino, hydroxyl, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl a cyano or nitro group; a pyridyl group unsubstituted or substituted by a halogen atom or a lower alkyl group; N-benzyl-pyridinium-2-yl; a naphthyl group; cyano; a carboxyl group; a lower alkoxycarbonyl group; a carbamoyl group; N- (lower alkyl) carbamoyl;

N, N-di- (lower alkyl) carbamoyl; N-benzylcarbamoyl; a formyl group; a lower alkanoyl group; a lower alkenyl group; a lower alkenyloxy group; or a lower alkyl group substituted by a halogen atom; a phenylamino group which is unsubstituted or substituted in the phenyl residue by a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkanoyloxy group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino or trifluoromethyl; lower alkoxy, cyano, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, mercapto-O, or a radical of formula R-S (O) _m - in which R ^j is lower alkyl and _m is 0, 1 or 2, or

b) when q is 0, one of the radicals ^R1 and ^R2 is unsubstituted lower alkyl or unsubstituted phenyl and the other of the radicals R and R has one of the meanings given above in paragraph a), with the exception of hydrogen, or

c) R ¹ and R ² together are 1,4-alkadienylene of 4 to 10 carbon atoms, substituted with lower alkanoylamino, nitro, halogen, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl N, N-di- (lower alkyl) -carbamoyl or cyano, or are aza-1,4-alkadienylene of up to 9 carbon atoms, or

d) when q is 1, R is hydrogen and R is unsubstituted phenyl, and

R ⁶ is hydrogen, lower alkyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl or N, N-di (lower alkyl) -carbamoyl, and salts thereof.

Also preferred are 7H-pyrrolo [2,3-d] pyrimidine derivatives of Formula Ia

where n is 1 to 3,

R is halogen, lower alkyl, hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di (lower alkyl) amino, or trifluoromethyl, wherein when the molecule contains several R radicals, the radicals may be the same or different,

a) R ¹ and R ² independently of each other are phenyl substituted by phenyl, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) -amino, hydroxyl, lower alkanoyloxy, carboxyl lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) carbamoyl, N, N-di- (lower alkyl) carbamoyl, cyano, or nitro; a hydrogen atom, a -pyridyl group, unsubstituted or substituted by a halogen atom or a lower alkyl group; N-benzyl-pyridinium-2-yl; a naphthyl group; cyano; a carboxyl group; a lower alkoxycarbonyl group; a carbamoyl group; N- (lower alkyl) carbamoyl; N, N-di- (lower alkyl) carbamoyl; a formyl group; a lower alkanoyl group; a lower alkenyl group; a lower alkenyloxy group; or a lower alkyl group substituted by a halogen atom, an amino group, a lower alkylamino group, a piperazine group, a di- (lower alkyl) amino group, a hydroxyl group, a lower alkoxy group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, N- ( lower alkyl) -carbamoyl, N, N-di (lower alkyl) -carbamoyl, mercapto, or a radical of formula R ³ -S (O) _m - in which R ³ is lower alkyl and _m is 0, 1 or 2 or

(b) one of the radicals R ¹ and R ² is an unsubstituted lower alkyl or unsubstituted phenyl group and the other of the radicals R ¹ - and R 1 has one of the meanings given in (a) above, except for a hydrogen atom; or

c) r! and R ² together are 1,4-alkadienylene of 4 to 10 carbon atoms, substituted with amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino, nitro, halogen, hydroxyl , lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl or cyano, or are aza-1,4-alkadienylene a group containing up to 9 carbon atoms, and salts thereof.

Very preferred are compounds of formula I wherein n is 1 to 3 and q is 0,

R is halogen, lower alkyl, hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di (lower alkyl) amino, or trifluoromethyl, wherein when the molecule contains several R radicals, the radicals may be the same or different,

a) R ¹ and R ² independently of each other are phenyl substituted by phenyl, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) -amino, hydroxyl, lower alkanoyloxy, carboxyl a lower alkoxycarbonyl group, a carbamoyl group, an N- (lower alkyl) carbamoyl group, an N, N-di- (lower alkyl) carbamoyl group, a cyano group, or a nitro group; pyridyl, unsubstituted or substituted by halogen or lower alkyl; N-benzyl-pyridinium-2-yl; a naphthyl group; cyano; a carboxyl group; a lower alkoxycarbonyl group; a carbamoyl group; N- (lower alkyl) carbamoyl; N, N-di- (lower alkyl) carbamoyl; a formyl group; a lower alkanoyl group; a lower alkenyl group; a lower alkenyloxy group; or a lower alkyl group substituted with a halogen atom, an amino group, a lower alkylamino group, a piperazine group, a di- (lower alkyl) amino group, a hydroxyl group, a lower alkoxy group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, N- (lower) alkyl) -carbamoyl,

N, N-di (lower alkyl) -carbamoyl, mercapto, or a radical of formula R ³ -S (O) _m - in which R ³ is lower alkyl and _m is 0, 1 or 2, or

(b) one of the radicals R ¹ and R ² is a hydrogen atom, an unsubstituted lower alkyl group or an unsubstituted phenyl group and the other of the radicals R ¹ and R ² has one of the meanings given in (a) above, or

c) R ³ and R ² together are 1,4-alkadienylene of 4 to 10 carbon atoms, substituted with amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino, nitro, halogen, hydroxyl, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl or cyano, or are aza- A 1,4-alkadienylene group containing up to 9 carbon atoms, and salts thereof.

Particularly preferred are compounds of formula I wherein n is 1 or 2 and q is 0,

R is a halogen atom, wherein when the molecule contains several R radicals, the radicals may be the same or different, and

a) R ¹ and R ² independently of each other are phenyl substituted with phenyl, amino, hydroxyl or nitro; a hydrogen atom; a pyridyl group; N-benzyl-pyridinium-2-yl; a naphthyl group; or a lower alkyl group substituted with a di- (lower alkyl) amino group, or

b) one of the radicals ^R1 and ^R2 is unsubstituted lower alkyl or unsubstituted phenyl and the other of the radicals ^R1 and ^R2 has one of the meanings given above in paragraph a) with the exception of hydrogen, or

c) R ¹ and R ² together are an aza-1,4-alkadienylene group containing up to 9 carbon atoms, and salts thereof.

Particularly preferred are special compounds of formula I wherein n is 1 or 2 and q is 0,

R is a halogen atom, wherein when the molecule contains several R radicals, the radicals may be the same or different, and

a) R ¹ is hydrogen or bold or substituted and R ² is phenyl lower alkyl unsubstituted (lower alkyl) amino substituted with phenyl, amino, hydroxyl or nitro; a pyridyl group; N-benzyl-pyridinium-2-yl; or a naphthyl group; or

-1 Q

b) R and R together are an aza-1,4-alkadienylene group containing up to 9 carbon atoms, and salts thereof.

Also highly preferred are compounds of formula I wherein q is 1, n is 0 to 3,

R is halogen, lower alkyl, hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di (lower alkyl) amino, or trifluoromethyl, wherein when the molecule contains several R radicals, the radicals may be the same or different

(a) R ¹ and R ² independently of each other are phenyl substituted by carbamoyl-methoxy, carboxy-methoxy, benzyloxycarbonyl-methoxy, lower alkoxycarbonyl-methoxy, phenyl, amino, lower alkanoylamino, lower alkylamino, N , N-di- (lower alkyl) -amino, hydroxyl, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, or nitro; hydrogen; pyridyl, unsubstituted or substituted by halogen or lower alkyl; N-benzyl-pyridinium-2-yl; a naphthyl group; cyano; a lower alkoxycarbonyl group; a carbamoyl group; N- (lower alkyl) carbamoyl; N, N-di- (lower alkyl) carbamoyl; N-benzylcarbamoyl; a formyl group; a lower alkanoyl group;

a lower alkenyl group; a lower alkenyloxy group; or a lower alkyl group substituted by a halogen atom, an amino group, a lower alkylamino group, a piperazine group, a di- (lower alkyl) amino group, a hydroxyl group, a lower alkoxy group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, N- (lower alkyl) -carbamoyl, N,

N-di (lower alkyl) -carbamoyl, mercapto, Ώ or a radical of formula R -S (O) _m - in which R is a lower alkyl group and _m is 0, 1 or 2, or

b) R ¹ and R ² together are 1,4-alkadienylene of 4 to 10 carbon atoms, substituted with an amino group, a lower alkanoylamino group, a lower alkylamino group, a N, N-di- (lower alkyl) amino group, a nitro group, an atom halogen, hydroxyl, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl or cyano, or are aza-1 A 4-alkadienylene group containing up to 9 carbon atoms, or

c) the radicals R ¹ and R ^2, independently of one another are unsubstituted lower alkyl or unsubstituted phenyl / y or have one of the meanings given under a), and R is H, lower alkyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl or N, N-di- (lower alkyl) -carbamoyl, and salts thereof.

Particularly preferred are also compounds of formula I wherein q is 0 or 1, n is 1 or 2 when q is 0, or n is 0 to 2 when q is 1,

R is a halogen atom or a lower alkyl group, wherein when the molecule contains several R radicals, the radicals may be the same or different, and

a) r! is a hydrogen atom or a lower alkyl group unsubstituted or substituted by a di- (lower alkyl) amino group, and R ² is a phenyl group substituted with a carbamoyl-methoxy group, a carboxymethoxy group, a benzyloxycarbonylmethoxy group, a lower alkoxycarbonylmethoxy group, , carboxyl, N, N-di- (lower alkyl) -carbamoyl, phenyl, amino, lower alkylamino, di- (lower alkyl) amino, lower alkanoylamino, hydroxyl or nitro; hydroxy-lower alkyl, amino-lower alkyl, di- (lower alkyl) amino-lower alkyl, piperazino-lower alkyl, formyl, cyano, carboxyl; a lower alkoxycarbonyl group; carbamoyl-4- (lower alkyl) -carbamoyl; N, N-di- (lower alkyl) carbamoyl, pyridyl; N-benzylcarbamoyl, N-benzyl-pyridinium-2-yl; or a naphthyl group, or

b) R ¹ and R ² together are 1-aza-buta-1,3-dien-1,4-ylene or

c) when q is 1, both R ¹ and R ² are methyl, and

R ⁶ is a hydrogen atom, a methyl group or a lower alkoxycarbonyl group, and salts thereof,

Also particularly preferred are compounds of formula I wherein q is 0 or 1, n is 1 or 2 when q is 0, or n is 0 to 2 when q is 1,

R is a halogen atom, wherein when the molecule contains several R radicals, the radicals may be the same or different, and

a) R ¹ is a hydrogen atom or a lower alkyl group unsubstituted or substituted with a di- (lower alkyl) amino group; and

R is phenyl substituted with carbamoylmethoxy, carboxymethoxy, benzyloxycarbonylmethoxy, methoxycarbonylmethoxy, ethoxycarbonyl, carboxyl, phenyl, amino, acetamine, hydroxyl or nitro; a carboxyl group; ethoxycarbonyl; N- (lower alkyl) carbamoyl; a pyridyl group; N-benzyl-pyridinium-2-yl; or a naphthyl group, or

b) R and R together are an aza-1,4-alkadienylene group containing up to 9 carbon atoms, or

c) when q is 1, R ¹ and R ² are both methyl and

R 8 is a hydrogen atom, a methyl group or a methoxycarbonyl group, and salts thereof.

Most preferred are the compounds of formula I as described in the Examples, and pharmaceutically acceptable salts thereof.

The invention also relates to the compound 4- (3-chloro-anilino) pyrimido [4,5-b] indole, which does not fall within the scope of formula (I), and which is obtained according to Example 15, and pharmaceutically acceptable salts thereof.

The compounds of formula I and their salts are prepared by methods known per se. The preparation process according to the invention is characterized in that:

a) the pyrrolo [2,3-d] pyrimidine derivative of the general formula II is reacted

(Π) wherein X is a suitable leaving group, Z is a hydrogen atom or a 1-aryl-substituted lower alkyl group and the other substituents are as defined above for the compounds of formula I, wherein any free functional groups present in the radicals R ¹ and R ² are optionally protected with readily removable protecting groups, with an amine of formula III

wherein R, R, naq are as defined above for compounds of formula I, wherein any free functional groups present in the R radical are protected, if necessary, with readily removable protecting groups, and all protecting groups present including 1-aryl-substituted lower alkyl radical Z if present, shall be removed, or

b) reacting a pyrrolo [2,3-d] pyrimidin-4-one derivative of the general formula IV with the above-mentioned amine of the formula III in the presence of a dehydrating agent and a tertiary amine

wherein Z ¹ is a 1-aryl-substituted lower alkyl group and R and R are as defined above for compounds of formula I, wherein any free functional groups present in the radicals R ¹ and R are protected, if necessary, with easily removable o 26 protecting groups, and all protecting groups present are removed, or

c) for the preparation of a compound of formula I in which the dimethylamino-methyl group is present and the other substituents are as defined above for the compounds of formula I, a compound of formula I wherein R ¹ is hydrogen and the remaining is reacted with N, N-dimethylmethylenammonium iodide the substituents are as defined above for the compounds of formula I, wherein any free functional groups present in the radicals R ¹ and R ² are protected, if necessary, with readily removable protecting groups, and all protecting groups present are removed, or

d) for the preparation of a compound of formula I in which at least one of the radicals R, R and R is a phenyl group substituted by a hydroxyl group and the other substituents defined above for compounds of formula I, a compound corresponding to formula I is reacted with boron tribromide of the radicals R, R ¹ and R ² is a phenyl group substituted with a methoxy group and the other substituents are as defined above for the compounds of formula I, wherein any free functional groups present in the radicals R, R ¹ and R ² are protected, if necessary, and all protecting groups present are removed, or

e) for the preparation of a compound of formula I in which at least one of the radicals R, R and R is an amino-substituted phenyl group and the other substituents are as defined above for compounds of formula I, a compound corresponding to formula I is subjected to catalytic hydrogenation; the radicals R, R and R are a phenyl group substituted by a nitro group and the other substituents are as defined above for the compounds of formula I, wherein any free functional groups present in the radicals R, R ¹ and R ² are protected, if necessary, by easily removable protecting groups; the protecting groups present are removed, then, after carrying out one of processes a) to e), if desired, converting the obtained free compound of formula I into the desired salt for the preparation of a salt, or converting the obtained salt of the compound of formula I into the free salt compound.

Detailed description of procedures

These procedures are described in detail below (see German Patent Application No. 30 36 390, published May 13, 1982 and A. Jorgenson et al., J. Heterocycl. Chem. 22, 859 (1985)). Unless otherwise indicated, in the following description, the radicals R, R ¹ and R ² and n are the same as defined for the compounds of formula I.

General points

The end products of formula I may contain substituents which may also be used as protecting groups in the starting materials for the preparation of other end products of formula I. Unless otherwise indicated by context, the term protecting group in this application is used to indicate an easily removable group which is an integral part of the finished product of formula I.

Procedure a)

A suitable leaving group in the compound of formula (II) is preferably a halogen atom such as bromine, iodine, or especially chlorine.

The 1-aryl-substituted lower alkyl group Z is preferably a 1-phenyl-substituted lower alkyl group, such as a 1-phenylethyl group, or especially a benzyl group.

Free functional groups protected by groups, if desired, are in particular an amino group.

-j 2 in the radicals R and R, which are readily removable protecting groups or lower alkylamine

Protective groups, their introduction and removal are described, for example, in the book Protective Groups in Organic Chemistry,

Plenum Press, London, New York 1973, in Metoden der organischem Chemie, Houben-Weyl, 4th edition, Vol. 15/1, Georg Thieme-Verlag, Stuttgart 1974, and in Theodor W. Green's book, Protective Groups in Organic Synthesis, John Wiley & Sons, New York 1981. Characteristic of protective groups is their easy removal, i. without undesired secondary reactions, for example by solvolysis, reduction, photolysis or else under physiological conditions.

The protected amine group may be present, for example, in the form of an easily cleavable acylamine group, an arylmethylamine group, an etherified mercaptoamine group, or a 2-acyl- (lower alk-1-enyl) amine group.

In such an acylamino group, acyl is, for example, an acyl radical of an organic carboxyl group containing, for example, up to 18 carbon atoms, in particular alkanecarboxylic acids, unsubstituted or substituted, for example, with halogen or aryl, or benzoic acids unsubstituted or substituted with, for example, halogen, lower alkoxy or nitro. or a semi-ester of carbonic acid. Such acyl groups are, for example, lower alkanoyl such as formyl, acetyl or propionyl, halogenated lower alkanoyl such as 2-haloacetyl, especially 2-chloroacetyl, 2-bromoacetyl, 2-iodoacetyl, 2,2,2- trifluoroacetyl or 2,2,2-trichloroacetyl, benzoyl unsubstituted or substituted, for example, by halogenated lower alkoxy or nitro, for example benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or lower alkoxycarbonyl position 1 of a lower alkyl radical or suitably substituted in position 1 or 2, in particular a tert-lower alkoxycarbonyl group, for example a tert-butylcarbonyl group, an arylmethoxycarbonyl group having one or two aryl radicals, which are preferably a phenyl group not being substituted bold or monosubstituted or polysubstituted, for example, by a lower alkyl group, in particular a tertiary lower alkyl group such as a tert-butyl group, a lower alkoxy group such as a methoxy group, a hydroxyl group, a halogen atom such as a chlorine atom or a nitro group such as 4-nitrobenzyloxycarbonyloxy or a substituted diphenylmethoxycarbonyl group, for example a benzhydryloxycarbonyl group or a di (4-methoxyphenyl) methoxycarbonyl group, an aroylmethoxycarbonyl group wherein the aroyl group is preferably a benzoyl group unsubstituted or substituted, for example, by a halogen atom such as a bromine atom, for example phenacyloxycarbonyl; (lower alkoxy) -carbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (trisubstituted silyl) ethoxycarbonyl in which the subst the ituents are independently an aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical containing up to 15 carbon atoms, which is unsubstituted or substituted, for example, by a lower alkyl group, a lower alkoxy group, an aryl group, a halogen atom or a nitro group such as the corresponding unsubstituted or alkyl, phenyl-substituted lower alkyl, cycloalkyl, or phenyl, for example a 2-tri- (lower alkylsilyl) ethoxycarbonyl group such as 2-trimethylsilylethoxycarbonyl or 2- (di-n-butyl-methylsilyl) ethoxycarbonyl group, or a 2-triarylsilylethoxycarbonyl group such as a 2-triphenylsilylethoxycarbonyl group.

In the arylmethylamino group, which is a mono-, di- and especially tri-arylmethylamino group, aryl radicals are in particular unsubstituted or substituted phenyl radicals. Such groups are, for example, benzylamino, diphenylmethylamino and especially tritylamino.

The etherified mercapto group in the amino group protected by such a radical is in particular an arylthio or aryl- (lower alkyl) thio group in which the aryl group is in particular a phenyl group unsubstituted or substituted, for example, by a lower alkyl group such as methyl or tert-butyl, lower alkoxy such as is a methoxy group, a halogen atom such as a chlorine atom, or a nitro group. The corresponding amine protecting group is, for example, 4-nitrophenylthio.

In the 2-acyl- (lower alk-1-en-1-yl) radical which may be used as an amine protecting group, acyl is, for example, the corresponding lower alkanecarboxylic acid radical, benzoic acid unsubstituted or substituted, for example, with a lower alkyl group such as methyl or tert-butyl, a lower alkoxy group such as a methoxy group, a halogen atom such as a chlorine atom, or a nitro group, or a semi-ester of carbonic acid such as (lower alkyl) hydrogen carbonate. Corresponding protecting groups are especially 1- (lower alkanoyl) -prop-1-en-2-yl such as 1-acetyl-prop-1-en-2-yl or 1- (loweralkoxy) carbonyl-prop-1. -en-2-yl, for example 1-ethoxycarbonyl-prop-1-en-2-yl.

Preferred amine protecting groups are acyl radicals of carbonic acid semi-esters, especially tert-butyloxycarbonyl, benzyloxycarbonyl unsubstituted or substituted, for example, as mentioned, for example 4-nitrobenzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-alkoxy such as (lower alkoxy) carbonyl (lower alkoxy) 2,2,2-trichloroethoxycarbonyl as well as trityl or formyl.

The reaction between the derivative of the formula II and the amine of the formula III is carried out in suitable inert polar solvents, in particular in alcohols, for example in lower alcohols such as methanol, propanol, isopromanol or especially ethanol or n-butanol. In some cases, it is preferred to add a solubilizing agent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) pyrimidone (DMPU). The reaction is carried out at an elevated temperature, for example in a temperature range of from 70 to 150 ° C, preferably at reflux.

When Z in the compound of formula II is a 1-aryl-substituted lower alkyl group, this group is removed from the obtained precursor of the compound of formula I (wherein Z is in place of the hydrogen atom on nitrogen). This is achieved, for example, by treatment with protic acids, such as hydrochloric acid, phosphoric acid or polyphosphoric acid, at temperatures preferably from 20 ° C to 150 ° C, if necessary in the presence of water (this method is particularly preferred for Z = 1-phenylethyl) ; or preferably by treatment with Lewis acids, in particular AlCl ₃ , in an aromatic solvent, in particular benzene or toluene, at elevated temperature, particularly at reflux (which is a particularly preferred variant when Z = benzyl; see also analogous procedure in Chem. Pharm. Bull., 39 (5), 1152 (1991)).

The deprotection, which is not an integral part of the desired end product of the formula I, is carried out by methods known per se, for example by solvolysis, in particular by hydrolysis, alcoholysis or acidolysis, or by reduction, in particular by hydrogenolysis or chemical reduction, respectively.

The protected amine group is liberated by various methods known in the art, depending on the nature of the protecting group, preferably by solvolysis or reduction. The 2-halo- (lower alkoxy) carbonylamino group (if desired after conversion of the 2-bromo- (lower alkoxy) carbonylamino group to the 2-iodo- (lower alkoxy) carbonyl group, aroylmethoxycarbonylamino group or 4-nitrobenzyloxycarbonylamino group may be cleaved, for example by treatment with a suitable chemical reducing agent such as zinc in the presence of a suitable carboxylic acid, for example aqueous acetic acid The aroylmethoxycarbonylamino group can also be cleaved by treatment with nucleophilic, in particular salt forming agents such as sodium thiophenolate and sodium 4-nitrobenzyloxycarbonylamino, for example with dithionite. The unsubstituted or substituted diphenylmethoxycarbonylamino group, the tert- (lower alkoxy) carbonylamino group or the 2-trisubstituted silylethoxycarbonylamino group may be cleaved by treatment with a suitable acid, for example formic acid and an unsubstituted or substituted benzyloxycarbonylamino group is cleaved, for example, by hydrogenolysis, i. by treating with hydrogen in the presence of a suitable hydrogenation catalyst such as a palladium catalyst; the unsubstituted or substituted triarylmethylamino or formylamino group may be cleaved, for example, by treatment with acids such as mineral acids such as hydrochloric acid or organic acids such as formic acid, acetic acid or trifluoroacetic acid, optionally in the presence of water; and an amino group protected with an organic silyl group can be liberated, for example, by hydrolysis or alcoholysis. An amino group protected with a 2-haloacetyl group, for example a 2-chloroacetyl group, can be liberated by treatment with thiourea in the presence of a base or with a thiolate salt of thiourea such as an alkali thiolate and subsequent solvolysis, for example alcoholysis or hydrolysis. The amine group protected by the 2-substituted silylethoxycarbonyl group can also be converted to the free amine group by treatment with hydrofluoric acid salts which provide fluoride anions.

Procedure b)

The 1-aryl-substituted lower alkyl group Z 'in the compound of formula IV is especially 1-phenylethyl and also benzyl.

The compound of formula IV exists in tautomeric equilibrium (lactam-lactim), the lactam form (formula IV) probably being predominant. Formula IV is used to represent both of these possible forms.

The lactime form has the formula IVa

(IVa) are as defined above for compounds also refer to novel compounds of formulas IV and IVa.

hydrating agents are used strong chemical wherein the radicals of formula IV.

invention

How to:

dehydrating agents, especially phosphorus pentoxide ^(p 4 ° 10 ⁾ ·

Particularly suitable as a tertiary amine are ammonia substituted by three radicals which are independently alkyl, in particular lower alkyl such as methyl or ethyl and cycloalkyl of 3 to 7 carbon atoms, in particular cyclohexyl, for example N, N-dimethyl- N-cyclohexylamine, N-ethyl-N, N-diisopropylamine or triethylamine, or further also pyridine, N-methylmorpholine or 4-dimethylaminopyridine.

The reaction between the pyrrolo-pyrimidinone of formula IV and the amine of formula III takes place at an elevated temperature, for example from 200 ° C to 250 ° C.

Procedure (c)

The reaction is carried out with the exclusion of moisture in a suitable inert solvent, for example in a suitable ether, for example a cyclic ether such as, in particular, tetrahydrofuran, at elevated temperature, preferably at reflux.

Procedure d)

The reaction is carried out with the exclusion of moisture in a suitable inert solvent, for example in a suitable halogenated hydrocarbon such as, in particular, methylene chloride, at a temperature of about -20 ° C to +50 ° C, preferably under ice cooling or at room temperature.

Procedure e)

The hydrogenation is carried out at elevated pressure or preferably at normal pressure in the presence of a suitable hydrogenation catalyst, such as especially Raney nickel, in an inert solvent or solvent mixture, especially a mixture of a suitable cyclic ether and a suitable lower alkanol such as tetrahydrofuran and methanol. at a temperature of about 0 ° C to + 50 ° C, preferably at room temperature.

Starting compounds

The starting compounds of formula (II) are novel and the invention also relates to them. They can be prepared by processes analogous to those described in German patent applications no. No. 28 18 676 (November 8, 1979); 30 36 390 (May 13, 1982).

The starting compounds of formula II wherein X is chlorine is obtained, for example, from a compound analogous to formula II wherein X is hydroxy by reaction with phosphorus oxychloride ((P = O) C 1 -C ₃₎ under reflux with exclusion of moisture. The reaction of the obtained starting compound of formula III, wherein X is a chlorine atom, with an amine of formula III can be carried out in the same vessel as the one pot reaction. In this case, upon completion of the reaction with phosphorus oxychloride, the reaction mixture is evaporated to dryness, the residue is suspended in a suitable solvent, such as n-butanol, and reacted with an amine of formula III.

A compound analogous to formula II wherein X is a hydroxyl group is obtained, for example, from a compound of formula V

H, N (V) wherein the symbols are as defined above by reaction with formic acid, which is preferably used in excess over the compound of formula V, for example in a 10 to 30 molar excess, if necessary in the presence of an inert solvent such as is dimethylformamide, at an elevated temperature, for example at 80 ° C to the boiling point.

Alternatively, it is possible to obtain compounds analogous to formula II wherein X is a hydroxyl group and the remaining symbols are as defined above, for example from a compound of formula VI

where R ⁴ is a lower alkyl group, preferably an ethyl group, and the other symbols are as defined above, which are reacted with a large excess of the formamide in a mixture of anhydrous dimethyl formamide and formic acid. The reaction is carried out at an elevated temperature, for example at 100 ° C to 150 ° C and preferably under a protective gas atmosphere.

The invention also relates to novel starting compounds of formulas V and VI.

1- ⁽¹ Z) -2-amino-3-cyano-pyrroles of formula V used as intermediates can be prepared in good yields by known methods already described (see, e.g., Roth, H. J., and Eger, K., Arch. Pharmaz., 308, 179 (1975)). For example, a compound of formula VII

HO (VII) is first reacted with an amine of formula Z'-NH ₂ to give a compound of formula VIII

(VIII) which is then converted by reaction with malendinitrile of formula CH ₂ (CN) ₂ to the desired intermediate of formula V. Reaction with the amine Z ¹ -NH ₂ is carried out under conventional condensation conditions, for example in the presence of a catalytic amount of a strong acid, e.g. p-toluenesulfonic acid, at elevated temperature (preferably boiling) in a suitable solvent, for example benzene or toluene, while removing water to give the corresponding σ-aminoketone of formula VIII. This is directly condensed without isolation with malendinitrile at elevated temperature and further water removal, possibly with the addition of a small amount of a base such as piperidine to give a compound of formula V.

p

Compounds of formula VI wherein R is N-benzyl-pyridinium-2-yl and the other symbols are as defined above, which are used as intermediates, are obtained from

for example by reacting compounds of formula VI wherein R is a hydrogen atom and the other symbols are as defined above with N-benzyl-2-bromo-pyridinium bromide in a suitable solvent, for example a halogenated hydrocarbon such as especially methylene chloride. The reaction is preferably carried out in a protective gas atmosphere, in the dark and under anhydrous conditions, at room temperature or at elevated temperature, for example at 20 ° C to 80 ° C and in the presence of 2,6-dimethylpyridine (2,6-lutidine). Other compounds of formula VI are prepared, for example, by reaction of a lower alkyl ester of 2-amidinoacetic acid of formula IX

(IX) wherein R ⁴ is as defined above with 2-X ¹ R ² -ethan-1-one derivatives of formula X

ABOUT

wherein the symbols are as defined above. The leaving substituent X is preferably a bromine atom. The 2-amidinoacetic acid (lower alkyl) ester of formula IX is liberated from its acid addition salt, preferably especially hydrochloride, by treatment with an equivalent amount of a base such as sodium ethoxide under ice-cooling prior to reaction. The reaction is carried out in a suitable solvent, in particular a lower alkanol, preferably ethanol, at temperatures preferably from 0 ° C to 50 ° C, in particular at room temperature.

General experimental conditions

The free compounds of formula I obtained, which can form salts, can be converted into their salts by known methods, for example by treatment with acids or suitable derivatives thereof, for example by adding a suitable acid to a compound of formula I dissolved in a suitable solvent, for example ether, preferably cyclic ether. such as dioxane or especially tetrahydrofuran.

The isomer mixtures obtained according to the invention can be separated into the individual isomers by known methods, the racemates can be separated, for example, by forming salts with optically pure salt forming agents and separating the resulting diastereoisomers, for example, by crystallization.

The reactions described above may be carried out under known reaction conditions, in the absence or usually in the presence of solvents or diluents, preferably those inert to the reagents used, in the absence or presence of catalysts, condensation agents (e.g. phosphorus pentoxide) or neutralizing agents, for example bases, especially nitrogen bases such as triethylamine hydrochloride, depending on the nature of the reaction or reactants at reduced, normal or elevated temperature, for example in the range of about -80 ° C to about 200 ° C, preferably about -20 ° C to about 150 ° C , for example at the boiling point of the solvent used, at atmospheric pressure or, if necessary, in a sealed container, at elevated pressure or under an inert atmosphere, for example under a nitrogen atmosphere.

Preferably, the reaction conditions specified for each case are used.

Solvents and diluents are, for example, water, alcohols, e.g. lower hydroxylated alkyls such as methanol, ethanol, propanol or especially butanol, diols such as ethylene glycol, triols such as glycerol, or aryl alcohols such as phenol, acid amides such as carboxylic acid amides such as dimethylformamide, dimethylacetamide; 3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU), carboxylic acids, especially formic acid or acetic acid, inorganic acid amides such as hexamethylphosphoric triamide, ethers such as cyclic ethers such as tetrahydrofuran or dioxane, or acyclic ethers such as diethyl ether or ethylene glycol dimethyl ether, halogenated hydrocarbons such as halogenated lower alkanes, e.g. , like her šie alkanes such as heptane, or aromatic compounds such as benzene, toluene or xylene (s), or mixtures of the solvents, wherein the solvents are selected according to the particular requirements which the reaction.

In the working up of the reaction mixtures in the preparation of the compounds of the formula I and their salts, customary processes are used, for example solvolysis of excess reagents; recrystallization; chromatography, for example, separation, ion, or gel chromatography; partitioning between inorganic and organic solvents39; single or multiple extraction, in particular after acidification or increase in basicity or salt content; drying over hygroscopic salts; Digestion; filtration; washing; dissolution; concentration by evaporation (under vacuum or high vacuum as necessary); distillation; crystallization, for example, of substances obtained in oily form or from mother liquors, optionally seeding with a crystal of the final product; or a combination of two or more of the foregoing, which may also be repeated, etc.

The starting compounds and intermediates can be used in pure form, for example after the aforementioned work-up, or in partially purified form, or also, for example, directly as a crude product.

Since there is a close relationship between the free form of the compounds of formula I and the form of their salts, all references to free compounds in this specification also apply to their corresponding salts for the sake of brevity and clarity, and conversely salt references also apply to free compounds, provided that these compounds contain salt-forming groups.

The substances, including their salts, may be obtained in the form of hydrates, or their crystals may contain, for example, solvent molecules used in crystallization.

In the processes according to the invention, the starting compounds are preferably those which lead to the novel compounds of the formula I described initially as particularly advantageous.

The invention also relates to processes in which a compound obtainable as an intermediate in any stage of the process is used as the starting compound and the remaining steps of the process are carried out, or the starting compound is formed under reaction conditions, or used as a derivative, e.g. salt.

In particular, the invention relates to a process for the preparation of 7H-py40 rolo [2,3-d] pyrimidine derivatives of the general formula Ia, which fall under the general formula I,

where n is 1 to 3,

R is hydrogen, halogen, lower alkyl, hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- ( lower alkyl) -carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) -amino, or trifluoromethyl, wherein when the molecule contains several R radicals these radicals may be same or different,

a) R ¹ and R ² independently of each other are phenyl substituted by phenyl, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl). -amino, hydroxyl, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, or nitro; a hydrogen atom; pyridyl, unsubstituted or substituted by halogen or lower alkyl; N-benzyl-pyridinium-2-yl; a naphthyl group; cyano; a carboxyl group; a lower alkoxycarbonyl group; a carbamoyl group; N- (lower alkyl) carbamoyl; N, N-di- (lower alkyl) carbamoyl; a formyl group; a lower alkanoyl group; a lower alkenyl group; a lower alkenyloxy group; or a lower alkyl group substituted by a halogen atom, an amino group, a lower alkylamino group, a piperazine group, a di- (lower alkyl) amino group, a hydroxyl group, a lower alkoxy group, an acid group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, N- (lower) alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, mercapto, or a radical of formula R ³ -S (O) _m - in which R ³ is lower alkyl and _m is 0, 1 or 2 or

b) one of the radicals ^R1 and ^R2 is unsubstituted lower alkyl or unsubstituted phenyl and the other of the radicals ^R1 and ^R2 has one of the meanings given above in paragraph a) with the exception of a hydrogen atom, or

c) R ¹ and R ² together are 1,4-alkadienylene of 4 to 10 carbon atoms, unsubstituted or substituted with an amino group, a lower alkanoylamino group, a lower alkylamino group, a N, N-di- (lower alkyl) amino group, a nitro group , halogen, hydroxyl, lower alkoxy, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl or cyano or are an aza-1,4-alkadienylene group containing up to 9 carbon atoms, and salts thereof,

a) reaction of a pyrrolo [2,3-d] pyrimidine derivative of formula (II)

wherein X is a suitable leaving group, Z is hydrogen or

The 1-aryl-substituted lower alkyl group and the other substituents are as defined above for compounds of formula Ia, wherein any free functional groups present in the radicals R ¹ and R ² are protected, if necessary, with readily removable protecting groups with an aniline derivative of formula IIIa.

wherein R and n are as defined above for the compound of formula Ia and all free functional groups in the R radical are protected, as appropriate, with readily removable protecting groups, and by removing any protecting groups present and the 1-aryl-lower alkyl group Z, if present, or

b) reacting the aforementioned phenylamine of formula IIIa, in the presence of a dehydrating agent and a tertiary amine, with a pyrrolo [2,3-d] pyrimidin-4-one derivative of formula IV

wherein Z 'is 1-aryl-substituted lower alkyl group, and R and R are as defined above for compounds of formula Ia, any free functional groups present in the radicals R ¹ n

and R are protected, if necessary, with readily removable protecting groups, and removing any protecting groups present; or

c) for the preparation of a compound of formula Ia in which R ¹ is a dimethylaminomethyl group and the other substituents are as defined above for compounds of formula Ia, by reacting N, N-dimethylmethylenimmonium iodide with a compound corresponding to formula Ia wherein R ¹ is hydrogen and the remaining the substituents are as defined above for the compounds of formula Ia, wherein any free functional groups present in the radicals R and R are protected, if necessary, by easily removable protecting groups, and by removal of any protecting groups present, or

d) for the preparation of a compound of formula Ia, in which at least one of the radicals R, R and R is a phenyl group substituted with a hydroxyl group and the other substituents defined above for a compound of formula Ia, by reacting boron tribromide with a compound corresponding to formula Ia in which at least one of the radicals R 1, R ¹ and R 2 is a phenyl group substituted with a methoxy group and the other substituents are as defined above for the compound of formula Ia, wherein any free functional groups present in the R, R and R radicals are protected, if necessary, with readily removable protecting groups; protective groups present, or

e) for the preparation of a compound of formula Ia in which at least one of the radicals R, R ^x and R is an amino-substituted phenyl group and the other substituents are as defined above for compounds of formula Ia, by catalytic hydrogenation of a compound corresponding to formula Ia in which at least one of the radicals R 1, R ¹ and R 2 are phenyl substituted by nitro and the other substituents are as defined above for compounds of formula (Ia), wherein any free functional groups present in the radicals R 1, R ¹ and R are protected, if necessary, by readily removable protecting groups; after carrying out one of processes a) to e), converting the obtained free compound of the formula Ia into the desired salt, if desired, or converting the obtained salt of the compound of the formula Ia into the free compound.

The invention also relates to pyrrolo [2,3-d] pyrimidine derivatives of formula IIa

wherein X 'is a hydroxyl group or a suitable leaving group,

Z is hydrogen or 1-aryl-substituted lower alkyl,

R ¹ is a hydrogen atom or a lower alkyl group unsubstituted or substituted with a di- (lower alkyl) amino group, and

R ² is

a) phenyl substituted by carbamoyl-methoxy, carboxy-methoxy, benzyloxycarbonylmethoxy, lower alkoxycarbonylmethoxy, phenyl, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino , hydroxyl, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) carbamoyl, cyano, or nitro;

b) a pyridyl group unsubstituted or substituted by a halogen atom or a lower alkyl group;

c) N-benzyl-pyridinium-2-yl; a naphthyl group; cyano; a carboxyl group; a lower alkoxycarbonyl group; a carbamoyl group; N- (lower alkyl) carbamoyl; N, N-di- (lower alkyl) carbamoyl; N-benzylcarbamoyl; formyl, lower alkanoyl; a lower alkenyl group; a lower alkenyloxy group; or

d) a lower alkyl group substituted by o;) a halogen atom, an amino group, a lower alkylamino group, a piperazine group, a di- (lower alkyl) amino group,

β) a phenylamino group which is unsubstituted or substituted in the phenyl residue by a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkanoyloxy group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, N- (lower alkyl) -carbamoyl group , N, N-di- (lower alkyl) -carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di (lower alkyl) amino, or trifluoromethyl,

t) hydroxyl, lower alkoxy, cyano, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) carbamoyl, N, N-di- (lower alkyl) -carbamoyl, mercapto, or

δ) a radical of formula R 1 -S (O) _m - in which R ² is a lower alkyl group and _m is 0, 1 or 2, and 4-ketoderivatives which are tautomeric with compounds of formula II wherein X 1 is a hydroxyl group, or salts of such compounds.

The invention also relates to pyrrolo [2,3-d] pyrimidine derivatives of formula IIa

(IIa) wherein X ¹ is a hydroxyl group or a leaving group,

Z is hydrogen or 1-aryl-substituted lower alkyl,

R ¹ and R ² independently of each other are phenyl substituted by carbamoylmethoxy, carboxymethoxy, benzyloxycarbonylmethoxy, lower alkoxycarbonylmethoxy, phenyl, amino, lower alkanoylamino, lower alkylamino, N, N -di- (lower alkyl) amino, hydroxy, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl cyano, or nitro; a hydrogen atom; a pyridine group unsubstituted or substituted by a halogen atom or a lower alkyl group; N-benzyl-pyridinium-2-yl; a naphthyl group; cyano; a carboxyl group; lower alkoxycarbonyl; a carbamoyl group; N- (lower alkyl) carbamoyl; N, N-di- (lower alkyl) carbamoyl;

N-benzylcarbamoyl; a formyl group; a lower alkanoyl group; a lower alkenyl group; a lower alkenyloxy group; or a lower alkyl group substituted by a halogen atom, an amino group, a lower alkylamino group, a piperazine group, a di- (lower alkyl) amino group, a phenylamino group which is unsubstituted or is. in the phenyl moiety substituted by a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkanoyloxy? lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino, or trifluoromethyl, hydroxyl, lower alkoxy, cyano, carboxyl, lower alkoxycarbonyl, carbamoyl,

N- (lower alkyl) -carbamoyl, N, N- (lower alkyl) -carbamoyl, mercapto, or a radical of formula R ³ -S (O) _m - in which R ³ is lower alkyl and _m is 0, 1 or 2, or

(b) one of the radicals R- ¹ and R is an unsubstituted lower alkyl or unsubstituted phenyl group and the other of the radicals R and R has one of the meanings given in (a) above, except for a hydrogen atom; or

c) R ¹ and R ² together are 1,4-alkadienylene of 4 to 10 carbon atoms, unsubstituted or substituted by amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino, nitro , halogen, hydroxyl, lower alkoxy, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl or cyano or are aza-1,4-alkadienylene group containing up to 9 carbon atoms, and 4-ketoderivatives that are tautomeric with compounds of formula IIa, wherein X 'is a hydroxyl group, and salts thereof.

In particular, the invention relates to pyrrolo [2,3-d] pyrimidine derivatives of formula IIa wherein X 'is a hydroxyl group or a leaving group,

Z is hydrogen or 1-aryl-substituted lower alkyl, and

a) R and R independently of each other are phenyl substituted by phenyl, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino, hydroxyl, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) carbamoyl, N, N-di- (lower alkyl) carbamoyl, cyano, or nitro; a hydrogen atom; a pyridyl group unsubstituted or substituted by a halogen atom or a lower alkyl group; N-benzyl-pyridinium-2-yl; a naphthyl group; cyano; a carboxyl group; a lower alkoxycarbonyl group; a carbamoyl group; N- (lower alkyl) carbamoyl; N, N-di- (lower alkyl) carbamoyl; a formyl group; t is a lower alkanoyl group; a lower alkenyl group; a lower alkenyloxy group; or a lower alkyl group substituted by a halogen atom, an amino group, a lower alkylamino group, a piperazine group, a di- (lower alkyl) amino group, a hydroxyl group, a lower alkoxy group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, N- ( lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, mercapto, or a radical of formula R ³ -S (O) _m - in which R ³ is lower alkyl and _m is 0, 1 or 2, or

b) one of the radicals ^R1 and ^R2 is unsubstituted lower alkyl or unsubstituted phenyl and the other of the radicals R and R has one of the meanings given above in paragraph a) with the exception of a hydrogen atom, or

c) r! and R ² together are a 1,4-alkadienylene group having 4 to 10 carbon atoms, unsubstituted or substituted with an amino group, a lower alkanoylamino group, a lower alkylamino group, a N, N-di- (lower alkyl) amino group, a nitro group, an atom halogen, hydroxyl, lower alkoxy, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) carbamoyl,

N, N-di- (lower alkyl) -carbamoyl or cyano, or are aza-1,4-alkadienylene of up to 9 carbon atoms, and 4-ketoderivatives which are tautomeric with compounds of formula IIa, wherein X 'is a hydroxyl group , and salts of these compounds.

Compounds of formula IIa and 4-ketoderivatives that are tautomeric with compounds of formula IIa, wherein X 'is a hydroxyl group, can be used as starting compounds of formulas II, IV and IVa above and are prepared analogously to these starting compounds.

The invention also relates to pyrrole derivatives of formula XI

wherein Z is hydrogen or 1-aryl-substituted lower alkyl,

(a) R ¹ is a hydrogen atom or a lower alkyl group unsubstituted or substituted by a di- (lower alkyl) amino group; and

R ² is

(a) phenyl substituted by carbamoyl-methoxy, carboxy-methoxy, benzyloxycarbonyl-methoxy, lower alkoxycarbonyl-methoxy, phenyl, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino, hydroxyl, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, or nitro;

S) pyridyl, unsubstituted or substituted by halogen or lower alkyl;

τ) N-benzyl-pyridinium-2-yl; a naphthyl group; cyano; a carboxyl group; a carbamoyl group; N- (lower alkyl) carbamoyl; N, N-di- (lower alkyl) carbamoyl; N-benzylcarbamoyl; a formyl group; a lower alkanoyl group; a lower alkenyl group; a lower alkenyloxy group; or

δ) a lower alkyl group substituted with δ, a) a halogen atom, an amino group, a lower alkylamino group, a piperazine group, a di- (lower alkyl) amino group, δ, β) a phenylamino group which is unsubstituted or substituted by a halogen atom in the phenyl moiety; lower alkyl, hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano , amino, lower alkanoylamino, lower alkylamino, N, N-di (lower alkyl) amino or trifluoromethyl, δ, t) hydroxyl, lower alkoxy, cyano, carboxyl, carbamoyl, N- (lower) alkyl) -carbamoyl, N, N- (lower alkyl) -carbamoyl, or δ, δ) a radical of the formula R ³ -S (O) _m - in which R ³ is a lower alkyl group and _m is 0, 1 or 2, or

b) R ^A and R together are an aza-1,4-alkadienylene group containing up to 9 carbon atoms, and

R ⁵ is cyano or lower alkoxycarbonyl, and salts of these compounds.

In particular, the invention relates to pyrrole derivatives of formula XI wherein Z is hydrogen or 1-aryl-substituted lower alkyl,

a) R ¹ and R ² independently of each other are phenyl substituted by phenyl, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino, hydroxyl, lower alkanoyloxy, carboxyl , lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, or nitro; a hydrogen atom; a pyridyl group unsubstituted or substituted by a halogen atom or a lower alkyl group; N-benzyl-pyridinium-2-yl; a naphthyl group; cyano; a carboxyl group; a lower alkoxycarbonyl group; a carbamoyl group; N- (lower alkyl) carbamoyl; N, N-di- (lower alkyl) carbamoyl; a formyl group; a lower alkanoyl group; a lower alkenyl group; a lower alkenyloxy group; or a lower alkyl group substituted by a halogen atom, an amino group, a lower alkylamino group, a piperazine group, a di- (lower alkyl) amino group, a hydroxyl group, a lower alkoxy group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, N- (lower) alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, mercapto, or a radical of formula R ³ -S (O) _m - in which R ³ is lower alkyl and _m is 0, 1 or 2 or

b) one of the radicals ^R1 and ^R2 is unsubstituted lower alkyl or unsubstituted phenyl and the other of the radicals R ¹ · R ^2, and has one of the meanings given above in paragraph a), with the exception of hydrogen, or

c) R ¹ and R ² together are a C 4 -C 10 1,4-alkadienylene group substituted with an amino group, a lower alkanoylamino group, a lower alkylamino group, an N, N-di- (lower alkyl) amino group, a nitro group, a halogen atom , hydroxyl, lower alkoxy, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl or cyano; aza-1,4-alkadienylene group containing up to 9 carbon atoms,

R ⁵ is cyano or lower alkoxycarbonyl, and salts of these compounds.

The pyrrole derivatives of the formula XI can be used as starting compounds of the formulas V and VI above and are prepared analogously to these starting compounds.

The invention also relates to intermediates of formula IIa and XI in which the substituents are defined so as to obtain compounds of formula I according to claim 1.

The invention also relates to pharmaceutical compositions containing as active ingredient one or more compounds of the formula I and which can in particular be used in the treatment of the diseases mentioned above. Especially preferred is enteral administration as nasal, buccal, rectal and especially oral, or parenteral administration as intravenous, intramuscular or subcutaneous, to warm-blooded animals, especially in human medicine. The formulations comprise the active ingredient per se or preferably with a pharmaceutically acceptable carrier. The dosage of the active ingredient depends on the disease being treated, the species, age, weight, condition and individual pharmacokinetic data, as well as the route of administration.

The invention further relates to the use of pharmaceutical compositions in methods of treating humans or animals, to methods of preparing such compositions (especially compositions for treating tumors), and to methods of treating cancer, particularly those mentioned above.

Preferred are pharmaceutical compositions containing the compounds of the formula I according to the invention or salts thereof (if they contain salt-forming groups) which are suitable for administration to warm-blooded animals, in particular humans suffering from diseases susceptible to protein kinase inhibition such as psoriasis or tumors. inhibiting protein kinase, together with at least one pharmaceutically acceptable carrier.

Pharmaceutical preparations contain about 1 to 95% of the active ingredient, the single dosage form preferably containing about 20% to about 90% of the active ingredient, and the non-single dosage forms preferably contain about 5% to about 20% of the active ingredient. Dosage forms are, for example, dragees, tablets, ampoules, vials, suppositories or capsules. Other forms of administration are, for example, ointments, creams, pastes, foams, elixirs, lipsticks, drops, sprays, dispersions, and the like. Examples are capsules containing from about 0.05 g to about 1.0 g of the active ingredient.

The pharmaceutical compositions of the invention are prepared by known methods, for example by conventional mixing, granulating, ready-to-mix, dissolving or lyophilizing processes.

It is preferred to use solutions of the active ingredient, as well as suspensions or dispersions thereof, in particular isotonic aqueous solutions, or dispersions or suspensions, which may be prepared prior to administration, for example in lyophilized formulations containing the active ingredient alone or with a carrier such as mannitol. The pharmacological preparations may be sterilized or may contain excipients such as preservatives, stabilizers, wetting or emulsifying agents, sulubilizers, salts for regulating osmotic pressure, or buffers, and are prepared by known methods, for example, by conventional dissolution and lyophilization processes. Said solutions or suspensions may contain viscosity enhancers such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

The oily suspensions contain vegetable, synthetic or semi-synthetic oils usually used in injection. Of particular note are liquid fatty acid esters containing, as the acid component, a long chain fatty acid having 8 to 22 carbon atoms, in particular 12 to 22 carbon atoms, such as lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid, or the corresponding unsaturated acid, for example oleic acid, elaidic acid, erucic acid, brasidic acid or linoleic acid, optionally with the addition of antioxidants such as vitamin E, β-carotene or 3,5-diototinic acid tert-butyl-4-hydroxytoluene. The alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and may be a monofunctional or polyfunctional alcohol, for example a monohydric alcohol, a diol or a triol, for example methanol, ethanol, propanol, butanol or pentanol or isomers thereof, but especially glycol and glycerol. The following fatty acid esters are therefore noteworthy: ethyl oleate, isopropyl myristate, isopropyl palmitate, Labrafil M 2375 (polyoxyethylene glycerol trioleate, Gattefossé, Paris), Labrafil M 1944 CS (unsaturated polyglycolized glycerides prepared by alcoholysis, apricot oil oils and polyglycerides containing glycerides; Gattefossé, France), Labrasol (saturated polyglycolized glycerides prepared by TCM alcoholysis and containing glycerides and esters of polyethylene glycol; Gattefossé, France) or Miglynol 812 (triglyceride of saturated fatty acids with a chain of 8 to 12 carbon atoms, Huls AG, Germany), but mainly vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and special peanut oil.

Injectable preparations are prepared in conventional manner under sterile conditions; the same applies to their filling into ampoules or vials and to the closure of containers.

Pharmaceutical preparations for oral administration are obtained, for example, by mixing the active ingredient with one or more solid carriers and optionally granulating the mixture obtained, and if necessary processing the mixture or granulate by adding additional excipients to tablets or dragee cores.

Suitable carriers are in particular fillers such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders such as starches, for example corn starch, wheat starch, rice starch or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium salt, carboxymethylcellulose or polyvinylpyrrolidone, or, optionally, disintegrants such as the above-mentioned starches and also carboxymethyl starch, cross-linked polyvinylpyrrolidone, alginic acid and its salts such as sodium alginate. Further excipients are in particular flow modifiers and lubricants, for example silicic acid, talc, stearic acid or salts thereof such as magnesium stearate or calcium stearate, or polyethylene glycol or derivatives thereof.

Dragee cores may be coated with suitable (possibly enteric) coatings, including concentrated sugar solutions, which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or for the preparation of enteric coatings , solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyestuffs or pigments may also be added to the tablets or dragee coatings, for example to identify or indicate different doses of the active ingredient.

Orally administrable pharmaceutical preparations also include gelatin capsules for solid dosage forms, as well as soft sealed capsules of gelatin and a plasticizer such as glycerol or sorbitol. Solid capsules may contain the active ingredient in the form of granules, for example in admixture with fillers such as corn starch, binders or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in a suitable liquid excipient such as fatty oils, paraffin oil, liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, to which stabilizers and detergents such as polyoxyethylene fatty acid esters can also be added. .

Other dosage forms for oral administration are, for example, syrups which are formulated in conventional manner and which contain the active ingredient, for example, in suspended form and in a concentration of about 5% to 20%, preferably about 10%, or a similar concentration corresponding to one suitable single dose when administered in an amount of 5 to 10 ml. Also suitable are, for example, liquid or powder concentrates for the preparation of mixed beverages, for example in milk. These concentrates may also be prepared in single dose packs.

Suitable pharmaceutical preparations for rectal administration are, for example, suppositories containing a mixture of the active ingredient and a suppository base. Suitable bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

For parenteral administration, aqueous solutions of the water-soluble form of the active ingredient, for example in the form of a water-soluble salt, or aqueous injection suspensions containing viscosity enhancers, for example sodium carboxymethylcellulose, sorbitol or dextran and optional stabilizers, are particularly preferred. The active ingredient, optionally together with excipients, may also be in the form of a lyophilisate and may be dissolved prior to parenteral administration by the addition of suitable solvents.

Solutions which have been used, for example, for parenteral administration can also be used as infusion solutions.

Preferred preservatives are, for example, antioxidants such as ascorbic acid, or microbicides such as sorbic acid or benzoic acid.

Ointments are oil-in-water emulsions containing up to 70%, but preferably from 20% to 50%, of water or an aqueous phase. Particularly suitable as the fatty phase are hydrocarbons, for example mineral petrolatum, paraffin oil or solid paraffins, which preferably contain suitable hydroxyl compounds such as fatty alcohols or esters thereof, for example cetyl alcohol or sheep wool alcohols such as lanolin to improve the water binding capacity. Corresponding lipophilic substances such as sorbitan fatty acid esters (Spany), for example sorbitan oleate or sorbitan isostearate, are used as emulsifiers. As additives for the aqueous phase, for example, humectants such as polyalcohols, for example glycerol, propylene glycol, sorbitol or polyethylene glycol are used; preservatives and perfumes are also added.

Fatty ointments are anhydrous and contain, in particular, hydrocarbons, for example, paraffin, mineral petrolatum or paraffin oil, as well as natural or partially synthetic fats, for example coconut fatty acid triglyceride, or preferably hardened oils, for example hydrogenated peanut oil or castor oil, or partly glycerol fatty acid esters, for example glycerol monostearate or glycerol distearate, as well as, for example, water absorption fatty alcohols, emulsifiers or additives already mentioned in connection with ointments.

Creams are oil-in-water emulsions containing more than 50% water. In particular, fatty alcohols such as lauryl alcohol, cetyl alcohol or stearyl alcohol, fatty acids such as palmitic or stearic acid, liquid to solid waxes such as isopropyl myristate, sheep wool or beeswax, or hydrocarbons such as petrolatum are used as the oil bases. or paraffin oil. Suitable emulsifiers are surfactants having predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, for example fatty acid esters of polyalcohols or their adducts with ethylene oxide such as fatty acid esters of polyglycerol, or fatty acid esters of polyethylene sorbitan (Tweeny), and also polyether ethers. and their fatty acid esters, or corresponding ionic emulsifiers such as alkali metal salts of fatty alcohol sulfates, for example sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are usually used in the presence of fatty alcohols such as cetyl alcohol or stearyl alcohol. The aqueous phase additives are, inter alia, anti-drying agents, for example polyalcohols such as glycerol, sorbitol, propylene glycol or polyethylene glycols, as well as preservatives and perfumes.

Pastes are creams and ointments which contain powder-absorbing components, such as metal oxides, for example titanium dioxide or zinc oxide, or talc or aluminum silicates, which are intended to bind any moisture or secretions.

Foams are applied from pressurized containers and are emulsions of liquid oil in water in aerosol form. As propellant, halogenated hydrocarbons such as lower alkanes substituted with chlorine and fluorine, for example dichlorodifluoromethane and dichlorotetrafluoroethane, or preferably non-halogenated gaseous hydrocarbons, air N ₂ O or carbon dioxide are used. The oily phase used includes, inter alia, the substances listed above as components in ointments and creams; the additives mentioned in this context are also used.

Tinctures and solutions generally have a hydroethanolic base to which inter alia evaporative reducing humectants such as polyalcohols such as glycerol, glycols or polyethylene glycol are added; lubricants such as fatty acid esters of low molecular weight polyethylene glycols, i. lipophilic substances which are soluble in the aqueous mixture as a replacement for fatty substances removed from the skin by ethanol. Other adjuvants and additives are also added as needed.

The invention also relates to a process or method for the treatment of the aforementioned pathological conditions, in particular conditions responsive to the inhibition of protein kinases. The compounds of the formula I according to the invention can be administered as such or in the form of pharmaceutical preparations, prophylactically or therapeutically, preferably in amounts effective against the disease, to warm-blooded animals, for example to people in need of such treatment. For individuals weighing about 70 kg, the daily dose is from about 0.1 g to about 5 g of a compound of the invention, preferably from about 0.5 g to about 2 g.

The following examples are provided to illustrate the invention without limiting its scope in any way.

DETAILED DESCRIPTION OF THE INVENTION

The following terms and abbreviations are used throughout the text:

Eluents (gradients):

HPLC Gradients:

Grad ₂ g 20% -> 100% a) in b) in 20 min.

Eluent a): acetonitrile + 0.05% TFA; eluent b): water + 0.05% TFA; column (250 x 4.6 mm) packed with reverse phase _C18 -Nucleosil ^R (average particle size 5 μ, τα, silica covalently derivatized with octadecylsilanes, Macherey & Nagel, Düren, Germany). Detection by UV light at 254 nm. Retention times (t _ret -) are given in minutes. Flow rate 1 ml / min.

abbreviations:

abs. absolute (anhydrous)

DEPC Diethylpyrocarbonate (Dicarbonic acid diethyl ester)

DMF dimethylformamide

DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone

DMSO dimethylsulfoxide

EI-MS mass spectroscopy, electron impact method

FAB-MS mass spectroscopy, fast atom bombardment method

HPLC high pressure liquid chromatography min minute (s)

MS mass spectroscopy brine saturated sodium chloride solution

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TLC-Rf Rf value at TLC

TPTU O- (1,2-dihydro-2-oxo-1-pyridyl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate

mp melting point

Abbreviations used in NMR spectra data:

b wide signal d doublet

J interaction constant m multiplet q quartet s singlet t triplet

note:

Hexane means a mixture of hexane isomers, butanol means n-butanol.

Example 1

4- (3-Chloro-anilino) -6- (pyrid-2-yl) -7 H -pyrrolo [2,3-d] pyrimidine

Under argon, 40 mL of DMPU was added to 6.53 g (28.3 mmol) of 4-chloro-6- (pyrid-2-yl) -7H-pyrrolo [2,3-d] pyrimidine and 4.46 mL ( 42.5 mmol) of 3-chloroaniline in 90 ml of n-butanol and the reaction mixture is stirred for 12 hours at 140 ° C. The dark brown suspension is cooled and filtered. Additional product can be obtained from the mother liquors by precipitation of 100 ml of water. Washing with ethanol-THF gives the desired product, m.p. ≫ 300 ° C; 1 H NMR (360 MHz, DMSO-d 6): 12.49 and 9.66 (2s, 2H), 8.63 (d, J = 5, 1H), 8.40 and

8.25 (2s, 2H), 7.91 (m, 2H), 7.84 (d, J = 8, 1H), 7.57 (s, 1H),

7.33 (m, 2H); 7.06 (d, J = 8, 1H); HPLC: t _ret (Grad ₂₀ ) = 10.1 min;

MS: (M) < ^{+ &gt}; = 321.

The starting compound is prepared as follows:

Stage 1.1:

- (5-amino-4-ethoxycarbonyl-ΙΗ-pyrrol-2-yl) -N-benzylpyridíniumbromid

Under argon, 658 mg (2.0 mmol) of N-benzyl-2-bromo-pyridinium bromide (preparation described in J. Heterocyclic Chem. 28, 1083 (1991)) is introduced into 20 ml of abs. methylene chloride and then 308 mg of -pyrrole-3-carboxylic acid Chem. 23, 1555 (1986)) (2.0 mmol) of ethyl 2-amino ester (preparation described in J. Heterocyclic) The reaction mixture is stirred for 2 days with light exclusion, because after this time the reaction is not complete, 232 μΐ ( 2-amino-2,6-lutidine and another 0.20 mmol of 2-amino-pyrrole-3-carboxylic acid ethyl ester After stirring for a further 12 hours, the reaction mixture is concentrated by evaporation and the residue is digested with isopropanol, filtered, washed with hexane and dried. product which still contains about 10% N-benzyl-2-bromo-pyridinium bromide according to ¹ H NMR spectrum, ¹ H NMR (300 MHz, DMSO-d 6), 11.45 (1H), 8.70 (d, J = 7, 1H), 8.38 (t, J = 7, 1H), 8.00 (d, J = 7, 1H), 7.67 (t, J = 7, 1H), 7.42 (m, 3H), 7.14 (d, J = 7, 2H), 6.85 (d, J = 3, 1H), 6.45 (sb, 2H), 5.91 (s, 2H), 4.13 (q, J = 7, 2H), 1.19 (t, J = 7, 3H) FAB-MS: (M + H) < ^{+ &gt}; = 322.

Grade 1,2:

6- (Pyridin-2-yl) -7 H -pyrrolo [2,3-d] pyrimidin-4-ol

A mixture of 27.07 g of 2- (5-amino-4-ethoxycarbonyl-1H-pyrrol-2-yl) -N-benzyl-pyridinium bromide, 195 ml of formamide, 97.6 ml of DMF (dried over 4 A molecular sieve), and 48 8 ml of formic acid are heated at 150 ° C for 16 hours in a protective gas atmosphere. The dark brown reaction mixture was cooled in an ice bath and the crystals of the precipitated title compound were filtered off with suction and washed with iso 62 propanol and diethyl ether. ¹ H NMR (300 MHz, DMSO-d 6): 12.5 and 11.9 (2s, 2H), 8.60 (d, J = 7, 1H), 8.05-7.8 (m, 3H) 7.28 (dd, J ₁ = 7, J ₂ = 9, 1H), 7.20 (s, 1H); FAB-MS: (M + H) < ^{+ &gt}; = 213.

Stage 1.3:

4-Chloro-6- (pyridin-2-yl) -7 H -pyrrolo [2,3-d] pyrimidine

A mixture of 7.05 g (33.2 mmol) of 6- (pyrid-2-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ol and 70 ml of phosphorus oxychloride is heated under reflux for 2 hours, excluding moisture . The dark brown suspension is concentrated by evaporation to a volume of 20 ml. The residue is introduced in portions into water, neutralized with solid NaHCO ₃ was added and 0.2 liters of ethyl acetate. Filtration and washing with hot tetrahydrofuran gave the desired product. ¹ H NMR (300 MHz, DMSO-d 6): 13.2 (sb, 1H), 8.72 (d, J = 7, 1H), 8.63 (s, 1H), 8.23 (d, J) = 11, 1H), 7.97 (t, J = 11, 1H), 7.46 (dd, J ₁ = 7, J ₂ = 11, 1H), 7.35 (s, 1H). Further product can be obtained from the filtrate and tetrahydrofuran wash solution, which is concentrated by evaporation and the residue is partitioned between ethyl acetate and water and digested in ethyl acetate-diethyl ether.

Example 2

4- (3-Chloro-anilino) -6- (pyrid-2-yl) -7H-pyrrolo [2,3-d] pyrimidine hydrochloride

1.48 g (4.6 mmol) of 4- (3-chloro-anilino) -6- (pyrid-2-yl) -7H-pyrrolo [2,3-d] pyrimidine (see Example 1) was suspended in 115 g. ml dioxane. 46 ml of 0.1N HCl (0.1N hydrochloric acid) are then added under cooling, and the suspension is stirred at room temperature for 2.5 hours. The suspension is concentrated by evaporation and the residue is stirred with 400 ml of hot methanol and filtered. The filtrate is hot filtered through activated carbon, the solvent is evaporated and the residue is digested with cold ethanol; mp 10.7 (2s, 2H), (m, 2H), 7.76 7.42 (m, 1H),

Mp 276-278 ° C. ^{Τ Η} NMR (200 MHz, DMSO-d?): 8.71 and 13.1 (d, J = 5, 1H), 8.45 and 8.08 (2s, 2H), 8.00 (d, J = 8, 1H), 7.68 (s, 1H), 7.50 (d, J = 8, 1H),

7.27 (d, J = 8, 1H).

Example 3

4- (3-Chloro-anilino) -5-dimethylaminomethyl-6- (pyrid-2-yl) -7 H -pyrrolo [2,3-d] pyrimidine

Excluding moisture, 60.1 mg (0.325 mmol) of N, N-dimethylmethylenimmonium iodide (Fluka, Buchs, Switzerland) are added to 80.4 mg (0.25 mmol) of 4- (3-chloroanilino) -6- (pyrid-2-yl) -7H-pyrrolo [2,3-d] pyrimidine (see Example 1) in 3 ml abs. THF and the reaction mixture was refluxed for 3 days. The reaction mixture was partitioned between ethyl acetate and saturated Na ₂ CO ₂ solution, the aqueous phase separated and extracted with two portions of ethyl acetate. The organic phase is washed three times with water and once with brine, dried over MgSO4 and concentrated by evaporation. Digest the residue with ethyl acetate

and diethyl ether yields the desired substance, 1.1. 247-251 C. ¹ H NMR (300 MHz, _DMSO-d6): 12.8 and 12.2 (2 s, 2H), 8.71 (m, 1H), 8.37 and 8.23 (2s, 2H), 7.93 (m, 1H), 7.80 (d, J = 8, 1 H), 7.47 (D, J = 8, 1H), 7.37 (m, 2H), 7.03 (d, J = 8, 1H), 4.18 (s, 2H), 2.40

(s, 6H); MS: (M) < ^{+ &gt}; = 378.

Example 4

4- (3-chloro-4-fluoro-anilino) -6- (pyrid-2-yl) -7 H -pyrrolo [2,3-d] pyrimidine

A mixture of 20 mg (0.09 mmol) of 6- (pyrid-2-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ol (see step 1.2) and 1 ml of phosphorus oxychloride was heated for 30 min. to boiling in a protective gas atmosphere. The reaction mixture is evaporated to dryness and the residue is suspended in 1 ml of n-butanol. 16.4 mg (0.108 mmol) of 3-chloro-4-fluoroaniline are added and the suspension is refluxed for 2 hours. The dark brown suspension is then concentrated by evaporation and the residue is dissolved in methanol. Silica gel was added and the solvent was evaporated. The powder was then applied to a silica gel column and eluted with ethyl acetate. The desired product is obtained. ^{Τ Η} NMR (400 MHz, DMSO-d₆): 12.5 (sb, NH), 9.64 (s, NH), 8.64 (d, J = 5, 1H), 8.38 (s, 1 H ), 8.35 (dd, J _{1 =} 7, J ₂ = 3, 1H), 7.92 (m, 2H), 7.83 (m, 1H), 7.53 (s, 1H), 7, 41 (t, J = 9, 1 H), 7.33 (m, 1 H); HPLC: t _ret (Grad ₂₀ ) = 10.4 min; MS: (M) < ^{+ &gt}; = 339.

Example 5

4- (3-Chloro-anilino) -5-methyl-6- (pyrid-2-yl) -7H-pyrrolo [2,3-d] pyrimidine and 4- (3-chloro-anilino) -5-methyl 6- (N-benzylpyrido £-ammonium-2-yl) -7 H -pyrrolo [2,3-d] pyrimidine bromide

To a solution of approximately 1.2 mmol of 4-chloro-5-methyl-6- (N-benzylpyridinium-2-yl) -7H-pyrrolo [2,3-d] pyrimidine in 10 ml of isopropanol, 529 μΐ ( 5,0 mmol)

Of 3-chloroaniline and the reaction mixture was refluxed for 3 hours. The solvent was evaporated and the residue was chromatographed on silica gel. Elution with methylene chloride / ethanol (7: 3) and methylene chloride / methanol (7: 3) yields first

4- (3-chloro-anilino) -5-methyl-6- (pyrid-2-yl) -7H-pyrrolo [2,3-d] pyrimidine (A) followed by 4- (3-chloro-anilino) -5-methyl-6- (N-benzyl-pyridinium-2-yl) -7H-pyrrolo [2,3-d] pyrimidine bromide (B). Compound A is also obtained by heating Compound B.

Compound A: mp 251-252 ° C; ¹ H NMR (200 MHz, DMSO-d 6): 12.75 and 9.25 (2sb), 8.75 (d, J = 5, 1H), 8.35 (s, 1H), 8.05-7 85 (m, 3H), 7.66 (d, J = 8, 1 H), 7.45 (m, 2H), 7.29 (d, J = 8, 1 H), 2.84 (s, 3H) ); FAB-MS: (M + H) ⁺ = 336. Compound B: mp 171-172 ° C (intense foaming); ¹ H NMR (200 MHz, DMSO-d 6): 12.65 (sb), 9.48 (d, J = 6, 1H), 8.80 (t, J = 8, 1H), 8.59 (sb) 1 H, 8.43 (s,

1H), 8.3 (m, 2H), 7.94 (m, 1H), 7.72 (d, J = 8, 1H), 7.40 (t,

J = 8, 1H), 7.28 (m, 3H), 7.17 (d, J = 8, 1H), 6.94 (m, 2H), 5.93 (s, 2H), 2.27 (s, 3H); FAB-MS: (M + H) < ^{+ &gt}; = 426.

The starting material was prepared as follows:

Step 5.1: 2- (5-Amino-4-cyano-3-methyl-1H-pyrrol-2-yl) -N-benzyl-pyridinium bromide

1.81 g (5.5 mmol) of N-benzyl-2-bromopyridinium bromide (preparation described in J. Heterocyclic Chem. 28, 1083 (1991)) was added to 605.5 mg (5.0 mmol) under argon. - amino-3-cyano-4-methylpyrrole (preparation described in Synthesis (1976), 51) in 40 ml of methylene chloride and 639 μΐ (5.5 mmol) of lutidine. The mixture was stirred at room temperature for 5.5 hours and then evaporated to about half volume. The suspension is filtered and washed with methylene chloride-ethyl acetate (1: 1) and ethyl acetate-hexane (1: 1). The desired product is obtained. ¹ H NMR (300 MHz, DMSO-d 6): 10.83 (s, 1H), 9.10 (d, J = 7, 1H), 8.49 (t, J = 7, 1H), 7.96 (m, 2H), 7.30 (m, 3H), 6.95 (m, 2H), 6.57 and 5.80 (2s, a 2H), 1.76 (S, 3H); FAB-MS: (M + H) < ^{+ &gt}; = 289.

Step 5.2: 5-Methyl-6- (N-benzyl-pyridinium-2-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ol

A mixture of 1.182 g (3.2 mmol) of 2- (5-amino-4-cyano-3-methyl-1H-pyrrol-2-yl) -N-benzyl-pyridinium bromide and 12 ml of formic acid is heated under a protective gas atmosphere 90 min to 110 ° C. The reaction mixture is concentrated by evaporation and the residue is lyophilized from water and then twice from dioxane containing a small amount of water to give the desired product. 1 H NMR (200 MHz, DMSO-d 6): 12.0 (sb), 9.40 (d, J = 8, 1H), 8.73 (t, J = 8, 1H), 8.25 (s) m, 2H), 7.98 (s, 1H), 7.27 (m, 3H), 6.90 (m, 2H), 5.92 (s, 2H), 2.04 (S, 3H); HPLC: t _ret (Grad ₂₀ ) = 5.8 min); FAB-MS: (M + H) < ^{+ &gt}; = 317.

Step 5.3: 4-Chloro-5-methyl-6- (N-benzyl-pyridinium-2-yl) -7H-pyrrolo [2,3-d] pyrimidine

A mixture of 500 mg (1.2 mmol) of 5-methyl-6- (N-benzyl-pyridinium-2-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ol and 15 ml of phosphorus oxychloride is heated to boiling 2 hours with exclusion of moisture. Concentration of the reaction mixture by evaporation gives the desired product; HPLC: t _ret (Grad ₂₀ ) = 8.8 min; FAB-MS: (M + H) < ^{+ &gt}; = 335.

Example 6

4- (3-chloro-4-fluoro-anilino) -5-methyl-6- (pyridin-2-yl) -7 H -pyrrolo [2,3-d] pyrimidine

The title compound was prepared analogously to Example 5 using 3-chloro-4-fluoroaniline; mp 277-278 ° C. @ ¹ H NMR (300 MHz, DMSO-d6): 9.3 (sb), 8.73 (d, J = 5, 1H), 8.33 (s, 1H), 7.96 (m, 2H), 7.88 (d, J = 8, 1H), 7.67 (m, 1H), 7.52 (t, J = 9, 1H), 7.40 (m, 1H), 2.83 (s, 3H); MS: (M) < ^{+ &gt};

353.

Example 7

4- (3-Chloro-anilino) -7 H -pyrrolo [2,3-d] pyrimidine

A mixture of 133 mg (0.866 mmol) of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (prepared according to Chem. Ber. 112, 3526 (1979)), 136 μΐ (1.3 mmol) of 3-chloroaniline, and 4 ml of n-butanol is heated to boiling for 90 min. The dark green reaction solution was diluted with ethanol and hot filtered through charcoal. The solvent is evaporated, the residue is stirred with isopropanol, the solid is filtered off with suction and recrystallized from hot isopropanol with a small amount of ethanol. The title compound is obtained, mp 230-233 ° C; ¹ H NMR: 12.5 and 10.7 (2sb, 2H), 8.42 and 7.97 (2s, 2H), 7.67 (d, J = 8, 1H), 7.48 (t, J = 8, 1H), 7.43 (m, 1H), 7.29 (d, J = 8, 1H), 6.93 (sb, 1H); FAB-MS: (M + H) < ^{+ &gt}; = 245.

Example 8

4- (3-Chloro-anilino) -6- (biphen-4-yl) -7H-pyrrolo [2,3-d] pyrimidine

A suspension of 220 mg (0.72 mmol) of 4-chloro-6- (biphen-4-yl) -7H-pyrrolo [2,3-d] pyrimidine and 151 μΐ (1.44 mmol) of 3-chloroaniline in 5 ml of butanol is heated to boiling overnight. After cooling, the product is filtered off with suction and washed with a large quantity of ethanol and finally with hexane. ¹ H NMR (200 MHz, DMSO-d 6): 12.46 (sb, 1H), 9.6 (s,

1H), 8.40 (s, 1H), 8.28 (m, 1H), 7.98 (d, J = 8, 2H), 7.8 (m,

5H), 7.52 and 7.38 (2t, J = 8 and 2H), 7.30 (s, 1H), 7.08 (db, J = 8,

1H); MS: (M) < ^{+ &gt}; = 397.

The starting material is prepared as follows:

Step 8.1: 2-Amino-3-ethoxycarbonyl-5- (biphen-4-yl) -1H-pyrrole

In an argon atmosphere, 1.65 g (10 mmol) of 2-amidinoacetic acid ethyl ester hydrochloride (prepared according to Liebigs Ann. Chem., 1895 (1977)) is mixed with 10 ml of ethanol. 0.73 g (10 mmol) of sodium ethoxide are then added at 0-5 ° C. The bright yellow suspension was stirred for 20 min and then 1.4 g (5 mmol) of 2-bromo-1- (biphen-4-yl) -ethan-1-one (2-bromo-4'-phenylacetophenone) was added, Aldrich, Milwaukee, USA). After stirring at room temperature for 48 hours, the reaction mixture is concentrated by evaporation and the residue is dissolved in ethyl acetate. The solution was washed with three portions of water and brine. The aqueous phases are extracted by shaking twice with ethyl acetate, the organic phases are dried over _MgSO4 and evaporated. Silica gel column chromatography in ethyl acetate-hexane (1: 1) and trituration with diisopropyl ether-hexane gave the desired product, mp 186-188 ° C; TLC-R1 = 0.17 (ethyl acetate-hexane (1: 1)); FAB-MS: (M + H) < ^{+ &gt}; = 306.

Step 8.2: 6- (Biphen-4-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ol

A mixture of 2-amino-3-ethoxycarbonyl-5- (biphen-4-yl) -1H-pyrrole (766 mg; 2.5 mmol), 5 mL formamide, 2.5 mL DMF, and 1.25 mL formic acid was stirred. 20 hours at 150 ° C. The reaction mixture is diluted with isopropanol, the product is filtered off with suction and washed with isopropanol and hexane; mp > 300 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 288.

Step 8.3: 4-Chloro-6- (biphen-4-yl) -7H-pyrrolo [2,3-d] pyrimidine

A mixture of 430.5 mg (1.5 mmol) of 6- (biphen-4-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ol and 6 ml of phosphorus oxychloride is heated to reflux for 4 hours under a protective gas atmosphere. . The reaction mixture was poured into ice water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. Evaporation of the solvent and trituration of the residue with hot THF-isopropanol gave the desired product, mp 295-300 ° C (dec.); FAB-MS: (M + H) < ^{+ &gt}; = 306.

Example 9

4- (3-Chloro-anilino) -6- (naphth-2-yl) -7H-pyrrolo [2,3-d] pyrimidine

A mixture of 98 mg (0.35 mmol) of 4-chloro-6- (naphth-2-yl) -7H-pyrrolo [2,3-d] pyrimidine, 73 μΐ (0.7 mmol) of 3-chloroaniline and 8 ml of butanol is heated to boiling for 5 hours. After cooling, the product is filtered off with suction and washed with isopropanol and hexane; mp 278-284 ° C; TLC-Rf = 0.5 (ethyl acetate-hexane (1: 1)); FAB-MS: (M + H) < ^{+ &gt}; = 371.

The starting material is prepared as follows:

Step 9.1: 2-Amino-3-ethoxycarbonyl-5- (naphth-2-yl) -1H-pyrrole

834 mg (5 mmol) of 2-amidinoacetic acid ethyl ester hydrochloride (prepared according to Liebigs Ann. Chem. 1895 (1977)) is mixed with 10 ml of ethanol under an argon atmosphere. 358 mg (5 mmol) of sodium ethoxide are then added at 0-5 ° C and the bright yellow suspension is stirred for 15 minutes. Was added 623 mg (2.5 mmol) of 2-bromo-l- (naphth-2-yl) ethan-l-one (2-bromo-2 ^one acetophenone; Aldrich, Milwaukee, USA). The mixture was stirred at room temperature for 3 days and then concentrated by evaporation. The residue is mixed with ethyl acetate and water, filtered, the organic phase is separated and washed with three portions of water and brine. The aqueous layers were extracted with ethyl acetate and the organic phases were dried over MgSO ₄ and concentrated by evaporation. Silica gel column chromatography with ethyl acetate-hexane (1: 1) and trituration with diethyl ether-hexane gave the desired product, mp 149-151 ° C; TLC-Rf = 0.5 (ethyl acetate-hexane (1: 1)); FAB-MS: (M + H) < ^{+ &gt}; = 281.

Step 9.2: 6- (Naphth-2-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ol

A mixture of 2-amino-3-ethoxycarbonyl-5- (naphth-2-yl) -1H-pyrrole (420 mg; 1.5 mmol), 3 mL formamide, 1.5 mL DMF, and 0.75 mL formic acid was stirred 22 hours at 150 ° C. The reaction mixture was diluted with isopropanol (ca. 1 mL), the product was filtered off with suction and washed with ethanol, isopropanol and hexane; mp > 300 ° C; ¹ H NMR (200 MHz, DMSO-d 6): 12.2 (sb), 8.39 (s, 1H), 8.0 (m, 2H), 7.9 (m, 3H), 7.53 ( m, 2H), 7.11 (s, 1 H).

Step 9.3: 4-Chloro-6- (naphth-2-yl) -7H-pyrrolo [2,3-d] pyrimidine

A mixture of 198.5 mg (0.76 mmol) of 6- (naphth-2-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ol and 3 ml of phosphorus oxychloride is heated under reflux for 5 hours. . The reaction mixture was poured into ice water and stirred for 1 hour to complete the decomposition. The crystals are aspirated and washed with water. The crude product was dissolved in THF-methanol, filtered through charcoal and the solvent was evaporated. Trituration with isopropanol and washing with hexane gave the desired product, mp 268-269 ° C (dec.); FAB-MS: (M + H) < ^{+ &gt}; = 280.

Example 10

4- (3-Chloro-anilino) -6- (2-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine hydrobromide

6.72 g (19.16 mmol) of 4- (3-chloro-anilino) -6- (2-methoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine are mixed in a dry apparatus under argon. 150 ml methylene chloride. A solution of 18.4 ml (191.6 mmol) of borontribromide in 100 ml of methylene chloride is then added dropwise over 1 hour with ice-cooling. After stirring for 3 hours in an ice bath, the suspension is poured into 0.5 liters of ice water and filtered off with suction. The residue was dissolved in ethyl acetate and the solution was washed with saturated NaHCO 3 solution, water and brine. The aqueous phases are extracted twice with ethyl acetate and the organic phases are dried over MgSO ₄ , concentrated by evaporation and the product is crystallized from ethanol-hexane, ¹ H NMR (300 MHz, DMSO-d 6): 8.41 (s, 1H), 7, 92 (s, 1H); 7.78 (d, J = 8, 1H); 7.64 (d, J = 8, 1H); 7.50 (m, 2H); Δ, 1H), 7.23 (m, 1H), 7.04 (d, J = 8, 1H), 6.95 (dd, J = 8, 1H); FAB-MS: (M + H) < ^{+ &gt}; = 337.

The starting material is prepared as follows:

Step 10.1: 2-Amino-3-ethoxycarbonyl-5- (2-methoxyphenyl) -1H-pyrrole

Analogously to step 8.1, 14.5 g (87 mmol) of 2-amidino-acetic acid ethyl ester hydrochloride in 150 ml of abs. ethanol was reacted with 5.9 g (87 mmol) of sodium ethoxide and 10.3 g (44 mmol) of 2-bromo-1- (2-methoxyphenyl) ethan-1-one (2-bromo-2'-). methoxy-acetophenone, Aldrich, Milwaukee, USA) to give the desired product, m.p. 128 [deg.] C .; TLC-Rf = 0.25 (2: 1 hexane-ethyl acetate).

Step 10.2: 6- (2-Methoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ol

A mixture of 2-amino-3-ethoxycarbonyl-5- (2-methoxyphenyl) -1H-pyrrole (7.66 g; 31 mmol), 63 ml of formamide, 31.5 ml of DMF and 17.7 ml of formic acid is passed through heated at 150 ° C in a protective gas atmosphere. The reaction mixture is worked up analogously to step 8.2 to give the desired product; TLC-Rf = 0.33 (hexane-ethyl acetate (1: 1)).

Step 10.3: 4-Chloro-6- (2-methoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine

A mixture of 6.2 g (25.7 mmol) of 6- (2-methoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ol and 62 ml of phosphorus oxychloride was heated.

1.5 hours at 125 ° C under argon. The reaction mixture was poured into ice water and extracted three times with ethyl acetate. The organic phases are washed with water, NaHCO ₃ solution and brine, dried over MgSO ₄ and concentrated by evaporation. Filtration through a silica gel column in ethyl acetate gave the desired product; TLC-Rf = 0.8 (hexane-ethyl acetate (1: 1)).

Step 10.4: 4- (3-Chloro-anilino) -6- (2-methoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine

A mixture of 6.6 g (25.4 mmol) of 4-chloro-6- (2-methoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine, 5.34 ml (50.8 mmol) of 3-chloroaniline and 100 ml of n-butanol is heated to boiling for 1.5 hours. The reaction mixture is cooled, the product is filtered off with suction and washed with diethyl ether and hexane. Flash chromatography on silica gel (applied to the column in the dry state; hexane-ethyl acetate (2: 1) → ethanol-acetone (1: 1)) afforded the desired product, mp 221-222 ° C; TLC-Rf = 0.3 (hexane-ethyl acetate (1: 1)); FAB-MS: (M + H) < ^{+ &gt}; = 351.

Example 11

4- (3-Chloro-anilino) -6- (3-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine hydrobromide

The title compound was prepared in analogy to Example 10 by reacting 4.53 g (12.91 mmol) of 4- (3-chloro-anilino) -6- (3-methoxy-phenyl) -7H-pyrrolo [2,3- d] pyrimidine in 150 mL of methylene chloride with 12.4 mL (129 mmol) of borontribromide in 150 mL of methylene chloride. HPLC: t _ret (Grad ₂₀ ) = 10.5 min; ¹ H NMR (500 MHz,

DMSO-d6) (s, 1H), 7.23 (s,

12.61, 10.07 and 9.68 (3sb, 3H), 8.35 (s, 1H), 8.09

7.76 (d, J = 8, 1H); 7.39 (dd, J = 8, 1H); 7.27 (m, 2H);

1H), 7.12 (1H), 7.11 (1H), 6.77 (m, 1H).

The starting material is prepared as follows:

Step 11.1: 2-Amino-3-ethoxycarbonyl-5- (3-methoxy-phenyl) -1H-pyrrole

Analogously to step 8.1, 14.5 g (87 mmol) of 2-amidino-acetic acid ethyl ester hydrochloride in 150 ml of abs. ethanol was reacted with 5.9 g (87 mmol) of sodium ethoxide and 10.3 g (44 mmol) of 2-bromo-1- (3-methoxyphenyl) ethan-1-one (2-bromo-3'-methoxy) acetophenone (Janssen) to give the desired product, m.p. 96-97 [deg.] C .; TLC-Rf = 0.2 (2: 1 hexane-ethyl acetate).

Step 11.2: 6- (3-Methoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ol

A mixture of 2-amino-3-ethoxycarbonyl-5- (3-methoxyphenyl) -1H-pyrrole (7.19 g; 29 mmol), 59 mL of formamide, 29.5 mL of DMF, and 14.7 mL of formic acid is passed through heated at 150 ° C in a protective gas atmosphere. The reaction mixture is worked up analogously to step 8.2 to give the desired product; TLC-Rf = 0.3 (hexane-ethyl acetate (1: 1)).

Step 11.3: 4-Chloro-6- (3-methoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine

A mixture of 5.28 g (21.9 mmol) of 6- (3-methoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ol and 53 ml of phosphorus oxychloride was heated.

1.5 hours to boiling without moisture. The reaction mixture was cooled and the product was filtered off with suction. The product was dissolved in ethyl acetate and the solution was washed with NaHCO 3 solution, water and brine. The aqueous phases are extracted once with ethyl acetate, dried over MgSO ₄ and concentrated by evaporation to give the desired product; TLC-Rf = 0.73 (hexane-ethyl acetate (1: 1)).

Step 11.4: 4- (3-Chloro-anilino) -6- (3-methoxy-phenyl) -7H-pyrrole72

- [2,3-d] pyrimidine

A mixture of 5.68 g (21.9 mmol) of 4-chloro-6- (3-methoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine, 4.59 ml (43.7 mmol) of 3-chloroaniline and 75 ml of n-butanol is heated to boiling for 1.5 hours. Analogous workup as described in Step 10.4 gives the desired product, mp 262-263 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 351.

Example 12

4- (3-Chloro-anilino) -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine hydrobromide

Excluding moisture, a solution of 6 ml of boron trifluoride in 100 ml of methylene chloride is added dropwise over about 40 minutes at about 0 ° C to 2.0 g (5.7 mmol) of 4- (3-chloroanilino) -6- (4-methoxy- phenyl) -7H-pyrrolo [2,3-d] pyrimidine in 60 mL of methylene chloride. The mixture is stirred for 21 hours at room temperature and then filtered. The crude product is precipitated from the filtrate by adding about 1 liter of hexane, filtered off with suction and washed with hexane. It is then mixed with 0.2 liters of water and 0.6 liters of ethyl acetate and neutralized with 5% NaHCO ₃ solution. The organic phase was separated, washed with water and brine, dried over MgSO ₄ and concentrated by evaporation. Crystallization from hot methanol with hexane gave the desired product. Analysis: Calculated for C ₁₈ H ₁₄ N ₄ OBrCl (+0.13 H ₂ 0): C 51.47%, H 3.36%, N 13.34%, Br 19.02%, Cl 8.44% ; found: C 51.58%, H 3.32%, N 13.37%, Br 19.29%, Cl 8.46%. ^{Χ Η} NMR (360 MHz, DMSO-d): 12.85 and 10.60 (2sb, 2H), 10.5-9.5 (sb), 8.37 (s, 1H), 7.92 (s (1H), 7.67 (d, J = 8, 2H), 7.63 (d, J = 8, 1H), 7.51 (dd, J = 8, 1H), 7.33 (d, J) = 8, 1H), 7.06 (s, 1H), 6.90 (d, J = 8, 2H).

The starting material is prepared as follows:

Step 12.1: 2-Amino-3-ethoxycarbonyl-5- (4-methoxy-phenyl) -1H-pyrrole

Analogous to step 8.1, 1.67 g (10 mmol) of 2-amidinoacetic acid ethyl ester hydrochloride in 20 ml of abs. ethanol is reacted with 716 mg (10 mmol) of sodium ethoxide and

1.145 g (5.0 mmol) of 4-methoxyphenacyl bromide (Fluka, Buchs, Switzerland) to give the desired product, mp 141-142 ° C; _TLC-Rf = 0.4 (hexane-ethyl acetate (1: 1)); FAB-MS: (M + H) < ^{+ &gt}; = 261.

Step 12.2: 6- (4-Methoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ol

A mixture of 2-amino-3-ethoxycarbonyl-5- (4-methoxyphenyl) -1H-pyrrole (611 mg; 2.3 mmol), 5 mL formamide, 2.5 mL DMF, and 1.25 mL formic acid was passed through heated at 150 ° C in a protective gas atmosphere. The reaction mixture was worked up analogously to step 8.2 to give the desired product, mp > 300 ° C FAB-MS: (M + H) ⁺ = 242.

Step 12.3: 4-Chloro-6- (4-methoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine

A mixture of 121 mg (0.50 mmol) of 6- (4-methoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ol and 1 ml of phosphorus oxychloride was heated.

1.5 hours to boiling without moisture. The reaction mixture was poured into ice water and extracted twice with ethyl acetate. The organic phases are washed three times with water, brine, dried with _MgSO4 and concentrated by evaporation. Stirring with diethyl ether gives the desired product, mp 248-249 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 260.

Step 12.4: 4- (3-Chloro-anilino) -6- (4-methoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine

A mixture of 95 mg (0.365 mmol) of 4-chloro-6- (4-methoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine, 77 μΐ (0.732 mmol) of 3-chloroaniline, 3 ml of n-butanol and several of drops of DMPU is heated to boiling for 2 hours. The reaction mixture is cooled, diluted with diethyl ether and isopropanol and the product is filtered off with suction, mp 294-295 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 351.

Example 13

4- (3-Chloro-anilino) -5-dimethylaminomethyl-6- (4-hydroxy-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine

In an argon atmosphere, 96.2 mg (0.52 mmol) of N, N-dimethylmethylenimmonium iodide (Fluka, Buchs, Switzerland) was added to 134.7 mg (0.40 mmol) of 4- (3-chloroanilino) -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine in 4.88 ml abs. THF and the reaction mixture was refluxed for 1.5 hours. Work-up is carried out as described in Example 3 and the product is recrystallized from hot ethanol; mp 269-271 ° C; _TLC-Rf = 0.31 (C ^ C ^ -methanol (10: 1)); MS: (M) < ^{+ &gt}; = 393; ¹ H NMR (500 MHz, DMSO-d 6): 12.48, 11.91 and 9.75 (3s, 3H) 8.32 and 8.25 (2s, 2H), 7.40 (d, J = 8) (1H), 7.34 (1H), 7.32 (d, J = 8, 2H), 7.00 (d, J = 8, 1H), 6.89 (d, J = 8, 2H), 3.72 (s, 2H).

2.36 (s, 6H).

Example 14

4- (3-Chloro-anilino) -5-dimethylaminomethyl-6-phenyl-7H-pyrrolo [2,3-d] pyrimidine

A mixture of 898.2 mg (2.80 mmol) of 4- (3-chloro-anilino) -6-phenyl-7H-pyrrolo [2,3-d] pyrimidine, 33.6 ml abs. THF and 673.7 mg (3.64 mmol) of Ν, Ν-dimethylmethylenimmonium iodide (Fluka, Buchs, Switzerland) were refluxed through the nose under an argon atmosphere. The reaction mixture was partitioned between ethyl acetate and 1N (= 1N) hydrochloric acid. The organic phase is separated and washed three times with water. The aqueous phases are extracted once with ethyl acetate and basified with solid sodium carbonate to form a suspension to which ethyl acetate is added, then the solid is concentrated in the organic phase. The organic phase is washed three times with water until neutral, and the aqueous phases are again extracted with ethyl acetate. The combined organic phases (suspensions) are concentrated by evaporation. Stirring the residue with diethyl ether gives the desired product; MS: (M) < ^{+ &gt}; = 377; ¹ H NMR (200 MHz, DMSO-d 6): 12.57 and 12.12 (2s, 2H), 8.38 (s, 1H), 8.29 (m, 1H), 7.55 (m, 4H) ), 7.5-7.3 (m, 3H), 7.04 (dm, J = 8, 1H), 3.79 (s, 2H), 2.38 (s, 6H).

The starting material is prepared as follows:

Step 14.1 6-Phenyl-7H-pyrrolo [2,3-d] pyrimidin-4-ol

A mixture of 2.30 g (10 mmol) of 2-amino-3-ethoxycarbonyl-5-phenyl-1H-pyrrole (prepared according to Synthesis 272 (1987)), 20 ml of formamide, 10 ml of DMF and 5 ml of formic acid is heated for 24 hours. to 150 ° C in a shielding gas atmosphere. The reaction mixture was cooled, the solid was filtered off with suction and washed with isopropanol-hexane. Stirring in hot isopropanol gave the desired product, mp > 300 ° C FAB-MS: (M + H) ⁺ = 212.

Step 14.2: 4-Chloro-6-phenyl-7H-pyrrolo [2,3-d] pyrimidine

A mixture of 1.795 g (8.5 mmol) of 6-phenyl-7H-pyrrolo [2,3-d] pyrimidin-4-ol and 27 ml of phosphorus oxychloride is heated to boiling for 3 hours with exclusion of moisture. The reaction mixture is poured into ice water, the solid is filtered off with suction and washed with hot isopropanol and hexane to give the desired product; FAB-MS: (M + H) < ^{+ &gt}; = 230.

Step 14.3: 4- (3-Chloro-anilino) -6-phenyl-7H-pyrrolo [2,3-d] pyrimidine

A suspension of 1.251 g (5.45 mmol) of 4-chloro-6-phenyl-7H-pyrrolo [2,3-d] pyrimidine, 1.15 ml (10.9 mmol) of 3-chloroaniline, 20 ml of n-butanol and 0.5 ml of DMPU is heated to boiling for 2 hours. The reaction mixture was cooled and the product was filtered off with suction. Mixing with hot THF / methanol gives the desired product, mp 285-286 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 321.

Example 15 (Reference example)

4- (3-Chloro-anilino) pyrimido [4,5-b] indole

5.7 g (15 mmol) of N-benzyl-4- (3-chloro-anilino) pyrimido [4,5-b] 76 indole was added to a suspension of 7.6 g of anhydrous AlCl ₃ in 50 ml of toluene and the reaction mixture was stirred at room temperature. Heat at 100 ° C for 45 min. The mixture was then cooled to room temperature, poured into ice water and stirred for about 30 minutes to precipitate the crude product. The crude product is filtered off with suction and washed with water. Discard the filtrate. The crude product was dissolved in THF-ethyl acetate, washed with 5% sodium bicarbonate solution and then brine, dried and concentrated. On standing in the refrigerator, crystals of 4- (3-chloro-anilino) pyrimido [4,5-b] indole are precipitated, which is completely precipitated by the addition of cyclohexane. The product was further purified by digesting with ethyl acetate. The title compound is obtained in the form of pinkish crystals; 1.1. ≫ 260 ° C; ¹ H NMR (360 MHz, DMSO-d 6): 12.20 (s, NH pyrrole), 8.97 (s, NH aniline), 7.1-8.5 (m, 8 aromatic and pyrimidine H); FAB-MS: (M + H) < ^{+ &gt}; = 295.

hydrochloride

2.8 g of 4- (3-chloro-anilino) pyrimido [4,5-b] indole was dissolved in hot THF, cooled to room temperature, and 2.8 ml of a 5 molar solution of HCl in diethyl ether was added with stirring. After addition of about 250 ml diethyl ether and cooling in an ice bath, 4- (3-chloro-anilino) pyrimido [4,5-b] indole hydrochloride precipitated as colorless crystals, m.p. Mp 280-286 ° C.

The starting material is prepared as follows:

Stage 15.1; 4-Hydroxy-5,6-tetramethylene-7-benzyl-pyrrolo [2,3-d] pyrimidine

A mixture of 15 g of 2-amino-1-benzyl-3-cyano-4,5,6,7-tetrahydroindole (prepared from 2-hydroxycyclohexanone, benzylamine and malendinitrile according to a known procedure; see HJ Roth and K. Eger, Ar. Pharmaz. 308, 179 (1975)) and 100 ml of 85% formic acid are boiled at 110 ° C for 5 hours. The reaction solution was cooled in an ice bath, pale brown crystals precipitated. The suspension is poured into about 200 ml of ice water and stirred for about 10 minutes. The precipitate is filtered off with suction and washed with water and hexane and dried. Mp 104-105 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 280.

Step 15.2: 4- (3-Chloro-anilino) -5,6-tetramethylene-7-benzyl-pyrrolo [2,3-d] pyrimidine

A mixture of 0.65 g of 4-chloro-5,6-tetramethylene-7-benzyl-pyrrolo [2,3-d] pyrimidine, 0.27 ml of 3-chloroaniline and 10 ml of ethanol is heated at reflux for 17 hours. The brown solution is evaporated to dryness, the residue is dissolved in ethyl acetate, the ethyl acetate solution is washed neutral with sodium bicarbonate and water, dried and concentrated by evaporation. The residue was taken up in ethyl acetate-hexane. The desired product is recrystallized from white crystals, mp 145-147 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 389.

Step 15.3: N-benzyl-4- (3-chloro-anilino) pyrimido [4,5-b] indole 14.1 g (62 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was added to a solution of 12.1 g (31 mmol) of 4- (3-chloro-anilino) -5,6-tetramethylene-7-benzyl-pyrrolo [2,3-d] pyrimidine in 260 mL of toluene. The dark red solution was refluxed for 30 min and then cooled to room temperature. The insoluble material is filtered off and the filtrate is concentrated by rotary evaporation. The crude product is chromatographed on silica gel (hexane-ethyl acetate). Colorless crystals of the title compound are obtained, mp 174-176 ° C; ¹ H NMR (360 MHz, CDCl ₃ ): 12.20 (s, NH pyrrole), 9.0 (s, aniline H), 7.0-8.6 (m, 13 aromatic H and one pyrimidine H) 5.66 (s, 2H, benzyl); FAB-MS: (M + H) < ^{+ &gt}; = 385.

Example 16

4- (3-Chloro-anilino) -5-methyl-6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine hydrobromide

The title compound is obtained as a colorless powder analogously to Example 10 by removing the methyl group from 5 g (6.85 mmol) of 4- (3-chloroanilino) -5-methyl-6- (4-methoxyphenyl). -7H-pyrrolo [2,3-d] pyrimidine by treatment with 4.4 g of borontribromide in 30 ml of methylene chloride; mp 295-296 ° C; ¹ H NMR (360 MHz, DMSO-d 6): 11.85 (s, NH pyrrole), 9.68 (s, H phenol), 8.29 (s, NH aniline), 8.27 (s, H pyrimidine) ), 7.94 (m, H arom.),

7.70 (m, aromatic H), 7.42 (d, 2H aromatic), 7.35 (t, aromatic H), 7.06 (m, aromatic H), 6.90 (d, 2H aromatic) 2H arom.), 2.58 (s, 3H); FAB-MS: (M + H) < ^{+ &gt}; = 351.

hydrochloride

To prepare the hydrochloride, 600 mg of 4- (3-chloro-anilino) -5-methyl-6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine hydrobromide is dissolved in 50 ml of hot ethyl acetate and at room temperature, the pH is adjusted to 9.5 by the addition of 1N NaOH and the organic phase is washed twice with water, dried and concentrated by evaporation. The residue is dissolved in 30 ml of ethanol and 5N (= 5 normal) ethanolic HCl solution is added. The mixture was cooled to 0 ° C and diethyl ether was added with stirring to give 4- (3-chloro-anilino) -5-methyl-6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-a] hydrochloride. -d] pyrimidine in the form of a colorless powder, m.p. 280-282 ° C.

The starting material is prepared as follows:

Step 16.1: 4-Chloro-5-methyl-6- (4-methoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine

The title compound was prepared analogously to step 1.3 by refluxing 4-hydroxy-5-methyl-6- (4-methoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine with phosphorus oxychloride.

FAB-MS: (M + H) < ^{+ &gt}; = 274.

Step 16.2: 4- (3-Chloro-anilino) -5-methyl-6- (4-methoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine

A mixture of 4 g of 4-chloro-5-methyl-6- (4-methoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine, 8.45 ml of 3-chloroaniline and 400 ml of n-butanol is boiled under 20 hours. The brown solution is concentrated to give the desired product. The mixture was allowed to stand overnight in the refrigerator and the product was then filtered off with suction and washed with hexane-ethyl acetate. The desired product is obtained in the form of colorless crystals, mp 265-268 ° C; FAB-MS: (M + H) < ^{+ &gt};

365th

Ί3

Example 17

4- (3-Chloro-anilino) -6- (4-nitro-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine

The title compound is obtained in the form of rusty brown crystals analogously to Example 5 by heating to boiling 0.25 g (0.91 mmol) of 4-chloro-6- (4-nitro-phenyl) -7H-pyrrolo [2, m.p. 3-d] pyrimidine with 0.19 ml of 3-chloroaniline in 5 ml of n-butanol; 1.1. ≫ 250 ° C. ¹ H NMR (360 MHz, DMSO-d 6): 12.95 (s, NH pyrrole), 10.3 (s, NH aniline), 8.45 (s, H pyrimidine), 8.24 (s, H aroma) 7.18-8.4 (7H arom. + 5H pyrrole); MS: (M) < ^{+ &gt}; = 365.

The starting material is prepared as follows:

Step 17.1: 2-Amino-3-ethoxycarbonyl-5- (4-nitro-phenyl) -pyrrole

In a dry three-necked flask, under an atmosphere of argon, mix 75 ml of abs. ethanol with 6.5 g (390 mmol) of 2-amidinoacetic acid ethyl ester hydrochloride Chem., 1895 (1977)). Then (390 mmol) of sodium ethoxide.

(prepared according to Liebigs Ann.) at 0-5 ° C was added 2.65 g

Next, 5 g (195 mmol) is added.

Of 2-bromo-1- (4-nitro-phenyl) -ethan-1-one, the reaction mixture is allowed to warm to room temperature and then stirred for 48 hours. The reaction mixture is partitioned between water and ethyl acetate, the ethyl acetate phase is washed three times with water and once with brine, dried, filtered and the filtrate is concentrated by evaporation. The red-brown residue was suspended in hexane and the precipitated crude product (purity 93%) was used in the next step without purification; MS: (M) < ^{+ &gt}; = 275.

Step 17.2: 4-Hydroxy-6- (4-nitro-phenyl) -7H-pyrrolo [2,3-d] pyrimidine

A mixture of 2.5 g (97 mmol) of 2-amino-3-ethoxycarbonyl-5- (4-nitrophenyl) pyrrole, 19.4 ml of formamide, 9.7 ml of DMF and 3.1 ml of formic acid is stirred at 150 DEG C. for 22 hours. C. 1 ml of isopropanol is added to the hot mixture, the mixture is cooled and the precipitated product is filtered off with suction and washed successively with ethanol (3 x 10 ml), isopropanol (2 x 10 ml) and hexane (2 x 10 ml). The desired product is obtained in the form of rusty brown crystals which are used directly in the next step. MS: (M) < ^{+ &gt}; = 256.

Step 17.3: 4-Chloro-6- (4-nitro-phenyl) -7H-pyrrolo [2,3-d] pyrimidine

Analogously to step 1.3, 4-chloro-6- (4-nitro-phenyl) -7H-pyrrolo [2,3-d] pyrimidine is prepared by heating 4-hydroxy-6- (4-nitro-phenyl) -7H -pyrrolo [2,3-d] pyrimidine with POCl ₃ (Purity 93%); mp > 280 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 275.

Example 18

4- (3-Chloro-anilino) -6- (4-amino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine

150 mg (0.41 mmol) of 4- (3-chloro-anilino) -6- (4-nitro-phenyl) -7H-pyrrolo [2,3-d] pyrimidine was hydrogenated for 5 hours to 50 mg of Raney nickel in 20 mL ml of THF-methanol mixture at room temperature and atmospheric pressure, whereupon the desired product precipitates. The mixture was filtered and the filter residue was washed with hot THF. The filtrate was evaporated to dryness. The crude product was purified by digestion with several portions of methanol and precipitated from THF-hexane as light beige crystals, mp> 290 ° C. ^{Χ Η} NMR (360 MHz, DMSO-d): 12.05 (s, pyrrole NH), 9.38 (s, aniline NH), 8.31 (s, pyrimidine H), 8.24 (s, arom H , 7.80 (d, H arom.), 7.53 (d, 2H arom.), 7.35 (t, H arom.), 7.05 (d, H arom.), 6.90 (s, pyrrole 5H), 6.64 (d, 2H arom.), 5.35 (s, _NH2); MS: (M) < ^{+ &gt}; = 335.

Example 19

4- (3-Chloro-phenylamino) -9H-pyrido [3 ', 2': 4,5] pyrrolo [2,3-d] pyrimidine

A mixture of 0.034 g (0.166 mmol) of 4-chloro-9H-pyrido [3 ', 2': 4,5] pyrrolo [2,3-d] pyrimidine (German Patent Application No. 1916050) and 0.524 ml (4, 99 mmol) of 3-chloroaniline was heated with stirring at 120 ° C under nitrogen atmosphere for one hour. The reaction mixture is cooled to room temperature and then 5 ml of ethanol are added. After further cooling to 0 ° C, the crystalline product is filtered off with suction and washed with ethanol and dried under high vacuum. The title compound obtained m.p. ≫ 260 ° C; EI-MS: M = 295

Example 20

Using the procedures described in this patent application, the following compounds were prepared:

(a) 4-benzylamino-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine hydrochloride, m.p. 115-117 ° C;

b) (R) -5,6-Dimethyl-4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine, m.p. 206-208 ° C

c) (S) -5,6-dimethyl-4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine, m.p. 206-207 ° C

d) (R) -6- (4-Amino-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine, m.p. 234-235 ° C, FAB-MS: (M + H) ⁺ = 330 (obtained by reduction of the corresponding nitro compound to Raney-nickel analogously to Example 18),

(e) (S) -6- (4-Amino-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine, mp 235-236 ° C, FAB-MS: (M + H) ⁺ = 330 (obtained by reduction of the corresponding nitro compound on Raney nickel analogously to Example 18),

f) 6- (4-amino-phenyl) -4-benzylamino-7H-pyrrolo [2,3-d] pyrimidine (obtained by reduction of the corresponding nitro compound on Raney nickel analogously to Example 18),

g) 6- (4-amino-phenyl) -4 - [(3-chloro-benzyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine (obtained by reduction of the corresponding nitro compound on Raney nickel in analogy to is described in the example

18),

(h) (R) -6- (4-Amino-phenyl) -4 - [(1-methoxycarbonyl-benzyl)] - amino-7H-pyrrolo [2,3-d] pyrimidine;

i) (S) -6- (4-Amino-phenyl) -4 - [(1-methoxycarbonyl-benzyl)] - amino-7H-pyrrolo [2,3-d] pyrimidine; j) 6- (4-acetylamino) -phenyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine, m.p. > 310 ° C, MS: (M) < ^{+ &gt}; = 377,

k) 6- (4-carbamoylmethoxyphenyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine, m.p. 297-298 ° C

l) 6- (4-amino-phenyl) -4- (3-methyl-anilino) -7H-pyrrolo [2,3-d] pyrimidine, m.p. 288-290 ° C (obtained by reduction of the corresponding nitro compound on Raney nickel analogously to Example 18),

m) 6- (4-Amino-phenyl) -4- (3-chloro-4-fluoro-anilino) -7H-pyrrolo [2,3-d] pyrimidine, m.p. ≫ 300 ° C, MS: (M) ⁺ = 353, (obtained by reduction of the corresponding nitro compound on Raney nickel analogously to Example 18),

n) 6- (3-acetylamino-phenyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine (preferably prepared analogously to Example 21), mp> 300 ° C, MS: (M) < ^{+ &gt}; = 377,

ο) 6- (3-Amino-phenyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine, m.p. 293-295 ° C (obtained by ducting the corresponding nitro compound on Raney nickel analogously to Example 18),

p) 6- (4-carboxymethoxy-phenyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine, m.p. 305-307 ° C

q) 6- (4- [benzyloxycarbonyl-methoxy] -phenyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine, m.p. 263-265 ° C

r) 6- (3-carbamoylmethoxy-phenyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine, m.p. 283-285 ° C

s) 4- (3-chloro-anilino) -6- (4-methoxycarbonylmethoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine, m.p. 262-264 ° C

t) 4- (3-chloro-anilino) -6- (3-methoxycarbonylmethoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine, m.p. 225-227 ° C

u) 6-carboxy-4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine, mp > 290 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 289,

v) 4- (3-chloro-anilino) -6-ethoxycarbonyl-7H-pyrrolo [2,3-d] pyrimidine, mp > 290 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 317,

w) 6-n-butylaminocarbonyl-4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine, m.p. 282-284 [deg.] C .; FAB-MS: (M + H) < ^{+ &gt}; = 344,

x) 4- (3-chloro-anilino) -6- (4-ethoxycarbonyl-phenyl) -7H-pyrrolo [2,3-d] pyrimidine, mp> 300 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 393,

y) 6- (4-carboxy-phenyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine, m.p. ≫ 300 ° C; Rf = 0.47 (ethyl acetate: methanol (6: 4)),

z) 6-benzylaminocarbonyl-4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine, mp 295 DEG C .; FAB-MS: (M + H) < ^{+ &gt}; = 378, za) 4- (3-chloro-anilino) -6- (N- [3-methyl-but-yl] carbamoyl) -7H-pyrrolo [2,3] -d] pyrimidine (see Example 45), mp 304-306 ° C; FAB-MS: (M + H) ⁺ = 358, zb) 5- (anilino-methyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine and zc) 5- ( anilino-methyl) -4- (3-chloro-anilino) -6-methyl-7H-pyrrolo [2,3-d] pyrimidine.

The above compounds of Examples 20a, 20d, 20e, 20f, 20g, 201 and 20m are preferably prepared by reducing the corresponding nitro compounds with Raney Nickel analogously to Example 18.

Example 21

6- (4-Acetylamino-phenyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine (see Example 20j)

0.05 ml (0.56 mmol) of acetic anhydride is added to 0.2 g (0.56 mmol) of 6- (4-amino-phenyl) -4- (3-chloro-anilino) -7H-pyrrolo [2]. 3-d] pyrimidine suspended in 0.5 ml of pyridine and the reaction mixture is stirred at 0 ° C for one hour until the starting compound is completely reacted by TLC. The reaction mixture is poured into 50 ml of ice-water and the precipitate is filtered off with suction and washed with hexane. The crude product is chromatographed on a silica gel column. The desired product was crystallized from THFr-ethyl acetate-hexane; mp > 310 ° C; MS: (M) < ^{+ &gt}; = 377.

Example 22

The following compounds were prepared according to the procedure of Example 1 or further examples:

a) 4- (3-chloro-anilino) -6- (4-propionylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine (prepared analogously to Example 21); mp > 300 ° C; MS: (M) < ^{+ &gt}; = 391,

b) 4- (3-Chloro-anilino) -6- (3-propionylamino-phenyl) -7H-pyrrole85

[2,3-d] pyrimidine (prepared analogously to Example 21); mp > 300 ° C; MS: (M) < ^{+ &gt}; = 391,

c) (R) -6- (4-Acetylamino-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine, (prepared analogously to Example 1) 21); mp 304-305 ° C, MS: (M) ⁺ = 371,

d) (R) 4 - [(1-Phenyl-ethyl) -amino] -6- (4-propionylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine; MS: (M) ⁺ = 385 (see Example 28a)

e) (R) -6- (3-Acetylamino-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine, mp 150-180 ° C, MS : (M) < ^{+ &gt}; = 371.

Example 23

4- (3-Chloro-anilino) -6- (4-isobutylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine

A mixture of 0.2 g (0.56 mmol) of 6- (4-amino-phenyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine, 0.064 ml (0.62 mmol) ) isobutyric acid chloride and 1 ml abs. of dimethylacetamide was stirred for 2 hours at 0 ° C until all of the starting compound (TLC) had reacted. The reaction mixture was poured into 20 mL of ice water to precipitate the product. This was extracted with ca. 50 mL ethyl acetate, ca. 2 mL THF and 20 mL 5% aqueous NaHCO ₃ . The organic phase is washed with water, dried and concentrated by evaporation. The desired product crystallized, filtered off with suction and washed with cold ethyl acetate. Further product is obtained from the mother liquor by the addition of hexane; 1.1. ≫ 300 ° C; MS: (M) < ^{+ >} - 405.

Example 24

Following the procedure of Example 23, the following compounds were prepared:

a) 4- (3-chloro-anilino) -6- (4-pivaloylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine; 1.1. ≫ 300 ° C; MS: (M) < ^{+ &gt}; = 419,

b) 4- (3-chloro-anilino) -6- [4- (DL-2-methyl-butyrylamino) -phenyl] -7H-pyrrolo [2,3-d] pyrimidine; mp > 300 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 420,

c) 4- (3-chloro-anilino) -6- (4-isovalerylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine; 1.1. ≫ 300 ° C; MS: (M) < ^{+ &gt}; = 419,

d) 4- (3-chloro-anilino) -6- (3-isobutyrylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine; 1.1. ≫ 300 ° C; MS: (M) < ^{+ &gt}; = 405.

Example 25

4- (3-Chloro-anilino) -6- (4-ethylamino-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine

110 μΐ (1.93 mmol) of acetaldehyde is added at 5 ° C to a solution of 0.3 g (0.89 mmol) of 6- (4-amino-phenyl) -4- (3-chloro-anilino) -7H-pyrrole [2,3-d] pyrimidine in 15 mL of THF and the reaction mixture was stirred at 5 ° C (orange solution) for 24 h. 75 mg (1.15 mmol) of sodium cyanoborohydride are then added. The reaction solution is stirred for an additional 5 hours at room temperature and then concentrated by evaporation in vacuo. The residue was dissolved in ethyl acetate and the pH was adjusted to 2 by addition of 1N HCl. The ethyl acetate phase is washed with water, dried and concentrated by evaporation. The crude product is chromatographed on a silica gel column. The title compound is obtained by crystallization from methanol-hexane or ethyl acetate-hexane; mp 265-270 ° C; MS: (M) < ^{+ &gt}; = 363.

Example 26

Following the procedure of Example 25, the following compounds were prepared:

a) (R) -6- (4-Diethylamino-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine, mp 286-287 ° C, MS : (M) ⁺ = 386.

b) 4- (3-chloro-anilino) -6- (4-dimethylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine; 1.1. 279-282 [deg.] C .; MS: (M) ⁺ = 363 (formed by the reaction of 6- (4-amino-phenyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine with formaldehyde),

c) 4- (3-chloro-anilino) -6- (3-ethylamino-phenyl) -7H-pyrrolo [2,3-d]

pyrimidine; MS: (M) < ^{+ &gt};

d) 6- (4-dimethylamino-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine.

Example 27

By reducing the corresponding nitro compounds on Raney nickel, analogously to Example 18, the following compounds were prepared:

a) 6- (4-Amino-phenyl) -4- (3-methyl-benzylamino) -7H-pyrrolo [2,3-d] pyrimidine, mp 291-293 ° C, FAB-MS: (M + H) ) ⁺ = 330

b) (R) -6- (3-Amino-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine, amorphous; FAB-MS: (M + H) < ^{+ &gt}; = 330,

c) (R, S) -6- (4-Amino-phenyl) -4 - [(1- (3-chloro-phenyl) -ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine, mp 281-283 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 364.

Example 28

Following the procedure of Example 21, the following compounds were prepared:

(a) (R) -4 - [(1-Phenyl-ethyl) -amino] -6- (4-propionylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine; MS: (M) ⁺ = 385 (cf. Example 22d),

b) (R) -4 - [(1-Phenyl-ethyl) -amino] -6- (3-propionylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine, MS: (M) ⁺ = 385 .

Example 29

Following the procedure of Example 23, the following compounds were prepared:

a) (R) -6- (3-isobutyrylamino-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine, mp 206-208 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 400,

b) (R) -6- (4-isobutyrylamino-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine, mp 296-297 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 400,

c) (R) -6- (4-pivaloylamino-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine, mp> 300 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 414, a

d) (R) -6- (3-pivaloylamino-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine, mp 148-152 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 414.

Example 30

4- (3-Chloro-anilino) -6- (4-ethoxycarbonyl-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine

A mixture of 900 mg (2.95 mmol) of 4-chloro-6- (4-ethoxycarbonylphenyl) -7H-pyrrolo [2,3-d] pyrimidine, 0.63 ml (6 mmol) of 3-chloroaniline and 22 ml of n -butanol was refluxed for 2.5 hours. The product is either chromatographed on a silica gel column or crystallized from tetrahydrofuran-diethyl ether; mp > 300 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 393.

The starting material is prepared as follows:

Step 30.1: 2-Amino-3-ethoxycarbonyl-5- (4-ethoxycarbonylphenyl) -1H-pyrrole

Analogously to step 8.1, 4.92 g (29.5 mmol) of 2-amidino-acetic acid ethyl ester hydrochloride in 40 ml of abs. ethanol was reacted with 2.0 g (29.5 mmol) of sodium ethoxide and 4.0 g (14.8 mmol) of 2-bromo- (4-ethoxycarbonyl) -acetophenone. The product obtained melts at 150-151 ° C; MS: (M) < ^{+ &gt}; = 302.

Step 30.2: 6- (4-Ethoxycarbonyl-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ol

Analogously to step 8.2, 2.6 g (8.6 mmol) of 2-amino-3-ethoxycarbonyl-5- (4-ethoxycarbonyl-phenyl) -ΙΗ-pyrrole was heated to 150 ° C overnight under a protective gas atmosphere. with 19 ml of formamide, 8 ml of DMF and 0.6 ml of formic acid. The mixture is worked up analogously to step 8.2 to give the desired product; mp > 250 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 284,

Step 30.3: 4-Chloro-6- (4-ethoxycarbonyl-phenyl) -7H-pyrrolo [2,3-d] pyrimidine

Analogously to step 8.3, 1.45 g of 6- (4-ethoxycarbonylphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ol was heated with 15 ml of phosphorus oxychloride for 2 hours under a protective gas atmosphere. . Workup gives the desired product, mp 250 ° C (dec.); TLC-Rf = 0.63 (ethyl acetate-hexane (1: 1)); FAB-MS: (M + H) < ^{+ &gt}; = 302.

Example 31

4- (3-Chloro-anilino) -6- (3-ethoxycarbonyl-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine

The title compound was prepared analogously to Example 30; mp > 300 ° C; TLC-Rf = 0.66 (ethyl acetate-hexane (1: 1)); FAB-MS: (M + H) < ^{+ &gt}; = 393.

The starting material is prepared as follows:

Step 31.1: 2-Amino-3-ethoxycarbonyl-5- (3-ethoxycarbonylphenyl) -1H-pyrrole

The title compound is prepared analogously to step 30.1; 1.1. 136-137 [deg.] C .; TLC-R1 = 0.37 (ethyl acetate-hexane (1: 1)); MS: (M) < ^{+ &gt}; = 302.

Step 31.2: 6- (3-Ethoxycarbonyl-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ol

The title compound is prepared analogously to step 30.2; mp > 250 ° C; TLC-Rf = 0.29 (ethyl acetate-hexane (1: 1)); FAB-MS: (M + H) < ^{+ &gt}; = 284.

Step 31.3: 4-Chloro-6- (3-ethoxycarbonyl-phenyl) -7H-pyrrolo [2,3-d] pyrimidine

The title compound is prepared analogously to step 30.3; mp > 250 ° C; TLC-Rf = 0.62 (ethyl acetate-hexane (1: 1)); FAB-MS: (M + H) < ^{+ &gt}; = 302.

Example 32

4- (3-Chloro-anilino) -6- (4-carboxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine (see Example 20y)

A solution of 0.2 g (0.51 mmol) of 4- (3-chloro-anilino) -6- (4-ethoxycarbonylphenyl) -7H-pyrrolo [2,3-d] pyrimidine in 1.2 ml of abs . of ethanol was refluxed with a solution of 62.7 mg (1.52 mmol) of lithium hydroxide in 1 mL of water until the starting compound (by TLC) completely disappeared from the reaction mixture (12 hours). The solution was cooled to room temperature and adjusted to pH 2 by addition of 1N NaOH solution. The desired product is collected, filtered off with suction and recrystallized from ethanol-water or THF-hexane; mp > 300 ° C; R f = 0.47 (ethyl acetate-methanol (60:40)); FAB-MS: (M + H) < ^{+ &gt}; = 365.

Example 33

4- (3-Chloro-anilino) -6- (3-carboxy-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine

Said compound was prepared analogously to Example 32; mp > 300 ° C; R f = 0.5 (ethyl acetate-methanol (60:40)); FAB-MS: (M + H) < ^{+ &gt}; = 365.

Example 34

4- (3-Chloro-anilino) -6- (4-methoxycarbonyl-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine

A suspension of 0.5 g (1.37 mmol) of 4- (3-chloro-anilino) -6- (4-carboxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine in 100 ml of methanol is refluxed for 24 hours with 0 1 ml of concentrated sulfuric acid. The solution was then concentrated and stirred with methanol-diethyl ether. The crystals are aspirated and suspended in methanol-water. The suspension is adjusted to pH 7-8 by addition of sodium bicarbonate solution and stirred at room temperature for 30 min. The crystals are sucked off, washed with water, methanol and diethyl ether and dried. The product is obtained in the form of colorless crystals, mp > 300 ° C; TLC-Rf = 0.6 (toluene-ethyl acetate (3: 7)); FAB-MS: (M + H) < ^{+ &gt}; = 378.

Example 35

The following compounds were prepared analogously to Example 34:

a) 4- (3-chloro-anilino) -6- (4-ethoxycarbonylphenyl) -7H-pyrrolo [2,3-d] pyrimidine; 1.1. ≫ 300 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 393,

b) 4- (3-chloro-anilino) -6- (4-propyloxycarbonylphenyl) -7H-pyrrolo [2,3-d] pyrimidine; mp > 250 ° C; R f = 0.41 (ethyl acetate-hexane (1: 1)); FAB-MS: (M + H) < ^{+ &gt}; = 407,

c) 4- (3-chloro-anilino) -6- (4-isopropyloxycarbonylphenyl) -7H-pyrrolo [2,3-d] pyrimidine mp > 250 ° C; _Rf = 0.41 (ethyl acetate-hexane (1: 1)); FAB-MS: (M + H) < ^{+ &gt}; = 407, a

d) 4- (3-chloro-anilino) -6- (4-isobutyloxycarbonylphenyl) -7H-pyrrolo [2,3-d] pyrimidine mp > 250 ° C; _Rf = 0.48 (ethyl acetate-hexane (1: 1)); FAB-MS: (M + H) < ^{+ &gt}; = 421.

Example 36

4- (3-Chloro-anilino) -6- (4-dimethylaminocarbonyl-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine

A mixture of 369 mg (1.01 mmol) of 6- (4-carboxyphenyl) -4- (3-chloroanilino) -7H-pyrrolo [2,3-d] pyrimidine, 0.4 ml (2.3 mmol) of dimethylamine 0.3 ml (1.51 mmol) of DEPC (Aldrich) and 10 ml of DMF are stirred for 1 hour at room temperature. The brown suspension is diluted with water, the crystals are filtered off with suction and washed with water, methanol and diethyl ether. The desired product is obtained in the form of colorless crystals, mp > 250 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 392.

Example 37

4- (3-Chloro-anilino) -6- (4-diethylaminocarbonyl-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine

Said compound was prepared analogously to Example 8; mp > 250 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 420.

Example 38

4- (3-Chloro-anilino) -6- (3-dimethylamino-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine

Said compound was prepared analogously to Example 25; mp 282-284 ° C; MS: (M) < ^{+ &gt}; = 363.

Example 39 (R) -6- (4-Hydroxy-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine

The title compound is obtained as a colorless powder, analogously to Example 10, by removing the methyl group from (R) -6- (4-methoxy-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H. -pyrrolo [2,3-d] pyrimidine by treatment with borontribromide; mp 216-218 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 331.

The starting compound is prepared as follows:

Step 39.1: (R) -6- (4-Methoxy-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine

The title compound is obtained analogously to Example 8 or 9 from 4-chloro-6- (4-methoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine and (R) - (+) - 1- phenyl-ethylamine in n-butanol; mp 256-257 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 345.

Example 40

4- (3-Chloro-anilino) -5-dimethylaminomethyl-6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine

The title compound was prepared in analogy to Example 3 from

4- (3-chloro-anilino) -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine and N, N-dimethyl-methylenammonium iodide; 1.1. 243-244 [deg.] C .; MS: (M) < ^{+ &gt}; = 393.

Example 41

4- (3-Chloro-anilino) -6-ethoxycarbonyl-7H-pyrrolo [2,3-d] pyrimidine

A mixture of 29.0 g (128 mmol) of 4-chloro-6-ethoxycarbonyl-7H-pyrrolo [2,3-d] pyrimidine, 18.0 ml (171 mmol) of 3-chloroaniline and 430 ml of n-butanol is stirred for 3 hours at 100 ° C under argon (the mixture almost dissolves per hour and then a thick suspension forms). The reaction mixture is cooled to about 50 ° C and then 400 ml of isopropanol-hexane (1: 1) is added. The reaction mixture is then cooled to room temperature and the product is filtered off with suction and washed with isopropanol and hexane. Mixing with diethyl ether gives the desired product; ¹ H NMR (DMSO-d 6): 13.0 and 10.53 (2sb, 2HN),

8.48 (s, 1H), 8.13 (m, 1H), 7.78 (dm, J = 8, 1H), 7.76 (s, 1H), 7.45 (t, J = 8, 1H), 7.21 (dm, J = 8, 1H), 4.37 (q, J = 7, 2H), 1.37 (t, J = 7, 3H).

The starting material is prepared as follows:

Step 41.1: 2-Amino-3,5-bis (ethoxycarbonyl) -1H-pyrrole 56.0 g (0.43 mol) of 2-amido-acetic acid ethyl ester (prepared according to Liebigs Ann.Chem., 1561 (1981)) at 0-5 ° C

172 ml DMPU. 56.0 ml (0.45 mol) of ethyl bromopyruvate are then added dropwise over 30 minutes and the reaction mixture is stirred for 3 hours at 60 ° C. The dark brown reaction solution was poured into 1 liter of ice water and extracted with 1 liter of ethyl94 acetate followed by two 0.5 liter portions of ethyl acetate. The organic phases are washed with water (3 x 0.5 L) and brine (3 x 0.5 L), dried (Na ₂ SO ₄ ) and concentrated by evaporation. Column chromatography (SiO ₂ , hexane-ethyl acetate (1: 1)) and crystallization from diethyl ether-hexane gave the desired product; mp 147-149 ° C; MS: (M) < ^{+ &gt}; = 226.

Step 41.2: 6-Ethoxycarbonyl-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine

A mixture of 51.5 g (227 mmol) of 2-amino-3,5-bis (ethoxycarbonyl) -1H-pyrrole, 455 ml of formamide, 227 ml of DMF and 113 ml of formic acid is stirred at 140 ° C for 27 hours without air. The resulting yellow suspension is cooled to 0-5 ° C and the product is filtered off with suction and washed with isopropanol and hexane; NMR (DMSO-d6): 13-12 (2 HX), 7.99 and 7.11 (2s, 2H), 4.31 (q, J = 7, 2H), 1.32 (t, J = 7, 3H).

Step 41.3: 4-Chloro-6-ethoxycarbonyl-7H-pyrrolo [2,3-d] pyrimidine

32.0 g (154 mmol) of 6-ethoxycarbonyl-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine are suspended in nitrogen at room temperature in 308 ml (338 mmol) of POCl ₃ and the suspension is heated with stirring to 120 ° C whereupon the solid dissolves. After stirring at 120 ° C for three hours, excess POCl _{3 is} distilled off (at an outside temperature of 65 ° C and 15 mbar). The residue is suspended in 50 ml of ice-cold toluene, the product is filtered off with suction and washed with toluene; mp 219-221 ° C; ¹ H NMR (DMSO-d 6): 8.77 and 7.24 (2s, 2H), 4.39 (q, J = 7, 2H), 1.36 (t, J = 7, 3H). Further product can be obtained from the filtrate by concentration and mixing the residue with ethyl acetate-water.

Example 42

6-Carboxy-4- (3-chloro-anilino) -7 H -pyrrolo [2,3-d] pyrimidine

A solution of 25 mg (0.6 mmol) of LiOH.H ₂ O in 0.4 mL of water was added dropwise to a suspension of 95 mg (0.30 mmol) of 4- (3-chloro-anilino) -6-ethoxycarbonyl-7H-pyrrolo [ 2,3-d] pyrimidine in 0.7 mL of methanol.

The reaction mixture is heated to boiling for 4.5 hours, then cooled in an ice bath and acidified with 0.6 ml of 1N HCl. The product is filtered off with suction and washed with water; HPLC: t _ret (Grad _2Q ) = 8.7; FAB-MS: (M + H) < ^{+ &gt}; = 289.

Example 43

6- (N-n-Butylcarbamoyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine

A mixture of 95 mg (0.30 mmol) of 4- (3-chloro-anilino) -6-ethoxycarbonyl-7H-pyrrolo [2,3-d] pyrimidine and 1 ml of n-butylamine is heated at 60 ° C for 20 hours. The light yellow solution is concentrated by evaporation and the residue is stirred with isopropanol, the product is filtered off with suction and washed with hexane; mp 282-284 ° C; TLC-R f = 0.45 (CH ₂ Cl ₂ -methanol 10: 1); FAB-MS: (M + H) < ^{+ &gt}; = 344.

Example 44

6-ethylaminocarbonyl-4- (3-chloro-anilino) -7 H -pyrrolo [2,3-d] pyrimidine

A mixture of 95 mg (0.30 mmol) of 4- (3-chloro-anilino) -6-ethoxycarbonyl-7H-pyrrolo [2,3-d] pyrimidine and 0.5 ml of benzylamine was heated at 100 ° C for 27 hours. The reaction mixture is cooled in ice water, treated with 1 ml of isopropanol and 1 ml of hexane, the product is filtered off with suction and dried; FAB-MS: (M + H) < ^{+ &gt}; = 378.

Example 45

4- (3-Chloro-anilino) -6- [N- (3-methyl-but-1-yl) -carbamoyl] -7H-pyrrolo [2,3-d] pyrimidine (see Example 20za)

A mixture of 95 mg (0.30 mmol) of 4- (3-chloro-anilino) -6-ethoxycarbonyl-7H-pyrrolo [2,3-d] pyrimidine and 1 ml of (3-methyl-but-1-yl) -amine is heated at 80 ° C for 12 hours. The reaction mixture is concentrated by evaporation, the residue is dissolved in THF and concentrated again by evaporation, triturated with diethyl ether and the desired product is filtered off with suction; mp 304-306 ° C; FAB-MS: (M + H) < ^{+ &gt}; = 358.

Example 46

4- (3-Chloro-anilino) -6- (Ν, Ν-dimethyl-carbamoyl) -7 H -pyrrolo [2,3-d] pyrimidine

Under a nitrogen atmosphere, 97.6 mg (0.338 mmol) of 6-carboxy-4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine is added to 7 mL of DMF and 119 mg (0) , 40 mmol) of TPTU and a solution of 164 mg (33% solution in ethanol; 1.2 mmol) of dimethylamine in 1 mL of DMF. After 2 hours, an additional 30 mg of TPTU was added to the reaction solution, and the mixture was stirred at room temperature for 2 days. It is then poured into 30 ml of ice-water, stirred, the product is filtered off with suction and washed with water; HPLC: t _ret (Grad _2Q ) = 9/5; TLC-R f = 0.38 (CH ₂ C1 ₂ -methanol 10: 1); FAB-MS: (M + H) < ^{+ &gt}; = 316.

Example 47

6-Aminocarbonyl-4- (3-chloro-anilino) -7 H -pyrrolo [2,3-d] pyrimidine

A mixture of 90 mg (0.2.85 mmol) of 4- (3-chloro-anilino) -6-ethoxycarbonyl-7H-pyrrolo [2,3-d] pyrimidine, 30 ml of methanol and about 5 g of ammonia is heated in an autoclave for 48 hours 120 [deg.] C. Silica gel was added to the reaction mixture, the solvent was evaporated and the bulk residue was applied to a silica gel column and eluted with methylene chloride-methanol-THF (210: 35: 10). Filtration of the solution in methanol through an alumina column and stirring with ethyl acetate yields the desired product; HPLC: t _ret (Grad ₂ cP ⁼ = 8.1; TLC-Rf = 0.18 (CH ₂ Cl ₂ -methanol 10: 1); MS (high resolution): (M + H) ⁺ = 288.0669 (calc. 288.0652).

Alternatively, said compound may also be prepared as follows:

A mixture of 2.165 g (7.5 mmol) of 6-carboxy-4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine (cf. Example 42), 60 ml of THF and 10 ml of DMPU is refluxed. 30 min and then cooled to 0 ° C to give a fine suspension. Then 824 μΐ (7.5 mmol) is added dropwise.

Of N-methylmorpholine and then chloroformate in 10 ml of THF. 824 μΐ of N-methylmorpholine and a solution of 981 μΐ (7,5 mmol) of isobutyl After 1 hour at 0 ° C, add 981 μΐ of isobutyl chloroformate. The mixture was stirred for 1 hour and then added dropwise to 70 ml of a saturated solution of NH ₃ in dioxane. After 3 hours, the mixture was concentrated in vacuo. The residue is poured into water, the precipitate is filtered off with suction and washed with water and boiling isopropanol to give the title compound. A further fraction can be isolated from the isopropanol filtrate.

Example 48

4- (3-Chloro-anilino) -6-methylaminocarbonyl-7H-pyrrolo [2,3-d] pyrimidine

In a sealed pressure tube, 95 mg (0.30 mmol) of 4- (3-chloro-anilino) -6-ethoxycarbonyl-7H-pyrrolo [2,3-d] pyrimidine is heated in 6 ml of methylamine solution (33% solution in ethanol) 96 hours at 50 ° C. The reaction mixture is concentrated by evaporation. Preparative HPLC and stirring in diethyl ether gave the desired product; HPLC: t _ret (Grad ₂₀ ) = 8.6; _TLC-Rf = 0.49 (CH ₂ C1 _{2-THF-ethanol} (6: 2: 1)); FAB-MS: (M + H) < ^{+ &gt}; = 302.

Example 49

4- (3-Chloro-anilino) -6-hydroxymethyl-7 H -pyrrolo [2,3-d] pyrimidine

Under a nitrogen atmosphere, 1.4 g (37 mmol) of lithium aluminum hydride are added in portions to 5.70 g (18 mmol) of 4- (3-chloroanilino) -6-ethoxycarbonyl-7H-pyrrolo [2,3-d] pyrimidine. in 300 mL THF. After stirring at 50 ° C for two hours, 100 ml of water was added dropwise to the reaction mixture, and the mixture was filtered through celite. Water was added to the filtrate and the product was extracted three times with ethyl acetate. The organic phases are washed three times with water and brine, dried _(MgSO4) and concentrated by evaporation. Recrystallization from isopropanol gives the desired product; HPLC: t _ret (grad _2?) = 8.2, -TLC-Rf = 0.11 (CH ₂ Cl ₂ -methanol (10: 1)); MS: (M) < ^{+ &gt}; = 274.

Example 50

4- (3-Chloro-anilino) -6-formyl-7H-pyrrolo [2,3-d] pyrimidine

1.9 g of manganese dioxide (85%) are added to a suspension of 715 mg (2.6 mmol) of 4- (3-chloro-anilino) -6-hydroxymethyl-7H-pyrrolo [2,3-d] pyrimidine, while cooling with ice. in 170 ml of methylene chloride, and the reaction mixture is stirred at room temperature for 20 hours. Then 20 ml of DMPU are added and stirring is continued for 1 hour. The mixture was then filtered through Hyflo. The filter residue is again stirred for 1 hour with 50 ml of methylene chloride-DMPU (1: 1) and filtered again. The two filtrates were combined, concentrated by evaporation, and the residue was mixed with ethyl acetate-THF-water. The aqueous phases are extracted twice with ethyl acetate and the organic phase was washed four times with water and brine, dried _(MgSO4) and concentrated by evaporation to a volume of about 20 ml. Diethyl ether is added and the precipitated product is filtered off with suction; HPLC: t _ret (Grad ₂₀ ) = ¹⁰ >; _TLC-Rf = 0.24 (CH ₂ Cl ₂ -methanol (10: 1)).

Example 51 (R) -6-Ethoxycarbonyl-4- (1-phenyl-ethylamino) -7H-pyrrolo [2,3-d] pyrimidine

A mixture of 902 mg (4.0 mmol) of 4-chloro-6-ethoxycarbonyl-7H-pyrrolo [2,3-d] pyrimidine (Step 41.3), 1.12 mL (8.8 mmol) of 1 (R) -phenyl of ethylamine and 10 ml of n-butanol are stirred for 17 hours at 150 ° C under a nitrogen atmosphere (first dissolving and then forming a thick suspension). The reaction mixture is cooled and the desired product is filtered off with suction and washed with isopropanol and hexane; HPLC: t _ret (grad ₂₀₎ ⁼ 10.6; _TLC-Rf = 0.49 (CH ₂ Cl ₂ -methanol (10: 1)); FAB-MS: (M + H) < ^{+ &gt}; = 311.

Example 52 (R) -6-Methylaminocarbonyl-4- (1-phenyl-ethylamino) -7H-pyrrolo [2,3-d] pyrimidine

155 mg (0.50 mmol) of 6-ethoxycarbonyl-4- [1 (R) -phenyl-ethylamino] -7H-pyrrolo [2,3-d] pyrimidine is heated in a pressure tube, 2.5 mg (0.05 NaCl and 4 ml of a 33% ethanolic methylamine solution at 50 ° C for 30 hours. The reaction mixture was dissolved in THF, 25 mL of water was added and the mixture was concentrated to about 25 mL by evaporation. The precipitated crystals are sucked off and washed with water. Recrystallization from hot THF and ethyl acetate gave the desired product; HPLC: t _ret (9 ^rd 2Q) = ^8.3; TLC-R f = 0.31 (CH ₂ Cl ₂ -methanol (10: 1));

FAB-MS: (M + H) < ^{+ &gt}; = 296.

Example 53

The following compounds were prepared analogously to the procedures described herein:

(a) (R) -6-carbamoyl-4- (1-phenyl-ethylamino) -7H-pyrrolo [2,3-d] pyrimidine;

(b) (R) -6-cyano-4- [1-phenyl-ethylamino] -7H-pyrrolo [2,3-d] pyrimidine [may be prepared from compound (a) above],

c) 4- (3-chloro-anilino) -6-cyano-7H-pyrrolo [2,3-d] pyrimidine [may be prepared from the compound described in Example 47; cf. Example 54]

(d) (R) -6-formyl-4- [1-phenyl-ethylamino] -7H-pyrrolo [2,3-d] pyrimidine;

e) (R) -6-aminomethyl-4- [1-phenyl-ethylamino] -7H-pyrrolo [2,3-d] pyrimidine [may be prepared by reductive amination of the above compound d)],

f) 6-aminomethyl-4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine [may be prepared by reductive amination from the compound described in Example 50],

(g) 4- (3-chloro-anilino) -6- (dimethylamino-methyl) -7H-pyrrolo [2,3-d] pyrimidine;

(h) 6- (dimethylamino-methyl) -4- [1 (R) -phenyl-ethylamino] -7H-pyrrolo [2,3-d] pyrimidine;

(i) 6- (piperazinomethyl) -4- [1 (R) -phenylethylamino] -7H-pyrrolo [2,3-d] pyrimidine;

j) 4- (3-chloro-anilino) -6- (piperazinomethyl) -7H-pyrrolo [2,3-d] pyrimidine.

Example 54

100

- (3-Chloro-anilino) -6-cyano-7H-pyrrolo [2,3-d] pyrimidine (cf. Example 53c)

To a mixture of 1.048 g (3.6 mmol) of 6-aminocarbonyl-4- (3-chloroanilino) -7H-pyrrolo [2,3-d] pyrimidine (see Example 47) and 0.7 ml of N, N-dimethyl acetamide 13 ml of phosphorus oxychloride are added. The mixture was stirred at room temperature for 1 hour and at 100 ° C for 4 hours and then poured into ice saturated NaHCO ₃ solution. Extract the mixture with ethyl acetate (3x), wash the organic layers with saturated NaHCO ₃ solution, water and brine, and dry (Na ₂ SO ₄ ). Concentration gives a solid which is chromatographed on SiO ₂ in ethyl acetate. Stirring the crude product in diethyl ether and hexane gives the desired product; 1.1. 284-287 [deg.] C .; _TLC-Rf = 0.71 (CH ₂ Cl ₂ -methanol (10: 1)); HPLC:

t _ret (grad ₂₀ ) = 11.8.

Example 55

4- (3-Chloro-anilino) -6-methoxymethyl-7H-pyrrolo [2,3-d] pyrimidine

To an ice-cooled suspension of 82.5 mg (0.30 mmol) of 4- (3-chloroanilino) -6-hydroxymethyl-7H-pyrrolo [2,3-d] pyrimidine (cf. Example 49) in 5 ml of diethyl ether in argon 14 μΐ (0.15 mmol) of phosphorothribromide is added to the atmosphere. The mixture was stirred at 0 ° C for 18 hours and at room temperature for 18 hours to give 4- (3-chloroanilino) -6-bromomethyl-7H-pyrrolo [2,3-d] pyrimidine. Methanol (2 ml) was added and the mixture was stirred for 2 hours. 1 ml of 5.4 M sodium methoxide solution is then added dropwise and after 18 hours the mixture is concentrated in vacuo, redissolved in methanol, silica gel is added and the mixture is evaporated to dry powder. This was transferred to a silica gel column (CH ₂ Cl ₂ -ethanol (2: 1)). Elution with CH ₂ Cl ₂ -ethanol (2: 1), concentration and washing with ethyl acetate-diethyl ether-hexane gave the title compound; mp 226-230 ° C; _TLC-Rf = 0.59 (CH ₂ C1 _2-methanol (10: 1)); HPLC:

: t _re t <grad ₂ o) = 9.7.

Example 56

6- (tert-Butyl-carbamoyl) -4- (3-chloro-anilino) -7 H -pyrrolo [2,3-d] pyrimidine

101

To a solution of 144 mg (0.50 mmol) of 6-carboxy-4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine (cf. Example 42) and 116 μΐ (1.1 mmol) of tert-butylamine in 5 ml of DMF is added 114 μΐ (0.75 mmol) of diethyl cyanophosphate (Aldrich; Milwaukee, USA). After 4 hours, the reaction mixture is poured into ice water, stirred for 30 minutes and finally filtered. The filter substance is redissolved in isopropanol, treated with charcoal and filtered. Concentration in vacuo and washing with dichloromethane-diethyl ether gave the desired product; HPLC: t _ret (Grad ₂₀ ) = 11.4; FAB-MS: (M + H) &lt; ^{+ &gt}; = 344.

Example 57

4- (3-Chloro-anilino) -6- (N, N-dimethylamino-methyl) -7H-pyrrolo [2,3-d] pyrimidine

A mixture of 109 mg (0.40 mmol) of 4- (3-chloro-anilino) -6-formyl-7H-pyrrolo [2,3-d] pyrimidine (cf. Example 50), 110 μΐ (0.8 mmol) 33 of a solution of dimethylamine in ethanol, 50 μΐ (0.88 mmol) of acetic acid in 6 ml of methanol and 1 ml of DMPU are shaken for 1 hour at 50 ° C. Approximately 20 mg of Raney nickel is then added and the mixture is hydrogenated at 50 ° C. The catalyst is filtered off, washed thoroughly with methanol and the filtrate is concentrated. The residue was partitioned between ethyl acetate and saturated NaHCO ₃ solution, the aqueous layer was separated and extracted twice with ethyl acetate. The organic phases are washed twice with water and brine, dried over MgSO ₄ and concentrated in vacuo. Flash chromatography (SiO ₂ , CH ₂ Cl ₂ -methanol (10: 1 → 8: 1)) yields the desired product; TLC-R f = 0.06 (CH ₂ Cl ₂ -methanol (10: 1)); HPLC: t _ret (Grad ₂₀ ) = 7.2.

Example 58

The following compounds are prepared according to the procedures described in this patent application:

(a) 6-carboxy-4- (3-chloro-anilino) -5-methyl-7H-pyrrolo [2,3-d] pyrimidine;

102

(b) 4- (3-chloro-anilino) -6-formyl-5-methyl-7H-pyrrolo [2,3-d] pyrimidine;

(c) 4- (3-chloro-anilino) -6-hydroxymethyl-5-methyl-7H-pyrrolo [2,3-d] pyrimidine;

(d) 5-carboxy-4- (3-chloro-anilino) -6-methyl-7H-pyrrolo [2,3-d] pyrimidine;

(e) 4- (3-chloro-anilino) -5-formyl-6-methyl-7H-pyrrolo [2,3-d] pyrimidine;

f) 4- (3-chloro-anilino) -5-hydroxymethyl-6-methyl-7H-pyrrolo [2,3-d] pyrimidine.

Example 59

Capsules filled with a dry mixture

5000 capsules, each containing as active ingredient 0.25 g of one of the compounds of the formula I mentioned in the preceding examples, are prepared as follows:

Ingredients:

active ingredient talc, wheat starch magnesium stearate lactose

Preparation:

1250 g 180 g 120 g 80 g 20 g

Said mesh screen. The gelatinous substance is pulverized and sieved through a 0.6 mm mixture of 0.33 g weight and filled into a filling machine.

103

Example 60

Soft capsules

5000 soft gelatin capsules, each containing as active ingredient 0.05 g of one of the compounds of the formula I mentioned in the preceding examples, are prepared as follows:

Ingredients:

active ingredient 250 g

Lauroglycol 2 liters

Preparation:

Said active compound is sprayed and suspended in Lauroglycol ^R (propylene glycol laurate, Gattefossé SA, Saint Priest, France) and comminuted in a wet pulverizer to a particle size of about 1 µm to 3 µτη. A portion of the mixture weighing 0.419 g is then filled into soft gelatin capsules in a filling machine.

Example 61

Soft capsules

5000 soft gelatin capsules, each containing as active ingredient 0.05 g of one of the compounds of the formula I mentioned in the preceding examples, are prepared as follows:

Ingredients:

active ingredient PEG 400 Tween 80

250 g 1 liter 1 liter

104

Preparation:

Said active compound is sprayed and suspended in PEG 400 (polyethylene glycol, M _r about 380 to about 420, Fluka, Switzerland) and Tween ^R- e 80 (polyethylene sorbitan monolaurate, Atlas Chem. Ind. Inc., USA, supplied by Fluka, Switzerland) and comminutes in a wet pulverizer to particles of about 1 gm to 3 μιη. A portion of the mixture weighing 0.43 g is then filled into soft gelatin capsules in a filling machine.

Claims (22)

First PATENT CLAIMS 7H-Pyrolo [2,3-d] pyrimidine derivatives of formula (I) d) is 0 or 1, is a 1 to 3 when q is 0, or n is 0 to 3 when q is 1, is a halogen atom, lower alkyl group, OH lower alkanoyloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino, or trifluoromethyl, wherein when the molecule contains several R radicals, these may be. same or different, a) R ¹ and R ^{2 are} independently of one another a) phenyl substituted by carbamoyl-methoxy, carboxy-methoxy, benzyloxycarbonylmethoxy, lower alkoxycarbonylmethoxy, phenyl, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino a hydroxyl group, a lower alkanoyloxy group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, an N- (lower alkyl) carbamoyl group, an N, N-di- (lower alkyl) carbamoyl group, a cyano group or a nitro group; S) a hydrogen atom; t) a pyridyl group unsubstituted or substituted by a halogen atom or a lower alkyl group; δ) N-benzyl-pyridinium-2-yl; a naphthyl group; cyano; a carboxyl group; a lower alkoxycarbonyl group; a carbamoyl group; N- (lower alkyl) carbamoyl; N, N-di- (lower alkyl) carbamoyl; N-benzylcarbamoyl; a formyl group; a lower alkanoyl group; a lower alkenyl group; a lower alkenyloxy group; or (e) a lower alkyl group substituted by e, (a) a halogen atom, an amino group, a lower alkylamino group, a piperazine group, a di- (lower alkyl) amino group, ε, β) a phenylamino group which is unsubstituted or substituted by a halogen atom in the phenyl moiety; lower alkyl, hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano , amino, lower alkanoylamino, lower alkylamino, N, N-di (lower alkyl) amino or trifluoromethyl, e, t) hydroxyl, lower alkoxy, cyano, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) carbamoyl, N, N-di- (ni Ší alkyl) carbamoyl, mercapto or 107 e, δ) a radical of the formula R ³ -S (O) _m - in which R ³ is a lower alkyl group and _m is 0, 1 or 2, or (b) when q is 0, one of the radicals R and R is an unsubstituted lower alkyl group or an unsubstituted phenyl group and the other of the radicals R and R has one of the meanings given in (a) above, except for a hydrogen atom; or c) R- ¹ - and R together are a 1,4-alkadienylene group having 4 to 10 carbon atoms, substituted with an amino group, a lower alkanoylamino group, a lower alkylamino group, a N, N-di- (lower alkyl) amino group, a nitro group, halogen, hydroxyl, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl or cyano, or are aza- a 1,4-alkadienylene group containing up to 9 carbon atoms; or d) when q is 1, the radicals R ¹ and R ² are independently unsubstituted lower alkyl or unsubstituted phenyl or have one of the meanings mentioned under a), and R ⁶ is H, lower alkyl, lower alkoxycarbonyl, carbamoyl, N (lower alkyl) carbamoyl or N, N-di (lower alkyl) carbamoyl, or a salt thereof, with the exception of compounds of formula I, where n is 0, q is 1, R ¹ and R ⁶ are n atoms and R is methyl. Compounds of formula I according to claim 1, wherein q is 0 or 1, n is 1 to 3 when q is 0, or n is 0 to 3 when q is 1, 108 R is halogen, lower alkyl, hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, Ν, Ν-di (lower alkyl) amino, or trifluoromethyl, wherein when the molecule contains several R radicals these radicals may be the same or different, , carboxyl, carbamoyl a) R 6 is a hydrogen atom and R ² is a phenyl group substituted with carbamoyl-methoxy, carboxy-methoxy, benzyloxycarbonyl-methoxy, lower alkoxycarbonyl-methoxy, phenyl, amino, lower alkanoylamino, lower alkylamino , N, N-di- (lower alkyl) amino, hydroxyl, lower alkanoyloxy, lower alkoxycarbonyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano or nitro; pyridyl, unsubstituted or substituted by halogen or lower alkyl; N-benzyl-pyridinium-2-yl; a naphthyl group; cyano; a carboxyl group; a lower alkoxycarbonyl group; a carbamoyl group; N- (lower alkyl) carbamoyl; N, N-di- (lower alkyl) carbamoyl; N-benzylcarbamoyl; a formyl group; a lower alkanoyl group; a lower alkenyl group; a lower alkenyloxy group; or a lower alkyl group substituted by a halogen atom, a phenylamino group which is unsubstituted or substituted in the phenyl residue by a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkanoyloxy group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, lower alkyl) -carbamoyl, N, N-di (lower alkyl) -carbamoyl, cyano, amino, lower alkanoylamino, lower 109 is an alkylamino group, N, N-di- (lower alkyl) amino group or trifluoromethyl group; lower alkoxy, cyano, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, mercapto or a radical of formula R ² -S (O _m - in which R ² is a lower alkyl group and _m is 0, 1 or 2, or (b) when q is 0, one of the radicals R and R is an unsubstituted lower alkyl group or an unsubstituted phenyl group and the other of the radicals R ¹ and R ² has one of the meanings given in (a) above, except for a hydrogen atom; or c) R ¹ and R ² together are 1,4-alkadienylene of 4 to 10 carbon atoms, substituted with lower alkanoylamino, nitro, halogen, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl N, N-di- (lower alkyl) -carbamoyl or cyano, or are aza- -1,4-alkadienylene or group containing up to 9 carbon atoms, d) when q is 1, R ^{2 -} is an atom □ hydrogen and R is unsubstituted a phenyl group, and R is a hydrogen atom, lower alkyl group, lower alkoxy- carbonyl, carbamoyl, N- (lower alkyl) -carbamoyl or N, N-di (lower alkyl) -carbamoyl, or salts thereof. Compounds of formula I according to claim 1, wherein q is 0 or 1, n is 1 to 3 when q is 0, or n is 0 to 3 when q is 1, R is a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkanoyloxy group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, an N- (lower alkyl) carbamoyl group, N, N-di- (lower alkyl) ) -carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino, or trifluoromethyl, wherein when the molecule contains several R radicals, the radicals may be the same or different . Ί 9 a) R and R independently of each other are phenyl substituted by carbamoylmethoxy, carboxymethoxy, benzyloxycarbonylmethoxy, lower alkoxycarbonylmethoxy, phenyl, amino, lower alkanoylamino, lower alkylamino, N, N-di - (lower alkyl) amino, hydroxyl, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano or nitro; a hydrogen atom; pyridyl, unsubstituted or substituted by halogen or lower alkyl; N-benzyl-pyridinium-2-yl; a naphthyl group; cyano; a carboxyl group; a lower alkoxycarbonyl group; a carbamoyl group; N- (lower alkyl) carbamoyl; N, N-di- (lower alkyl) carbamoyl; N-benzylcarbamoyl; a formyl group; a lower alkanoyl group; a lower alkenyl group; a lower alkenyloxy group; or a lower alkyl group substituted by a halogen atom; amino, lower alkylamino, piperazine, di- (lower alkyl) -amino, hydroxyl, lower alkoxy, cyano, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N , N-di- (lower alkyl) -carbamoyl, mercapto, or a radical of formula R ³ -S (O) _m - in which R ³ is lower alkyl and _m is 0, 1 or 2, or (b) when q is 0, one of the radicals R ¹ and R ² is an unsubstituted lower alkyl group, or the unsubstituted phenyl moiety and the other of the radicals R ¹ and R ² have one of the meanings given in (a) above, or c) R ¹ and R ² together are 1,4-alkadienylene of 4 to 10 carbon atoms, substituted with amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino, nitro, a halogen atom, a hydroxyl group, a carboxyl group, a carbamoyl lower alkanoyloxy lower alkoxycarbonyl group, a group, a group, an N- (lower alkyl) -carbamoyl group, an N, N-di- (lower alkyl) -carbamoyl group or a cyano group; A -1,4-alkadienylene group containing up to 9 carbon atoms, or d) when q is 1, the radicals R ¹ and R ² are ^x independently of each other an unsubstituted lower alkyl group or an unsubstituted phenyl group or have the meaning given in (a); and R ⁶ is hydrogen, lower alkyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl or N, N-di (lower alkyl) -carbamoyl, or salts thereof, with the exception of a compound of formula I, where n is 0, q is, R and R are hydrogen, R ² is a methyl group. Compounds of formula I according to claim 1, wherein Λ q is 0, -y n is 1 to 3, R is halogen, lower alkyl, hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino12, Ν, Ν-di (lower alkyl) amino, or trifluoromethyl, wherein when the molecule contains several R radicals these radicals may be. same or different, a) R ¹ and R ² independently of each other are phenyl substituted by phenyl, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) -amino, hydroxyl, lower alkanoyloxy, carboxyl lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) I -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, or nitro, hydrogen, pyridyl, unsubstituted or substituted by halogen or lower alkyl; N-benzyl-pyridinium-2-yl; a naphthyl group; cyano; a carboxyl group; a lower alkoxycarbonyl group; a carbamoyl group; N- (lower alkyl) carbamoyl; N, N-di- (lower alkyl) carbamoyl; a formyl group; a lower alkanoyl group; a lower alkenyl group; a lower alkenyloxy group; or a lower alkyl group substituted with a halogen atom, an amino group, a lower alkylamino group, a piperazine group, a di- (lower alkyl) amino group, a hydroxyl group, a lower alkoxy group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, N- (lower) alkyl) -carbamoyl, N, N-di (lower alkyl) -carbamoyl, mercapto q, or a radical of the formula R -S (O) _m - ₍ in which R is _t lower alkyl and _m is 0, 1 or 2 or Ί eb 9) one of the radicals R ^A and R is unsubstituted lower alkyl or unsubstituted phenyl and the other of the radicals R and R ² has one of the meanings given above in paragraph a) with the exception of a hydrogen atom, or c) R and R together are 1,4-alkadienylene having 4 to 10 carbon atoms, substituted with an amino group, a lower alkanoylamino group, a lower alkylamino group, a N, N-di- (lower alkyl) amino group, a nitro group, an atom 113 are halogen, hydroxyl, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl or cyano, or are aza- A 1,4-alkadienylene group containing up to 9 carbon atoms, or salts thereof. Compounds of formula I according to claim 1, wherein q is 0, n is 1 or 2 R is a halogen atom, wherein when the molecule contains several R radicals, the radicals may be the same or different, and a) R ¹ and R ² independently of each other are phenyl substituted with phenyl, amino, hydroxyl or nitro; a hydrogen atom; a pyridyl group; N-benzyl-pyridinium-2-yl; a naphthyl group; or a lower alkyl group substituted with a di- (lower alkyl) amino group, or b) one of the radicals R and R is an unsubstituted lower alkyl group or an unsubstituted phenyl group; and -i p the other of the radicals R and R has one of the meanings given in (a) above except for a hydrogen atom, or c) R and R 'together are an aza-1,4-alkadienylene group containing up to 9 carbon atoms, or salts thereof. Compounds of formula I according to claim 1, wherein q is 0, n is 1 or 2, R is a halogen atom, wherein when the molecule contains several R radicals, the radicals may be the same or different, and 114 a) R ¹ is a hydrogen atom or bold or substituted with n and R is phenyl lower alkyl unsubstituted (lower alkyl) amino substituted with phenyl, amino, hydroxyl or nitro; a pyridyl group; N-benzyl-pyridinium-2-yl; or a naphthyl group; or b) R ¹ and R ² together are an aza-1,4-alkadienylene group containing up to 9 carbon atoms, or salts thereof. Compounds of formula I according to claim 1, wherein q is 0 or 1, n is 1 or 2 when q is 0, or n is 0 to 2 when q is 1, R is a halogen atom or a lower alkyl group, wherein when the molecule contains several R radicals, the radicals may be the same or different, and a) R ¹ is a hydrogen atom or a lower alkyl group unsubstituted or substituted by a di- (lower alkyl) amino group, and R is a phenyl group substituted by a carbamoylmethoxy group, a carboxymethoxy group, a benzyloxycarbonylmethoxy group, a lower alkoxycarbonylmethoxy group, lower alkoxycarbonyl, carboxyl, N, N-di- (lower alkyl) -carbamoyl, phenyl, amino, lower alkylamino, di- (lower alkyl) amino, lower alkanoylamino, hydroxyl or nitro; hydroxy-lower alkyl, amino-lower alkyl, di- (lower alkyl) amino-lower alkyl, piperazino-lower alkyl, formyl, cyano, carboxyl; a lower alkoxycarbonyl group; carbamoyl, N- (lower alkyl) carbamoyl; N, N-di- (lower alkyl) carbamoyl, pyridyl; N-benzylcarbamoyl, N-benzyl-pyridinium-2-yl; or naphthyl 115 group, or b) R ¹ and R ² together are 1-aza-buta-1,3-dien-1,4-ylene or c) when q is 1, R ² and R ² are both methyl, and R 8 is a hydrogen atom, a methyl group or a lower alkoxycarbonyl group, or a pharmaceutically acceptable salt thereof. Compounds of formula I according to claim 1, wherein q is 0 or 1, n is 1 or 2 when q is 0, or n is 0 to 2 when q is 1, R is a halogen atom, wherein when the molecule contains several R radicals, the radicals may be the same or different, and a) R ¹ is a hydrogen atom or a lower alkyl group unsubstituted or substituted with a di- (lower alkyl) amino group, and ABOUT R ¹⁶ is phenyl substituted by carbamoyl-methoxy, carboxy-methoxy, benzyloxycarbonyl-methoxy, methoxycarbonyl-methoxy, ethoxycarbonyl, carboxyl, phenyl, amino, acetamine, hydroxyl or nitro; a carboxyl group; ethoxycarbonyl; N- (lower alkyl) carbamoyl; a pyridyl group; N-benzyl-pyridinium-2-yl; or a naphthyl group, or b) R and R together are an aza-1,4-alkadienylene group containing up to 9 carbon atoms, or (c) when q is 1, both R ¹ and R ² are methyl and R ⁶ is a hydrogen atom, a methyl group or a methoxycarbonyl group, 116 or a salt thereof. Compounds of formula (I) according to claim 1, or pharmaceutically acceptable salts thereof, selected from the group consisting of 4- (3-chloro-anilino) -6- (pyrid-2-yl) -7H-pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6- (pyrid-2-) hydrochloride yl) -7H-pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -5-dimethylaminomethyl-6- (pyrid-2-yl) -7H-pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-4-fluoro-anilino) -6- (pyrid-2-yl) -7 H -pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -5-methyl-6- (pyridin-2-yl) -7 H -pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -5-methyl-6- (N-benzylpyridinium-2-yl) -7 H -pyrrolo [2,3-d] pyrimidine bromide, 4- (3-chloro-4-fluoro-anilino) -5-methyl-6- (pyrid-2-yl) -7H-pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -7 H -pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6- (biphen-4-yl) -7 H -pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6- (naphth-2-yl) -7H-pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6- (2-hydroxy-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6- (3-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine; 4- (3-chloro-anilino) -6- (4-hydroxy-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -5-dimethylaminomethyl-6- (4-hydroxy-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -5-dimethylaminomethyl-6-phenyl-7H-pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -5-methyl-6- (4-hydroxy-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine, 117 4- (3-chloro-anilino) -6- (4-nitro-phenyl) -7H-pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6- (4-amino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-phenylamino) -9H-pyrido [3 ', 2': 4,5] pyrrolo [2,3-d] pyrimidine, and pharmaceutically acceptable acid addition salts thereof. Compounds of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of (a) 4-benzylamino-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine; (b) (R) -5,6-Dimethyl-4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine; (c) (S) -5,6-Dimethyl-4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine; d) (R) -6- (4-Amino-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine, (e) (S) -6- (4-Amino-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine; f) 6- (4-Amino-phenyl) -4-benzylamino-7H-pyrrolo [2,3-d] pyrimidine; (g) 6- (4-amino-phenyl) -4 - [(3-chloro-benzyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine; (h) (R) -6- (4-Amino-phenyl) -4 - [(1-methoxycarbonyl-benzyl)] - amino-7H-pyrrolo [2,3-d] pyrimidine; i) (S) -6- (4-Amino-phenyl) -4 - [(1-methoxycarbonyl-benzyl)] - amino-7H-pyrrolo [2,3-d] pyrimidine; j) 6- (4-acetylamino) -phenyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine, (k) 6- (4-carbamoylmethoxy-phenyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine; (l) 6- (4-amino-phenyl) -4- (3-methyl-anilino) -7H-pyrrolo [2,3-d] pyrimidine; 118 m) 6- (4-Amino-phenyl) -4- (3-chloro-4-fluoro-anilino) -7H-pyrrolo [2,3-d] pyrimidine; (n) 6- (3-acetylamino-phenyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine; o) 6- (3-Amino-phenyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine; p) 6- (4-carboxymethoxy-phenyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine; q) 6- (4- [benzyloxycarbonyl-methoxy] -phenyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine, (r) 6- (3-carbamoylmethoxy-phenyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine; (s) 4- (3-chloro-anilino) -6- (4-methoxycarbonylmethoxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine; t) 4- (3-chloro-anilino) -6- (3-methoxycarbonylmethoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine, u) 6-carboxy-4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine; (v) 4- (3-chloro-anilino) -6-ethoxycarbonyl-7H-pyrrolo [2,3-d] pyrimidine; (w) 6- (N-n-butyl-carbonyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine; (x) 4- (3-chloro-anilino) -6- (4-ethoxycarbonylphenyl) -7H-pyrrolo [2,3-d] pyrimidine; y) 6- (4-carboxy-phenyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine, z) 6- (N-benzylcarbamoyl) -4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine, z) 4- (3-chloro-anilino) -6- (N - [3-methyl-but-1-yl] -carbamoyl) -7H-pyrrolo [2,3-d] pyrimidine, and pharmaceutically acceptable salts thereof. Compounds of formula (I) according to claim 1, or pharmaceutically acceptable salts thereof, selected from the group consisting of 119 (a) 4- (3-chloro-anilino) -6- (4-propionylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine; (b) 4- (3-chloro-anilino) -6- (3-propionylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine; (c) (R) -6- (4-Acetylamino-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine; d) (R) 4 - [(1-Phenyl-ethyl) -amino] -6- (4-propionylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine, (e) (R) -6- (3-Acetylamino-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine; (f) 4- (3-chloro-anilino) -6- (4-isobutyrylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine; (g) 4- (3-chloro-anilino) -6- (4-pivaloylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine; (h) 4- (3-chloro-anilino) -6- [4- (DL-2-methyl-butyrylamino) -phenyl] -7H-pyrrolo [2,3-d] pyrimidine; (i) 4- (3-chloro-anilino) -6- (4-isovalerylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine; (j) 4- (3-chloro-anilino) -6- (3-isobutyrylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine; (k) 4- (3-chloro-anilino) -6- (4-ethylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine; (l) 6- (4-ethylamino-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine; m) 4- (3-chloro-anilino) -6- (4-dimethylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine; (n) 4- (3-chloro-anilino) -6- (3-ethylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine; o) 6- (4-dimethylanilino-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine, and pharmaceutically acceptable salts thereof. 120 A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 6- (4-Amino-phenyl) -4- (3-methyl-benzyl) -7H-pyrrolo [2,3-d] pyrimidine, (R) -6- (3-Amino-phenyl) -4- [ (1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine, (R, S) -6- (4-amino-phenyl) -4 - [(1- (3-chloro- phenyl) -ethyl) amino] -7H-pyrrolo [2,3-d] pyrimidine, (R) -4 - [(1-phenyl-ethyl) -amino] -6- (4-propionylamino-phenyl) -7H- pyrrolo [2,3-d] pyrimidine, (R) -4 - [(1-phenyl-ethyl) -amino] -6- (3-propionylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine, (R) -6- (3-isobutyrylamino-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine, (R) -6- (4-isobutyrylamino) -phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine, (R) -6- (4-pivaloylamino-phenyl) -4 - [(1- phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine, (R) -6- (3-pivaloylamino-phenyl) -4 - [(1-phenyl-ethyl) -amino] -7H- pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6- (3-ethoxycarbonyl-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6- (3-carboxy-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6- (4-methoxycarbonyl-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6- (4-propyloxycarbonyl-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6- (4-isopropyloxycarbonyl-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6- (4-isobutyloxycarbonyl-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine, 121 4- (3-chloro-anilino) -6- (4-dimethylaminocarbonyl-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6- (4-diethylaminocarbonyl-phenyl) -7H-pyrrolo [2,3-d] pyrimidine, (R) -6- (4-diethylamino-phenyl) -4- [ (1-Phenyl-ethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6- (3-dimethylamino-phenyl) -7H-pyrrolo [2,3-d] pyrimidine, (R) -6- (4-hydroxy-phenyl) -4 - [( 1-phenyl-ethyl) amino] -7 H -pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -5-dimethylaminomethyl-6- (4-hydroxy-phenyl) -7 H -pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6- (Ν, Ν-dimethyl-carbamoyl) -7 H -pyrrolo [2,3-d] pyrimidine, 6-aminocarbonyl-4- (3-chloro-anilino) -7 H -pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6-methylaminocarbonyl-7H-pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6-hydroxymethyl-7 H -pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6-formyl-7H-pyrrolo [2,3-d] pyrimidine, (R) -6-ethoxycarbonyl-4- [1-phenyl-ethylamino] -7H-pyrrolo [2, d. 3-d] pyrimidine, (R) -6-methylaminocarbonyl-4- [1-phenyl-ethylamino] -7H-pyrrolo [2,3-d] pyrimidine, (R) -6-carbamoyl-4- [1-phenyl] -ethylamino] -7H-pyrrolo [2,3-d] pyrimidine, (R) -6-cyano-4- [1-phenyl-ethylamino] -7H-pyrrolo [2,3-d] pyrimidine, 4- (3-Chloro-anilino) -6-cyano-7H-pyrrolo [2,3-d] pyrimidine, (R) -6-formyl-4- [1-phenyl-ethylamino] -7H-pyrrolo [2, 3-d] pyrimidine, (R) -6-aminomethyl-4- [1-phenyl-ethylamino] -7H-pyrrolo [2,3-d] pyrimidine, 122 6-Aminomethyl-4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6- (dimethylamino-methyl) -7H-pyrrolo [2,3-d] pyrimidine, (R) -6- (dimethylamino-methyl) -4- [1-phenyl- ethylamino] -7H-pyrrolo [2,3-d] pyrimidine, (R) -6- (piperazinomethyl) -4- [1-phenyl-ethylamino] -7H-pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6- (piperazinomethyl) -7H-pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6-methoxymethyl-7H-pyrrolo [2,3-d] pyrimidine, 6- (N-tert-Butyl-carbamoyl) -4- (3-chloro-anilino) -7 H -pyrrolo [2,3-d] pyrimidine, 4- (3-Chloro-anilino) -6- (N, N-dimethylamino-methyl) -7 H -pyrrolo [2,3-d] pyrimidine, 6-carboxy-4- (3-chloro-anilino) -5-methyl-7H-pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6-formyl-5-methyl-7H-pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -6-hydroxymethyl-5-methyl-7H-pyrrolo [2,3-d] pyrimidine, 5-carboxy-4- (3-chloro-anilino) -6-methyl-7H-pyrrolo [2,3-d] pyrimidine; 4- (3-chloro-anilino) -5-formyl-6-methyl-7 H -pyrrolo [2,3-d] pyrimidine, 4- (3-chloro-anilino) -5-hydroxymethyl-6-methyl-7 H -pyrrolo [2,3-d] pyrimidine. and pharmaceutically acceptable salts thereof. Compounds of formula I according to any one of claims 1 to 12 or pharmaceutically acceptable salts thereof, characterized in that they are used in methods of treatment of the human or animal body. 14. Pharmaceutical preparations characterized by 123 comprising a compound of formula I according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, together with a pharmaceutical carrier. Pharmaceutical compositions for the treatment of tumors in warm-blooded animals, including humans, comprising, in doses effective to treat the tumor, a compound of formula I according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, together with a pharmaceutical carrier. Use of the compounds of formula I according to any one of claims 1 to 12, or pharmaceutically acceptable salts thereof, for the preparation of pharmaceutical compositions intended for the chemotherapy of tumors. Use of the compounds of formula I according to any one of claims 1 to 12, or pharmaceutically acceptable salts thereof, in cancer chemotherapy. A method of treating a warm-blooded animal, including a human, comprising administering to a warm-blooded animal suffering from a tumor at a dose effective against a tumor, a compound of formula I according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof. A process for the preparation of 7H-pyrrolo [2,3-d] pyrimidine derivatives of the formula I wherein q is 0 or 1, n is 1 to 3 when q is 0, or n is 0 to 3 when q is 1, R is halogen, lower alkyl, hydroxyl, lower alkanoyloxy, lower alkoxy 124, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino, or trifluoromethyl, wherein when the molecule contains several R radicals, the radicals may be the same or different, a) R ¹ and R ^{2 are} independently of one another a) phenyl substituted by carbamoyl-methoxy, carboxy-methoxy, benzyloxycarbonylmethoxy, lower alkoxycarbonylmethoxy, phenyl, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino , hydroxyl, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, or nitro; β) a hydrogen atom; t) a pyridyl group unsubstituted or substituted by a halogen atom or a lower alkyl group; δ) N-benzyl-pyridinium-2-yl; a naphthyl group; cyano; a carboxyl group; a lower alkoxycarbonyl group; a carbamoyl group; N- (lower alkyl) carbamoyl; N, N-di- (lower alkyl) carbamoyl; N-benzylcarbamoyl; a formyl group; a lower alkanoyl group; a lower alkenyl group; a lower alkenyloxy group; or e) lower alkyl substituted by e, a] halogen, amino, lower alkylamino 125, piperazine, di- (lower alkyl) amino, ε, β) phenylamino which is unsubstituted or substituted in the phenyl residue by a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkanoyloxy group, a lower alkoxy group, a carboxyl group , lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di (lower alkyl) amino or trifluoromethyl, e, t) hydroxyl, lower alkoxy, cyano, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N- (lower alkyl) ) -carbamoyl, mercapto, or e, δ) a radical of formula R ³ -S (O) _m -, wherein R ³ is e is a lower alkyl group and m is 0, 1 or 2, or (b) when q is 0, one of the radicals R 1 and R 2 is an unsubstituted lower alkyl group or an unsubstituted phenyl group and the other of the radicals R 1 and R 2 has one of the meanings given in (a) above, except for a hydrogen atom; c) R and R together are 1,4-alkadienylene of 4 to 10 carbon atoms, substituted with amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino, nitro, halogen, hydroxyl, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl or cyano, or are aza-1,4 an alkadienylene group containing up to 9 carbon atoms, or 126 d) when q is 1, the radicals R ¹ and R ² are independently unsubstituted lower alkyl or unsubstituted phenyl or have one of the meanings mentioned under a), and R® is H, lower alkyl, lower alkoxycarbonyl, carbamoyl, N (lower alkyl) -karN, N-di (lower alkyl) carbamoyl Skui wherein n is 0, q is 1, R ¹ and R are atoms group characterized in that a) reacting a pyrrolo [2,3-d] pyrimidine derivative of the general formula II with a bamoyl or pin, and salts thereof, with the exception of a compound of the formula hydrogen and R ² is methyl wherein X is a suitable leaving group, Z is a hydrogen atom; -aryl-substituted lower alkyl and other substituents are as defined above for compounds of formula I, wherein any functional groups present in the radicals R ¹ and R ² are easily removable, if desired, easily protected with an amine of formula III (R) " (CHR ⁶ ), (III) H g wherein R, R, to q are as defined above for compounds of Formula I, wherein any free functional groups present in the R radical are protected, if necessary, with readily removable protecting groups, and all protecting groups present including 1-aryl-substituted lower alkyl radical FROM, 127 if present, shall be removed, or b) reacting a pyrrolo [2,3-d] pyrimidin-4-one derivative of the general formula IV in which Z 'is a 1-aryl-substituted lower alkyl group in the presence of a dehydrating agent and a tertiary amine; R ^x and R are as defined above for compounds of formula I, any free functional groups present in the radicals R ¹ n and R ^z are protected with readily removable protecting groups, if desired, and all protecting groups present are removed, or c) for the preparation of a compound of formula I in which R ¹ is a dimethylamino-methyl group and the other substituents defined above for compounds of formula I, a compound corresponding to formula I in which R ¹ is a hydrogen atom is reacted with N, N-dimethyl-methylenimmonium iodide and the remaining substituents are as defined above for the compounds of formula I, wherein any free functional groups present in the R and R radicals are protected, if necessary, with readily removable protecting groups, and all protecting groups present are removed, or d) for the preparation of a compound of formula I in which at least one of the radicals R, R and R is a phenyl group substituted by a hydroxyl group and the other substituents defined above for compounds of formula I, the compound corresponding to formula I is reacted with boronibromide. of radicals Ί Q R, R and R ^x are phenyl substituted by methoxy and the other substituents are as defined above for compounds of formula I, wherein any free functional groups present in the radicals R, R ¹ and R ² are protected, if necessary, with readily removable protecting groups, and all of the och128 morning groups present are removed, or e) for the preparation of a compound of formula I in which at least one of the radicals R, R ¹ and R ² is an amino-substituted phenyl group and the other substituents are as defined above for compounds of formula I, a compound corresponding to formula I is subjected to catalytic hydrogenation one of the radicals R, R and R is a phenyl group substituted by a nitro group and the other substituents are as defined above for the compounds of formula I, wherein any free functional groups present in the radicals R, R ¹ and R ² are protected by readily removable protecting groups, and all protecting groups present are removed, then after carrying out one of processes a) to e), converting the obtained free compound of formula I into the desired salt as required, or to obtain the free compound, converting the obtained salt of the compound of formula I into free compound. A process for the preparation of 7H-pyrrolo [2,3-d] pyrimidine derivatives of the general formula la wherein n is 1 to 3, R is halogen, lower alkyl, hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di (lower alkyl) amino, or trifluoromethyl, wherein when the molecule contains several R radicals these radicals may be. same or different, 129 a) R ¹ and R ² independently of each other are phenyl substituted by phenyl, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) -amino, hydroxyl, lower alkanoyloxy, carboxyl lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) carbamoyl, N, N-di- (lower alkyl) carbamoyl, cyano, or nitro; a pyridyl group unsubstituted or substituted by a halogen atom or a lower alkyl group; N-benzyl-pyridinium-2-yl; a naphthyl group; cyano; a carboxyl group; a lower alkoxycarbonyl group; a carbamoyl group; N- (lower alkyl) -carbamoyl; N, N-di- (lower alkyl) -carbamoyl; a formyl group; a lower alkanoyl group; a lower alkenyl group; a lower alkenyloxy group; or lower alkyl substituted by halogen, amino, lower alkylamino, piperazine, di- (lower alkyl) amino, hydroxyl, lower alkoxy, cyano, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di (lower alkyl) -carbamoyl, mercapto, or a radical of formula R ³ -S (O) _m -, wherein R ³ is lower alkyl and _m is 0, 1 or 2, or (b) one of the radicals R- ¹ and R is an unsubstituted lower alkyl or unsubstituted phenyl group and the other of the &quot; 1 radicals R and R 'has one of the meanings given in (a) above except for a hydrogen atom; or c) R ^x and R ¹⁶ together are a 1,4-alkadienylene group having 4 to 10 carbon atoms, substituted with an amino group, a lower alkanoylamino group, a lower alkylamino group, a N, N-di- (lower alkyl) amino group, a nitro group, halogen, hydroxyl, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl 130, N, N-di- (lower alkyl) -carbamoyl or cyano, or an aza-1,4-alkadienylene group containing up to 9 carbon atoms, and salts thereof, characterized in that: a) a pyrrolo [2,3-d] pyrimidine derivative of the Formula II (H) wherein X is a suitable leaving group, Z is a hydrogen atom or a 1-aryl-substituted lower alkyl group and the other substituents are. as defined above for compounds of formula I, wherein any functional groups present in the radicals R ¹ and R ² are protected, if necessary, with readily removable protecting groups, are reacted with an aniline derivative of the formula IIIa (R> n) NH, (IIIa) wherein R and n are as defined above for the compounds of formula Ia, and all free functional groups in the R radical are protected as necessary with readily removable protecting groups, and all protecting groups present including 1-aryl-lower alkyl Z, if present, it shall be removed, or b) the aforementioned phenylamine of the formula IIIa in the presence of a dehydrating agent and a tertiary amine is reacted with a pyrrolo [2,3-d] pyrimidin-4-one derivative of the formula IV Wherein Z 1 is a 1-aryl-substituted lower alkyl group and R and R are as defined above for compounds of Formula Ia, wherein any free functional groups present in the radicals R ¹ and R ² are protected, if necessary, with readily removable protecting groups, and all protecting groups present are removed, or c) for the preparation of a compound of formula Ia in which R ¹ is a dimethylamino-methyl group and the other substituents defined above for compounds of formula Ia, a compound corresponding to formula Ia wherein R ¹ is a hydrogen atom is reacted with N, N-dimethylmethylenimmonium iodide and the other substituents are as defined above for the compounds of formula Ia, wherein any free functional groups present in the radicals R ¹ and R ² are protected, if necessary, with readily removable protecting groups, and all protecting groups present are removed, or d) for the preparation of a compound of formula Ia in which at least one of the radicals R, R and R is a phenyl group substituted with a hydroxyl group and the other substituents defined above for compounds of formula Ia, a compound corresponding to formula Ia is reacted with boronibromide. of the radicals R, R- and R is a phenyl group substituted by a methoxy group and the other substituents are as defined above for the compounds of formula Ia, wherein any free functional groups present in the radicals R, R and R are protected, if necessary, by easily removable protecting groups , and all protecting groups present are removed, or e) for the preparation of a compound of formula Ia, wherein at least one of the radicals R, R and R ^R is phenyl substituted by amino and the other substituents are as defined above for compounds of formula Ia, is subjected to catalytic hydrogenation a compound corresponding to formula Ia, wherein the at least one of the radicals R, R and R is a phenyl group substituted by a nitro group and the other substituents are as defined above for compounds of formula Ia, wherein any free functional groups present in the radicals R, R ¹ and R ² are protected, if necessary, with readily removable protective and, after carrying out one of processes a) to e), the obtained free compound of formula Ia is converted to the desired salt, if desired, or the obtained salt of the compound of formula Ia is converted to the desired salt, free compound. A pyrrolo [2,3-d] pyrimidine derivative of the general Formula IIa wherein X ¹ is a hydroxyl group or a suitable leaving group, Z is hydrogen or 1-aryl-substituted lower alkyl; is a hydrogen atom or a lower alkyl group unsubstituted or substituted by a di- (lower alkyl) amino group, and R ² is a) phenyl substituted by carbamoyl-methoxy, carboxy-methoxy, benzyloxycarbonylmethoxy, lower alkoxycarbonylmethoxy, phenyl, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino , hydroxyl, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) carbamoyl, cyano, or nitro; b) pyridyl, unsubstituted or substituted 133 with a halogen atom or a lower alkyl group; c) N-benzyl-pyridinium-2-yl; a naphthyl group; cyano; a carboxyl group; a lower alkoxycarbonyl group; a carbamoyl group; N- (lower alkyl) carbamoyl; N, N-di- (lower alkyl) carbamoyl; N-benzylcarbamoyl; formyl, lower alkanoyl; a lower alkenyl group; a lower alkenyloxy group; or d) lower alkyl substituted a) a halogen atom, an amino group, a lower alkylamino group, a piperazine group, a di- (lower, alkyl) amino group, β) a phenylamino group which is unsubstituted or substituted in the phenyl residue by a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkanoyloxy group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, N- (lower alkyl) -carbamoyl group , N, N-di- (lower alkyl) -carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di (lower alkyl) amino, or trifluoromethyl, t) hydroxyl, lower alkoxy, cyano, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) carbamoyl, N, N-di- (lower alkyl) -carbamoyl, mercapto, or o δ) a radical of formula R -S (O) _m - in which R is a lower alkyl group and _m is 0, 1 or 2, and 4-ketoderivatives which are tautomeric with compounds of formula II wherein X 'is a hydroxyl group, or salts of such compounds. 134 22. Pyrrole derivatives of formula XI wherein Z is hydrogen or 1-aryl-substituted lower alkyl, a) R ³ is a hydrogen atom or a lower alkyl group unsubstituted or substituted by a di- (lower alkyl) amino group, and R ² is (a) phenyl substituted by carbamoyl-methoxy, carboxy-methoxy, benzyloxycarbonyl-methoxy, lower alkoxycarbonyl-methoxy, phenyl, amino, lower alkanoylamino, lower alkylamino, N, N-di- (lower alkyl) amino, hydroxyl, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano, or nitro; β) a pyridyl group unsubstituted or substituted by a halogen atom or a lower alkyl group; ) N-benzyl-pyridinium-2-yl; a naphthyl group; cyano; a carboxyl group; a carbamoyl group; N- (lower alkyl) carbamoyl; N, N-di- (lower alkyl) carbamoyl; N-benzylcarbamoyl; formyl 135 group; a lower alkanoyl group; a lower alkenyl group; a lower alkenyloxy group; or δ) a lower alkyl group substituted by δ, d) a halogen atom, an amino group, a lower alkylamino group, a piperazine group, a di- (lower alkyl) amino group, δ, β) a phenylamino group which is unsubstituted or substituted by a halogen atom in the phenyl moiety; lower alkyl, hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N-di- (lower alkyl) -carbamoyl, cyano , amino, lower alkanoylamino, lower alkylamino, N, N-di (lower alkyl) amino or trifluoromethyl, δ, jp) hydroxyl, lower alkoxy, cyano, carboxyl, carbamoyl, N- (lower alkyl) -carbamoyl, N, N- (lower alkyl) -carbamoyl or (QQ δ, δ) a radical of the formula R -S (O) _m - in which R is a lower alkyl group and _m is 0, 1 or 2, or b) R 1 and R ² together are an aza-1,4-alkadienylene group containing up to 9 carbon atoms, and r 5 is a cyano group or a lower alkoxycarbonyl group, and salts of these compounds.