SK77992A3 - Cycloalkyl- and azacycloalkylpyrolepirimidines - Google Patents

Abstract

Cycloalkyl- and azacycloalkyl-pyrrolopyrimidine derivs. of formula (I), and their salts, are new. R1, R2= H or 1-6C alkyl; X= H or OH; W= phenyl, thienyl or pyridyl (all opt. substd. by 1 or 2 of halogen, OH, 1-6C alkyl, amino, mono- and di- (1-6Calkyl)amino, or 1-6C alkoxy); Y= N3, CO, CR6OR5, CR6COR5, CR6COOR5, CR60C0R5, CR5R6, CR6CONR7R8, CR6(CH2)MNR7R8, CR6NR9COOR10, CR6C(OH)R11R11, or a gp. (a); m, n= 0-2; R3= H, 1-6C alkyl, phenyl, pyridyl, phenyl 1-6C alkyl, 1-6C aminoalkyl, mono- or di-(1-6C alkyl)1-6C aminoalkyl, or 1-indamyl, 4-(thio)chromanyl or 1-(1,2,3,4-tetrahydronaphthyl) (all three opt. monosubstd. by halogen, 1-6C alkyl, or 1-6C alkoxy), COR4 or SO2R4. R4= 1-6C alkyl, phenyl, phenyl 1-6C alkyl or phenyl 1-6C alkoxy; R5, R8= H, 1-6C alkyl, phenyl, pyridyl or phenyl 1-6C alkyl; R6, R7= H or 1-6C alkyl; or NR7R8= morpholyl, piperidyl, pyrrolidyl or N-alkylpiperazinyl; R11, R12= 1-6C alkyl, phenyl or phenyl 1-6C alkyl; T= CH2 or O; Z= T, NR14 or CHCONR14; and R9, R10, R13, R14 = as R5.

Description

Cycloalkyl- and azacycloalkylpyrolopyrimidines of the formula I and their pharmaceutically acceptable salts, wherein n is 0, 1 or 2 and R ¹ , R ² , X, Y and W have the meaning of the various substituents described herein are selective agonists, antagonists or inverse agonists GABA? brain receptors or prodrugs thereof, and are useful in the diagnosis and treatment of anxiety, sleep and seizure disorders, overdoses of benzodiazepine-like drugs and as stimulants.

Technical field

The invention relates to certain cycloalkyl and azacycloalkylpyrrolopyrimidines that selectively bind to GABAα receptors. The invention also relates to pharmaceutical compositions comprising these compounds. The compounds of the invention may be used in the treatment of anxiety, sleep disorders and seizure. Furthermore, they can also be used in the treatment of conditions associated with an overdose of benzodiazepine-type drugs or as a stimulant. The interaction of the pyrrolopyrimidines of the invention with GABA binding sites and benzodiazepine (BDZ) receptors is also described herein. This interaction results in various types of pharmacological activity of these compounds.

BACKGROUND OF THE INVENTION

Β-aminobutyric acid (GABA) is considered to be one of the major inhibitory amino acid-type transmitters in the mammalian brain. 30 years have elapsed since its presence in the brain was detected (Roberts and Frankel, J. Biol. Chem. 187, pp. 55-63, 1950; Udenfriend, J. Biol. Chem. 187, pp. 65-69, 1950) . Since then, immense efforts have been devoted to the role of GABA in the etiology of seizure, sleep disorders, anxiety disorders and cognitive disorders (Tallman and Gallager, Ann. Rev. Neuroscience 8, pp. 21-44, 1985). GABA, which is largely albeit unevenly distributed in the mammalian brain, is reported to be a transmitter at approximately 30% of brain synapses. In most areas of the brain, GABA is associated with local inhibitory neurons, and in only two areas is GABA associated with longer projections. GABA mediates much of its action through a complex of proteins that are located on both the cell surface and the nerve endings; these are called GABAa receptors. Postsynaptic responses to GABA are mediated by changes in the conductivity of chloride ions, which usually, though not necessarily, leads to hyperpolarization of cells. Recent investigations have shown that the protein complex associated with postsynaptic responses to GABA is a major site of action for a number of structurally different compounds capable of modifying the postsynaptic response to GABA. Depending on the mode of interaction, these compounds are capable of providing a broad spectrum of different types of activity (either sedative, anxiolytic, and anticonvulsant, or stimulatory, anxiotic, and convulsive).

The ₄ 1,4-benzodiazepines patfí the drug, which in the world still widely used. Among the most successful benzodiazepines, chlordiazepoxide, diazepam, flurazepam and triazolan are the most important. These compounds are widely used as anxiolytics, sedatives and hypnotics, muscle relaxants and anticonvulsants. Many of these compounds are very potent drugs; this potency indicates a site of action with high affinity and specificity for individual receptors. Early electrophysiological studies have shown that the major action of benzodiazepines is to stimulate GABAergic inhibition. Benzodiazepines are capable of stimulating presynaptic inhibition of the monosynaptic reflex of Radix ventralis, a GABA-mediated effect (Schmidt et al., 1967, Ar. Exp. Path. Pharmacol. 285, pp. 69-82). All other electrophysiological studies (reviewed by Tallmann et al., 1980, Science 207, pages 274-281; Haefley et al., 1981, Hand. Exptl. Pharmacol. 33, pages 95-102) generally confirm this finding and in the mid-1970s. More or less, there has been a consensus among electrophysiologists that benzodiazepines can stimulate the effects of GABA.

When the benzodiazepine receptor was discovered and the nature of the interaction between GABA and benzodiazepines was defined, it appeared that the interactions of benzodiazepines with various neurotransmitter systems, which interactions are important from a behavioral point of view, are largely due to the increased ability of the

GABA to modify these systems. Furthermore, any modified system may be associated with an expression of behavior.

Studies of the mechanistic nature of these interactions depended on the demonstration of a high affinity binding site (receptor) for benzodiazepines. Such a receptor is present in the CNS of all vertebrates that are phylogenetic younger than bony fish (Squires and Braestrup 1977, Nature 166: 732-34, Mohler and Okada, 1977, Science 198: 854-51, Mohler and Okada, 1977, Br. J. Psychiatry 133: 261-68). Using tritiated diazepam and various other compounds, it has been demonstrated that these benzodiazepine binding sites meet many of the criteria of pharmacological receptors. Binding to these in vitro sites is rapid, reversible, stereospecific and saturable. More importantly, a highly significant correlation has been found between the ability of benzodiazepine to displace diazepam from its binding site and efficacy in many animal behavioral tests that can be used to predict the strength of benzodiazepine (Braestrup and Squires 1978, Br. J. Psychiatry 133: 249 - 60, Mohler and Okada, 1977, Science 198: 854-51, Mohler and Okada, 1977, Br. J. Psychiatry 133: 261-68). The average therapeutic doses of these drugs in human medicine also correlate with receptor potency. (Tallman et al., 1980, Science 207: 274-281).

In 1978, it became apparent that GABA and similar analogs could act on the low affinity GABA binding site (1, while stimulating benzodiazepine binding to a clonazepan-sensitive site (Tallman et al., 1978, Nature 274: 383-385)) This stimulation is due to an increase in the affinity of the benzodiazepine binding site due to the occupation of the GABA site, and the data was interpreted as indicating that the GABA site and the benzodiazepine site are allosterically coupled to the membrane as part of the protein complex. diazepam binding and 50% of the maximum, and the ability to inhibit GABA binding to brain membranes by 50%.

GABA receptor (+) bicucullin. The stereoisomer (-) bicucullin is much less effective (Tallman et al., 1978, Nature 274: 383-385).

Soon after the discovery of high affinity binding sites for benzodiazepines, it was found that triazolopyridazine can act on benzodiazepine receptors in numerous brain regions in a manner consistent with receptor heterogeneity or negative cooperativity. In these studies, Hill coefficients with significantly lower values than 1, such as cortex, hippocampus, and striatum, were found in numerous areas of the brain. In the cerebellum, thioazolopyridazine acts on benzodiazepine sites with Hill coefficient I (Squires et al., 1979, Pharma. Biochem. Behav. 10: 825-830; Klepner et al., 1979, Pharmacol. Biochem. Behav. 11: 457-462). Thus, numerous benzodiazepine receptors have been predicted in the cortex, hippocampus, striatum, but not in the cerebellum.

Based on these studies, extensive autoradiographic receptor localization studies were performed at the light microscope level. Although receptor heterogeneity has been demonstrated (Young and Kuhar, 1980, J. Pharmacol. Exp. Ther. 212: 337-346, Young et al., 1981, J. Pharmacol. Exp. Ther. 216: 425-430, Niehoff et al. 1982, J. Pharmacol. Exp. Ther. 221: 670-675), but these early studies did not show a simple correlation between the location of receptor subtypes and the behavior associated with this region. In addition, in the cerebellum, where one receptor was predicted based on binding studies, autoradiography showed receptor heterogeneity ((Niehoff et al., 1982, J. Pharmacal. Exp. Ther. 221: 670-675)).

The physical basis of the differences in drug specificity for the two apparent subtypes of benzodiazepine sites was shown by Sieghart and Karobath, 1980, Nature 286: 285-287. Using gel electrophoresis in the presence of sodium dodecyl sulfate, several benzodiazepine receptors with different molecular weights were detected.

Receptors have been identified by the covalent incorporation of radioactive flunitrazepam, a benzodiazepine that can covalently label all types of receptors. Major labeled bands have molecular weights of 50,000 to 53,000, 55,000 and 57,000, and triazolopyridazines inhibit labeling of slightly higher molecular weight forms (53,000, 55,000 and 57,000) (Seighart et al., 1983, Eur. J. Pharmacol. 88: 291-299).

At that time, the possibility that multiple receptor forms were considered to be isoreceptors or multiple allelic forms of the receptor was considered (Tallman and Gallager, 1985, Ann. Rev. Neurosci. 8: 21-44). Although common to enzymes, genetically distinct forms of receptors have generally not been described. Based on the study of receptors already started using specific radioactive probes and electrophoretic techniques, it is almost certain that isoreceptors will prove important in research into the etiology of psychiatric disorders in humans.

GABA A receptor subunits have been cloned from a bovine and human cDNA library (Schoenfield et al., 1988; Duman et al., 1989). A variety of cDNAs have been identified as subunits of the GABAα receptor complex by cloning and expression. These various cDNAs are categorized as Oc, β,, d -, S and provide a molecular basis for GABAα receptor heterogeneity and distinctive regional pharmacology (Shivvers et al., 1980, Levitan et al., 1989). The J * subunit appears to allow drugs such as benzodiazepines to modify GABA responses (Pritchett et al., 1989). The presence of low Hill coefficients in ligand binding to the GABAa receptor shows unique profiles of subtype-specific pharmacological activity.

Drugs that can act on the GABA receptor may exhibit a spectrum of pharmacological activities depending on their ability to modify the action of GABA. For example, beta-carbolines were first isolated based on their ability to competitively inhibit the binding of diazepam to its binding site (Nielsen et al. 1979, Life Sci. 25: 679-686). The biological activity of these compounds cannot be fully predicted by a receptor binding assay. Agonists, partial agonists, inverse agonists and antagonists can inhibit binding. Having determined the structure of beta-carboline, numerous analogs could be synthesized and tested for how these compounds affect behavior. It has been immediately recognized that beta-carbolines can antagonize the behavioral effects of diazepam (Tenen and Hirsch, 1980, Nature 288: 609-610). In addition to this antagonism, beta-carbolines have their own intrinsic activity, which is opposite to that of benzodiazepines. These agents are known as inverse agonists.

In addition, numerous other specific benzodiazepine receptor antagonists have been developed based on the ability to inhibit benzodiazepine binding. The best studied compound of this type is imidazodiazepine (Hunkeler et al., 1981, Nature 290: 514-516). This compound is a competitive inhibitor of the binding of benzodiazepines and beta-carboline, which is characterized by high affinity so that it is able to block the pharmacological action of both classes of these compounds. By itself, it has little intrinsic pharmacological activity in animals and humans (Hunkeler et al., 1981, Nature 290: 514-516; Darragh et al., 1983, Eur. J. Clin. Pharmacol. 14: 569-570). When the radiolabelled form of this compound has been studied (Mohler and Richards, 198X, Nature 294: 763-765), i. It was assured that they act at the same number of sites as the benzodiazepines and beta-carbolines and that the interactions of these compounds are purely competitive. This compound is a preferred ligand for binding to GABAα receptors since it does not exhibit specificity for the receptor subtype and measures each receptor state.

Interaction studies of a large number of similar compounds lead to their categorization. Currently, those compounds that show similar activity to benzodiazepines are termed agonists. Compounds showing opposite activity to benzodiazepines are termed inverse agonists, and compounds blocking both types of activity are termed antagonists. This categorization was developed to emphasize the fact that a number of different compounds exhibit a spectrum of pharmacological effects, to show that compounds can act on the same receptors to produce opposite effects, and to show that beta-carbolines and antagonists with intrinsic anxiogenic effects are not synonyms. A biochemical assay of the pharmacological and behavioral properties of compounds that act on the benzodiazepine receptor further emphasizes the interaction with the GABAergic system. In contrast to benzodiazepines that have an increased affinity due to GABA (Tallman et al., 1978, Nature 274: 383-385; Tallman et al., 1980, Science, 207: 274-281) compounds with antagonistic properties show little shift due to GABA (i.e., a change in receptor affinity due to GABA) (Mohler and Richards, 1981, Nature, 294: 763-765) and inverse agonists show a decrease in affinity due to GABA (Braestrup and Nielson 1981, Nature, 294: 472-474). Thus, the shift due to GABA can generally serve to predict the expected behavioral properties of these compounds.

Various compounds have been prepared as benzodiazepine agonists and antagonists. For example, U.S. Pat. No. 3,455,943, 4,435,403, 4,596,808, 4,623,649, and 4,719,210, DE patent no. No. 3,246,932 and Liebigs Ann. Chem. 1986, 1749 discloses various benzodiazepine agonists and antagonists and related antidepressant compounds and compounds having central nervous system activity.

U.S. Pat. No. 3,455,943 discloses compounds of the general formula

where

R 6 is hydrogen or lower alkoxy,

R2 is hydrogen or lower alkoxy,

R 6 is hydrogen or lower alkyl;

X represents a bivalent radical selected from the group consisting of formulas

and their non-toxic acid salts.

U.S. Pat.

435,403 discloses compounds of the general formula

where

is hydrogen, lower alkyl, alkoxyalkyl of up to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl of up to 8 carbon atoms or the remainder of the formula (CH _n ) OR n where R is alkyl of up to 6 carbon atoms, cycloylcalsyl C 3-6 carbon atoms or aralkyl of up to 8 carbon atoms and n is an integer from 1 to 3;

Y is O, 2 hydrogen, or a group of the formula NOR4, wherein it is hydrogen, lower alkyl, aryl or aralkyl of up to 6 carbon atoms, or group 2 of the formula COR, _n or g or or

R is lower alkyl of up to 6 carbon atoms,

Y is CHCOOR ³ wherein

R is hydrogen or lower alkyl

5

Y represents a group of the formula NNR R, wherein

5

R and R, which are the same or different, each represent a hydrogen atom, a lower alkyl group, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, or

7 a group of the formula CONR R, wherein

7

And R, which may be the same or different, each represent a hydrogen atom or a lower alkyl group;

R ⁴ and r ⁵ , together with the connecting nitrogen atom, represent a 5- or 6-membered heterocyclic ring, which optionally also contains an oxygen atom or up to 3 nitrogen atoms and which is optionally substituted by a lower alkyl group;

is hydrogen, alkoxy of up to 10 carbon atoms, aralkoxy of up to 10 carbon atoms, each of which is optionally substituted by hydroxy or is alkyl of up to 6 carbon atoms, aryl of 6 to 10 carbon atoms, or aralkyl of 7 to 10 atoms each of which is optionally substituted with a group

10 of the formula COOR or CONR R, wherein g

R is alkyl of up to 6 carbon atoms and

910

R and R, which are the same or different, each represent a hydrogen atom or an alkyl group of up to 6 carbon atoms, or

10,910 represents a group of the formula NRR, where R and R are as defined above, or represents a group of the formula NR 1, CH 2 R 1, R 2, wherein

12

R and R are each hydrogen or both together form a double bond N = C,

R is C1 -C10 alkyl or NR @ ⁴ R @ ⁴ R @ ⁴ , wherein R @ ⁴ a, which are the same or different, are each hydrogen, hydroxy or alkyl of up to 6 carbon atoms or alkoxy of up to 6 carbon atoms the sky

13

R and R together introduce! an oxygen atom, in which case R 1 represents a hydrogen atom; the sky

2

Z is COOR, wherein R is as defined above;

or Y and Z, together with the connecting carbon atom represent! or a six-membered heterocyclic ring containing an oxygen atom, adjacent oxygen and nitrogen atoms, or up to 4 nitrogen atoms and optionally substituted with a lower alkyl, hydroxy or oxo group.

U.S. Pat. No. 4,596,808 disclose compounds of the general formula

where

R is hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, methyl, trifluoromethyl,

17 methylthio, a group NR R or NHCOR ^16, wherein

17

R and R, which are the same or different, are each hydrogen or alkyl, alkenyl or alkynyl, each containing up to 6 carbon atoms or aralkyl or cycloalkyl, each containing up to 10 carbon atoms, or

17

R and R together form a saturated or unsaturated three-membered heterocyclic ring.

U.S. Pat. No. 4,623,649 discloses compounds of the general formula wherein

represents an oxadiazole radical of formula

R is lower alkyl of up to 3 carbon atoms or g is an ester group of the formula -C -CR Rg, g

wherein R is hydrogen or lower alkyl of up to 3 carbon atoms,

R 4 is hydrogen, lower alkyl of up to 3 carbon atoms, or CH ₂ OR wherein

R is lower alkyl of up to 3 carbon atoms,

R is phenyl or a hydrocarbon radical containing from 2 to 10 carbon atoms, which is cyclic or acyclic, saturated or unsaturated, branched or unbranched and which is optionally substituted with oxo, formyl, hydroxy, O-alkyl of up to 3 carbon atoms or phenyl, in this cyclic hydrocarbon radical, the CH ₂ group is optionally replaced by an oxygen atom.

U.S. Pat. No. 4,719,210 disclose compounds of the general formula

wherein r 1 represents a hydrogen atom or a protecting group;

R is -CH = C (R) 2 or -C = CR, wherein R 1 is hydrogen or halogen,

R is hydrogen, lower alkyl or lower alkoxyalkyl,

R ^A represents inter alia. hydrogen, OR ⁷ , lower alkyl optionally substituted by aryl, lower alkoxy or NR 6 R 6, wherein:

6

R and R, which are the same or different, each represent a hydrogen atom, a lower alkyl group, or both together with the nitrogen atom represent a 5- to 6-membered ring optionally containing an additional heteroatom,

R ⁷ is lower alkyl, optionally substituted aryl or aralkyl, each of which may contain one or more A radicals R other than hydrogen.

These compounds differ from the compounds of this invention. The cited US patents disclose carbocyclic compounds containing a pyridine or piperidine core. However, unlike the compounds of the present invention, these known compounds do not contain a pyrimidine core.

German Patent DE 3 246 932 describes compounds of the general formula

H where

R is halogen, nitro, carboxy, 2-carboxy, R-O, R-S (O), n is 0 to 2, and R is -O; represents a hydrogen atom, an alkyl group, a cycloalkyl group, an aralkyl group, an aryl group, a carboxy group, an amino group, a R 2 group of the formula R-O or R -S (O) _n wherein:

R ^X

R ³

In Liebigs Ann. Chem. 1986, of the general formula

1749 to 1764 disclose a

is hydrogen, methyl, benzyloxy or methoxy and is ethoxycarbonyl.

Also, the above compounds differ from the compounds of this invention. They are neither tetrahydroindoles nor tetrahydropyridopyrrols and, moreover, they do not contain these known compounds. ring substituents that are present in the compounds of the invention.

J. Org. Chem. 45: 3827-3831 (1980) describes the synthesis of a compound of formula

NH ₂

However, no data is provided that relates to the pharmaceutical activity of this compound.

SUMMARY OF THE INVENTION

The present invention provides novel compounds of formula I which interact with the GABAα binding site, the benzodiazepine receptor.

The present invention also provides pharmaceutical compositions comprising compounds of Formula I. In addition, the present invention provides compounds useful as stimulants for the treatment of seizure, anxiety and sleep disorders, and for treating benzodiazepine overdoses. In the broadest aspect, the present invention provides compounds of formula I W

(I) and pharmaceutically acceptable non-toxic salts thereof, wherein the number is 0, 1 or 2;

and R2, which may be the same or different, each represents a hydrogen atom or a straight or branched lower alkyl group containing from 1 to 6 carbon atoms;

X is hydrogen or hydroxy;

W is phenyl, thienyl or pyridyl, each optionally mono- or disubstituted with halogen, hydroxy, straight or branched chain alkyl of 1 to 6 carbon atoms, amino, mono- or dialkylamino, each of which is lower alkyl; a straight or branched chain having from 1 to 6 carbon atoms or a lower alkoxy group having a straight or branched chain having from 1 to 6 carbon atoms;

Y represents a group of the formula N-R 6, wherein

R ^ is hydrogen, straight or branched lower alkyl of 1 to 6 carbon atoms, phenyl, pyridyl or phenylalkyl, wherein the alkyl group is lower alkyl of straight or branched chain of 1 to 6 carbon atoms;

an aminoalkyl group wherein the alkyl group is a straight or branched chain lower alkyl group having 1 to 6 carbon atoms, or a mono- or dialkylaminoalkyl group wherein each of the alkyl radicals is a lower alkyl group having a straight or branched chain having 1 to 6 carbon atoms;

1-indanyl, 4- (thio) chromanyl or

A 1- (1,2,3,4-tetrahydronaphthyl) group, each optionally monosubstituted by halogen, a straight or branched lower alkyl group having 1 to 6 carbon atoms or a lower alkoxy group having a straight or branched chain having 1 to 6 atoms alkyl; -COR 6 or -SO 2 R 6, wherein the straight or branched lower alkyl is C 1 -C 6, phenyl, phenylalkyl, in which the alkyl group is straight or branched and contains 1 to 6 carbon atoms, or phenylalkoxy wherein the alkoxy group is straight or branched and contains 1 to 6 carbon atoms; the sky

Y is C = O, CRgORg, CRgCORg, CRgCCgRg,

CRgOCORg and CRgRg, where

R @ 1 represents a hydrogen atom, a straight or branched lower alkyl group having 1 to 6 carbon atoms, a phenyl group, a pyridyl group or a phenylalkyl group in which the alkyl group is straight or branched and contains 1 to 6 carbon atoms and

R 8 is a hydrogen atom or a straight or branched lower alkyl group having 1 to 6 carbon atoms; the sky

Y is CR 8 CONR 8 R 8 or CR 8 (CH ₂ ) _n NR ₇ R ₈ , wherein n is 0, 1 or 2;

R 8 and R 6, which are the same or different, each represent a hydrogen atom, a straight or branched chain lower alkyl group having 1 to 6 carbon atoms and a hydrogen atom, a straight or branched chain alkyl group having 1 to 6 carbon atoms, a phenyl, pyridyl or phenylalkyl group in which the alkyl group is straight or branched and contains 1 to 6 carbon atoms; the sky

NR 1, R ₀ is morpholyl, piperidyl, pyrrolidyl or N-alkylpiperazyl; the sky

Y represents a group of the formula CRgNRgCC1R-LQ, wherein

R 8 represents a hydrogen atom or a straight or branched chain alkyl group having 1 to 6 carbon atoms, and

Rg and _Rq , which are the same or different, each represent a hydrogen atom, a straight or branched lower alkyl group having 1 to 6 carbon atoms, a phenyl group, a pyridyl group or a phenylalkyl group in which the alkyl group has a straight or branched chain and contains 1 to 6 a carbon atom; the sky

Y is -CR 8 C (OH) wherein

R @ 1 ^{and R} @ 12 'which are the same or different are in each case a lower alkyl group having a straight or branched chain containing from 1 to 6 carbon atoms, phenyl or phenylalkyl in which the alkyl group has a straight or branched chain and contains 1 to 6 carbon atoms;

R 8 is a hydrogen atom or a straight or branched chain lower alkyl group having 1 to 6 carbon atoms; the sky

Y represents a group of the general formula

where m is 0, 1 or 2,

R @ 1 represents a hydrogen atom, a straight or branched lower alkyl group having 1 to 6 carbon atoms, a phenyl group, a pyridyl group or a phenylalkyl group in which the alkyl group has a straight or branched chain and contains 1 to 6 carbon atoms;

Z is methylene, oxygen atom, a group NR ₄ or CHCONR ^^, wherein R ₁₄ is H, lower straight or branched chain of 1 to 6 carbon atoms, phenyl, pyridyl, or phenylalkyl in which the alkyl a straight or branched chain group containing from 1 to 6 carbon atoms; and

T represents a methylene group or an oxygen atom.

These compounds are highly selective agonists, antagonists or inverse agonists of the GABAa receptor in the brain or prodrugs thereof, and are useful in the diagnosis and treatment of anxiety, sleep disorders, seizure, benzodiazepine drug overdose and as a memory enhancer.

The present invention also relates to compounds of formula II

(II)

R1 and R2, which are the same or different, each represent a hydrogen atom or a straight or branched chain alkyl group having from 1 to 6 carbon atoms;

R 8 represents a hydrogen atom, a straight or branched chain lower alkyl group having 1 to 6 carbon atoms, a phenyl group, a pyridyl group or a phenylalkyl group in which the alkyl group has a straight or branched chain and contains 1 to 6 carbon atoms; and

W is phenyl, thienyl, or pyridyl, each optionally mono- or disubstituted with halogen, hydroxy, straight or branched lower alkyl of 1 to 6 carbon atoms, amino, mono- or di-alkylamino, wherein each alkyl is a primary or branched alkyl group; branched and contains 1 to 6 carbon atoms or a lower straight or branched chain alkoxy group containing 1 to 6 carbon atoms.

The present invention also provides compounds of formula III (III) wherein

in each case represents an atom in ^R1

R _2, which are identical or sulphide or a lower alkyl straight or branched having 1 to 6 carbon atoms;

W is phenyl, thienyl or pyridyl, each optionally mono- or disubstituted with halogen, hydroxy, straight or branched lower alkyl of 1 to 6 carbon atoms, amino, mono- or dialkylamino, in which each alkyl is primary or primary branched and contains 1 to 6 carbon atoms or a lower straight or branched chain alkoxy group containing 1 to 6 carbon atoms;

represents a hydrogen atom, a straight or branched chain lower alkyl group having 1 to 6 carbon atoms, a phenyl group, a pyridyl group or a phenylalkyl group wherein the alkyl group is a straight or branched lower alkyl group having 1 to 6 carbon atoms; an aminoalkyl group wherein the alkyl group is a straight or branched chain alkyl group having 1 to 6 carbon atoms, or a mono- or dialkylaminoalkyl group wherein each of the alkyl radicals is a lower alkyl group having a straight or branched chain having 1 to 6 carbon atoms;

1-indanyl, 4- (thio) chromanyl or 1- (1,2,3,4-tetrahydronaphthyl), each optionally monosubstituted by halogen, a lower alkyl group having a straight or branched chain of 1 to 6 carbon atoms or a lower alkoxy group a straight or branched chain containing from 1 to 6 carbon atoms; or a group of formula -COR 4 or -SC 4 R 6, wherein the straight or branched lower alkyl is C 1 -C 6, phenyl, phenylalkyl, in which the alkyl group is straight or branched and contains 1 to 6 carbon atoms, or a phenylalkoxy group in which the alkoxy group is straight or branched and contains 1 to 6 carbon atoms.

The present invention also relates to compounds of formula IV wherein

(IV)

W is phenyl, thienyl or pyridyl, each optionally mono- or disubstituted with halogen, hydroxy, straight or branched lower alkyl of 1 to 6 carbon atoms, amino, mono- or dialkylamino, in which each alkyl is primary or primary branched and contains 1 to 6 carbon atoms or a lower straight or branched chain alkoxy group containing 1 to 6 carbon atoms;

Z is methylene, oxygen atom, a group NR ₁₄ or CHCONR _14, wherein R ₁₄ is H, lower straight or branched chain group having from 1 to 6 carbon atoms, phenyl, pyridyl, or phenylalkyl in which the alkyl group is linear or a branched chain containing from 1 to 6 carbon atoms;

T is methylene or an oxygen atom; and

U is methylene or carbonyl.

The term "non-toxic pharmaceutically acceptable salts" refers to: acid salts such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, hydroiodic, acetic and the like. A wide range of non-toxic pharmaceutically acceptable acid addition salts are well known to those skilled in the art.

Representative compounds of the present invention that are within the scope of Formula I include the compounds of the following formulas and their pharmaceutically acceptable salts.

H

H

OMe

Compound 9

H

H Compound 12

I Compound 15 H

Η Compound 26

I Compound 32 H

However, the compounds of formula I are not limited to the specific compounds listed above.

The term "lower alkyl" as used herein refers to straight or branched chain alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl , isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl.

The term lower alkoxy as used herein means! straight or branched chain alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2- hexoxy, 3-hexoxy and 3-methylpentoxy.

The term halogen as used herein refers to fluorine, bromine, chlorine and iodine.

As used herein, N-alkylpiperazyl groups of the formulas are each R is lower alkyl with a natural chain as defined above.

or branched

The term 4- (thio) chromanyl group refers to a group of the formula

The pharmaceutical utility of the compounds of the invention can be illustrated by the following assay for GABAα-receptor activity.

Assays are performed as described by Thomas and Tallman (J. Bio. Chem. 156: 9838-9842, J. Neurosci. 3: 433-440, 1983). Rat cortical tissue is dissected and homogenized in 25 volumes (w / v) of 0.05M Tris HCl buffer (pH 7.4 at 4 ° C). The tissue homogenate is centrifuged cold (4 ° C) (20,000 g for 20 minutes). The supernatant was decanted and the pellet re-homogenized in the same volume of buffer. The mixture is centrifuged again at 20,000 g, the supernatant is decanted and the pellet is frozen at -20 ° C overnight. The pellet is then thawed and re-homogenized in 25 volumes (original weight / volume) of buffer. This procedure is performed twice in total. Finally, the pellet is resuspended in 50 volumes (w / v)

0.05M Tris HCl buffer, pH 7.4, 40 ° C).

. Incubation mixtures contain 100 µl of tissue homogenate, 100 µl

3'3 radioligand, 0.5 nM (H-RO 15-1788 (H-Flumazenil) with a specific activity of 80 Ci / mmol), drug or blocker and buffer to a total volume of 500 µL. Incubation is performed for 30 minutes at 4 ° C and then the mixture is rapidly filtered through a GFB filter to separate the free and bound ligand. The filter was washed twice with fresh 0.05M Tris HCl buffer (pH 7.4, 4 ° C) and counted in a liquid scintillation chamber. 1.0 µM diazepam was added to some tubes to detect non-specific binding. All assays are reproduced 3 times, the measured values are averaged and the percent inhibition of specific binding total is calculated. Specific binding total means the difference of total binding and non-specific binding. In some cases, the amount of unlabeled drug varies and total binding displacement curves are constructed. The data is converted to a form suitable for calculating ΙΟ ^ θ and Hill coefficient (nH).

The values determined for the compounds of this invention are shown in Table I.

Table I

Compound number

IC ₅₀ (/ UM)

0,100

0,110

1.00

0,100

0,039

0,018

0,009

0,050

0,025

0,050

0,400

0,013

Due to their ability to bind to GABAα receptors, the compounds of the present invention are particularly preferred compounds no. 7, 9, 10, 12 and 32, which are therefore preferred embodiments of the invention.

The compounds of formula (I) may be administered orally, topically, parenterally, by inhalation or spray, or rectally in unit dosage form containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. By parenteral administration is meant herein subcutaneous, intravenous, intramuscular or intrasternal injection or infusion. The present invention also provides pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier. One or more compounds of formula (I) may be included in one preparation in association with one or more non-toxic pharmaceutical carriers and / or diluents and / or adjuvants and optionally other active ingredients. Pharmaceutical compositions containing the compounds of Formula I may be in a form suitable for oral administration such as tablets, pills, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups and exillers.

Formulations for oral administration may be prepared by any of the known methods of making pharmaceutical compositions of this type. These formulations may contain one or more substances selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, in order to obtain pharmaceutically acceptable formulations which are easy to ingest. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are commonly used in the manufacture of tablets. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate and sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders, for example starch, gelatin or acacia;

and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay their disintegration and absorption in the gastrointestinal tract and to provide a prolonged duration of action. Glyceryl monostearate or glyceryl distearate are, for example, suitable for achieving such deferred activity.

Oral formulations may also be in the form of hard gelatin capsules which contain a mixture of the active ingredient with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules in which the active ingredient is mixed with water or oil. a medium such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active ingredients in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia; dispersing or wetting agents, such as naturally occurring phosphatides, for example lecithin, or fatty acid alkylene oxide condensation products, for example polyoxyethylene stearate, or long chain aliphatic alcohols, e.g. hexitol such as polyoxyethylene sorbitol monooleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydride such as polyoxyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be prepared by suspending the active ingredients in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin. The oily suspensions may contain thickeners such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those mentioned above and flavor enhancers (flavoring agents) may be added to these taste-enhancing oral preparations. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension comprise the active ingredient in admixture with a dispersing or wetting agent, suspending agent and at least one preservative. Suitable dispersing and wetting agents as well as suspending agents are mentioned above. Sweetening, flavoring and coloring agents may also be present as additional excipients.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil or a mineral oil, for example paraffin or a mixture thereof. Suitable emulsifiers include naturally occurring resins such as gum or tragacanth, naturally occurring phosphatides such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate and condensation products of these partial esters with these partial esters. ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be prepared using sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. These preparations may also contain irritants, preservatives, flavors and coloring agents.

The pharmaceutical preparations of the invention may also take the form of sterile injectable suspensions in water or oils. These suspensions may be prepared by known methods using suitable dispersing or wetting agents and suspending agents as hereinbefore described. The sterile injectable preparation may also be in the form of a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Suitable vehicles and solvents include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any non-irritating, fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.

The compounds of formula (I) may also be administered in the form of a suppository for rectal administration of the drug. The suppositories may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but which is liquid at the rectal temperature and which will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

The compounds of formula I may be administered parenterally in a sterile medium. The drug may be present in the form of a suspension or solution, depending on the type of vehicle and concentration used. Advantageously, various adjuvants, such as local anesthetics, preservatives and buffers, can also be dissolved in the vehicle.

The dosage level of the compounds of Formula I is in the order of from about 0.1 to about 140 mg / kg body weight per day (about 0.5 mg to 7 g per patient per day). This dose is useful in the treatment of the above conditions. The amount of active ingredient to be mixed with the carrier in the manufacture of unit dosage forms will depend on the patient being treated and the particular mode of administration chosen. Dosage unit forms usually contain from about 1 mg to about 500 mg of the active ingredient.

However, the specific dose level for each particular patient will depend on a number of factors including the efficacy of the compound, age, body weight, general health, sex and diet of the patient, time of administration, route of administration, elimination rate, combination of drugs administered. and severity of the disease being treated.

The preparation of the compounds of the present invention is illustrated in Scheme I. It will be apparent to those skilled in the art that in the preparation of the compounds of the present invention starting materials can be varied and additional production steps can be added as shown in the Examples below.

Scheme I

CO ₂ Me

CO ₂ Me

WC (NH ₂₎ = NH

HNO3. HOAc

POC1 ₃ . PhNEt _; <---------

wherein n is 0, 1 or 2;

and R ₂ , which may be the same or different, each represents a hydrogen atom or a straight or branched chain alkyl group having 1 to 6 carbon atoms;

X is hydrogen or hydroxy;

W is phenyl, thienyl or pyridyl, each optionally mono- or disubstituted with halogen, hydroxy, straight or branched chain alkyl of 1 to 6 carbon atoms, amino, mono- or dialkylamino, each of which is lower alkyl; a straight or branched chain containing from 1 to 6 carbon atoms or a lower alkoxy group having a straight or branched chain of carbon;

N-R ^, hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms, phenyl, pyridyl or phenylalkyl, wherein the alkyl group is straight or branched chain of 1 to 6 carbon atoms;

an aminoalkyl group wherein the alkyl group is a straight or branched chain lower alkyl group having 1 to 6 carbon atoms, or a mono- or dialkylaminoalkyl group wherein each of the alkyl radicals is a lower alkyl group having a straight or branched chain having 1 to 6 carbon atoms;

1-indanyl, 4- (thio) chromanyl or 1- (1,2,3,4-tetrahydronaphthyl), each optionally monosubstituted with halogen, a straight or branched lower alkyl group containing from 1 to 6 atoms

Y represents a group wherein

R @ 1 represents a carbon atom of up to 6 carbon atoms or a lower or straight or branched chain alkoxy group containing from 1 to 6 carbon atoms; -COR ^ or -SC ^R ^, wherein the straight or branched lower alkyl is C 1 -C 6, phenyl, phenylalkyl, wherein the alkyl group is straight or branched and contains 1 to 6 carbon atoms or phenylalkoxy wherein the alkoxy group is primary or branched and contains 1 to 6 carbon atoms; the sky

Y represents C = 0, ^ CRgOR, CRgCORg, CRgCC ^ R, CR, OCOR _{c c} R _c and R _r,

5 5 6 where

R ₅ represents a hydrogen atom, a straight or branched lower alkyl group having 1 to 6 carbon atoms, a phenyl group, a pyridyl group or a phenylalkyl group in which the alkyl group is straight or branched and contains 1 to 6 carbon atoms, and

R 8 is a hydrogen atom or a straight or branched lower alkyl group having 1 to 6 carbon atoms; the sky

Y represents a group of the formula CR 8 CONR 7 ^R 8 or CR 8 ^{(CH 2} 'n ^NR 7 ^R 8' wherein n is 0, 1 or 2 and

R 1 and R 2, which are the same or different, each represent a hydrogen atom, a straight or branched lower alkyl group having 1 to 6 carbon atoms, and

R @ 1 is hydrogen, straight or branched chain lower alkyl having 1 to 6 carbon atoms, phenyl, pyridyl or phenylalkyl in which the alkyl group is straight or branched and contains 1 to 6 carbon atoms; the sky

NR 1 -R q is morpholyl, piperidyl, pyrrolidinyl or N-alkylpiperazyl; the sky

Y represents a group of the formula CR 8 NR 8 C 8 R 8, wherein

R 8 represents a hydrogen atom or a straight or branched chain alkyl group having 1 to 6 carbon atoms, and

R _q and R _n , which are the same or different, are each hydrogen, a straight or branched lower alkyl group having 1 to 6 carbon atoms, a phenyl group, a pyridyl group or a phenylalkyl group in which the alkyl group is straight or branched. a is a chain of 1 to 6 carbon atoms; the sky

Y is -CR 8 C (OH) wherein ^R 11 ^{and R} 12 ', which are the same or different, are in each case a straight or branched lower alkyl group having 1 to 6 carbon atoms, a phenyl group or a phenylalkyl group in which the alkyl group has a direct or a branched chain containing from 1 to 6 carbon atoms; and

R 8 represents a hydrogen atom or a straight or branched lower alkyl group having 1 to 6 carbon atoms; the sky

Y represents a group of the general formula

where m is 0, 1 or 2,

R @ ₁₃ is hydrogen, straight or branched lower alkyl having 1 to 6 carbon atoms, phenyl, pyridyl or phenylalkyl in which the alkyl group has a straight or branched chain and contains 1 to 6 carbon atoms;

Z is methylene, oxygen atom, a group NR ₁₄ or CHCONR. ^, Wherein R ₄ represents a hydrogen atom, a lower alkyl straight or branched, having 1 to 6 carbon atoms, phenyl, pyridyl, or phenylalkyl in which the alkyl a straight or branched chain group containing from 1 to 6 carbon atoms; and

T represents a methylene group or an oxygen atom.

The invention is illustrated by the following examples. These examples are illustrative only and in no way limit the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

HO

OH

A mixture of benzamidine (7.42 g) and dimethyl malonate (8.09 g) in dry dimethylsulfoxide (7 mL) was allowed to stand at room temperature for 24 hours. The precipitated product was collected and washed with water and ether. 2-Phenyl-4,6-dihydroxypyrimidine is obtained as a white solid.

To a suspension of 2-phenyl-4,6-dihydroxypyrimidine (12 g) in 35 ml of acetic acid was added 12 ml of 90% nitric acid and the mixture was heated at 50 ° C for 45 minutes. The resulting reaction mixture is diluted with 150 ml of water and the resulting product is collected, washed with water and ethanol and dried in an oven. 2-Phenyl-5-nitro-4,6-dihydroxypyrimidine is obtained as a pink solid.

A mixture of 2-phenyl-5-nitro-4,6-dihydroxypyrimidine (10 g), diethylaniline (6 g) and phosphorus oxychloride (100 mL) was refluxed for 40 minutes. The reaction mixture was concentrated in vacuo and the residue was partitioned between 50% diethyl ether and 50% ethyl acetate and water. The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was filtered through silica gel, eluting with ether / dichloromethane. 2-Phenyl-5-nitro-4,6-dichloropyrimidine is obtained as a yellow solid.

A mixture of cyclohexanone (98 mg) and pyrrolidine (71 mg) and molecular sieve 4A (500 mg) in 1 ml benzene was allowed to stand at room temperature until the enamine formation was complete (approximately 16 hours). The resulting enamine solution was added dropwise to a solution of 2-phenyl-5-nitro-4,6-dichloropyrimidine (270 mg) and diisopropylethylamine (129 mg) in 5 liters of methylene chloride. After 30 minutes at room temperature, the reaction mixture was concentrated in vacuo and 3 ml of 3N hydrochloric acid and 3 ml of ethanol were added. The reaction mixture was concentrated again and the residue was flash chromatographed on silica gel using 20% ethyl acetate in hexane as eluent. 2- [4- (2-Phenyl-5-nitro-6-chloropyrimidinyl)] cyclohexan-1-one is obtained as a white solid.

Example 5

H (Compound 1)

A mixture of 2- / 4- (2-phenyl-5-nitro-6-chloropyrimidinyl) / cyclohexan-1-one (280 mg), triethylamine (300 mg) and 10% palladium on carbon catalyst (25 mg) in 10 ml of ethanol was hydrogenated under hydrogen at 10 psi at room temperature for 16 hours.

The mixture was filtered through celite and the solvent from the filtrate was evaporated in vacuo. The residue was flash chromatographed on silica gel using ethyl acetate / hexane (1: 1) as eluent. There was obtained 2-phenyl-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine, m.p. 197-198 ° C (compound 1) after trituration in a mixture of hexane and ether.

Example 6

The following compounds were prepared in a similar manner to Example 5:

a) 2-phenylcyclopent (g) -5H-pyrrolo [3,2-d] pyrimidine (Compound 2);

b) 2-phenylcyclohept (g) -pyrrolo [3,2-d] -5H-pyrimidine (compound 3), m.p. 201-203 ° C;

c) 2-phenyl-8-methoxy-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyridmidine (compound 4), m.p. 172-173 ° C;

d) 2-phenyl-8-benzyloxy-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 5), m.p. 153-155 ° C; .

e) 2-phenyl-8-n-propoxy-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 6), m.p. 185-188 ° C;

f) 2- (4-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 7), m.p. 180-182 ° C;

g) 2- (2-fluorophenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 8), m.p. 247-249 ° C;

h) 2- (4-methoxyphenyl) cyclopent (g) -5H-pyrrolo [3,2-d] pyrimidine (compound 9), mp 231-232 ° C;

i) 2- (2-thienyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 10), m.p. 235-237 ° C.

Example 7

To a mixture of 4-bromo-1-butene (1.0 g) and magnesium turnings (1.77 g) in dry tetrahydrofuran (10 mL) was added iodine crystal and the mixture was stirred at room temperature until the reaction was complete. To this was added 1,4-cyclohexanedione monoethylene ketal (780 mg) in tetrahydrofuran (1 mL) at 0 ° C. After 1 hour at 0 ° C and 1 hour at room temperature, the reaction mixture was diluted with ammonium chloride solution and the product was extracted with ether. The extract was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was flash chromatographed using 25% ethyl acetate in hexane as eluent. There was thus obtained 4- (3-butenyl) -4-hydroxycyclohexanone ethylene ketal as an oil.

Example

OH

A mixture of 4- (3-butenyl) -4-hydroxycyclohexanone ethylene ketal (1.8 g) in methanol (40 mL) was ozonated at -70 ° C until a blue color was obtained. The ozone was quenched with excess sodium borohydride at -60 ° C. The reaction mixture was concentrated in vacuo and the residue was partitioned between brine and ethyl acetate. The aqueous layer was extracted several more times with ethyl acetate, and the combined organic extracts were dried over magnesium sulfate and the solvent was removed by vacuum distillation. The residue was purified by flash chromatography using ethyl acetate as eluent. There was thus obtained 4- (3-hydroxypropyl) -4-hydroxycyclohexanone ethylene ketal as an oil.

A solution of cuprous chloride (30 mg) and palladium dichloride (5 mg) in dimethylformamide (7.5 ml) and water (3 ml) was bubbled through the air for 2 hours. To the mixture was added 4- (3-butenyl) -4-hydroxycyclohexanone ethylene ketal (300 mg) and the reaction was allowed to proceed for 36 hours. The reaction mixture was then diluted with water and the product was extracted with dichloromethane. The extract was dried over magnesium sulfate and the solvent was distilled off in vacuo. The residue was dissolved in ethanol and excess sodium borohydride was added. After 2 hours at room temperature, the reaction mixture was worked up as usual and the residue was flash chromatographed using ethyl acetate as eluent. There was thus obtained 4- (3-hydroxybutyl) -4-hydroxycyclohexanone ethylene ketal as an oil.

A mixture of 4- (3-hydroxypropyl) -4-hydroxycyclohexanone ethylene ketal (1.4 g) and diisopropylethylamine (3.37 mL) in methylene chloride (100 mL) was treated with trifluoroacetic anhydride (1.64 mL) at -78 ° C. . After 30 minutes, the reaction mixture was washed with water, the solvent layer was dried over magnesium sulphate and then the solvent was evaporated in vacuo. The residue was dissolved in 30 ml of tetrahydrofuran and 15 ml of 3% hydrochloric acid. After 5 hours at room temperature, the reaction mixture was diluted with water and the product was extracted with ether. The extract was dried over magnesium sulfate and the solvent was removed by vacuum distillation. 1-Oxaspiro (4,5) decan-8-one is obtained as an oil.

Example 11

A mixture of cyclohexane-1,4-dione monoethylene ketal (2.0 g), N-methylhydroxylamine hydrochloride (1.079 g), sodium bicarbonate (1.09 g) and ethanol (20 mL) was stirred at room temperature for 18 hours. The ethanol was evaporated in vacuo and the residue was taken up in 30 ml of toluene. The mixture was filtered, ethyl acetate (2.2 g) was added to the filtrate, and the mixture was heated at 100 ° C for 4 hours. The solvent was evaporated in vacuo and the resulting isoxazole derivative was purified by flash chromatography on silica gel using 50% ethyl acetate in hexane as eluent. This material was hydrogenated at 50 psi in 50 mL of acetic acid in the presence of 10% palladium on carbon catalyst (400 mg) for 16 hours at room temperature. The mixture was filtered and the solvent was removed from the filtrate. The residue was purified by filtration through silica gel, eluting with ethyl acetate. 3-Hydroxy-1-methyl-1-azaspiro [4,5] decane-2,8-dionethylene ketal was obtained as an oil.

Example 12

To a mixture of 3-hydroxy-1-methyl-1-azaspiro [4,5] decane-2,8-dionethylene ketal (1.0 g), triethylamine (1.73 mL) and dichloromethane (10 mL) was added methanesulfonyl chloride (950). mg) dissolved in methylene chloride (5 mL) dropwise at 0 ° C. After 30 minutes, the reaction mixture was washed with water, the organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue is filtered over silica gel, eluting with ethyl acetate. 3-Methanesulfonyloxy-1-methyl-1-azaspiro [4,5] decane-2,8-dionethylene ketal was obtained as an oil.

Example 13

A mixture of 3-methanesulfonyloxy-1-methyl-1-azaspiro [4,5] decane-2,8-dionethylene ketal (1.28 g), sodium iodide (1.8 g) and acetone (20 mL) is refluxed with stirring 90 minutes. The solvent was evaporated in vacuo and the residue was dissolved in methylene chloride. The solution was washed with water, dried (MgSO4) and freed from solvent by vacuum distillation. The residue was dissolved in toluene (20 mL) and tri-n-butyltin hydride (1.75 g) and azobisisobutyronitrile (20 mg) were added. The resulting mixture was heated at 110 ° C for 1 hour. After removal of the solvent, the resulting residue was chromatographed on silica gel using ethyl acetate as eluent. The resulting product was stirred in a mixture of water (5 mL), 3N hydrochloric acid (1.5 mL) and acetic acid (2 mL) for 16 h. The resulting product was extracted three times with methylene chloride, the extracts were washed with sodium bicarbonate solution, dried over magnesium sulfate and the solvent was evaporated in vacuo. 1-methyl-1-azaspiro [4,5] decane-2,8-dione is obtained as an oil.

Example 14

A mixture of 1-methyl-1-azaspiro [4,5] decane-2,8-dione (100 mg) and pyrrolidine (43 mg), along with a 4Ά molecular sieve (500 mg) in 1 ml of benzene, was allowed to stand at room temperature. until the enamine formation is complete (about 16 hours). The resulting enamine solution was added to a solution of 2-phenyl-5-nitro-4,6-dichloropyrimidine (162 mg) and diisopropylethylamine (78 mg) in 3 mL of dichloromethane. The reaction mixture was allowed to stand at room temperature for 3 hours and then 2 ml of 3N hydrochloric acid and 3 ml of water were added and stirring was continued for 20 minutes. The organic layer was separated, dried (MgSO4) and freed from solvent by vacuum distillation. The residue was flash chromatographed on silica gel using

Of ethyl acetate as eluent. There was thus obtained 1-methyl-7- [4- (2-phenyl-5-nitro-6-chloropyrimidinyl)] - 1-azaspiro [4,5] decane-2,8-dione * as a white solid.

(Compound 11)

A mixture of 1-methyl-7- [4- (2-phenyl-5-nitro-6-chloropyrimidinyl)] - 1-azaspiro [4,5-] decane-2,8-dione (92 mg), triethylamine (60 mg) ) and 10% palladium on carbon (15 mg) as a catalyst in 5 ml of isopropanol and 1 ml of ethyl acetate were hydrogenated under 1 atm of hydrogen at room temperature for 16 hours. The mixture was filtered through celite and the solvent was evaporated in vacuo. The residue was flash chromatographed on silica gel using 2.5% methanol in ethyl acetate as eluent. 1'-methyl-2-phenyl-5,6,7,9-tetrahydrospiro (indolo [3,2-d] pyrimidin-2 ', 8-pyrrolidin-5'-one) (compound 11), m.p. 310 to 315 ° C after trituration was mixed with hexane and ether.

Example 16

The following compounds were prepared essentially as described in Example 15:

a) 2'-phenyl-5 ', 6', 7 ', 9'-tetrahydrospiro ((1,3) dioxolane-2,8'-indolo (3,2-d) pyrimidine) (compound 12), m.p. Mp 192-193 ° C;

b) 2- phenyl-4,5,5 ', 6', 7 ', 9'-hexahydro (furan-2,8' (3H) -indole / 3 _t 2 d / pyrimidine) (compound 13) a mp 199-202 ° C;

c) 2 '- (4-methoxyphenyl) -5', 6 ', 7', 9'-tetrahydrospiro ([1,3] dioxolane-2,8'-indolo [3,2-d] pyrimidine) (compound 14) mp 197-199 ° C;

d) 2 '- (4-methoxyphenyl) -4,5,5', 6 ', 7', 9'-hexahydrospiro (furan-2,8 '(3H) -indolo [3,2-d] pyrimidine) ( compound 15), m.p. 93 DEG C .;

e) 2 '- (2-fluorophenyl) -4,5,5', 6 ', 7', 9'-hexahydrospiro (furan-2,8 '(3H) -indolo [3,2-d] pyrimidine) ( compound 16) mp 208-210 ° C;

f) 2 '- (N -fluorophenyl-D' (6 ') - (1' '- 4' - tetrahydrospiro [1/1] dioxolane-2,8'-indolo (3,2-d) pyrimidine) (compound 17) o mp 108-109 ° C;

(g) 5-methyl-2'-phenyl-4,5,5 ', 6', 7 ', 9'-hexahydrospiro (furan-2,8' (3H) -indolo [3,2-d] pyrimidine) ( compound 18);

h) 1-'-methyl-2- (2-fluorophenyl) -5,6,7-9-tetrahydrospiro (indolo- [3,2-d] pyrimidin-2', 8-pyrrolidin-5'-one) (compound) 19) melting point above 260 ° C;

i) 1'-methyl-2- (4-methoxyphenyl) -5,6,7-9-tetrahydrospiro (indolo- [3,2-d] pyrimidin-2 ', 8-pyrrolidin-5'-one) (compound) 20) mp 340-343 ° C;

j) 2 '- (2-fluorophenyl) -5', 6 ', 7', 9'-tetrahydrospiro ([1,3] dioxolane-2,8'-indolo [3,2-d] pyrimidine) (compound 21) mp 218-220 ° C;

k) 2 '- (3-fluorophenyl) -5', 6 ', 7', 9'-tetrahydrospiro (1,3-dioxolane-2,8'-indolo) 3,2-d) pyrimidine 22) mp 214-216 ° C;

l) 1'-methyl-2-thienyl-5,6,7,9-tetrahydrospiro (indolo [3,2-d] pyrimidine-2,8'-pyrrolidin-5'-one) (compound 23), m.p. 335 ° C (dec.);

m) 1'-benzyl-2-phenyl-5,6,7,9-tetrahydrospiro (indolo [3,2-d] pyrimidin-2 ', 8-pyrrolidin-5'-one) (compound 24), m.p.

Mp 296-298 ° C.

Example 17

A mixture of 1-benzoylpiperidin-4-one (244 mg) and pyrrolidine (85 mg) and molecular sieve 4A (500 mg) in 2 ml benzene was allowed to stand at room temperature until the enamine formation was complete (about 24 hours). The resulting enamine solution was added to a solution of 2-phenyl-5-nitro-4,6-dichloropyrimidine (325 mg) and triethylamine (200 mg) in 4 mL of chloroform. After 30 minutes at room temperature, 4 ml of 2N hydrochloric acid was added to the reaction mixture and stirring was continued for 20 minutes. The organic layer was separated and dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was flash chromatographed on silica gel using 30% ethyl acetate in hexane as eluent. There was obtained 1-benzoyl-3- [4- (2-phenyl-5-nitro-6-chloropyrimidinyl)] piperidin-4-one as a white solid.

Η (compound 25)

A mixture of 1-benzoyl-3- [4- (2-phenyl-5-nitro-6-chloropyrimidinyl)] piperidin-4-one (100 mg), triethylamine (100 mg) and 10% palladium on carbon (100 mg) as of the catalyst in 6 ml of ethanol is hydrogenated under 1 atm of hydrogen for 5 hours at room temperature. The mixture was filtered through celite and the solvent was evaporated in vacuo. The residue was flash chromatographed on silica gel using 30% ethyl acetate in hexane as eluent. 8-Benzoyl-2-phenyl-5,6,7,9-tetrahydro-5H-pyrido [4,3-b] pyrimidino [4,5-d] pyrrole (compound 25), m.p. 264 DEG-266 DEG, is obtained. C after trituration with ether.

Example 19

The following compounds were prepared essentially as described in Example 17:

(a) 2-phenyl-5,6,7,9-tetrahydro-5H-pyrano [4,3-b] pyrimidino] 4,5-d] pyrrole (Compound 26);

b) 8-ethoxycarbonyl-2- (4-methoxyphenyl) -5,6,7-9-tetrahydro-5H-pyrido [4,3-b] pyrimidino] 4,5-d] pyrrole (compound 27).

(compound 28)

A mixture of 2- / 4- (2- (4-methoxyphenyl) -5-nitro-6-chloropyrimidinyl) / cyclopentan-1-one (200 mg) and 10% palladium on carbon (100 mg) as a catalyst in 10 ml of ethanol was added. hydrogenation under 1 atm of hydrogen at room temperature for 2 hours. The mixture was filtered through celite and the solvent was evaporated in vacuo. The residue was flash chromatographed on silica gel using 20% ethyl acetate in hexane as eluent. There was thus obtained 4-chloro-2- (4-methoxyphenyl) cyclopent (g) -5H-pyrrolo [3,2-d] pyrimidine (compound 28) as a white solid.

Example 21

The following compound was prepared essentially as described in Example 20:

a) 8-ethoxycarbonyl-4-chloro-2- (4-methoxyphenyl) -5,6,7,9-tetrahydro-5H-pyrido [4,3-b] pyrimidino] 4,5-d] pyrrole (compound 29) ).

Sloučenina (compound 30)

2'-Phenyl-6 mixture of ¹ , 7 ', 8', 9 ^1- Tetrahydrospiro [(1,3) dioxolane-2,8 '(5H) indolo [3,2-d] pyrimidine] (200 mg), 3N sulfuric acid (1.5 mL) and methanol (1.5 mL) were kept at room temperature for 2 days. The reaction mixture was neutralized with 2N ammonium hydroxide and the product was extracted with methylene chloride. The extracts were dried (MgSO4) and the solvent removed by vacuum distillation. The residue was recrystallized from ether-hexane to give 2-phenyl-5,6,7,9-tetrahydro-8H-indolo [3,2-d] pyrimidin-8-one (compound 30), m.p. 247 ° C.

Example 23

(Compound 31)

A mixture of 2-phenyl-5,6,7,9-tetrahydro-8H-indolo [3,2-d] pyrimidin-8-one (200 mg) and dry tetrahydrofuran (5 ml) was mixed with lithium aluminum hydride (100 mg), which is added in one dose. After one hour at room temperature, the reaction was quenched with 1 N sodium hydroxide and filtered through celite. The solvent was distilled off from the filtrate and the residue was subjected to flash chromatography on silica gel eluting with% methanol in methylene chloride. There was thus obtained 8-hydroxy-2-phenyl-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 31), m.p. 211-212 ° C.

Example 24

The following compounds were prepared essentially as described in Example 15:

a) 8-Benzyl-2-phenyl-5,6,7,9-tetrahydro-5H-pyrido [4,3-b] pyrimidino [4,5-d] pyrrole monohydrochloride (Compound 32), m.p. 264-265 C;

b) 8-benzyl-2- (4-methoxyphenyl) -5,6,7,9-tetrahydro-5H-pyrido [4,3-b] pyrimidino] 4,5-d] pyrrole monohydrochloride (compound 33);

c) 8-benzyl-2- (2-fluorophenyl) -5,6,7,9-tetrahydro-5H-pyrido [4,3-b] pyrimidino] 4,5-d] pyrrole monohydrochloride (compound 34);

d) 8-methyl-2-phenyl-5,6,7,9-tetrahydro-5H-pyrido [4,3-b] pyrimidino] 4,5-d] pyrrole monohydrochloride (compound 35), m.p. 212-213 C;

e) 1'-methyl-2-phenyl-5,6,7,9-tetrahydrospiro (indolo [3,2-d] pyrimidine-2 ', 8-pyrrolidine) (compound 36), m.p. 187-190 ° C ;

f) 4-chloro-8-methyl-2-phenyl-5,6,7,9-tetrahydro-5H-pyrido [4,3-b] pyrimidino [4,5-d] pyrrole monohydrochloride (compound 37) at a temperature of mp 218-220 ° C.

Example 25

\ H

A mixture of 2-phenyl-5,6,7,9-tetrahydro-8H-indolo [3,2-d] pyrimidin-8-one (100 mg), trifluoroacetic acid (15 mg) and 1-phenyl-1,2- ethanediol (53 mg) in benzene (10 mL) was refluxed in a Dean-Stark apparatus for 10 hours. The solvent was removed in vacuo and the residue was subjected to flash chromatography. 2-Phenyl-2'-phenyl-6 ', 7', 8 ', 9'-tetrahydrospiro [(1,3) dioxolane-2,8' (5H) -indolo (3,2-d) pyrimidine] was obtained. (compound 38) as an amorphous solid.

Example 26

\

H (compound 39)

A mixture of 8-benzoyl-2-phenyl-5,6,7,9-tetrahydro-5H-pyrido [4,3-b] pyrimidino] 4,5-d] pyrrole (180 mg), 50% sodium hydroxide (1 mL) ) and ethanol (1 mL) was refluxed for 4 hours with stirring. The reaction mixture was neutralized with dilute hydrochloric acid and the product was extracted into chloroform. The extract was dried (MgSO4) and the solvent evaporated in vacuo. Hydrogen chloride in isopropyl alcohol was added to the residue to give 2-phenyl-5,6,7,9-tetrahydro-5H-pyrido [4,3-b] pyrimidino] 4,5-d] pyrrole monohydrochloride (compound 39) at a temperature of mp 284-287 ° C.

Example 27

H (compound 40)

A mixture of 2-phenyl-5,6,7,9-tetrahydro-5H-pyrido [4,3-b] pyrimidino] 4,5-d] pyrrole monohydrochloride (46 mg), potassium carbonate (100 mg), allyl bromide (18). U1) and dimethylformamide (3 ml) were heated at 100 ° C for 1 hour with stirring. The resulting reaction mixture was poured into water and the product was extracted with dichloromethane. After drying with magnesium sulfate, the solvent is distilled off from the extract.

Ethanolic hydrogen chloride / ether mixture was added to give 8-allyl-2-phenyl-5,6,7,9-tetrahydro-5H-pyrido [4,3-b] pyrimidino [4,5-d] pyrrole monohydrochloride (compound 40), m.p. 216-221 ° C.

Example 28

The following compounds were prepared essentially as described in Examples 1 to 5:

(a) 2- (3-methylphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 41), m.p. 118-121 ° C;

b) 2- (2-thienyl) -8-isopropoxycarbonyl-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 42), m.p. 176-180 ° C;

c) 2- (4-ethoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 43), m.p. 210-212 ° C;

d) 2- (4-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 44), m.p. 160-162 ° C;

e) 2- (4-methoxyphenyl) -7-methyl-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 45), m.p. 197-181 ° C;

f) 2- (4-methoxyphenyl) -8-methoxycarbonyl-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (Compound 46), m.p. 204-206 ° C;

g) 2- (2-fluoro-4-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 47), m.p. 215-217 ° C;

h) 2- (5-methyl-2-thienyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 48);

i) 2- (3-ethoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 49), m.p. 115-116 ° C;

j) 2- (3-methoxyphenyl) cyclopent (g) -5H-pyrrolo [3,2-d] pyrimidine (compound 50), m.p. 199 DEG-201 DEG C .;

k) 2- (3,4-methylenedioxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (Compound 51);

l) 2- (3-methoxyphenyl) cyclohept (g) -pyrrolo [3,2-d] -5H-pyrimidine (compound 52), m.p. 176-177 ° C;

m) 2- (3-hydroxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (Compound 53), m.p. 239-243 ° C;

n) 2- (3-ethylphenyl) -6,7,9,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (Compound 54), m.p. 140-141 ° C;

o) 2- (3,5-dimethoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (Compound 55), m.p. 289-290 ° C;

p) 2- (3-fluorophenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (Compound 56), m.p. 148-150 ° C;

q) 2- (2-fluoro-3-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (Compound 57), m.p. 214-216 ° C;

r) 2- (2-fluoro-5-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 58), m.p. 186-189 ° C;

s) 2- (4-bromo-3-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 59), m.p. 281-287 ° C;

t) 2- (3-chlorophenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 60), m.p. 87-90 ° C;

u) 2- (4-methoxyphenyl) -8-methyl-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (Compound 61), m.p. 215-217 ° C;

v) 2- (4-methoxyphenyl) -8-isopropoxycarbonyl-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 62), m.p. 159-161 ° C;

w) 2- (3-aminophenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 63), m.p. 256-258 ° C;

x) 2- (3-fluoro-4-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 64), m.p. 198-191 ° C;

y) 2- (4-fluoro-3-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 65), m.p. 167-169 ° C;

z) 2- (3-fluorophenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (Compound 66).

Example 29

The following compounds were prepared essentially as described in Examples 6 to 17:

a) 1'-benzyl-2- (4-methoxyphenyl) -5,6,7,9-tetrahydrospiro (indolo [3,2-d] pyrimidin-2 ', 8-pyrrolidine) (compound 67), m.p. 103 ° C;

b) 1'-benzyl-2-phenyl-5,6,7,9-tetrahydrospiro (indolo [3,2-d] pyrimidin-2 ', 8-pyrrolidine) (compound 68), m.p. 138-139 ° C ;

c) 2 '- (4-ethoxyphenyl) -5', 6 ', 7', 9'-tetrahydrospiro ([1,3] dioxolane-2 ', 8-indolo [3,2-d] pyrimidine) (compound 69) mp 210-212 ° C;

d) 2- (4-methoxyphenyl) -8-methylamino-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 70), m.p. 244-246 ° C;

e) 2- (4-methoxyphenyl) -8-dimethylamino-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 71), m.p. 157-160 ° C;

f) 1'-benzyl-2- (2-thienyl) -5,6,7,9-tetrahydrospiro (indolo / 3,2-d) pyrimidin-2 ', 8-pyrrolidin-5'-one (compound 72) mp 290-292 ° C;

g) 1'-benzyl-2- (2-thienyl) -5,6,7,9-tetrahydrospiro (indolo [3,2-d] pyrimidine-28-pyrrolidine) (compound 73), m.p.

227-230 ° C;

h) 2- (4-methoxyphenyl) -8- (N, N-dimethylcarboxamido) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 74), m.p. 242 ° C;

i) 2- (4-methoxyphenyl) -8- (N, N-dimethylaminomethyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (compound 75), m.p. 85 ° C;

j) 2- (4-methoxyphenyl) -8- (hydroxymethyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (Compound 76), m.p. 174-177 ° C;

k) 2- (4-methoxyphenyl) -8- (acetoxymethyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (Compound 77), m.p. 240-242 ° C.

In the above description, the invention is described in its particularly preferred specific embodiments. The present invention is not limited to these specific embodiments and is intended to include various modifications and modifications that one of ordinary skill in the art can make without departing from the spirit of the invention. Only the claims that follow are critical to the scope of the invention.

I r y r 77 '7c

Claims (91)

1-indanyl, 4- (thio) chromanyl or 1- (1,2,3,4-tetrahydronaphthyl), each optionally monosubstituted by halogen, a lower alkyl group having a straight or branched chain of 1 to 6 carbon atoms or a lower alkoxy group a straight or branched chain containing from 1 to 6 carbon atoms; or a group of the formula -COR 4 or -SC 4 R 6, wherein R 6 is a straight or branched chain lower alkyl group * containing 1 to 6 carbon atoms, phenyl, phenylalkyl, wherein the alkyl group is straight or branched and contains 1 to 6 carbon atoms or phenylalkoxy, wherein the alkoxy group is straight or branched and contains 1 to 6 carbon atoms. A 1- (1,2,3,4-tetrahydronaphthyl) group, each optionally monosubstituted by halogen, a straight or branched lower alkyl group having 1 to 6 carbon atoms or a straight or branched lower alkoxy group having 1 to 6 atoms alkyl; -COR 4 or -SC 4 R 6, wherein R 6 is a straight or branched lower alkyl group having 1 to 6 carbon atoms, phenyl, phenylalkyl, wherein the alkyl group is straight or branched and contains 1 to 6 carbon atoms or a phenylalkoxy group in which the alkoxy group is straight or branched and contains 1 to 6 carbon atoms; the sky Y represents C = 0, CRgORg, CRgCORg, CRgCC ^ R> CR OCOR _{c c c} R _c and R _c, 1-indanyl, 4- (thio) chromanyl or Cycloalkyl and azacycloalkylpyrrolopyrimidines of the general formula I in H (I) and pharmaceutically acceptable non-toxic salts thereof, wherein the number is 0, 1 or 2; in _R2t which are the same or different, each represents a hydrogen atom or a straight or branched lower alkyl group having from 1 to 6 carbon atoms; is hydrogen or hydroxy; is phenyl, thienyl or pyridyl, each optionally mono- or disubstituted with halogen, hydroxy, straight or branched chain alkyl of 1 to 6 carbon atoms, amino, mono- or dialkylamino, each of which is lower alkyl. or a branched chain containing 1 to 6 atoms. a straight or branched chain alkoxy group having 1 to 6 carbon atoms; represents a group of the formula N-R 6 wherein my or branched chain having 1 to 6 carbon atoms, phenyl, pyridyl or phenylalkyl, wherein the alkyl group is a straight or branched chain alkyl having 1 to 6 carbon atoms; An aminoalkyl group wherein the alkyl group is a straight or branched chain lower alkyl group having 1 to 6 carbon atoms, or a mono- or dialkylaminoalkyl group wherein each of the alkyl radicals is a lower alkyl group having a straight or branched chain having 1 to 6 carbon atoms; Compounds according to claim 1 of the general formula II (II) v wherein n is 0, 1 or 2; and R 2, which may be the same or different, each represents a hydrogen atom or a straight or branched chain alkyl group having 1 to 6 carbon atoms; a hydrogen atom, a straight or branched lower alkyl group having 1 to 6 carbon atoms, a fepyridyl group or a phenylalkyl group in which the straight or branched chain is carbon-containing; and phenyl, thienyl or pyridyl, each optionally mono- or disubstituted with halogen, hydroxy, straight or branched lower alkyl of 1 to 6 carbon atoms, amino, mono- or dialkylamino, in which each alkyl group is primary or branched; and contains 1 to 6 carbon atoms or a straight or branched chain alkoxy group having 1 to 6 carbon atoms. is a branched nyl group having an alkyl group of 1 to 6 W represents Compounds according to claim 1 of the general formula (III): wherein (III) is different, it is in each case essential or non-atom R 2 is a straight or branched chain alkyl group having from 1 to 6 carbon atoms; W is phenyl, thienyl or pyridyl, each optionally mono- or disubstituted with halogen, hydroxy, lower alkyl with a direct VI or a branched chain of 1 to 6 carbon atoms, an amino, mono- or dialkylamino group in which each alkyl group is straight or branched and contains 1 to 6 carbon atoms or a lower alkoxy group of a straight or branched chain containing 1 to 6 carbon atoms; represents a hydrogen atom, a straight or branched lower alkyl group having 1 to 6 carbon atoms, a phenyl group, a pyridyl group or a phenylalkyl group in which _t . alkyl represents a straight or branched lower alkyl group having 1 to 6 carbon atoms; J) an aminoalkyl group wherein the alkyl group is a straight or branched chain lower alkyl group having 1 to 6 carbon atoms, or a mono- or dialkylaminoalkyl group wherein each of the alkyl radicals is a lower alkyl group having a straight or branched chain having 1 to 6 carbon atoms; Compounds according to claim 1 of the general formula IV (IV) VII where W is phenyl, thienyl or pyridyl, each optionally mono- or disubstituted with halogen, hydroxy, straight or branched chain alkyl of 1 to 6 carbon atoms, amino, mono- or dialkylamino, wherein each alkyl group is primary or branched; branched and contains 1 to 6 carbon atoms or a lower straight or branched chain alkoxy group containing 1 to 6 carbon atoms; Z is methylene, oxygen, NR6 or CHCONR6 wherein H is lower, straight or branched lower alkyl having 1 to 6 carbon atoms, phenyl, pyridyl or phenylalkyl in which the alkyl is straight or branched a chain of 1 to 6 carbon atoms; T is methylene or an oxygen atom; and U is methylene or carbonyl. Compounds according to claim 1, wherein Y is -NR 1, X is hydrogen, n is 1 and R 1 and R ₂ are each hydrogen. 6. A compound according to claim 5, wherein R1 is optionally substituted benzyl. 6 5 5 6 where R 8 represents a hydrogen atom, a straight or branched lower alkyl group having 1 to 6 carbon atoms, a phenyl group, a pyridyl group or a phenylalkyl group in which the alkyl group is straight or branched and contains 1 to 6 carbon atoms, and R 8 is a hydrogen atom or a straight or branched lower alkyl group having 1 to 6 carbon atoms; the sky Y is CR 8 CONR 8 R 8 or CR 8 (CH ₂ ) _n NR ₇ R ₈ , wherein n is 0, 1 or 2; III R 8 and R 8, which are the same or different, each represent a hydrogen atom, a straight or branched lower alkyl group having 1 to 6 carbon atoms, and R 8 is a hydrogen atom, a straight or branched lower alkyl group having 1 to 6 carbon atoms, a phenyl group, a pyridyl group or a phenylalkyl group in which the alkyl group is straight or branched and contains 1 to 6 carbon atoms; the sky NR-yRg is morpholyl, piperidyl, pyrrolidyl or N-alkylpiperazyl; the sky Y represents a group of the formula CRgNRgCC1R-LQ, wherein R 8 represents a hydrogen atom or a straight or branched chain alkyl group having 1 to 6 carbon atoms, and R 8 and R ₁₀ , which are the same or different, each represent a hydrogen atom, a straight or branched lower alkyl group having 1 to 6 carbon atoms, a phenyl group, a pyridyl group or a phenylalkyl group in which the alkyl group has a straight or branched chain. a carbon atom; the sky Y is -CR 8 C (OH) wherein ^R 11 ^{and R} 12 ', which are the same or different, are each a straight or branched lower alkyl group having 1 to 6 carbon atoms, a phenyl group or a phenylalkyl group in which the alkyl group has a direct or a branched chain containing from 1 to 6 carbon atoms; and R 8 represents a hydrogen atom or a straight or branched chain lower alkyl group containing from 1 to 6 carbon atoms; the sky IV Y represents a group of formula wherein m is 0, 1 or 2, represents a hydrogen atom, a straight or branched chain lower alkyl group having from 1 to 6 atoms, carbon, phenyl, pyridyl or phenylalkyl in which the alkyl group has a straight or branched chain and contains 1 to 6 carbon atoms; Z is methylene, oxygen, NR6 or CHCONR4, wherein R6 is hydrogen, straight or branched lower alkyl having 1 to 6 carbon atoms, phenyl, pyridyl or phenylalkyl in which it has an alkyl group; a straight or branched chain group containing from 1 to 6 carbon atoms; and T represents a methylene group or an oxygen atom. 7 ', 9'-hexahydrospiro (furan-2,8' (3H) -indolo [3,2-d] pyrimidine). x Compounds according to claim 1, wherein Y represents a group of the formula -NCOR 4, X represents a hydrogen atom, n represents a number 1 and R 1 and R ₂ each represent a hydrogen atom. 8-methyl-2-phenyl-5,6,7,9-tetrahydro-5H-pyrido [4,3-b] pyrimidino [4,5-d] pyrrole. Compounds according to claim 7, wherein they represent a phenyl group. VIII Compounds according to claim 1, wherein Y represents a group of the formula -R 8 R 8, X represents a hydrogen atom, n represents a number 0 or 1 and R 1 and R ₂ each represent a hydrogen atom. Compounds according to claim 9, wherein R 8 represents a hydrogen atom and R 8 represents a branched lower alkyl group having 1 to 6 carbon atoms. Compounds according to claim 1, wherein Y represents a group of the formula -CHOCOR 8, X represents a hydrogen atom, n represents a number 0 or 1 and R 1 and R ₂ each represent a hydrogen atom. The compounds of claim 11, wherein R 8 is ethyl. Compounds according to claim 1, wherein Y is -C = O, X is hydrogen, n is 1 and R 1 and R ₂ are each hydrogen. Compounds according to claim 1, wherein Y represents a group of the formula -CH ₂ -, X represents a hydrogen atom, n represents a number 0 or 1 and R 1 and R ₂ each represent a hydrogen atom. • Compounds according to claim 1, wherein Y is 1,3-dioxolane, X is hydrogen, n is 1 and R. R ^{@ 1} and R @ ₂ are each hydrogen. 16. The compound of claim 1 which is 2-phenyl-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 2-phenylcyclopent (g) -5H-pyrrolo [3,2-d] pyrimidine. IX The compound of claim 1 which is 2-phenylcyclohept (g) -5H-pyrrolo [3,2-d] pyrimidine. The compound of claim 1 which is 2-phenyl-8-methoxy-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 2-phenyl-8-benzyloxy-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. 21. The compound of claim 1 which is 2-phenyl-8-n-propoxy-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 2- (4-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 2- (2-fluorophenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 2- (4-methoxyphenyl) cyclopent (g) -5H-pyrrolo [3,2-d] pyrimidine. 25. A compound according to claim 1 which is 2- (2-thienyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 1'-methyl-2-phenyl-5,6,7,9-tetrahydrospiro (indolo / 3,2-d) pyrimidin-2 ', 8-pyrrolidin-5'-one) . 27. The compound of claim 1 which is 2 '- phenyl 5', 6 ', 7 ^1, 9'-tetrahydrospiro (/ 1,3 / 2,8-dioxolan ¹ indolo / 3,2-d / pyrimidine) . A compound according to claim 1 which is 2'-phenyl-4,5,5 ', 6', - The compound of claim 1 which is 2 '- (4-methoxyphenyl) -5', 6 ', 7', 9 '- tetrahydrospiro (1,3-dioxolane-2,8'-indolo) 3,2- d / pyrimidine). The compound of claim 1 which is 2 '- (4-methoxyphenyl) -4,5,5', 6 ', 7', 9'-hexahydrospiro (furan-2,8 '(3H) -indolo / 3', 2-d (pyrimidine). A compound according to claim 1 which is 2 '- (2-fluorophenyl) -4,5,5', 6 ', 7', 9'-hexahydrospiro (furan-2,8 '(3H) -indolo / 3', 2-a / pyrimidine). The compound of claim 1 which is 2- (4-fluorophenyl) -5 ', 6', 7 ', 9'-tetrahydrospiro (1,3-dioxolane-2,8'-indolo) 3,2-d). pyrimidine). A compound according to claim 1 which is 5-methyl-2'-phenyl 4,5,5 ', 6', 7 ', 9'-hexahydrospiro (furan-2,8' (3H) -indolo / 3,2- d (pyrimidine). 34. The compound of claim 1 which is 1 ^1-methyl-2- (2- (fluorophenyl) -5,6,7,9-tetrahydrospiro (indolo [3,2-d] pyrimidin-2 ', 8-pyrrolidin-5'-one). 35. The compound of claim 1 which is 1'-methyl-2- (4-methoxyphenyl) -5,6,7,9-tetrahydrospiro (indolo [3,2-d] pyrimidin-2 ', 8-pyrrolidine-5]. '-one). 36. The compound of claim 1 which is 2 '- (2-fluoro-phenyl) -5', 6 ', 7', 9'-tetrahydrospiro (/ 1,3 / 2,8-dioxolan ¹ indolo / 3,2 d / pyrimidine). The compound of claim 1 which is 2 ^1- (3-fluorophenyl) -5 ', 6', 7 ', 9'-tetrahydrospiro ([1,3] dioxolane-2,8'-indolo) 3,2- d / pyrimidine). XI The compound of claim 1 which is 1'-methyl-2-thienyl-5,6,7,9-tetrahydrospiro (indolo [3,2-d] pyrimidin-2 ', 8-pyrrolidin-5'-one). The compound of claim 1 which is 1'-benzyl-2-phenyl-5,6,7,9-tetrahydrospiro (indolo [3,2-d] pyrimidin-2 ', 8-pyrrolidin-5'-one) . The compound of claim 1 which is 8-benzoyl-2-phenyl-5,6,7,9-tetrahydro-5H-pyrido [4,3-b] pyrimidino] 4,5-d] pyrrole. 41. The compound of claim 1 which is 2-phenyl-5,6,7,9-tetrahydro-5H-pyrano [4,3-b] pyrimidino [4,5-d] pyrrole. A compound according to claim 1 which is 8-ethoxycarbonyl-2- (4-methoxyphenyl) -5,6,7,9-tetrahydro-5H-pyrido [4,3-b] pyrimidino (4,5-d) pyrrole . The compound of claim 1 which is 4-chloro-2- (4-methoxyphenyl) cyclopent (g) -5H-pyrrolo [3,2-d] pyrimidine. The compound of claim 1 which is 8-ethoxycarbonyl-4-chloro-2- (4-methoxyphenyl) -5,6,7-9-tetrahydro-5H-pyrido [4,3-b] pyrimidino] 4,5 d / pyrrole. 45. The compound of claim 1 which is 2-phenyl-5,6,7-9-tetrahydro-8H-indolo [3,2-d] pyrimidin-8-one. 46. A compound according to claim 1 which is 8-hydroxy-2-phenyl-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 8-benzyl-2-phenyl-5,6,7,9-tetrahydro-5H-pyrido [4,3-b] pyrimidino] 4,5-d] pyrrole monohydrochloride. XII The compound of claim 1, which is 8-benzyl-2- (4-methoxyphenyl) -5,6,7,9-tetrahydro-5H-pyrido [4,3-b] pyrimidino (4,5-d) monohydrochloride pyrrole. The compound of claim 1 which is 8-benzyl-2- (2-fluorophenyl) -5,6,7,9-tetrahydro-5H-pyrido [4,3-b] pyrimidino (4,5-d) monohydrochloride pyrrole. λ The compound of claim 1 which is a monohydrochloride The compound of claim 1 which is 1'-methyl-2-phenyl-5,6,7,9-tetrahydrospiro (indolo [3,2-d] pyrimidine-2 ', 8-pyrrolidine). 52. The compound of claim 1 which is 4-chloro-8-methyl-2-phenyl-5,6,7,9-tetrahydro-5H-pyrido [4,3-b] pyrimidino [4,5-d] monohydrochloride. pyrrole. The compound of claim 1 which is 2-phenyl-2'-phenyl-6 ', 7', 8 ', 9'-tetrahydrospiro (1,3-dioxolane-2,8 ¹ (5H) -indolo) 3,2 d / pyrimidine). The compound of claim 1 which is 2-phenyl-5,6,7,9-tetrahydro-5H-pyrido [4,3-b] pyrimidino] 4,5-d] pyrrole monohydrochloride. The compound of claim 1, which is 8-allyl-2-phenyl-5,6,7,9-tetrahydro-5H-pyrido [4,3-b] pyrimidino (4,5-d) pyrrole monohydrochloride. XIII The compound of claim 1 which is 2- (3-methylphenyl) 6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. 57. A compound according to claim 1 which is 2- (2-thienyl) -8-isopropoxycarbonyl-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 2- (4-ethoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. < The compound of claim 1 which is 2- (3-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 2- (4-methoxyphenyl) -7-methyl-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 2- (4-methoxyphenyl) -8-methoxycarbonyl-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 2- (2-fluoro-4-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. 63. A compound according to claim 1 which is 2- (5-methyl-2-thienyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 2- (3-ethoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 2- (3-methoxyphenyl) cyclopent (g) -5H-pyrrolo [3,2-d] pyrimidine. XIV The compound of claim 1 which is 2- (3,4-methylenedioxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 2- (3-methoxyphenyl) cyclohept (g) pyrrolo [3,2-d] -5H-pyrimidine. The compound of claim 1 which is 2- (3-hydroxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. r 69. The compound according to claim 1 which is 2- (3-ethylphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 2- (3,5-dimethoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. 71. The compound of claim 1 which is 2- (3-fluorophenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. A compound according to claim 1 which is 2- (2-fluoro-3-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. 73. A compound according to claim 1 which is 2- (2-fluoro-5-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. 74. A compound according to claim 1 which is 2- (4-bromo-3-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 2- (3-chlorophenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. XV A compound according to claim 1 which is 2- (4-methoxyphenyl) -8-methyl-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 2- (4-methoxyphenyl) -8-isopropoxycarbonyl-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 2- (3-aminophenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. * f The compound of claim 1 which is 2- (3-fluoro-4-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 2- (4-fluoro-3-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 2- (3-fluorophenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 1'-benzyl-2- (4-methoxyphenyl) -5,6,7,9-tetrahydrospiro (indolo [3,2-d] pyrimidin-2 ', 8-pyrrolidine). ' The compound of claim 1 which is 1'-benzyl-2-phenyl-5,6,7,9-tetrahydrospiro (indolo [3,2-d] pyrimidine-2 ', 8-pyrrolidine). The compound of claim 1 which is 2 '- (4-ethoxyphenyl) -5', 6 ', 7', 9'-tetrahydrospiro (1,3-dioxolane-2,8'-indolo) 3,2- d / pyrimidine). A compound according to claim 1 which is 2- (4-methoxyphenyl) -8-methylamino-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. XVI 86. The compound of claim 1 which is 2- (4-methoxyphenyl) -8-dimethylamino-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 1'-benzyl-2- (2-thienyl) -5,6,7,9-tetrahydrospiro (indolo / 3,2-d) pyrimidin-2 ', 8-pyrrolidin-5' -one). 88. A compound according to claim 1 which is 1'-benzyl-2- (2-thienyl) -5,6,7,9-tetrahydrospiro (indolo [3,2-d] pyrimidin-2 ', 8-pyrrolidine]. ). T * ŕ 89. A compound according to claim 1 which is 2- (4-methoxyphenyl) -8- (N, N-dimethylcarboxamido) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. The compound of claim 1 which is 2- (4-methoxyphenyl) -8- (N, N-dimethylaminomethyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. 91. A compound according to claim 1 which is 2- (4-methoxyphenyl) -8- (hydroxymethyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine. _r 92. The compound of claim 1 which is 2- (4-methoxyphenyl) ^*,% 8- (acetyloxymethyl) -6,7,8,9-tetrahydro-5H-indolo / 3,2-d / pyrimidine.