BG60516B1 - Cycloalkyl and azacycloalkyl pyrrolpyridimines - Google Patents

Abstract

The cycloalkyl and azacycloalkyl pyrrolpyrimidines are strongly selective agonists, antagonists and inversion agonists of aminobutyric acid cerebral receptors. The medicaments produced from them are used in the diagnostics and treatment of low mood, sleepiness and other similar disorders in overdosing of drugs of the type of benzodiazepines and for improving the concentration. The compounds have the formula where n has the value of 0, 1 or 2 and R1, R2, X, Y & W have different meanings. The invention also relates to their pharmaceutically acceptable nontoxic salts.

Description

The invention also relates to the use of these compounds in the treatment of poor mood, drowsiness and similar discomfort, overdose with benzodiazepine drugs, and to enhance attention. The interaction of the pyrrolpyrimidines of the invention with the binding site of the BABA, benzodiazepine (BDZ) receptor is described. This interaction results in the pharmacological activity of the compounds described.

Gamma-aminobutyric acid (€ ABA) is considered to be one of the most important amino acid transport inhibitors in the mammalian brain

nicks. It has been over 30 years since her (1, 2) presence in the brain was first demonstrated. Great efforts have been made to demonstrate unequivocally the involvement of GABA in the etiology of seizures, sleep disturbances, cognitive ability and anxiety (3). For eAWA, widely distributed, though

Unevenly, throughout the mammalian brain, it is said to be the carrier of approximately 30% of the synapses in the brain. In most areas of the brain, eBAA binds to local inhibitory neurons and in only two areas does eBAA bind to longer outgrowths. eAVA mediates much of its action through a complex of proteins localized to both the cell body and nerve endings; these are called GABA receptors. The postsynaptic response of GABA is mediated by changes in chloride conductivity, which, although not always, generally leads to hyperpolarization of the cell. Recent studies have shown that the complex of proteins associated with the postsynaptic response of CABA is a major site of action for a number of structurally unrelated compounds capable of modifying the postsynaptic response of GABA. Depending on the mode of interaction, these compounds are capable of producing a wide range of actions (both analgesic, anxiolytic and anticonvulsant, and insomnia, seizures and anxiety).

me

1,4-Benzodiazepines continue to be among the most widely used drugs in the world. The main benzodiazepines on the market are chlordiazepoxide, diazepam, flurazepam and triazolam. These compounds are widely used as anxiolytics, sedatives, hypnotics, muscle relaxants and anticonvulsants. A number of these compounds are extremely potent drugs; their strength indicates a site of action with high affinity and specificity for individual receptors. Early electrophysiological studies have shown that the main action of benzodiazepines is to enhance BAVA-ergic inhibition. Benzodiazepines are capable of enhancing the presynaptic inhibition of the ventricular monosynaptic reflex, a bAVA-mediated phenomenon (4). All subsequent electrophysiological studies (5, 6) have generally confirmed this finding, and by the mid-1970s, there was widespread agreement among electrophysiologists on the possibility of benzodiazepines to enhance the action of SABA.

By discovering the benzodiazepine receptor and subsequently defining the nature of the interaction between GABA and benzodiazepines, it is clear that the behavioral interactions of benzodiazepines with different neurotransmitter systems are due to much of the increased ability of GABA itself to alter these systems. Each modified system, in turn, may be associated with the expression of a behavior.

The study of the mechanistic nature of these interactions depends on the demonstration of a high affinity benzodiazepine binding site (receptor). Such a receptor is found in the CNS of all vertebrae, phylogenetically newer than bone fishes (7, 8, 9). With tritium diazepam-treated and a wide variety of other compounds, it has been shown that these benzodiazepine binding sites meet many of the pharmacological receptor criteria; connecting to these sites in vitro is rapid, reversible, stereospecific and saturable. And importantly, very significant correlations have been demonstrated between the ability of benzodiazepines to displace diazepam from its binding site and the activity in a series of animal behavioral tests indicative of the potential capabilities of benzodiazepines (10, 8, 9). The average therapeutic doses of these

4 medicines in humans also correlate with receptor efficacy (5).

In 1978, it became clear that SABA and similar analogs could interact at the low affinity (1 μΜ) SABA binding site to enhance the binding of benzodiazepines to the clone-sensitive site (11). This enhancement is caused by an increase in the affinity of the benzodiazepine binding site as a result of the employment of the SAVA site.

The interpretation of the data was that both the CABA and benzodiazepine binding sites were allosterically linked to the membrane as part of a complex of proteins. For a number of SAVA analogues, a direct relationship could be made between their ability to amplify

i diazepam binding by 50% maximum and the ability to inhibit the binding of CABA to brain membranes by 50%. Increased benzodiazepine binding to CABA agonists is blocked by the CABA antagonist (+) bicuculline; the stereoisomer (-) bicuculin is much less active (11).

Shortly after the detection of high affinity binding sites for benzodiazepines, it was found that triazolpyridazine could interact with the benzodiazepine receptors in a number of brain regions in a manner consistent with heterogeneity or negative receptor cooperativity. In these studies, Hill coefficients were observed significantly smaller than unity in a number of brain regions, including the cortex, hippocampus, and striatum. In the cerebellum, triazolpyridazine interacts with benzodiazepine sites with a Hill 1 ratio (12, 13). In this way, it was envisaged

the presence of numerous benzodiazepine receptors in the cortex, hippocampus, striatum, but not in the cerebellum.

Based on these studies, extensive studies have been conducted to authorradiographically locate light-micro 5- receptors

the Skopje level. Although the heterogeneity of the receptor (14, 15, 16) was demonstrated from earlier studies, no simple correlation was drawn between the localization of receptor subtypes and site-related behavior. In addition, in cerebellum, where one receptor was predicted from binding studies, autoradiography revealed receptor heterogeneity (16).

The physical basis for differences in the specificity of the drug at the two apparent subtypes of benzodiazepine sites was demonstrated in (17). The presence of several molecular weight receptors for benzodiazepines by gel electrophoresis in the presence of sodium dodecyl sulfate has been reported. Receptors have been identified by covalently incorporating radioactive flunitrazepam, a benzodiazepine that can covalently label all types of receptors. The major labeled bands have molecular weights of 50,000 to 53,000, 55,000, and 57,000, with triazolpyridazines inhibiting the labeling of low molecular weight forms (53,000, 55,000, 57,000) (18).

At the same time, multiple receptors have been shown to represent isoreceptors or multiple allelic receptors (3). Although common to enzymes, no genetically distinct receptor forms have been described in principle. As we begin to study receptors using specific radioactive samples and electrophoretic methods, it is almost certain that some isoreceptors will emerge as important in studies of the etiology of human psychiatric disorders.

SABA receptor subunits were cloned from bovine and human cDNA banks (19; 20). A number of different cDNAs have been identified as subunit 6AVA receptor complexes by cloning and separation. They are categorized as cL, β,, 6, and represent a molecular basis for the heterogeneity of the 6ABA receptor and the distinguishing site

X

6 on pharmacology (21; 22). Gamma has been shown to allow drugs such as benzodiazepines to modify ΘΑΒΑ's response (23). The presence of a low Hill factor in binding ligands to the ΘΑΘΑ receptor indicates unique profiles of the specific pharmacological action of the subtype.

Drugs that interact at the ΘΑΒΑ receptor may have a range of pharmacological actions, depending on their ability to modify the activity of ΘΑΒΑ. For example.

beta-carbolines were isolated for the first time based on their ability to competitively inhibit diazepam binding

he was not connected to the place of connection (24)

The assay is fully indicative of the biological receptor activity of these compounds; agonists, partial agonists, inverse agonists, and antagonists may inhibit binding. When the beta-carboline structure was determined, it was possible to synthesize a number of analogs and test these compounds behaviourally. It immediately became clear that beta-carbolines could antagonize the action of diazepam behaviorally (25). In addition to this antagonism, beta-carbolines have their own activity opposite to that of benzodiazepines; they are already known as inverse agonists.

In addition, a number of other specific benzodiazepine receptor antagonists have been developed based on their ability to inhibit the binding of benzodiazepines. The best studied of these compounds is imidazodiazepine (26). This compound is a competitive inhibitor of high affinity benzodiazepines and beta-carboline binding, and is capable of blocking the pharmacological action of both classes of these compounds. By itself, it has little inherent pharmacological activity in animals and humans (26; 27).

The radiolabelled form of this compound (28) has been shown to be able to interact with the same number of sites as benzodiazepines and beta-carbolines, and that the interactions of these compounds are purely competitive. This compound is the preferred ligand for binding to the θΑΒΑ receptors because it lacks the specificity of the receptor subtype and measures each receptor state.

Studies of the interactions of a large number of compounds similar to the above have led to their categorization. Compounds with benzodiazepine-like activity are now called agonists. Compounds with an activity opposite to the benzodiazepine are called inverse agonists and compounds blocking both types of activity are antagonists. This categorization was developed to emphasize the fact that a wide variety of compounds are capable of presenting a wide variety of pharmacological effects; to indicate that the compounds may interact at the same receptor to produce adverse effects; and to be known to be * α-carbolines and antagonists with a characteristic anxiogenic effect are not synonymous. The biochemical test for the pharmacological and behavioral properties of compounds that interact with the benzodiazepine receptor emphasized even more the interaction with the bAVAergic system. In contrast to benzodiazepines, which show an increase in their affinity due to GABA (11, 5), compounds with antagonistic properties exhibit a slight change in GABA (ie, a change in receptor affinity due to CABA) (28) , and inverse agonists actually show a decrease in affinity due to SABA (29). Therefore, the CABA change is broadly indicative of the expected behavioral properties of the compounds. Various compounds such as benzodiazepine agonists and

8 antagonists. For example, from Al, A2, A3, A4, and A5, G1 and (30) we already know about selected benzodiazepine agonists and antagonists and related anti-depressants and central nervous system active compounds. In A1, compounds of the formula are disclosed:

wherein R 1 is a member of a group consisting of hydrogen and lower alkoxy; R2 is a member of a group consisting of hydrogen and lower alkoxy; R 1 is a member of a group consisting of hydrogen and lower alkyl; and X is a two-strand radical selected from the group consisting of

h lower alkyl lower alkyl

lower alkyl and their non-toxic acid addition salts.

From A2 we know about compounds of formula:

where

rC is hydrogen, lower alkyl, alkoxyalkyl of up to C atoms, cycloalkyl of up to 6 C atoms, aralkyl of 8 C atoms, or (ΌΗ2) η ^οκ2 θ where r20 is alkyl of up to 6 C atoms, cycloalkyl of 3 up to 6 C atoms or aralkyl having up to 8 C atoms and η is an integer from 1 to 3;

Y is oxygen, two hydrogen atoms or NOR ¹ , where R ¹ is hydrogen, lower alkyl, aryl or aralkyl having up to 6 C atoms,

COR ² , where R ² is lower alkyl of up to 6 C atoms, or Y is CHCOOR ³ , where R ³ is hydrogen or lower alkyl, or Y is NNR 4 rS, where R ⁴ and R ³ may be the same or different and each is hydrogen, lower alkyl, C 1-6 aryl, C 7-10 aralkyl, or CONR 16 R 8, where r 6 and R 7 are; may be the same or different and each is hydrogen or lower alkyl or R ⁴ and R ³ together with a N-linking bond form a 5- or 6-membered heterocyclic ring which optionally may also contain an O-atom or up to 3 N atoms and which optionally can be

where substituted by a lower alkyl group;

Z is hydrogen, or alkoxy or aralkoxy each of up to 1 ° C-atoms and each optionally substituted by hydroxy, or Z is alkyl of up to b carbon atoms, Cg _10 ^_ aryl or S7_10-aralkyl, any of which may optionally be substituted by COORS or CONR ⁹ R ¹ ® group wherein r ⁸ is alkyl of up to 6 C atoms, and R ⁹ and R ¹ ® may be the same or different and each is hydrogen or alkyl of up to 6 C atoms; or Z is NR ^ R ¹ ®, where R ⁹ and _R 10 are as defined above;

or Z is NR ^{1; L} CHR ¹² R ¹³ where R ¹¹ and R ¹² are each hydrogen or together form a N = C double bond where R ¹³ is C 1-10 alkyl or NR ¹⁴ R ¹⁵ ,

15 where R and R are the same or different and each is hydrogen, OH or alkyl or alkoxy each having up to 6 C atoms, or where R ¹² _and R ¹³ together are oxygen, in which case R ¹¹ is B or A4 compounds are disclosed with the formula:

where

R3 is an oxadiazolyl moiety of the formula

where r5 represents lower alkyl of up to 3 carbon atoms or an ester -co ₂ r ₆ with R 4 being hydrogen or lower alkyl of up to 3 carbon atoms, R ⁴ being hydrogen, lower alkyl of up to 3 carbon atoms, or CH ₂ OR 4 wherein R1 is lower alkyl of up to 3 carbon atoms, rA _{is a} phenyl or hydrocarbon moiety containing 2-10 carbon atoms which may be cyclic or acyclic, saturated or unsaturated, branched or unbranched, and which may be optionally substituted by oxo, formyl OH, O-alkyl having up to 3 carbon atoms or phenyl, and wherein in a cyclic hydrocarbon residue, CH ₂ -group mozh be substituted by oxygen.

Compounds of the formula are disclosed in A5:

Ri!

And where r1 is hydrogen or a protecting group,

R ² is -CH = CR ⁴ ₂ or -C = CR ⁴ ,

R ⁴ is hydrogen or halogen, r 3 θ is hydrogen, lower alkyl or lower alkoxyalkyl,

R ^a is, inter alia, hydrogen OR ?, lower alkyl, which is optionally substituted by aryl, lower alkoxy or NR ⁵ R ⁶ ,

R ⁵ and R 6 may be the same or different and in any case

Hydrogen, lower alkyl or, together with a nitrogen atom, a 5-6 membered ring which may contain another heteroatom.

R? is lower alkyl, optionally substituted aryl or aralkyl, and each compound may contain one or more radicals other than hydrogen.

These compounds are different from the compounds of the present invention. The above US patents present compounds with pyridine or piperidine rings, but which lack the pyrimidine ring present in the compounds of the present invention.

In G1, compounds of the formula are disclosed:

where

R = halo, NO 2 ' ^C 2 ^H ' modified CO ² H, R ² O, R ² S (O) _n ; η = 0-2; and r1 = H, alkyl, cycloalkyl, aralkyl, aryl, CO2H, amino R ² O,

C R ² S (O) _n .

From (30) we are aware of compounds of the formula:

Where R ^x is hydrogen, methyl, benzyloxy or methoxy, and R is carboxy.

j These compounds are different from the compounds of the present invention. These compounds are not tetrahydroindoles or tetrahydropyrs dopirols and also lack the various ring substituents of the compounds of the present invention.

In (31) the synthesis of a compound of the formula is disclosed:

but the pharmaceutical activity of the compound is not disclosed.

The present invention provides a new class of compounds of Formula I that interact with the CABA binding site, the benzodiazepine receptor.

The invention provides pharmaceutical compositions comprising compounds of Formula I. The invention also provides compounds useful for enhancing vitality in the treatment of seizures, anxiety psychosis, sleep disorders, and treatment of benzodiazepine overdoses.

Also, a broad embodiment of the invention is directed to compounds of Formula I:

I and their pharmaceutically acceptable non-toxic salts wherein η is 0, 1 or 2;

14R1 and R2 are the same or different and represent straight or branched hydrogen or lower alkyl of 1-6 carbon atoms;

X is hydrogen or hydroxy;

W is phenyl, thienyl, or pyridyl;

phenyl, thienyl, or pyridyl, each of which may be mono- or di-substituted with halogen, hydroxy, straight or branched chain 1-6 carbon atoms, amino, mono or dialkylamino, where each alkyl is lower alkyl with straight or branched chain with 1-

carbon atoms or lower alkoxy straight or branched chain 1-6 carbon atoms;

N-R3 where R3 is hydrogen, straight or branched lower alkyl of 1-6 carbon atoms, phenyl, pyridyl or phenylalkyl, wherein alkyl is straight or branched lower alkyl of 1-6 carbon atoms;

aminoalkyl, wherein alkyl is straight or branched lower alkyl of 1-6 carbon atoms, or mono or dialkyl aminoalkyl, where each alkyl is straight or branched lower alkyl of 1-6

carbon atom; 1-indanyl, 4- (thio) chromanyl, 1- (1,2,3,4-tetrahydronaphthyl); 1-indanyl, 4- (thio) chromanyl, 1- (1,2,3,4-tetrahydronaphthyl) * each

which is monosubstituted by halogen, straight or branched lower alkyl of 1-6 carbon atoms, or lower straight or branched lower alkoxy of 1-6 carbon atoms;

-COR4 or -SO2R4 wherein R4 is straight or branched lower alkyl of 1-6 carbon atoms, phenyl, phenylalkyl, where alkyl is straight or branched lower alkyl of 1-6 carbon atoms, or phenylalkoxy, where alkoxy is lower straight or branched alkoxy of 1-6 carbon atoms;

15C = O, CRgOR5rCRgCORg, CRgCC ^ Rs, CR5OCOR5 /, and CRgRg, where R5 is straight, branched or branched chain 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl, wherein alkyl is straight or branched alkyl with straight or branched alkyl. a chain of 1-6 carbon atoms, and

Rg is straight, branched or branched chain lower alkyl of 1-6 carbon atoms;

CRgCONRyRg or CRg (CH2) _n ^NR 7 ^R 8 ^where η is 0, 1 or 2, and

R8 and R7 are the same or different and represent straight, branched or branched hydrogen, 1-6 carbon atoms; and »Rg is hydrogen, straight or branched lower alkyl of 1-6 carbon atoms, phenyl, pyridyl or phenylalkyl, wherein alkyl is straight or branched lower alkyl of 1-6 carbon atoms; or

NRyRg is morpholyl, piperidyl, pyrrolidyl, or N-alkyl piperazyl;

CRgNRgCC ^ Rio, where

Rg is straight or branched chain straight or branched alkyl of 1-6 carbon atoms; and

Rg and Rjq are the same or different and represent hydrogen, lower alkyl, straight or branched chain 1-6 carbon atoms, phenyl,

pyridyl or phenylalkyl wherein the alkyl is a lower straight or branched chain alkyl of 1-6 carbon atoms;

-CRgC (OHJRj ^ Rj2γ where Ru and R ^ 2 ^{are the} same or different and represent a lower straight or branched lower alkyl group having 1-6 carbon atoms, phenyl, or phenylalkyl, where alkyl is a lower straight or branched chain alkyl of 1- 6 carbon atoms, and Rg is hydrogen or lower alkyl, straight or branched chain 1-6 carbon atoms, or a group of the formula:

16 where m is 0, 1 or 2, ^R 13 ^is hydrogen, straight or branched lower alkyl with 1-6 carbon atoms, phenyl, pyridyl or phenylalkyl, where alkyl is straight or branched lower alkyl of 1-6 carbon atoms;

Z is methylene, oxygen, NR14 or CHCONR14, where R14 is hydrogen, straight or branched lower alkyl of 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl * where alkyl is straight or branched lower alkyl of 1-6 carbon atoms; and

T is methylene or oxygen.

These compounds are highly selective agonists, antagonists or inverse agonists for GABA brain receptors or their prodrugs in the treatment of anxiety psychosis, sleep disorders, seizures, overdose with benzodiazepine drugs, and memory enhancement.

Figures 1A-L show typical cycloalkyl and azacycloalkyl pyrrolpyrimidines of the present invention.

The new class of compounds included in the present invention can be described by the following general formula I:

and their pharmaceutically acceptable non-toxic salts x / where:

η is 0, 1 or 2;

R 1 and R 2 are the same or different and represent straight or branched hydrogen or lower alkyl having 1-6 carbon atoms;

X is hydrogen or hydroxy;

W is phenyl, thienyl, or pyridyl;

phenyl, thienyl or pyridyl, each of which may be mono-or

halogen, hydroxy, lower alkyl, straight or branched chain 1-6 carbon atoms, amino, mono- or dialkylamino * where each alkyl is lower straight or branched chain 1-6 carbon atoms, or lower alkoxy straight or a branched chain of 16 carbon atoms;

B; e

N-3 * where R3 is hydrogen, straight or branched lower alkyl of 1-6 carbon atoms, phenyl, pyridyl or phenylalkyl * where alkyl is straight or branched lower alkyl of 1-6 carbon atoms;

aminoalkyl * wherein alkyl is straight or branched lower alkyl of 1-6 carbon atoms, or mono or dialkyl aminoalkyl * where each alkyl is straight or branched lower alkyl of 1-6 carbon atoms;

1-indanyl, 4- (thio) chromanyl, 1- (1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4- (thio) chromanyl, 1- (1,2,3,4-tetrahydronaphthyl) each of which is monosubstituted with halogen, lower alkyl having a straight or branched chain of 1-6 carbon atoms, or lower alkoxy with straight or a branched chain of 1-6 carbon atoms;

-COR4 or-SO2R4, wherein R4 is a straight or branched lower alkyl group having 1-6 carbon atoms, phenyl, phenylalkyl * where alkyl is

lower straight or branched chain alkyl having 1-6 carbon atoms or phenylalkoxy ₇ where alkoxy is lower straight or branched chain alkoxy chain having 1-6 carbon atoms;

C = O, CRgORg / CRgCORg, CRgCO2R5, CRgOCORg, and CRgRg, where R5 is straight, branched, or branched chain 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl, where straight or branched alkyl is straight or branched alkyl. a chain of 1-6 carbon atoms; and

Rg is straight or branched chain straight or branched alkyl of 1-6 carbon atoms;

CRgCONR7Rg or CRg (CH2) _n NR? R8 * where η is 0, 1 or 2, and

Rg and R7 are the same or different and represent hydrogen or lower alkyl having a straight or branched chain of 1-6 carbon atoms; and

R 8 is hydrogen, straight or branched lower alkyl of 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl wherein alkyl is straight or branched lower alkyl of 1-6 carbon atoms; or NR 7 R 8 is morpholyl, piperidyl, pyrrolidyl, or N-alkyl piperazyl; CRgNRgCC ^ R10, where

Rg is straight or branched chain straight or branched alkyl of 1-6 carbon atoms; and

Rg and Riq are the same or different and represent hydrogen, straight or branched lower alkyl with 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl where alkyl is straight or branched lower alkyl with 1-6 carbon atoms;

-CRgC (OH) RuR12 ^ where Rn and Rj2 are the same or different and represent a straight or branched lower alkyl of 1-6 carbon atoms, phenyl, or phenylalkyl, where the alkyl is a straight or branched lower alkyl of 1- 6 carbon atoms /: and Rg is hydrogen or lower alkyl, straight or branched chain having 1-6 carbon atoms; or a group of the formula:

wherein me is 0, 1, or 2 ^R 13 θ hydrogen, straight or branched lower alkyl of 1-6 carbon atoms, phenyl, pyridyl, or phenylakyl, where alkyl is straight or branched lower alkyl of 1-6 carbon atoms ;

Z is methylene, oxygen, NRj4 or CHCONRj4, where Rj4 is hydrogen, straight or branched chain lower alkyl of 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl, where alkyl is straight or branched lower alkyl of 1-6 carbon atoms; and

T is methylene or oxygen.

The present invention also includes compounds of general formula II:

where:

η is 0, 1 or 2;

Rj and R2 are the same or different and represent straight or branched chain straight or branched lower chain alkyl or lower alkyl of ^r5 is /

Hydrogen, straight or branched lower alkyl of 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl wherein alkyl is straight or branched lower alkyl of 1-6 carbon atoms; and

W is phenyl, thienyl, or pyridyl; or phenyl, thienyl, or pyridyl, each of which may be mono- or di-substituted with halogen, hydroxy, lower alkyl, straight or branched chain 1-6 carbon atoms, amino, mono- or dialkylamino _in which each alkyl is lower alkyl straight or branched chain 1-6 carbon atoms or lower alkoxy straight or branched chain 16 carbon atoms.

The present invention also includes compounds of general formula III:

.7 where

R 1 and R 2 are the same or different and represent hydrogen or lower alkyl having a straight or branched chain of 1-6 carbon atoms;

W is phenyl, thienyl, or pyridyl; or phenyl, thienyl, or pyridyl, each of which may be mono or di-substituted with halogen, hydroxy, lower alkyl, straight or branched chain 1-6 carbon atoms, amino, mono- or dialkylamino, wherein each alkyl is lower alkyl with straight or branched chain 1-6 carbon atoms or lower alkoxy straight or branched chain 121b carbon atoms;

R ₃ is hydrogen, straight or branched lower alkyl of 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl, where alkyl is straight or branched lower alkyl of 1-6 carbon atoms;

aminoalkyl, wherein alkyl is straight or branched lower alkyl of 1-6 carbon atoms, or mono or dialkyl aminoalkyl, wherein each alkyl is straight or branched lower alkyl of 1-6 carbon atoms;

1-indanyl, 4- (thio) chromanyl, 1- (1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4- (thio) chromanyl, 1- (1,2,3,4-tetrahydro-naphthyl), each of which is monosubstituted with halogen, lower alkyl of straight or branched chain 1-6 carbon atoms, or lower straight or branched alkoxy of 1-6 carbon atoms; or

-COR4 or -SO2R4, wherein R4 is lower straight or branched lower chain 1-6 carbon atoms, phenyl, phenylalkyl wherein lower alkyl is straight or branched chain 1-6 carbon atoms, or phenylalkoxy * where alkoxy is lower straight- or branched-chain alkoxy having 1-6 carbon atoms.

The present invention also includes compounds of general formula IV:

where

W is phenyl, thienyl, or pyridyl;

phenyl, thienyl, or pyridyl, each of which may be mono- or two

22 substituted with halogen, hydroxy, straight or branched chain 1-6 carbon atoms, amino, mono- or dialkylamino, where each alkyl is lower straight or branched chain 1-6 carbon, or lower straight alkoxy or a branched chain of 16 carbon atoms;

Z is methylene, oxygen, NR14 or CHCONR14, where R14 is hydrogen, straight or branched lower alkyl, 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl) wherein alkyl is straight or branched lower alkyl of 1-6 carbon atoms;

T is methylene or oxygen; and

U is methylene or carbonyl.

Non-toxic pharmaceutical salts include acid salts such as hydrochloric acid, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluene sulfonic, hydrochloric, acetic, and the like. similar. Those skilled in the art will discover a wide variety of non-toxic pharmaceutically acceptable addition salts.

Typical compounds of the present invention that are included in Formula I include, but are not limited to, the compounds of Figure I and their pharmaceutically acceptable salts.

By lower alkyl in the present invention is meant a straight or branched chain alkyl group of 1-6 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.

By lower alkoxy in the present invention is meant a straight or branched chain alkoxy group of 1-6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tertiary-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy.

23hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

Under the halogen of the present invention and iodine.

The term N-alkylpiperazyl in the invention is intended to mean fluorine, bromine, chlorine, radicals of the formula:

N N - R wherein R is a straight or branched lower alkyl as defined above. By 4- (thio) chromanyl is meant a radical of the form-

lats:

The pharmaceutical utility of the compounds is indicated by the following assays for the zeptor.

The assays were performed as described in a section of rat cortical tissue that undergoes CABA re (32). Homogenized dib was made in 25 volumes (w / v) of 0.05

M Tris HCl buffer solution (pH 7.4 at 4 ° C).

The tissue homogenate was centrifuged in cold (4 ^ 0 at 20,000 x g for 20 '. The supernatant was decanted and the tablet was rehomogenized in the same volume of buffer solution and centrifuged again at

20,000 x e. The supernatant at -20 ° C was decanted overnight and the tablet frozen.

The tablet was then thawed and rehomogenized in 25 volumes (originally wt / vol) of buffer solution and the procedure was performed twice. The tablet was resuspended in 50 volumes (w / vol of 0.05 M Tris HCl buffer solution (pH 7.4 at 40 ° C)

24 Incubates contain 100 μΐ tissue homogenate, 100 μΐ radioligand

0.5 nM (3h-RO15-1788 [^ H-Flumazenil) specific activity 80 (Ci / mmol), drug or blocker and buffer solution to a total volume of 500 μΐ. The incubations are carried out for 30 min at 4 ° C and then quickly filtered through CPB filters to separate free and bound ligands The filters were washed twice with fresh 0.05 M Tris HCl buffer solution (pH 7.4 at 4 ° C) and counted in a liquid scintillation counter. added 1.0 μΜ diazepam to determine nonspecific binding Data are collected in triplicate determinations, averaged, and% incl. dialing the total specific binding Total Specific Binding = 06what - Non-specific In some cases, the amount of unlabelled preparation is varied and curves of the total binding displacement are drawn.

The data is converted to IC5Q calculation and the coefficient of

Hill (Mon).

The details of the compounds of the invention are shown in Table

TABLE I

we Number! 1Schp (IM) 1 0.100 2 0.110 3 1.00 5 0.100 7 0.039 9 0.018 10 0.009 11 0.050 12 0.025 15 0.050 26 0.400 32 0.013

^ Compound Number refers to the compounds shown in Figure

Compounds 7, 9, 10, 12 and 13 are particularly preferred embodiments of the present invention because of their potential binding strength.

25 at the GABA receptor.

The compounds of general formula I may be administered orally, topically, parenterally, by inhalation or spraying or rectally in unit dosage formulations containing traditional non-toxic pharmaceutically acceptable carriers, grafts and carriers. The term parenteral, as used herein, includes subcutaneous injections, intravenous, intramuscular, sterile injection or infusion techniques. In addition, there is a pharmaceutical composition (formulation) comprising a compound of general formula I and a pharmaceutically acceptable carrier. One or more compounds of the general formula may be encountered

And together with one or more non-toxic pharmaceutically acceptable carriers and / or solvents and / or grafts and, if desired, other active ingredients.

Pharmaceutical compositions containing compounds of general formula may be in a form suitable for oral use, such as tablets, small tablets, lozenges, aqueous or oily suspensions, soluble powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. .

Compositions for oral use may be prepared according to any method known in the art of manufacturing pharmaceutical compositions, and these compositions may contain one or more agents selected from the group consisting of sweeteners, flavors, colorants and preservatives so as to obtain a pharmaceutically sophisticated and pleasing preparation. The tablets contain the active ingredient in admixture with a non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets. Such excipients may be, for example, inert solvents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginate

26acid; binding agents such as starch, gelatin or gum arabic, and lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated according to known techniques for delaying digestion and absorption in the gastrointestinal tract and, therefore, for sustained action for a longer period. For example, glyceryl monostearate or glyceryl distearate may be used, which are time-delaying products.

The formulations for oral use may also be in the form of hard gelatin capsules, where the active ingredient is mixed with an inert solid solvent, such as calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatin capsules, where the active ingredient is mixed with water or with oily media such as peanut oil, liquid paraffin or olive oil.

The aqueous suspensions contain the active materials in admixture with excipients suitable for the production of excipients are suspending agents carboxymethylcellulose, methylcellulose, sodium alginate, polyvinylpyrrolidone.

of aqueous suspensions. Such as sodium hydropropylmethylcellulose a, tragacanth and gum arabic;

dispersing and wetting agents may be naturally occurring phosphatides such as lecithin or condensation products of alkylene oxide fatty acids, such as natrimer polyoxyethylene stearate, or condensation products of ethylene oxide with aliphatic alcohols, such as long chain acetate, such as hexacetate, e.g. ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters enes fatty acid hexitol anhydrides such as

polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl or η-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, one or more sweeteners, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in vegetable oil, such as peanut, olive, sesame or coconut oil, or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickener such as beeswax, hard paraffin or cetyl alcohol. Sweeteners, such as those listed above, may also be added to flavors in order to produce taste-like oral preparations. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.

Soluble powders and granules suitable for the preparation of an aqueous suspension by the addition of water offer the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrated by those already mentioned above. Additional excipients, such as sweeteners, flavorings and colorants, may also be involved.

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, such as olive or peanut oil, or a mineral oil, such as liquid paraffin or a mixture thereof. Suitable emulsifying agents may be naturally occurring gums, such as gum arabic or tragacanth, naturally occurring phosphatides, such as soy, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, such as sorbitan monoleate condensing

The products of these partial esters of ethylene oxide, such as polyoxyethylene sorbitan monoleate. Emulsions may also contain sweeteners and flavors.

Syrups and elixirs can be formulated with sweeteners, such as glycerol, propylene glycol, sorption or sucrose. The above formulations may also contain a sedative, preservative and flavoring and colorant. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagin suspension. This suspension can be formulated according to the prior art using a suitable dispersing or wetting agent and suspending agents that have already been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable solvent or diluent, such as a solution in

1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils have traditionally been used as a diluent or suspending medium. For this purpose, any weakly bound oil, including synthetic mono- or diglycerides, may be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The compounds of general formula I may also be administered in the form of a suppository for rectal administration of the drug. These compositions may be prepared by mixing the preparation with a suitable non-irritant excipient that is solid at normal temperature but liquid at rectal temperature and will therefore melt in the rectum, separating the preparation. Such materials are coconut oil and polyethylene glycols.

The compounds of general formula I may be administered parenterally in a sterile medium. The preparation, depending on the vehicle and the concentration used, can either be suspended or dissolved in the vehicle. Adhesives such as topical anesthetics, preservatives and buffering agents dissolved in the carrier may be advantageously used.

In treating the above conditions (approx

0.5 mg to about a cent / day) dosage amounts in the range of about 0.1 mg to about

140 mg per kilogram body weight per day

The amount of active component that

can be combined with the carrier material, to obtain a single dosage form will vary depending on the treated host and the particular route of administration of the preparation. The unit dosage forms generally contain between about 1 mg to about 500 mg of the active ingredient.

However, it should be known that the specific amount of dose for each individual patient will depend on many factors, including the activity of the particular compound used, age, body weight, overall health, gender, diet, time of administration, route of administration, and rate of release, drug combination, and severity of the particular disease to be treated

An illustration for the preparation of the compounds of the present invention is presented in Scheme I. Those skilled in the art will find that the starting materials can be varied and additional steps may be used in the preparation of the compounds included in the present invention, as shown by the following exemplary embodiments

COGMe <

COjMe f

Scheme I

WC (NH ₂ ) = NH.

HNO3, HO Ac

where:

n is 0, 1 or 2;

R1 and R2 are the same or different and represent straight or branched hydrogen or lower alkyl of 1-6 carbon atoms

31ί

X is hydrogen or hydroxy;

W is t

j is phenyl, thienyl or pyridyl;

phenyl, thienyl, or pyridyl, each of which may be mono- or di-substituted with halogen, hydroxy, lower alkyl, straight or branched chain 1-6 carbon atoms, amino, mono- or dialkylamino, where each alkyl is lower alkyl with straight or branched chain 1-6 carbon atoms or lower alkoxy straight or branched chain 1-6 carbon atoms;

With y e

N-R3 * where R3 is hydrogen, straight or branched lower alkyl of 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl * where alkyl is straight or branched lower alkyl of 1-6 carbon atoms;

aminoalkyl where alkyl is a straight or branched lower alkyl group having 1-6 carbon atoms, or mono- or dialkyl aminoalkyl, where

each alkyl is a straight or branched lower alkyl group having 1-6 carbon atoms;

1-indanyl, 4- (thio) chromanyl, 1- (1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4- (thio) chromanyl, 1- (1,2,3,4-tetrahydronaphthyl), each of which is monosubstituted with halogen, lower straight or branched chain alkyl of 1-6 carbon atoms, or lower alkoxy having a straight or branched chain of 1-6 carbon atoms;

-COR4 or -SO2R4, where ^{k is} 4 n ^issh alkyl straight or branched having 1-6 carbon atoms, phenyl, phenylalkyl _f wherein alkyl is lower alkyl straight or branched having 1-6 carbon atoms or phenylalkoxy where alkoxy is a straight or branched lower alkoxy chain having 1-6 carbon atoms;

C = O, CRgOR5, CRgCORj, CRgCC ^ Rsr CRgOCOR5, and CR ^ Rg, where

R 5 is hydrogen, straight or branched lower alkyl of 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl _y wherein alkyl is straight or branched lower alkyl of 1-6 carbon atoms; and

Rg is straight or branched chain straight or branched alkyl of 1-6 carbon atoms;

CRgCONRyRg or CRg (CH2) _n NR7 ^R8 , where η is 0.1 or 2, and

R ₆ and R _? are the same or different and represent straight or branched chain straight or branched lower alkyl or 1-6 carbon atoms; and

Rg is hydrogen, straight or branched chain lower alkyl of 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl _? wherein alkyl is straight or branched lower alkyl of 1-6 carbon atoms; or NR ^{7 R} g is morpholyl, piperidyl, pyrrolidyl, or N-alkyl piperazyl; CRgNRgCC ^ Rlo where

R 8 is hydrogen, straight or branched chain lower alkyl of 1-6 carbon atoms; and

Rg and Rj_θ are the same or different and represent hydrogen, straight or branched chain lower alkyl of 1-6 carbon atoms, phenyl,

I

I i

I pyridyl, or phenylalkyl where alkyl is a straight or branched lower alkyl group having 1-6 carbon atoms;

-CRgC (OH) Rii ^R ij2, where VC and Rj2 are the same or different and are lower alkyl straight or branched having 1-6 carbon atoms, phenyl, or phenylalkyl wherein alkyl ^ is lower alkyl of straight or branched chain with 1 -6 carbon atoms, and Rg is hydrogen, lower alkyl or straight or branched chain 1-6 carbon atoms; or a group of the formula:

wherein n is 0, 1 or 2;

R 13 ^is hydrogen, straight or branched lower alkyl of 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl wherein alkyl is straight or branched lower alkyl of 1-6 carbon atoms;

Z is methylene, oxygen, NR14 or CHCONR14 where R14 is hydrogen, straight or branched lower alkyl of 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl where alkyl is straight or branched lower alkyl of 1-6 carbon atoms ; and

T is methylene or oxygen.

The invention is further illustrated by the following exemplary embodiments, which should not be construed as limiting the invention in volume or spirit to the particular methods and compounds described in these embodiments.

EXAMPLE IMPLEMENTATION

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

34 EXAMPLE II

To a suspension of 2-Phenyl-4,6-dihydroxy-pyrimidine (12 g) in 35 mb acetic acid, 12 ngE of 90% nitric acid was added and the mixture was heated at 50 ° C for 45 min. The reaction mixture was diluted with 150 ml of water were collected, the product was washed, washed with water and ethanol and dried in an oven to give 2-Phenyl-5-nitro-4,6-dihydroxy-pyrimidine as a pink solid.

EXAMPLE IMPLEMENTATION III

A mixture of 2-Phenyl-5-nitro-4,6-dihydroxy-pyrimidine (10 g), diethylaniline (6 g) and phosphorus oxychloride (100 mg) was heated at reflux temperature for 40 minutes. The reaction mixture was concentrated. in vacuo and the residue was partitioned between 50% ether in ethyl acetate and water. The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was filtered through silica gel with ether / methylene chloride as eluent to give 2-Phenyl -5-nitro-4,6-dichloro-pyrimidine as a yellow solid.

35 EXAMPLE IMPLEMENTATION IV

A mixture of cyclohexanone (98 mg) and pyrrolidine (71 mg) and 4A molecular sieves (500 mg) in 1 mJ benzene was allowed to stand at room temperature until the formation of enamine (ca. 16 h) was complete. The resulting enamine solution is cannulated in a solution of 2-Phenyl-5-nitro-4,

6-dichloro-pyrimidine (270 mg) and diisopropylethyl-amine (129 mg) in 5µl methylene chloride. After 30 min at room temperature, the reaction mixture was concentrated in vacuo and treated with 3 mt 3N HCl and 3 mt ethanol. The reaction mixture was concentrated again and the residue was subjected to flash chromatography on silica gel with 20% ethyl acetate / hexane as eluent to give 2- [4- (2-Phenyl-5-nitro-6-chloropyrimidinyl)] - cyclohexane -1- as a white solid.

EXAMPLE IMPLEMENTATION

(Compound 1)

Mixture of 2- [4- (2-Phenyl-5-nitro-6-chloro-pyrimidinyl)] -cyclohexane-1 (280 mg), triethylamine (300 mg) and 10% Pd / C catalyst (25 mg) in 10 mi ethanol is hydrogenated in 1 atmosphere of hydrogen at room temperature

For 16 h. After filtration through celite, the solvent was removed in vacuo and the residue was flash chromatographed on silica gel with 50% ethyl acetate / hexane as eluent * to give 2-Phenyl-6,7. 8,9-tetrahydro-5H-indolo [3,2-0] -pyrimidine, melting at 197-198 ° C (Compound 1) after trituration with hexane / ether.

EXAMPLE IMPLEMENTATION VI

The following compounds were essentially prepared according to the procedure described in Example V:

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

2).

b) 2-Phenyl-cyclohept (e) -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] -pyrimidine (Compound 4), m.p. Mp 172-173 ° C

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

e) 2-Phenyl-8-n-propyloxy-6,7,8,9-tetrahydro-5H-indolo {3,2-d] pyrimidine (Compound 6), m.p. 185-188 ° C.

e) 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] pyri

37midine (Compound 8), m.p. Mp 247-249 ° C.

h) 2- (4-Methoxyphenyl) -cyclopent (n) -5H-pyrrolo [3,2-d] -pyrimidine (Compound 9), m.p. 231-232 ° C.

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

EXAMPLE VII

To a mixture of 4-bromo-1-butene (1.0

I

d) and magnesium chips (1.77 g) in dry tetrahydrofuran (10 mi) was added a iodine crystal and the mixtures were stirred at room temperature until

To this mixture was added 1,4-cyclohexanedione mg) in tetrahydrofuran (1 mL) at 0 ° C. After a complete reaction.

monoethylene ketal (780 h at 0 ° C and 1 h at room temperature the reaction mixture was diluted with ammonia solution.

sodium chloride and the product is extracted with ether. After drying over magnesium sulfate, the solvent was removed in vacuo and the residue was flash chromatographed with 25% ethyl acetate / hexane as eluent to give 4- (3-Butenyl) -4-hydroxy-cyclohexanone ethylene ketal as an oil.

EXAMPLE VIII

Mixture of 4- (3-Butenyl) -4-hydroxy-cyclohexanone ethylene ketal (1.8

d) ozone at -70 ° C in methanol (40 mL) _? until a steady blue color is obtained. The ozone is decomposed with excess sodium borohydride at -60 ° C. The reaction was concentrated in vacuo and the residue 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 in vacuo. The residue was purified by flash chromatography with ethyl acetate as eluent to give 4- (3-Hydroxypropyl) -4hydroxy-cyclohexanone ethylene ketal as an oil.

EXAMPLE IX

Air was bubbled into a solution of copper chloride (30 mg) and palladium dichloride (5 mg) in dimethylformamide (7.5 mb) and water (3 ml) for 2 h. 4- (3-Butenyl) -4- hydroxy-cyclohexanone ethylene ketal (300 mg) and the reaction continued for 36 h. The reaction mixture was diluted with water and the product extracted with methylene chloride. After drying over magnesium sulfate, the solvent was removed in vacuo. The residue was dissolved in ethanol and treated with excess sodium borohydride. After 2 h at room temperature, the reaction was treated as above and the residue was subjected to flash chromatography with ethyl acetate as eluent to give 4- (3-Hydroxybutyl) -4-hydroxy-cyclohexanone ethylene ketal as an oil.

EXAMPLE X

A mixture of 4- (3-Hydroxypropyl) -4-hydroxy-cyclohexanone ethylene ketal (1.4 g) and diisopropylethylamine (3.37 mi) in methylene chloride (100 IU) at -78 ° C was treated with triflic anhydride (1.64 mt). After 30 min re-

the action mixture was washed with water, the solvent was dried over magnesium sulfate and separated in vacuo. The residue was dissolved in 30 mt tetrahydrofuran and 15 mt 3% HCl. After 5 h at room temperature, the reaction mixture was diluted with water and the product extracted with ether. After drying over magnesium sulfate, the solvent was removed in vacuo to give 1-Oxaspiro [4.5] decane-8 as an oil.

EXAMPLE XI

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 mt) was stirred at room temperature for 18 h. separates in vacuo and the residue is taken up in 30 mt of toluene. After filtration, ethyl acrylate (2.2 g) was added to the filtrate and the resulting mixture heated at 100 ° C for 4 h. The solvent was removed in vacuo and the isoxazole derivative obtained was purified by flash chromatography on silica gel with 50% ethyl acetate / hexane as eluent. This material was hydrogenated at 45 psi in 50 ml of acetic acid on 10% palladium on a catalyst

40 carbon (400 mg) at room temperature for 16 hours. After filtration and solvent removal, the residue was purified by filtration through silica gel with ethyl acetate as eluent to give 3-Hydroxy-1-methyl-1-azaspiro [ 4,5] -decane-2,8-dione ethylene ^ ketal as an oil.

EXAMPLE XII

To a mixture of 3-Hydroxy-1-methyl-1-azaspiro [4.5] decane-2,8-dione ethylene ketal (1.0 g), triethylamine (1.73 mt ·) and methylene chloride (10 m 2) was added methanesulfonyl chloride (950 mg) dissolved in methylene chloride (5 mfc) dropwise at 0 ° C. After 30 min, the reaction mixture was washed with water, the organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The resulting residue was filtered

rubbed through silica gel with ethyl acetate as eluent to give. '53' *

3-Mesyloxy-1-ethyl-1-azaspiro (4.5] decane-2,8-diene ethylene ketal-

d.

then the oil.

EXAMPLE XIII

A mixture of 3-Mesyloxy-1-methyl-1-methyl-1-azaspiro [4.5] decane-2,8-dione ethyl ketal (1.28 g), sodium iodide (1.8 g) and acetone (20 mt) was heated with reflux with stirring for 90 min.

41The solvent was removed in vacuo and the residue was dissolved in methylene chloride and washed with water. After drying over magnesium sulfate, the solvent was removed in vacuo. The residue was dissolved in toluene (20 mt) and treated with tri-n-butyltin hydride (1.75 g) and AIBN (20 mg) and the resulting mixture heated at 110 ° C for 1 hour.

After the solvent was removed, the residue was chromatographed on silica gel with ethyl acetate as eluent. The resulting product was stirred with a mixture of water (5 mt), 3N HCl (1.5 mt) and acetic acid (2 mt) for 16 h. The resulting product was extracted 3 times with methylene chloride, washed with sodium bicarbonate solution. dried over magnesium sulphate and the solvent removed yn ca quo _in order to obtain 1-methyl-1-azaspiro [4.5] decane-2,8-dione as a mass lo.

EXAMPLE XIV

A mixture of 1-Methyl-1-azaspiro [4.5] decane-2,8-dione (100 mg) and pyrrolidine (43 mg) and 4A molecular sieves (500 mg) in 1 mt of benzene was allowed to stand at room temperature until formation of en min is completed (ca. 16 h). The resulting enamine solution was cannulated in a solution of 2-Phenyl-5-nitro-4,6-dichloro-pyrimidine (162 mg) and diisopropylethyl-amine (78 mg) in 3 mt methylene chloride. After 3 h at room temperature, the reaction mixture was treated with 2 mt 3N HCl and 3 mt water and stirring continued for another 20 min. The organic layer was separated,

42 was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was flash chromatographed on silica gel with ethyl acetate as eluent to afford 1-Methyl-7- [4- (2-phenyl-5-nitro-6-chloro-pyrimidinyl)] -1-azaspiro 4.5 decane -2,8-dione as a white solid.

EXAMPLE XV

(Compound 11)

Mixture of 1-Methyl-7- [4- (2-phenyl-5-nitro-6-chloro-pyrimidinyl)] -1-azaspiro [4.5] decane-2,8-dione (92 mg), triethylamine (60 mg ) and 10% Pd / C catalyst (15 mg) in 5 mt isopropanol and 1 mt ethyl acetate were hydrogenated in 1 atmosphere of hydrogen at room temperature for 16 h. After filtration through celite, the solvent was removed in vacuo and the residue was subjected to flash chromatography on silica gel with 2.5% methanol in ethyl acetate as eluent ₇ to give 1'-Methyl-2-phenyl-5,6,7,9-tetrahydro-spiro [indolo [3,2-d] - pyrimidin-2 ', 8-pyrrolidin-5'} (Compound 11), m.p. 310-315 ° C after trituration with hexane / ether.

EXAMPLE XVI

The following compounds were essentially prepared in accordance with the procedure described in Example XV:

43a) 2'-Phenyl-5 ', 6', 7 ', 9'-tetrahydro-spiro [(1,3) dioxolane-2,8'-indole! 3,2-d] -pyrimidine] (Compound 12), m.p. Mp 192-193 ° C.

b) 2'-Phenyl-4,5,5 ', 6', 7 ', 9'-hexahydro-spiro [furan-2,8' (3H) -indolo [3,2-d] -pyrimidine} (Compound 13), m.p. 199-202 ° C.

c) 2 '- (4-Methoxyphenyl) -5', 6 ', 7', 9'-tetrahydro-spiro [(1,3) dioxolane-2,8'-indolo [3,2-d] pyrimidine] (Compound 14), m.p. Mp 197-199 ° C.

X ') 2' - (4-Methoxyphenyl) -4,5,5 ', 6', 7 ', 9' -hexahydro-spiro [furan-2,

8 '(3H) -indolo [3,2-d] -pyrimidine] (Compound 15), m.p. 90-93 ° C.

e) 2 '- (2 (Fluorophenyl) -4,5,5', 6 ', 7', 9'-hexahydro-spiro [furan-2,8 ¹ (3H) -indoloI,3,2-d] -pyrimidine] (Compound 16), mp 208-210 ° C.

e) 2 '- (4-Fluorophenyl) -5', 6 ', 7', 9'-tetrahydro-spiro (1,3) dioxolane-2, 8 '-indolo [3, 2-d] -pyrimidine! (Compound 17), m.p. 108-109 ° C.

g) 5-Methyl-2'-phenyl-4,5,5 ', 6', 7 ', 9'-hexahydro-spiro [furan-2,8' (3H) -indolo [3,2-d] - pyrimidine] (Compound 18).

h) 1'-Methyl-2- (2-fluorophenyl) -5,6,7,9-tetrahydro-spiro [indolo [3,2-b] pyrimidin-2 ', 8-pyrrolidin-5'] (Compound 19), m.p. > 260 ° C.

i) 1'-Methyl-2- (4-methoxyphenyl) -5,6,7,9-tetrahydro-spiro [indolo [3,2-b] pyrimidin-2 ', 8-pyrrolidin-5'] (Compound 20), m.p. 340343 ° C.

j) 2 '- (2-Fluorophenyl) -5', 6 *, 7 J9'-tetrahydro-spiro [(1,3) dioxalan-2,8'-indolo [c _f 2-d] ~ ^PI ₽ ^IMI D ^IN J (Compound 21), m.p. 218-220 ° C.

44K) 2 '- (3- (fluorophenyl) -5- ^ 6 ^ 7 ^1, 9 ' -tetrahydro-spiro [(1,3) dioxolane-2,8'-indolo [3,2-d] - pyrimidine] ( Compound 22), mp 214-216 ° C.

l) 1'-Methyl-2-thienyl-5,6,7,9-tetrahydro-spiro [indolo [3,2-d] pyrimidin-2 ', 8-pyrrolidin-5'] (Compound 23), m .t. 335 ° C (dec).

m) 1'-Benzyl-2-phenyl-5,6,7,9-tetrahydro-spiro [indolo [3,2-0] -pyrimidin-2 ', 8-pyrrolidin-5 ¹ ] (Compound 24), m .t. 296-298 ° C.

A mixture of 1-benzoyl-piperidine-4- (244 mg) and pyrrolidine (85 mg) and 4A molecular sieves (500 mg) in 2 mt benzene was allowed to stand at room temperature until the enamine formation was complete (ca. 24 h ). The resulting enamine solution was cannulated in a solution of 2-Phenyl-5-nitro-4,6-dichloro-pyrimidine (325 mg) and triethyl-amine (200 mg) in 4 mt chloroform. After 30 min at room temperature, the reaction mixture was treated with 4 mL of 2N HCl and stirring continued for about 20 min. The organic layer was separated and dried over magnesium sulfate and the solvent removed in vacuo. The residue was subjected to flash chromatography on silica gel with 30% ethyl acetate in hexane as eluent to afford 1-Benzoyl-3- [4- (2-phenyl-5-nitro-6-chloropyrimidinyl)] -piperidine -4 as a white solid.

H (Compound 25)

Mixture of 1-Benzoyl-3- [4- (2-phenyl-5-nitro-6-chloropyrimidinyl)] - piperidine-4 (100 mg), triethylamine (100 mg) and 10% Pd / C catalyst (100 mg) in 6 mb ethanol was hydrogenated in 1 atmosphere at room temperature for 5 h. After filtration through celite, the solvent was removed in vacuo and the residue was subjected to flash chromatography on silica gel with 30% ethyl acetate in hexane as eluent * to give 8-Benzoyl-2-phenyl-5,6,7,9-tetrahydro-5H-pyrido [4,3-b] -pyrimidino [4,5-b] -pyrrole (Compound 25), m.p. 264-266 ° C after trituration with ether.

EXAMPLE XIX

The following compounds were essentially prepared in accordance with the procedure described in Example XVIII:

a) 2-Phenyl-5,6,7,9-tetrahydro-5H-pyrano [4,3-b] -pyrimidino [4,5 ~ a] pyrrole (Compound 26).

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

N.

(Compound 28)

A mixture of 2- [4- (2- (4-Methoxyphenyl-5-nitro-6-chloropyrimidinyl)] -cyclopentane-1 (200 mg) and 10% Pd / C catalyst (100 mg) in 10 ethanol was hydrogenated in 1 hydrogen atmosphere at room temperature for 2 h. After filtration through celite, the solvent was removed in vacuo and the residue was subjected to flash chromatography on silica gel with 20% ethyl acetate in hexane to give eluent.

4-Chloro-2- (4-methoxyphenyl) -cyclopent (g) -5H-pyrrolo [3,2-d] -pyrimidine (Compound 28) as a white solid.

p

EXAMPLE XXI

The following compounds were essentially prepared according to the procedure described in Example XX:

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

47 EXAMPLE IMPLEMENTATION

H (Compound 30)

Mixture of 2'-Phenyl-6 ', 7', 8 ', 9'-tetrahydro-spiro [(1,3) dioxolane-2,8' (5H) -indolo [3,2-d] -pyrimidine] ( 200 mg), 3N sulfuric acid (1.5 m 2) and methanol (1.5 mt) 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. After drying on magnesium sulfate, the solvent was removed in vacuo and the residue was crystallized from ether / hexane to give 2-Phenyl-5,6,7,9-tetrahydro-8H-indolo [3,2- <3 ] -pyrimidin-8 (Compound 30) melted at 24b-247 ° C.

EXAMPLE XXIII

(Compound 31)

To a mixture of 2-Phenyl-5,6,7,9-tetrahydro-8H-indolo [3,2-d] -pyrimidine8 (200 mg) and dry tetrahydrofuran (5 mt) was added lithium aluminum hydride (100 mg) in one part. After 1 h at room temperature, the reaction was quenched (cooled) with 1N NaOH, the reaction filtered through celite, and the solvent removed in vacuo and the residue was subjected to flash chromatography on silica gel with 10% methanol in methylene chloride as eluent, to obtain 8-Hydroxy-2-phenyl-6,

7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (Compound 31) melted at 211-212 ° C.

EXAMPLE XXIV

The following compounds were essentially prepared according to the procedure described in Example XV:

a) 8-Benzyl-2-phenyl-5,6,7,9-tetrahydro-5H-pyrido [4,3-b] -pyrimidino [4,5-0] -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] -pyrrol monohydrochloride (Compound 33) .

c) 8-Benzyl-2- (2-fluorophenyl) -5,6,7,9-tetrahydro-5H-pyrido [4, 3-b]

-pyrimidino [4,5- <1] -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-tetrahydro-spiro [indolo [3,2-d] -pyrimidin-2 ', 8-pyrrolidine] (Compound 36), m.p. 187-190 ° C.

e) 4-Chloro-8-methyl-2-phenyl-5,6,7,9-tetrahydro-5H-pyrido [4, 3-b] -pyrimidino [4,5- 3] -pyrrol monohydrochloride (Compound 37 ), m.p. 218-220 ° C.

49 EXAMPLE XXV

Mixture of 2-Phenyl-5,6,7,9-tetrahydro-8H-indolo [3,2-d] -pyrimidine-8

(100 mg), trifluoroacetic acid (15 mg) and 1-Phenyl-1,2-ethanediol (53 mg) in benzene (10 mg) were refluxed for 10 h in a Dean-Stark apparatus. The solvent was removed in vacuo and the residue was flash chromatographed to give 2-Phenyl-2'-phenyl-6 ', 7', 8 ', 9 * -tetrahydro-spiro [(1,3) dioxolane2,8 '(5H) -indolo [3,2-d] -pyrimidine] (Compound 38) as an amorphous solid.

EXAMPLE XXVI

(Compound 39)

Mixture of 8-Benzoyl-2-phenyl-5,6,7,9-tetrahydro-5H-pyrido [4,3-b] -pyrimidino [4,5 ~ d] ftnHpon (180 mg), 50% sodium hydroxide ( 1 mt) and ethanol (1 mi) is heated at reflux with stirring for 1 hour.

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-carboisopropoxy-6,7,8,9-tetrahydro-5H-indolo [3,2-d] -pyrimidine (Compound 42), m.p. 17b-180 ° C.

c) 2- (4-Ethoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-c3] -pyrimidine (Compound 43), m.p. 210-212 ° C.

d) 2- (3-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. 179-181 ° C.

e) 2- (4-Methoxyphenyl) -8-carbomethoxy-6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (Compound 46), m.p. Mp 204-206 ° C.

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

p

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-b] -pyrine (Compound 49), m.p. 115-116 ° C.

j) 2- (3-Methoxyphenyl) -cyclopent (d) -5H-pyrrolo [3,2-d] -pyrimidine (Compound 50), m.p. 199-201 ° C.

k) 2- (3,4-Methylenedioxyphenyl) -6,7,8,9-tetrahydro-5H-indole (3,2-d]

52-pyrimidine (Compound 51).

l) 2- (3-Methoxyphenyl) -cyclohept (e) -pyrrolo [3,2- b] -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) -6,7,8,9-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.

n) 2- (3-Fluorophenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-0] -pyrimidine (Compound 56), m.p. Mp 148-150 ° C.

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

p

c) 2- (2-Fluoro-5-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] -pyrimidine (Compound 58), m.p. 186-189 ° C.

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

y) 2- (3-Chlorophenyl) -6,7,8,9-tetrahydro-5H-indolo (3,2-d] -pyrimidine (Compound 60), mp 87-90 ° C.

u) 2- (4-Methoxyphenyl) -8-methyl-6,7,8,9-tetrahydro-5H-indolo [3,2-d]

53 Pyrimidine (Compound 61), m.p. Mp 215-217 ° C.

x) 2- (4-Methoxyphenyl) -8-carboisopropoxy-6,7,8,9-tetrahydro-5Hindolo [3,2-d] -pyrimidine (Compound 62), m.p. Mp 159-161 ° C.

m) 2- (3-Aminophenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-c3] -pyrimidine (Compound 63), m.p. 256-258 ° C.

h) 2- (3-Fluoro-4-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d]

-pyrimidine (Compound 64), m.p. Mp 189-191 ° C.

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

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

EXAMPLE XXIX

The following compounds were essentially prepared according to the procedures described in Examples VI-XVII:

a) 1'-Benzyl-2- (4-methoxyphenyl) -5,6,7,9-tetrahydro-spiro [indolo [3,2-d] -pyrimidin-2 ', 8-pyrrolidine] (Compound 67), mp 101-103 ° C.

b) 1'-Benzyl-2-phenyl-5,6,7,9-tetrahydro-spiro [indolo [3,2-d] -nrimidine-2 ', 8-pyrrolidine] (Compound 68), m.p. 138-139 ° C.

c) 2 '- (4-Ethoxyphenyl) -5', 6 ', 7', 9'-tetrahydro-spiro (1,3) dioxolane-2,8 ¹ -indolo [3,2-d] pyrimidine] (Compound 69), m.p. 210-212 ° C.

54d) 2- (4-Methoxyphenyl) -8-methylamino-6,7,8,9-tetrahydro-5H-indolo [3,2-a] pyrimidine (Compound 70), m.p. Mp 244-246 ° C.

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

e) 1'-Benzyl-2- (2-thienyl) -5,6,7,9-tetrahydro-spiro [indolo [3,2-d] pyrimidin-2 ', 8-pyrrolidin-5'] (Compound 72 ), m.p. 290-292 ° C.

g) 1'-Benzyl-2- (2-thienyl) -5,6,7,9-tetrahydro-spiro [indolo [3,2- (3] pyrimidin-2 ', 8-pyrrolidine] (Compound 73), mp 227-230 ° C.

h) 2- (4-Methoxyphenyl) -8- (N, N-dimethylcarboxamido) -6,7,8,9-tetrahydro-5H-indolo [3,2-a] pyrimidine (Compound 74), m.p. . 240-242 ° C.

i) 2- (4-Methoxyphenyl) -8- (N, N-dimethylaminomethyl) -6,7,8,9-tetrahydro-5H-indolo [3,2-d] pyrimidine (Compound 75), m.p. . 81-85 ° C.

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

k) 2- (4-Methoxyphenyl) -8- (acetyloxymethyl) -6,7,8,9-tetrahydro-5Hindolo [3,2-d] pyrimidine (Compound 77), m.p. 240-242 ° C.

The invention, methods and methods of preparation, and use thereof, are described in full, clearly, concisely and in precise terms, so that it will be possible for anyone with experience in the art to use and use the invention. It should be known that the foregoing description is preferred embodiments of the invention and that it is possible to amend them without deviation

55 of the spirit or scope of the present invention as set forth in the claims. The following claims specifically state and clearly state the subject matter of the present invention.

Claims (92)

Claims 1. Cycloalkyl and azacycloalkyl pyrrolpyrimidines of formula W Mr. Ch and pharmaceutically acceptable non-toxic salts thereof, wherein formula η is 0.1 or 2; R 1 and R ₂ are the same or different and denote a straight or branched hydrogen or lower alkyl group having 1 to 6 carbon atoms; X is hydrogen or hydroxy; W is a phenyl, thienyl or pyridyl group; a phenyl, thienyl or pyridyl group, each of which may be monoyl or substituted by halogen, a hydroxy group, a straight or branched lower alkyl group having 1 to 6 carbon atoms, amino-mono- or dialkylamino groups, in which each alkyl is a lower alkyl a straight or branched group having 1 to 6 carbon atoms or a lower alkoxy group having a straight or branched chain of 1 to 6 carbon atoms; Y is NR ₃ in which R ₃ is hydrogen, a straight or branched lower alkyl group having 1 to 6 carbon atoms, a phenyl, pyridyl or phenylalkyl group in which alkyl is a straight or branched chain alkyl of 1 to 6 carbon atom; an aminoalkyl group in which alkyl is straight or branched lower alkyl of 1 to 6 carbon atoms or a mono- or dialkylaminoalkyl group wherein each alkyl is straight or branched lower alkyl of 1 to 6 carbon atoms, 1-indan-yl , 4 (thio) chromanyl, 1- (1,2,3,4-tetrahydronaphthyl) group, 1-indanyl, 1- (thio) chromanyl, 1- (1,2,3,4-tetrahydronaphthyl) group, each of which is monosubstituted by halogen, straight or branched lower alkyl of 1 to 6 carbon atoms or lower straight or branched alkoxy of 1 to 6 carbon atoms; the groups -COR ₄ or -SO ₂ R ₄ in which R ₄ is a straight or branched lower alkyl group having from 1 to 6 carbon atoms, a phenyl group, a phenylalkyl group in which the alkyl is a straight or branched chain alkyl with 1 up to 6 carbon atoms or a phenylalkoxy group in which the alkoxy is a lower straight or branched alkoxy chain having 1 to 6 carbon atoms; C = O, CR ₆ O R _s , CR ₆ COR ₅ , CR ₆ CO ₂ R ₅ , CR ₆ OCOR ₅ and CR _S R ₆ in which R _s is hydrogen, a straight or branched chain alkyl group having 1 to 6 carbon atoms, a phenyl, pyridyl or phenylalkyl group in which alkyl is a straight or branched chain alkyl of 1 to 6 carbon atoms; and R ₆ is hydrogen or lower alkyl having a straight or branched chain of 1 to 6 carbon atoms; CR ₆ CONR ₇ R ₈ or CR ₆ / CH ₂ / _n NR ₇ R ₈ in which η is 0, 1 or 2 and R ₆ and R _? are the same or different and represent hydrogen, a straight or branched chain lower alkyl group having 1 to 6 carbon atoms; and R 1 is hydrogen, a straight or branched lower alkyl group having 1 to 6 carbon atoms, a phenyl, pyridyl or phenylalkyl group in which alkyl is a straight or branched chain alkyl of 1 to 6 carbon atoms; or NR ₇ R 1 is a morpholyl, piperidyl, pyrrolidyl or N-alkylpiperazyl group; CR ₆ NR ₉ CO ₂ R ₁₀ in which R ₆ is hydrogen, a straight or branched lower alkyl group having 1 to 6 carbon atoms; and R ₉ and R ₁₀ are the same or different and represent hydrogen, a straight- or branched-chain lower alkyl group having 1 to 6 carbon atoms, a phenyl, pyridyl or phenylalkyl group in which the alkyl is a straight- or branched-chain alkyl of 1 to 6 carbon atoms; -CR ₆ C / OH / R _n R ₁₂ in which R _{t |} and R ₂ is the same or different and denotes a straight or branched lower alkyl group of 1 to 6 carbon atoms, a phenyl or phenylalkyl group in which the alkyl is lower alkyl is a straight or branched chain of 1 to 6 carbon atoms and R ₆ is hydrogen or a lower alkyl group is a straight or branched chain is 1 to 6 carbon atoms; or a group is a formula: in which m is 0.1 or 2; R ₃ is hydrogen, a lower alkyl group is a straight or branched chain is 1 to 6 carbon atoms, a phenyl, pyridyl or phenylalkyl group in which the alkyl is lower alkyl is a straight or branched chain is 1 to 6 carbon atoms; Z is a methylene group, oxygen, NR _{| 4} or CHCONR _M , in which R ₁₄ is hydrogen, straight or branched chain straight or branched chain 1 to 6 carbon atoms, phenyl, pyridyl or phenylalkyl, in which alkyl is lower alkyl straight or a branched chain having from 1 to 6 carbon atoms; and T is a methylene group or oxygen. 2. The pyrrolimidines according to claim 1, characterized in that they are of formula 'N in which η is 0.1 or 2; R 1 and R ₂ are the same or different and denote hydrogen or a lower alkyl group being a straight or branched chain having 1 to 6 carbon atoms; R ₃ is hydrogen, a straight or branched chain lower alkyl group is 1 to 6 carbon atoms, a phenyl, pyridyl or phenylalkyl group in which alkyl is a straight or branched chain alkyl of 1 to 6 carbon atoms; and W is a phenyl, thienyl or pyridyl group; or a phenyl, thienyl, or pyridyl group, each of which may be mono- or di-substituted by halogen, hydroxy, straight or branched chain lower alkyl is 1 to 6 carbon atoms, amino, mono- or dialkylamino group in which each alkyl is a straight or branched lower alkyl of 1 to 6 carbon atoms or a lower straight or branched alkoxy of 1 to 6 carbon atoms. 3. The pyrrol pyrimidines according to claim 1, characterized in that they are of the formula in which R ₍ and R ₂ are the same or different and denote straight or branched chain straight or branched alkyl group of 1 to 6 carbon atoms; W is phenyl, a thienyl or pyridyl group; or a phenyl, thienyl or pyridyl group, each of which may be mono- or di-substituted with halogen, hydroxy, lower alkyl, is a straight or branched chain of 1 to 6 6 011 6 carbon atoms, an amino, mono- or dialkylamine group in which each alkyl is a straight or branched lower alkyl chain having 1 to 6 carbon atoms or a lower alkoxy is a straight or branched chain chain of 1 to 6 carbon atoms; and R ₃ is hydrogen, a straight or branched lower alkyl group having 1 to 6 carbon atoms, a phenyl, pyridyl or phenylalkyl group in which alkyl is a straight or branched chain alkyl of 1 to 6 carbon atoms; an aminoalkyl group in which alkyl is straight or branched lower alkyl having 1 to 6 carbon atoms or a mono- or dialkylaminoalkyl group in which each alkyl is lower alkyl is straight or branched chain having 1 to 6 carbon atoms; 1-indanyl, 4- (thio) chromanyl, 1- (1,2,3,4-tetrahydronaphthyl) group; 1-indanyl, 4- (thio) chromanyl, 1- (1,2,3,4-tetrahydronaphthyl) group, each of which is monosubstituted by halogen, a straight or branched chain alkyl group having 1 to 6 carbon atoms or lower straight or branched alkoxy group having 1 to 6 carbon atoms; or -COR ₄ or -SO ₂ R ₄ in which R ₄ is a straight or branched lower alkyl group having 1 to 6 carbon atoms, a phenyl, phenylalkyl group in which alkyl is a straight or branched lower alkyl group with 1 to A 6 carbon atom or a phenylalkoxy group in which the alkoxy is a lower straight or branched alkoxy chain having 1 to 6 carbon atoms. Pyrrolimyrimidines according to claim 1, characterized in that they are of formula wherein W is a phenyl, thienyl or pyridyl group; a phenyl, thienyl or pyridyl group, each of which may be mono- or disubstituted by halogen, hydroxy, lower or branched chain straight or branched alkyl groups of 1 to 6 carbon atoms, amino, mono- or dialkylamino, in which each alkyl is lower straight or branched alkyl having 1 to 6 carbon atoms or lower straight or branched alkoxy chain having 1 to 6 carbon atoms; Z is a methylene group, oxygen, NR _U or CHCONR _{| 4} in which R ₁₄ is hydrogen, a straight or branched lower alkyl group having 1 to 6 carbon atoms, a phenyl, pyridyl or phenylalkyl group in which alkyl is lower alkyl with straight or branched chain 1 to 6 carbon atoms; T is a methylene group or oxygen; and U is a methylene group or a carbonyl group. 5. Pyrrolpyrimidine according to claim 1, wherein Y is -NR ₃ , X is hydrogen, ne 1 and R and R 1 is C hydrogen. Pyrrolopyrimidine according to claim 5, characterized in that R ₃ is a benzyl group or a substituted benzyl group. 7. The pyrrolimidine according to claim 1, wherein Y is -NCOR ₄ , X is hydrogen, η is 1 and R, and R1Ca is hydrogen. The pyrrolpyrimidine according to claim 7, wherein R ₄ is a phenyl group. Pyrrolpyramidine according to claim 1, characterized in that Y is -CR ₅ R ₆ , X is hydrogen, η is 0 or 1 and R, and R 1 are hydrogen. The pyrrol pyrimidine according to claim 9, wherein R ₅ is hydrogen and is a straight or branched lower alkyl group having 1 to 6 carbon atoms. The pyrrol pyrimidine according to claim 1, wherein Y is -CHOCOR 2, X is hydrogen, η is 0 or 1 and R and R ₂ are hydrogen. Pyrrolpyrimidine according to claim 11, wherein R ₅ is an ethyl group. 13. The pyrrolimidine according to claim 1, wherein Y is -C = O, X is hydrogen, η is 1 and R ₁ and R ₂ are hydrogen. The pyrrol pyrimidine according to claim 1, wherein Y is -CH ₂ -, X is hydrogen, η is 0 or 1 and R, and are hydrogen. The pyrrolpyrimidine according to claim 1, wherein Y is a 1,3-dioxolane group, X is hydrogen, nelnR'H1 is hydrogen. Pyrrolimidine according to claim 1, characterized in that it is 2-phenyl-6,7,8,9tetrahydro-5H-indole (3,2-0) -pyrimidine. Pyrrolimidine according to claim 1, characterized in that it is 2-phenyl-cyclopent N-5H-pyrrole / 3,2- (1-pyrimidine). Pyrrolimidine according to claim 1, characterized in that it is 2-phenyl-cyclohept (g) -5H-pyrrole (3,2-d) -pyrimidine. The pyrrolimidine according to claim 1, which is 2-phenyl-8-methoxy-6,7,8,9-tetrahydro-5H-indole / 3,2- (1-pyrimidine). 20. Pyrrolimidine according to claim 1, characterized in that it is 2-phenyl-8-benzyloxy-6,7,8,9-tetrahydro-5H-indole (3,2-d) -pyrimidine. The pyrrolimidine according to claim 1, which is 2-phenyl-8-propyloxy-6,7,8,9-tetrahydro-5H-indole (3,2-0) -pyrimidine. 22. Pyrrolimidine according to claim 1, characterized in that it is 2- (4-methoxyphenyl) -6,7,8,9, -tetrahydro-5H-indole (3,2-0) -pyrimidine. 23. Pyrrolimidine according to claim 1, characterized in that it is 2- (2-fluorophenyl) 6-7,8,9-tetrahydro-5H-indole (3,2-d) -pyrimidine. The pyrrolimidine according to claim 1, characterized in that it is 2- (4-methoxyphenylAcyclopent N-5H-pyrrole) 3,2- (1H-pyrimidine). 25. Pyrrolimidine according to claim 1, characterized in that it is 2- (2-thienyl) 6,7,8,9, -tetrahydro-5H-indole / 3,2- (1) -pyrimidine. 26. Pyrrolimidine according to claim 1, characterized in that it is 1'-methyl-2phenyl-5,6,7,9-tetrahydro-spiro (indole) 3,2- (1) -pyrimidin-2 ', 8- pyrrolidin-5'-one). 27. The pyrrolimidine according to claim 1, wherein it is 2'-phenyl-5 ', 6', 7 ', 9'-tetrahydro-spiro (1,3) -dioxolane-2,8'-indole / 3, 2-d (pyrimidine). 28. The pyrrolimidine according to claim 1, characterized in that it is 2'-phenyl4,5,5 ', 6'7', 9'-hexahydro-spiro (furan-2,873H) -indole (3,2-0) pyrimidine. 29. The pyrrolimidine according to claim 1, characterized in that it is 2 '- (4-methoxyphenyl) -5', 6'7 ', 9'-tetrahydro-spiro (1,3) dioxolane-2,8'-indole (3,2-0) -pyrimidine /. 30. The pyrrolimidine according to claim 1, characterized in that it is 2 '- (4-methoxyphenyl) -4,5,5', 6'7 ', 9'-hexahydro-spiro / furan-2,8' / 3H (-indole) 3,2-0 (pyrimidine). The pyrrolimidine according to claim 1, characterized in that it is 2 '- (2-fluorophenyl) -4,5,5', 6 ', 7', 9'-hexahydro-spiro (furan) -2,873H / - indole (3,3-0) (pyrimidine). The pyrrolpyrimidine according to claim 1, characterized in that it is 2 '- (4-fluorophenyl) 5', 6 ', 7', 9'-tetrahydro-spiro (1,3) dioxolane-2,8'-indole (3,2 ^ Apyrimidine). 33. Pyrrolpyrimidine according to claim 1, characterized in that it is 5-methyl-2'-phenyl-4,5,5 ', 6', 7 ', 9'-hexahydro-spiro (furan-2,873H) -indole (3,2-4) -pyrimidine /. 34. Pyrrolpyrimidine according to claim 1, which is N-methyl-2- (2fluorophenyl) 5,6,7,9-tetrahydro-spiro (indole) - (3,2-0) -pyrimidin-2 ' , 8'-pyrrolidin-5'-one). 35. Pyrrolpyrimidine according to claim 1, which is 1'-methyl-2- (4methoxyphenyl) -5,6,7,9-tetrahydro-spiro (indole) - (3,2-o) pyrimidine-2 ', 8-pyrrolidin-5'-one'. The pyrrolpyrimidine according to claim 1, characterized in that it is 2 '- (2-fluorophenyl) -5', 6 ', 7', 9 ^, -tetrahydro-spiro (1,3) dioxolane-2,8'- indole (3,2- (1 (pyrimidine)). 37. Pyrrol pyrimidine according to claim 1, characterized in that it is 2 '- (3-fluorophenyl) -5', 6 ', 7', 9'-tetrahydro- (spiro) 1,3) dioxolane-2, 8'-indole / 3,2- (1 / -pyrimidine). 38. Pyrrolpyrimidine according to claim 1, characterized in that it is 1'-methyl-2thienyl-5,6,7,9-tetrahydro-spiro (indole) 3,2- (1) -pyrimidine-2'8-pyrrolidine -5'-he /. 39. Pyrrolimidine according to claim 1, characterized in that it is 1'-benzyl-2-phenyl-5,6,7,9-tetrahydro-spiro (indole) 3,2-cis-pyrimidin-2 ', 8- pyrrolidin-5 ^, -one). 40. Pyrrolpyrimidine according to claim 1, characterized in that it is 8-benzoyl-2phenyl-5,6,7,9-tetrahydro-5H-pyrido (4,3-0) -pyrimidine (4,5-0) - pyrrole. The pyrrolpyrimidine according to claim 1, which is 2-phenyl-5,6,7,9tetrahydro-5H-pyran (4,3-b) pyrimidine (4,5-0) -pyrrole. 42. Pyrrolimidine according to claim 1, characterized in that it is 8-carboethoxy-2/4-methoxyphenyl) -5,6,7,9-tetrahydro-5H-pyrido (4,3-b) -pyrimidine / 4, 5- (1H-pyrrole). 43. Pyrrolpyrimidine according to claim 1, characterized in that it is 4-chloro-2- (4-methoxyphenyl) -cyclopent (g) -5H-nHpoao (3,2-d) -pyrimidine. The pyrrolpyrimidine according to claim 1, characterized in that it is 8-carboethoxy-4chloro-2- (4-methoxyphenyl) -5,6,7,9-tetrahydro-5H-pyrido (4,3-b) -pyrimidine (4,5-0) -pyrrole. 45. The pyrrolpyrimidine according to claim 1, wherein it is 2-phenyl-5,6,7,9tetrahydro-8H-indole (3,2-4) -pyrimidin-8-one. 46. Pyrrolimidine according to claim 1, characterized in that it is 8-hydroxy-2phenyl-6,7,8,9-tetrahydro-5H-indole (3,2-4) -pyrimidine. The pyrrolpyrimidine according to claim 1, characterized in that it is 8-benzyl-2-phenyl- 5.6.7.9-tetrahydro-5H-pyrido (4, 3-b) -pyrimidino (4,5-d) -pyrrol-monohydrochloride. The pyrrolpyrimidine according to claim 1, characterized in that it is 8-benzyl-2- (4-methoxyphenyl) -5,6,7,9-tetrahydro-5H-pyrido- (4, 3-b) -pyrimidino / 4, 5-d / -pyrrole-monohydrochloride. 49. Pyrrolimidine according to claim 1, characterized in that it is 8-benzyl-2- (2fluorophenyl) 5,6,7,9-tetrahydro-5H-pyrido (4,3-b) -pyrimidino / 4,5- d / pyrrole monohydrochloride. 50. Pyrrolpyrimidine according to claim 1, characterized in that it is 8-methyl-2phenyl-5,6,7,9-tetrahydro-5H-pyrido (4,3 ^) - pyrimidino (4,5-d) pyrrol monohydrochloride . 51. Pyrrolpyrimidine according to claim 1, characterized in that it is N-methyl-2-phenyl- 5.6.7.9-tetrahydro-spiro (indole) 3,2-N-pyrimidin-2 ', 8-pyrrolidine]. 52. Pyrrolpyrimidine according to claim 1, characterized in that it is 4-chloro-8-methyl- 2-Phenyl-5,6,7,9-tetrahydro-5H-pyrido (4,3-b) -pyrimidino (4,5-d) -pyrrole monohydrochloride. 53. Pyrrol pyrimidine according to claim 1, characterized in that it is 2-phenyl-2'-phenyl-6 ', 7', 8 ', 9'-tetrahydro-spiro (1,3) dioxolane-2,8' / 5H (indole) 3,2-b (pyrimidine). 54. Pyrrol pyrimidine according to claim 1, characterized in that it is 2-phenyl-5,6,7,9tetrahydro-5H-pyrido (4,3-L) -pyrimidine (4,5-4) -pyrrol monohydrochloride. 55. Pyrrol pyrimidine according to claim 1, characterized in that it is 8-allyl-2-phenyl-5,6,7,9-tetrahydro-5H-pyrido (4,3-b) -pyrimidino / 4,5-0 / -pyrrole monohydrochloride. 56. Pyrrolpyrimidine according to claim 1, characterized in that it is 2- (3-methylphenyl) -6,7,8,9-tetrahydro-5H-indolo (3,2-pyrimidine). 57. Pyrrolpyrimidine according to claim 1, characterized in that it is 2- (2-thienyl) -8-carbisopropoxy-6,7,8,9-tetrahydro-5H-indolo (3,2-d) -pyrimidine. 58. Pyrrolimidine according to claim 1, characterized in that it is 2- (4-ethoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo / 3,2- (1) -pyrimidine. 59. Pyrrolpyrimidine according to claim 1, characterized in that it is 2- (3-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo (3,2-d) pyrimidine. 60. Pyrrolpyrimidine according to claim 1, characterized in that it is 2- (4-methoxyphenyl) -7-methyl-6,7,8,9-tetrahydro-5H-indolo (3,2-d) pyrimidine. 61. The pyrrolimidine according to claim 1, characterized in that it is 2- (4-methoxyphenyl) -8-carbmethoxy-6,7,8,9-tetrahydro-5H-indolo (3,2-0) -pyrimidine. 62. The pyrrol pyrimidine according to claim 1, which is 2- (2-fluoro-4-methoxyphenyl) 6,7,8,9-tetrahydro-5H-indolo (3,2-d) -pyrimidine. 63. The pyrrolimidine according to claim 1, characterized in that it is 2- (5-methyl-2-thienyl) -6,7,8,9-tetrahydro-5H-indolo (3,2-d) -pyrimidine. 64. The pyrrol pyrimidine according to claim 1, which is 2- (ethoxyphenyl) -6,7,8,9-tetrahydro-5H-indole (3,2- 1) -pyrimidine. 65. The pyrrolimidine according to claim 1, characterized in that it is 2- (3-methoxyphenyl) -cyclopent (g) -5H-pyrrolo (3,2-d) -pyrimidine. 66. Pyrrolpyrimidine according to claim 1, characterized in that it is 2- (3,4-methylenedioxyphenyl) -6,7,8,9-tetrahydro-5H-indolo- (3,2-d) -pyrimidine. 67. Pyrrolidin-imidine according to claim 1, characterized in that it is 2- (3-methoxyphenyl) -cyclohept (g) -pyrrolo / 3,2-d / -5H-pyrimidine. 68. Pyrrolimidine according to claim 1, characterized in that it is 2- (3-hydroxyphenyl) -6,7,8,9-tetrahydro-5H-indolo (3,2-6) -pyrimidine. 69. Pyrrolpyrimidine according to claim 1, characterized in that it is 2- (3-ethylphenyl) - 6.7.8.9- tetrahydro-5H-indolo (3,2-0) -pyrimidine. The pyrrolpyrimidine according to claim 1, which is 2- (3,5-dimethoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo (3,2-6) -pyrimidine. 71. Pyrrolpyrimidine according to claim 1, characterized in that it is 2- (3-fluorophenyl) -6,7,8,9-tetrahydro-5H-indolo (3,2-0) -pyrimidine. 72. Pyrrolpyrimidine according to claim 1, characterized in that it is 2- (2-fluoro-3methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo (3,2-0) -pyrimidine. 73. Pyrrolimidine according to claim 1, characterized in that it is 2- (2-fluoro-5-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo (3,2-0) -pyrimidine. 74. Pyrrolpyrimidine according to claim 1, characterized in that it is 4- (4-bromo-3-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo- (3,2-6) -pyrimidine. 75. Pyrrolpyrimidine according to claim 1, characterized in that it is 2- (3-chlorophenyl) - 6.7.8.9-tetrahydro-5H-indolo (3,2-6) -pyrimidine. 76. Pyrrolimidine according to claim 1, characterized in that it is 2- (4-methoxy-phenyl) -8-methyl-6,7,8,9-tetrahydro-5H-indolo (3,2-0) -pyrimidine . 77. Pyrrolpyrimidine according to claim 1, characterized in that it is 2- (4-methoxyphenyl) -8-carboisopropoxy-6,7,8,9-tetrahydro-5H-indolo (3,2-6) -pyrimidine. 78. Pyrrol pyrimidine according to claim 1, characterized in that it is 2- (3-aminophenyl) -6,7,8,9-tetrahydro-5H-indolo (3,2-6) -pyrimidine. 79. Pyrrolpyrimidine according to claim 1, characterized in that it is 2- (3-fluoro-4-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo / 3,2- (1-pyrimidine). 80. Pyrrolpyrimidine according to claim 1, characterized in that it is 2- (4-fluoro-3-methoxyphenyl) -6,7,8,9-tetrahydro-5H-indolo- (3,2-b) -pyrimidine. 81. Pyrrolpyrimidine according to claim 1, characterized in that it is 2- (3-fluorophenyl) -6,7,8,9-tetrahydro-5H-indolo (3,2-6) -pyridine. 82. Pyrrolpyrimidine according to claim 1, characterized in that it is 1'-benzyl-2- (4-methoxyphenyl) -5,6,7,9-tetrahydro-spiro / indolo (3,2-d) -pyrimidine- 2'-8-pyrrolidine). 83. Pyrrolpyrimidine according to claim 1, characterized in that it is N-benzyl-2-phenyl-5,6,7,9-tetrahydro-spiro (indole) 3,2-O-pyrimidin-2 ', 8- pyrrolidine). 84. Pyrrolpyrimidine according to claim 1, characterized in that it is 2 '- (4-ethoxyphenyl) 5', 6 ', 7', 9'-tetrahydro-spiro (1,3) -dioxolane-2,8'- indole (3,2-0) (pyrimidine). 85. The pyrrol pyrimidine according to claim 1, which is 2- (4-methoxyphenyl) -8-methylamino-6,7,8,9-tetrahydro-5H-indolo (3,2-0) -pyrimidine. 86. Pyrrolimidine according to claim 1, characterized in that it is 2- (4-methoxyphenyl) -8-dimethylamino-6,7,8,9-tetrahydro-5H-indolo (3,2-0) -pyrimidine. 87. Pyrrolpyrimidine according to claim 1, characterized in that it is 1'-benzyl-2- (2-thienyl) -5,6,7,9-tetrahydro-spiro (indole) 3,2-6-pyrimidin-2 ' , 8-pyrrolidin-5'-one). 88. Pyrrolimidine according to claim 1, characterized in that it is 1'-benzyl-2- (2-thienyl) -5,6,7,9-tetrahydro-spiro (indole) 3,2-6-pyrimidin-2 ' , 8-pyrrolidine). 89. Pyrrolpyrimidine according to claim 1, characterized in that it is 2- (4-methoxyphenyl) -8- (N, N-dimethylcarboxamide) -6,7,8,9-tetrahydro-5H-indolo (3,2- b / -pyridine. 90. Pyrrolpyrimidine according to claim 1, characterized in that it is 2- (4-methoxyphenyl) -8- (N, N-dimethylaminomethyl) -6,7,8,9-tetrahydro-5H-indolo / 3,2-b / -pyrimidine 91. Pyrrolpyrimidine according to claim 1, characterized in that it is 2- (4-methoxyphenyl) -8- (hydroxymethyl) -6,7,8,9-tetrahydro-5H-indolo (3,2-6) -pyrimidine . 92. Pyrrolpyrimidine according to claim 1, characterized in that it is 2- (4-methoxyphenyl) -8- (acetoxymethyl) -6,7,8,9-tetrahydro-5H-indolo (3,2-b) - pyrimidine.