IL101285A - Certain cycloalkyl and azacycloalkyl pyrrolopyrimidines - a new class of gaba brain receptor ligands - Google Patents

Description

CERTAIN CYCLOALKYL AND AZACYCLOALKYL PYRROLOPYRIMIDINES; A NEW CLASS OF GABA BRAIN RECEPTOR LIGANDS tV ΚΠΠ AID -tP^'piNl p'-i-n-iNI D7 '" i^NI ^jf'X D'.'TD'TS^lTa GABA A1DD nil. 'ϋ"7Τ i7"7 D'TJA'1? NEUROGEN CORPORATION C: 14368 101285/2 - 1 - Certain Cycloalkyl and Azacycloalkyl Pyrrolopyrimid ines ; A New Class of GABA Brain Receptor Ligands BACKGROUND OF THE INVENTION Eki ] nf In vent ion This invention relates to certain cycloalkyl and azacycloal kyl pyrroloyri midines which selectively bind to GABAa receptors. This invention also relates to pharm aceutical compositions compris ing suc h compounds. These compounds axe . useful ' in treating anxiety, sleep and seizure disorders, and overdoses of benzodiazepine-type drugs, and enhancing alertness. The interaction of pyrrolopyrimidines of the invention with a GABA binding site, the benzodiazepines (BDZ) receptor, is described. This interaction results in the pharmacological activities of these compounds.

Description of the Related Art γ-Am inobutyric acid (GA B A) is regarded as one of the major inhibitory amino acid transmitters in the mammalian brain. Over 30 years have elapsed since its presence in the brain was demonstrated (Roberts & Frankel. J. Biol. Chem 1&2: 55-63. 1950; Udenfriend. J. Biol. Chem. 181: 65-69, 1950). Since that time, an enormous amount of effort has been devoted to implicating GABA in the etiology of seizure disorders, sleep, anxiety and cognition (Tallman and Gallager, Ann. Rev. Neuroscience 21 -44, 1985). Widely, al though unequal ly , d istributed through the mammal ian brain , GABA is said to be a transmitter at approximately 30% of the synapses in the brain. In most regions of the brain, GABA is associated with local inhibitory neurons and only in two regions is GABA associated with longer projections. GABA mediates many of' its actions through a complex of proteins localized both on cell bodies and nerve endings; these are called GABAa receptors. Postsynaptic responses to G A B A are mediated through alterations i n chloride conductance that gene ral ly, although not invari ably, lead to hyperpolarization of the cel l. Recent investigations have indicated that the complex of proteins associated with postsynaptic GABA responses is a major site of action for a number of structurally unrelated compounds capable of modify ing postsynaptic responses to GABA. Depending on the mode of interac t ion, these compounds are capable of producing a spectrum o f activities (either sedative, anxiolytic, and anticonvulsant, or wakefulness, seizures, and anxiety). 1 ,4-Benzodiazepines continue to be among the most widely used drugs in the world. Principal among the benzodi azepines marketed are chlordiazepoxide. diazepam, flurazepam, and triazolam. These compounds are widely used as anxiolytics, sedative-hypnotics, muscle relaxants, and anticonvulsants. A number of these compounds are extremely potent drugs; such potency indicates a site of action with a high affinity and specificity for individual receptors. Early electrophysiological studies indicated that a major action of benzodiazepines was enhancement of GABAergic inhibition. The benzodiazepines were capable of enhancing presynaptic inhibition of a monosynaptic ventral root reflex, a GABA-mediated event (Schmidt et at., 1967. Arch." Exp. Path. Pharmakol. 2 5 8 : 69-82). All subsequent electrophysiological studies (reviewed in Tallman et al. 1980, Science 2112:274-81. Haefley et al.. 1981. Handb. Exptl. Pharmacol. 11:95- 102) have generally confirmed this finding, and by the mid- 1970s, there was a general consensus among electrophysiologists that the benzodiazepines could enhance the actions of GABA.

With the discovery of the "receptor" for the benzodiazepines and the subsequent definition of the nature of the interaction between GABA and the benzodiazepines, it appears that the behaviorally important interactions of the benzodiazepines with different neurotransmitter systems are due in a large part to the enhanced ability of GABA itself to modify these systems. Each modified system, in turn, may be associated with the expression of a be h av i o r.

Studies on the mechanistic nature of these interactions depended on the demonstration of a high-affinity benzodiazepine binding site (receptor). Such a receptor is present in the CNS of all vertebrates phylogenetically newer than the boney fishes (Squires & Braestrup 1977, Nature 1 : 732-34, Mohler .& Okada. 1977. Science 1 98 : 854-51 , Mohler & Okada, 1977, Br. J. Psychiatry Hi: 261-68). By using tritiated diazepam, and a variety of other compounds, it has been demonstrated that these benzodiazepine binding sites fulfill many of the criteria of pharmacological receptors; binding to these sites in v i tro is rapid, reversible, stereospecific. and saturable. More importantly, highly significant correlations have been shown between the ability of benzodiazepines to displace diazepam from its binding site and activity in a number of animal behavioral tests predictive of benzodiazepine potency (Braestrup & Squires 1978, Br. J. Psychiatry } 33 : 249-60. ohlcr & Okada. 1977. Science I£S_: 854-51, Mohler &. Okada. 1977. Br. J. Psychiatry 133: 261-6S). The average therapeutic doses of these drugs in man also correlate with receptor potency (Tallman et al. 1980, Science 207: 274-281).

In 1978. it became clear that GABA and related analogs could interact at the low affinity (1 Μ) GABA binding site to enhance the binding of benzodiazepines to the clonazepan-sensitive site (Tallman et al. 1978. Nature, 27_4: 383-85). This enhancement was caused by an increase in the affinity of the benzodiazepine binding site due to occupancy of the GABA site. The data were interpreted to mean that both GABA and benzodiazepine sites were allosterically linked in the membrane as part of a complex of proteins. For a number of GABA analogs, the ability to enhance diazepam binding by 50% of maximum and the ability to inhibit the binding of GABA to brain membranes by 50% could be directly correlated. Enhancement of benzodiazepine binding by GABA agonists is blocked by the GABA receptor antagonist (+) bicuculline; the stereoisomer (-) bicuculline is much less active (Tallman et al., 1978, Nature. 2_74: 383-85).

Soon after the discovery of high affinity binding sites for the benzodiazepines, it was discovered that a triazolopyridazine could interact with benzodiazepine receptors in a number of regions of the brain in a manner consistent with receptor heterogeneity or negative cooperativity. In these studies, Hill coefficients significantly less than one were observed in a number of brain regions, including cortex, hippocampus, and striatum. In cerebellum, triazolopyridazine interacted with benzodiazepine sites with a Hill coefficient of 1 (Squires et al., 1979, Pharma. Biochem. Behav. 1Q_: 825-30, Klepner et al. 1979. Pharmacol. Biochem. Behav. J_L: 457-62). Thus, multiple benzodiazepine receptors were predicted in the cortex, hippocampus, striatum, but not in the cerebellum.

Based on these studies, extensive receptor autoradiographic localization studies were carried out at a light microscopic level. Although receptor heterogeneity has . been demonstrated (Young & Kuhar 1980, J. Pharmacol. Exp. Ther. 212: 337-46, Young et al.. 1981 J. Pharmacol Exp. Trier. 2_Li.: 425-430, Niehoff et al. 1982. J. Pharmacol. Exp. Ther. 221 : 670-75). no simple correlation between localizatio of receptor subtypes and the behaviors associated with the region has emerged from the early studies..; In addition, in the cerebellum, where one receptor was predicted from binding studies, autoradiography revealed heterogeneity of receptors (Niehoff et al.. 19S2, J. Pharmacol. Exp. Ther. 221:. 670-75).

A physical basis for the differences in drug specificity for the two apparent subtypes of benzodiazepine sites has been demonstrated by Sieghart & Karobath, 1980. Nature 286 : 285-87. Using gel electrophoresis in the presence of sodium dodecyl sulfate, the presence of several molecular weight receptors for the benzodiazepines has been reported. The receptors were identified by the covalent incorporation of radioactive flunitrazepam, a benzodiazepine which can covalently label all receptor types. The major labeled bands have moelcular weights of 50,000 to 53,000, 55,000, and 57,000 and the triazolopyridazines inhibit labeling of the slightly higher molecular weight forms (53,000, 55,000, 57,000) (Seighart et al. 1983, Eur. J. Pharmacol. 8J.: 291-99).

At that time, the possibility was raised that the multiple forms of the receptor represent "isoreceptors" or multiple allelic forms of the receptor (Tallman & Gallager 1985, Ann. Rev. Neurosci. £L, 21-44). Although common for enzymes, genetically distinct forms of receptors have not generally been described. As we begin to study receptors using specific radioactive probes and electrophoretic techniques, it is almost certain that isoreceptors will emerge as important in investigations of the etiology of psychiatric disorders in people.

The GABAa receptor subunits have been cloned from bovine and human cDNA libraries (Schoenfield et al., 1988; Duman et al., 1989). A number of distinct cDNAs were identified as subunits of the GABAa receptor complex by cloning and expression. These are categorized into « , β, γ, δ, e , and provide a molecular basis for the GABAa receptor heterogeneity and distinctive regional pharmacology (Shivvers et al., 1980; Levitan et al . , 1989). The γ subunit appears to enable drugs like benzodiazepines to modify the GABA responses (Pritchett et al., 1989). The presence of low Hill coefficients in the binding of ligands to the GABAa receptor indicates unique profiles of subtype specific pharmacological action.

Drugs that interact at the GABAa receptor can possess a spectrum of pharmacological activities depending on their abilities to modify the actions of GABA. For example, the beta-carbolines were first isolated based upon their ability to inhibit competitively the binding of diazepam to its binding site (Nielsen et al., 1979, Life Sci. 2 : 679-86). The receptor binding assay is not totally predictive about the biological activity of such compounds; agonists, partial agonists, inverse agonists, and antagonists can inhibit binding. When the beta-carboline structure was determined, it was possible to synthesize a number of analogs and test these compounds behaviorally.

It was immediately realized that the beta-carbolines could antagonize the actions of diazepam behaviorally (Tenen & Hirsch, 1980. Nature ?8 g : 609- 10). In addition to this antagonism, beta-carbolines possess intrinsic activity of their own opposite to that of the benzodiazepines; they become known as inverse agonists.

In addition, a number of other specific antagonists of the benzodiazepine receptor were developed based on their ability to inhibit the binding of benzodiazepines. The best studied of these compounds is an imidazodiazepine. (Hunkeler et al., 1981 , Nature 290 : 514-5 16). This compound is a high affinity competitive inhibitor of benzodiazepine and beta-carboline binding and is capable of blocking the pharmacological actions of both these classes of compounds. By itself, it possesses little intrinsic pharmacological activity in animals and humans (Hunkeler et al., 1981 , Nature 220.'· 514-16; Darragh et al.. 1983, Eur. J. Clin. Pharmacol. 14 : 569-70). When a radiolabeled form of this compound was studied (Mohler & Richards, 1981 , Nature 294 : 763-65), it was demonstrated that this compound would interact with the same number of sites as the benzodiazepines and beta-carbolines, and that the interactions of these compounds were purely competitive. This compound is the ligand of choice for binding to GABAa receptors because it does not possess receptor subtype specificity and measures each state of the receptor.

The study of the interactions of a wide variety of compounds similar to the above has led to the categorizing of these compounds. Presently, those compounds possessing activity similar to the benzodiazepines are called agonists. Compounds possessing activity opposite to benzodiazepines are called inverse agonists, and the compounds blocking both types of activity have been termed antagonists. This categorization has been developed to emphasize the fact that a wide variety of compounds can produce a spectrum of pharmacological effects, to indicate that compounds can interact at the same receptor to produce opposite effects, and to indicate that beta-carbolines and antagonists with intrinsic anxiogenic effects are not synonymous. A biochemical test for the pharmacological and behavioral properties of compounds that interact with the benzodiazepine receptor continues to emphasize the interaction with the GABAergic system. In contrast to the benzodiazepines, which show an increase in their affinity due to GABA (Tallman et al.. 1978. Nature 221: 383-85, Tallman et al., 1980. Science -?07 : 274-81). compounds with antagonist properties show little GABA shift (i.e., change in receptor affinity due to GABA) (Mohler & Richards 1981 , Nature 294 : 763-65), and the inverse agonists actually show a decrease in affinity due to GABA (Braestrup & Nielson 1981 , Nature 294 : 472-474). Thus, the GABA shift predicts generally the expected behavioral properties of the compounds.

Various compounds have been prepared as benzodiazepine agonists and antagonists. "For Example, U.S. Patents Nos. 3 ,455,943, 4,435 ,403. 4,596,808, 4,623,649, and 4,719,210, German Patent No. DE 3.246,932, and Liebigs Ann. Chem. 1986, 1749 teach assorted benzodiazepine agonists and antagonists and related anti-depressant and central nervous system active compounds. U.S. Patent No. 3.455,943 discloses compounds of the formula: wherein R \ is a member of the group consisting of hydrogen and lower alkoxy; R2 is a member of the group consisting of hydrogen and lower alkoxy; R3 is a member of the group consisting of hydrogen and lower alkyl; and X is a divalent radical selected from the group consisting of lower alkyl and the non-toxic acid addition salts thereof.

U.S. Patent No. 4,435.403 teaches compounds of the formula: wherein RC is .hydrogen, lower alkyl, alkoxyalkyl of up to 6 C-atoms, cycloalkyl of 3-6 C-atoms, aralkyl of up to 8 C-atoms, or (CH2)nOR20 wherein R2^ is alkyl of up to 6 C-atoms, cycloalkyl of 3-6 C-atoms or aralkyl of up to 8 C-atoms and n is an integer of 1 to 3; Y is oxygen, two hydrogen atoms or NOR*, wherein R^ is hydrogen, lower alkyl, aryl or aralkyl of up to 6 C-atoms, COR2, wherein R2 is lower alkyl of up to 6 C-atoms, or Y is CHCOOR3. wherein R3 is hydrogen or lower alkyl or Y is NNR4R5. wherein and R^ can be the same or different and each is hydrogen, lower alkyl„ C6-10-aryl. C7. lfj-aralkyl or CONR^R?, wherein R6 and R7 can be the same or different and each is hydrogen or lower alkyl or R^ and R^ together with the connecting N-atom, 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 may be substituted by a lower alkyl group; Z is hydrogen, or alkoxy or aralkoxy each of up to 10 C-atoms and each optionally substituted by hydroxy, or Z is alkyl of up to 6 C-atoms, C6- 10-aryl or C7.10-aralkyl each of which may optionally be substituted by a COOR8 oraCONR9R10 group, wherein R8 is alkyl of up to 6 C-atoms, and R^ and R1^ can be the same or different and each is hydrogen or alkyl of up to 6 C-atoms; or Z is NR^RIO^ wherein R^ and R'" are as defined above; orZ is NRnCHR1 R13, wherein R^ and R^2 each is hydrogen or together form a N=C double bond, wherein R13 is Cj-iQ-alkyl or NR14R15, 101285/2 -8- wherein R14 and R15 are the same or different and each is hydrogen. OH or alkyl or alkoxy each of up to 6 C-atoms, or wherein R1^ and R1^ together are oxygen, in which case, R1 1 is hydrogen; or Z is COOR^ wherein R^ is as defined above; or Y and Z, together with the connecting C-atom, may form a 5- or 6-membered heterocyclic ring which contains an O-atom, adjoining O- and N-atoms or up to a 4 N atoms and which optionally may be substituted by a lower alkyl group, hydroxy or oxo.

U.S. Patent No. 4,596,808 discloses compounds of the formula: wherein RA is H. F. 01, Br. I, NO2. CN, CH3. CF3. SCH3. NR16R17 or NHCOR16, wherein R'6 0f R17 are tne safne or different and each is hydrogen or alkyl. alkenyl or alkynyl each of up to 6 C-atoms, aralkyl or cycloalkyl each of up to 10 C-atoms, or wherein R^ and R^ together form a saturated or unsaturated 3-7 membered heterocyclic ring.

U.S. Patent No. 4,623,649 teaches compounds of the formula: wherein R3 is an oxadiazolyl residue of the formula wherein Rg stands for lower alkyl of up to 3 carbon atoms or an ester -CO2 6 with R. being hydrogen or lower alkyl of up to 3 carbon atoms, 4 is hydrogen, lower alkyl of up to 3 carbon atoms, or CH2OR9 wherein R^ is lower alkyl of up to 3 carbon atoms.

RA is phenyl or a hydrocarbon residue containing 2-10 carbon atoms which can be cyclic or acyclic, saturated or unsaturated, branched or unbranched. and which can optionally be substituted by oxo, formyl OH, O-akyl of up to 3 carbon atoms or phenyl, and wherein in a cyclic hydrocarbon residue, a CH2 -group can be replaced by oxygen.

U.S. Patent No. 4,719.210 discloses compounds of the formula: wherein Rj is hydrogen or a protecting group. 2 is -CH=CR42 or -C=CR . is hydrogen or halogen.

R3 is hydrogen, lower alkyl or lows: alkoxyalkyl. is. infer alia. ■■ hydrogen. OR', lower alkyl. which optionally is substituted with aryl. lower alkosy or NR5R5, ^ and R^ can be the same or different and in each case is hydrogen, lower .alkyl or together with the nitrogen atom a 5-6 member ring, which can contain another heteroatom. is lower alkyl. optionally substituted aryl or aralkyl. and each compound can contain one or more R^ radicals which are not hydrogen.

These compounds differ from the compounds of the present invention: These U.S. Patents teach carbocyclic compounds having pyridinc or pipcridine rings but lacking the pyrimidine ring present in compounds of the present invention.

German Patent No. DE 3,246.932 discloses compounds of the formul H wherein R = ha!o. ΝΌ2. CO2H. modified CC H, R20, R2S(0)n: n = 0-2; and ¾ = H, alkyl. cycloalkyl. aralkyl. aryl. CO2H. amino R20. R2S(0)n.

Liebigs Ann. Chem. 1986, 1749-1764 teaches compounds of the form u 1 a : Where is hydrogen, methyl, benzyloxy. or methoxy, and R3 is carboethoxy.

These compounds differ from the compounds 0: the present invention. These compounds are not . tetrahydroindoles or tetrahydropyrridopyrroles and also lack the various ring substituents of the compounds of the present invention. fai ls to di sc lose any pharmaceutical acti vity for the ' compound.

SUMMARY OF THE INVENTION This invention provides novel compounds of Formula I which interact with a GABAa binding site, the benzodiazepine receptor.

The invention provides pharmaceutical compositions comprising compounds of Formula I. The invention also provides compounds useful in enhancing alertness, treatment of seizure, anxiety, and sleep disorders, and treatment of benzodiazepine overdoses. Accordingly, a broad embodiment of the invention is directed to compounds of Formula I: 101285/2 12 - and pharmaceutically acceptable salts thereof wherein: n is 0, 1 or 2; R I and 2 are the same or different and represent hydrogen or straight chain or branched alkyl having 1- 6 carbon atoms; X is hydrogen, hydroxy or chloroj W is phenyl, thienyl, or pyridyl; phenyl, thienyl, or pyridyl, each of which may"' be mono or disubstituted with halogen, hydroxy, straight or branched chain alkyl having 1-6 carbon atoms, amino, mono or dialkylamino where each alkyl is straight or branched chain having 1-6 carbon atoms, or straight or branched chain alkoxy having 1-6 carbon atoms; Y is Oj N-R3 where R3 is hydrogen, straight or ')ra chain alkyl having 1-6 carbon atoms, j phenyl, pyridyl, or phenylalkyl where the alkyl is straight or branched chain having 1-6 carbon atoms; aminoalkyl where the alkyl is a straight or branched chain · having 1-6 carbon atoms, or mono or dialkyl aminoalkyl where each alkyl is a straight or branched chain . . having 1-6 carbon atoms; 101285/3 - 13 - l-inclanyl, 4-(th|o)chromanyl, I -( 1.2,3 ,4-tetrahydro- napluliyl); 1-indanyl, 4-(lh|o)chromanyl, ! -( 1 ,2,3.4-letrahydro- naphihyl) each pf which is monosubstiuiled with halogen, straight or branched chain · alky 1 having 1-6 carbon atoms, or straight or branched chain nlkoxy having 1-6 carbon atoms; -COR4 or -SO2R4 where R4 is straight or branched chain or alkoxy alkyl j having 1-6 carbon atoms. phenyl, phenylalkyl where the alkyl is a straight or branched chain . having 1-6 carbon atoms, or phenylalkoxy where the alkoxy is a straight or branched chain alkoxy having 1-6 carbon atoms; C=0. CR6OR5. CR6COR5. CR6CO2R5. CR6OCOR5. and CR5R6. where 5 is hydrogen, straight or branched chain 'alkyl having 1-6 carbon atom's, phenyl, pyridyl, or phenylalkyl where the alkyl is straight or branched chain having 1-6 carbon atoms; and R 6 is hydrogen, or straight or branched chain alkyl having 1-6 carbon atoms; C CO R7R8 or C (Cll2)nN 7 8 where n is 0, 1, or 2, and R fi and R7 are the same or different and represent hydrogen, or straight or branched chain -alkyl having 1-6 carhon atoms; and g is hydrogen, straight or branched chain - alkyl having 1-6 carbon alomsi phenyl, pyridyl, or phenylalkyl where the alkyl is straight or branched chain having 1-6 carbon atoms; or NR7R8 is morpholyl, piperidyl, pyrrolidyl, or N-alkyl piperazyl; C 6 R9CO2 10 where R 6 is hydrogen, or straight or branched ' chain alkyl having 1-6 carbon .atoms, and 101285/2 - 3 - R9 and R\o are the same or different and represent hydrogen, straight or branched chain - alkyl having 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl where the alkyl is straight or branched chain liaving 1-6 carbon atoms; -CR6C(OH)Rj i R 12 where R\ \ and R\2 are Ihe same or different and represent straight o branched chain alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where the alkyl is straight or branched chain ' having 1-6 carbon atoms, and R6 is hydrogen, or straight or branched chain alkyl having 1-6 carbon atoms; or group of the formula: where m is 0, 1. or 2 Rl3 is hydrogen, straight or branched chain alkyl having 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl where the alkyl is straight or branched chain having 1-6 carbon atoms; Z is methylene, oxygen, NR1 or CHCONR14 where Rj4 is hydrogen, straight or branched chain alkyl having 1-6 carbon atoms, phenyl, pyridyl, or phenylalkykl where the alkyl is straight or branched chain having 1-6 carbon atoms; and T is methylene or oxygen. 101285/2 -15- These compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs thereof and are useful in the diagnosis and treatment of anxiety, sleep, and seizure disorders, overdose with benzodiazepine drugs, and enhancement of memory.

BRIEF DESCRIPTION OF THE DRAWING Figures 1A-L show representative cycloalkyl and azacycloalkyl pyrroiopyrimidines of the present invention. 101285/2 - 17 - DETAILED DESCRIPTION OF THE INVENTION The novel compounds encompassed by the instant invention can described by the following general formula I: and pharmaceutically acceptable > salts thereof wherein: n is 0, 1 or 2; R I and J¾2 are the same or different and represent hydrogen or straight chain or branched alkyl having 1- 6 carbon atoms; X is hydrogen, hydroxy or chloroj W is phenyl, thienyl, or pyridyl; phenyl, thienyl, or pyridyl, each of which may'- be mono or disubstituted with halogen, hydroxy, straight or branched chain alkyl having 1-6 carbon atoms, amino, mono or dialkylamino where each alkyl is straight or branched chain having 1-6 carbon atoms, or straight or branched chain alkoxy having 1-6 carbon atoms; Y is 0| N-R3 where R3 is hydrogen, straight or chain alkyl having 1-6 carbon a henyl, pyridyl, or phenylalkyl where the alkyl is straight or branched chain haying 1-6 carbon atoms; aminoalkyl where the alkyl is a straight or branched chain having 1-6 carbon atoms, or mono or dialkyl aminoalkyl where each alkyl is a straight or branched chain . having 1-6 carbon atoms; 101285/3 - 18 - l-indanyl, 4-(ih!o)clfromanyl, 1 -( 1.2.3 , -leiruhytl ro- naphlhyl); l-indanyl, 4-(ih|o)chroinanyl, I -( 1 ,2,3,4-tetrahydro- napiitliyl) eacli of which is nionosuhstilutecl with ' halogen, slraight or branched chain ■ alkyl having 1-6 carbon aloms, or straight or branched chain alkoxy having 1-6 carhdn aloms; -COR or -SO2R4 where R4 is slraight or branched chain or l oxy alkyl j having 1-6 carbon atoms. phenyl, phenylalkyl where the alkyl is a slraight or branched chain . having 1-6 carbon atoms, or phenylalkoxy where the alkoxy is a slraight or branched chain alkoxy having 1-6 carbon aloms; C=0. CR6OR5. CR6COR5; CR6CO2 5. CR6OCOR5, and CR5R6. where 5 is hydrogen, straight or branched chain . 'alkyl having 1-6 carbon aloms, phenyl, pyridyl, or phenylalkyl where (lie alkyl is straight or branched chain having 1-6 carbon aloms; and fi is hydrogen, or straight or branched chain alkyl having 1-6 carbon aloms; CR6CONR7R8 or CR (CIl2)nN 7 8 where n is 0, I, or 2, and R and R7 are the same or different and represent hydrogen, or straight or branched chain -alkyl having 1-6 carbon atoms; and Rfi is hydrogen, slraight or branched chain - alkyl having 1-6 carbon phenyl, pyridyl, or phenylalkyl where the alkyl is slraight or branched chain having 1-6 carbon atoms; or NR7 8 's inorpholyl, piperidyl, pyrrolidyl, or N-alkyl piperazyl; C R9CO2R10 where Rfi is hydrogen, or straight or branched chain . alkyl having 1-6 carbon" atoms, and 101285/2 - 19 - Ro and R|0 are ,ne same or different and represent hydrogen, straight or branched chain - alky 1 having 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl where the alky 1 is straight or branched chain . liaving 1-6 carbon aloms; -CR6C(OH)Ri i 12 where Rn and R12 are the same or different and represent straight or branched chain alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where the alkyl is straight or branched chain '.having 1-6 carbon atoms, and R6 is hydrogen, or straight or branched chain- alkyl having 1-6 carbon atoms; or group of the formula: where m is 0, 1, or 2 Rj3 is hydrogen, straight or branched chain alkyl having 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl where the alkyl is straight or branched chain having 1-6 carbon atoms; Z is methylene, oxygen, NR|4 or CHCONRH where Rj is hydrogen, straight or branched chain alkyl having 1-6 carbon atoms, phenyl, pyridyl, or phenylalkykl where the alkyl is straight or branched chain having 1-6 carbon atoms; and T is methylene or oxygen. 101285/3 - 20 - The present invention also encompasses compounds of general formula II!.: 5 wherein: n is 0. 1 or 2; R ] an id 1*2 are lite same or different and represent hydrogen or straight or branched chain alkyl having 1- 10 6 carbon atoms; R5 is hydrogen, straight or branched ohain alkyl having 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl where the alkyl 15 is straight or branched chain . having 1-6 carbon aioms; and W is phenyl, "thienyl, or pyridyl; or 20 phenyl, thicnyl, or pyridyl, each of which may be mono or disiibstituted with halogen, hydroxy, straight or branched chain - alkyl having - 1-6 carbon atoms, amino, mono or dialkylamino where each alkyl is straight or branched chain 25 having 1-6 carbon atoms, or straight or branched chain alkoxy having 1-6 carbon atoms. 101285/3 - 21 - The present invention also,, encompasses compounds of general formula III» R I and R2 are the same or different and represent hydrogen or straight or branched chain -alkyl having 1- 6 carbon atoms; W is phenyl, thienyi, or pyridyl; or phenyl, thienyi, or pyridyl, each of which may be mono or distibstituted with halogen, hydroxy, straight or branched chain alkyl havin 1-6 carbon atoms, amino, mono or 15 dialkylamjno where each alkyl is straight or branched chain having 1-6 carbon atoms, or straight or branched chain alkoxy having 1-6 carbon atoms; and R3 is · 20 hydrogen, straight or branched chain alkyl having 1-6 carbon atoms, phenyl, pyridyl, or phcnylalkyl where the alkyl is straight or branched chain 'having 1-6 carbon atoms; ^ 25 aminoalkyl where the alkyl is a straight or branched chain having 1-6 carbon atoms, or mono or dialkyl aminoalkyl where each alkyl is , straight or branched chain . 'having 1-6 cnrbon atoms; 1-indanyl, 4-(ihio)chromanyl, I -( 1 ,2,3,4-tetraliydro- n a p h I h y I ) ; 1-indanyl, 4-(lhio)chromanyl, 1 -( 1 ,2,3,4-lclrahydro-naphthy I) each of which is monosnbslitiilcd with halogen, straight or 101285/2 - 22 - branched chain - alkyl having 1-6 carbon aloms, or straight or branched chain - alkoxy having 1-6 carbon atoms; or -COR4 or -SO2R4 where R4 is straight or branched chain alkyl, having 1-6 carbon atoms, phenyl, phenylalkyl where the alkyl is a straight or branched chain having 1-6 carbon atoms, or phenyjalkoxy where the alkoxy is a straight or branched chain ' alkoxy having 1-6 carbon atoms.

The present invention also encompasses eompounds of general formula IV: ;;' ' : " '·' here phenyl, thienyl, or pyridyl; phenyl, thienyl, or pyridyl. each of which may be mono or d i substituted with halogen, hydroxy, straight or branched chain . alkyl having 1-6 carbon atoms, amino, mono or dialkylamino where each alkyl is straight or branched chain having 1-6 carbon atoms, or straight or branched chain alkoxy having 1-6. carbon atoms; Z is methylene, oxygen, N 14 or CHCONR14 where R14 is hydrogen, straight or branched chain - alkyl having 1-6 carbon atoms, phenyl, pyridyl. or phenylalkykl where the alkyl is straight or branched chain having 1-6 carbon atoms; T is methylene or oxygen; and methylene or carbonyl. acceptable ,.

Pharmaceutically ■ j ■■ ^nlis include sails θΓ acids such as hydrochloric, phosphoric . hydrobromic. sulfuric, sulfinic, formic, toluene sulfonic, hydricdic, acetic and (lie like. Those skilled in the an will recognize a wide variety of pharmaceutically acceptable addition sails.

Representative compounds of the present invention, which are encompassed liy Formula I. include, but are not Jimiicd to the compounds in Figure I and . (heir pharmaceutically acceptable salts.

By alkyl in the present invention is meant straight or branched chain alkyl groaps having 1-6 carbon aioms, such as.- for example, methyl, ethyl, propyl, isopropyl. n-butyl, sec-butyl, tert-buiyl. pentyl, 2 -pen ( y I . isopentyl, neopentyl, hcxyl, 2-hc.xyl, 3-liexyl. and 3- ni e t h y I pe n ty I .

By alkoxy in the present invention is meant straight or branched chain alkoxy groups having 1.-6 carbon atoms, sucli as, for example, mcihoxy, ethoxy, propoxy. isopropoxy. n-buioxy, sec-butoxy, ten- butoxy, · pentylox , isopentyloxy , neopentyloxy , hexylory, 2-hexyloxy, ·. 3-hexyloxy, and 3-methylpentylox .

By halogen in the present invention is meant fluorine, bromine, chlorine, and iodine.

By N-aIkylpipera2y I in t'ne invention is meant radicals of the form u I a : — \ / where II is a straight or branched chain alkyl as defined above.

B 4-(thio)chronianyl is meant a radical of the formula: The pharmaceutical utility of compounds of this invention are indicated by the following assay for GABAa receptor activity.

Assays arc carried out as described in Thomas and Talimn (J. Bio. Chan. JLli: 983S-9342 . J. curosci. 1:433-440. 1 83). Rat cortical tissue is dissected and homogenized in 25 volumes (w/v) οΓ 0.05 M Tris IICI buffer (pil 7.4 at 4nC). The tissue homogcnnii is ccntri fiigctl in the cold 4°C at , 20,000 x g for 20'. The supernatant is decanted and the pellet is rehomogenized in the same volume of buffer and again centrifuged at 20,000 x g. The supernatant is decanted and the pellet is frozen at -20° C overnight. The pellet is then thawed and rehomogenized in 25 volume (original wt/vol) of buffer and the procedure is carried out twice. The pellet is finally resuspended in 50 volumes (w/vol of 0.05 M Tris HCl buffer (pH 7.4 at 40°C).

Incubations contain 100 μ ΐ of tissue homogenate, 100 μ ΐ of radioligand 0.5 nM (3 H-R015- 1788 [3 H-Flumazenil] specific activity 80 Ci/mmol), drug or blocker and buffer to a total volume of 500 μ ΐ . Incubations are carried for 30 min at 4°C then are rapidly filtered through GFB filters to separate free and bound ligand. Filters are washed twice with fresh 0.05 M Tris HCl buffer (pH 7.4 at 4° C) and counted , in a liquid scintillation counter. 1.0 μΜ diazepam is added to some tubes to determine nonspec ific binding. Data are collected in triplicate determinations, averaged and % inhibition of total specific binding is calculated. Total Specific Binding = Total - Nonspecific. In some cases, the amounts of unlabeled drugs is varied and total displacement curves of binding are carried out. Data are converted to a form for the calculation of IC50 and Hill Coefficient (nH).

Data for the compounds of this invention are listed in Table I.

TABLE I Compou nd Nu mber 0.100 2 0. 1 10 3 1.00 5 0.100 7 0.039 9 0.018 10 0.009 1 1 0.050 1 2 0.025 1 5 0.050 26 0.400 32 0.013 Compound numbers relate to compounds shown in Figure I. 101285/3 Compounds 7, 9. 10. 12 and 32 are particularly preferred embodiments of the present invention because of their potency in binding to the OABAa receptor.

The compounds of general formula I n ay be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous. intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier. One or more compounds of general formula I may be present in association with one or more pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other, active ingredients. The pharmaceutical compositions containing compounds of general formula I may be in a form suitable for oral use. for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or, more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearale, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient i ' mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin , or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such e x c i p i e n ts a re s u spend i ng agen ts , fo r e x am p l e s od i u m c arbox meth lcellu l ose , methylcel l ulose , hydropropy lmethy lcellu lose , sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethy lene oxide with long chain al iphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate. or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example 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.

Oi ly suspensions may be formulated by suspending the active ingredients in a vegetable oil. for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the . addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. S u itable dispersing or wetting agents and suspending agents are exempl ified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

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 liquid paraffin 101285/2 - 27- or m ix tures of these. Sui table emulsi fying agents may be natu ral ly- occurring gums, for example gum acacia or gum tragacanth, naturally - occ urring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hex ilol , anhydrides, for example sorbi tan monooleate , and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan nonooleate . The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated . wi th sweetening agents, for ex ample glycerol, propylene glycol, sorbitol or sucrose . Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formu lated according to the known art using those suitable dispersing or welting agents and suspending agents which have been mentioned above . The sterile injectable preparation may also be sterile injectable solution or suspension in a parentally acceptable di luent or solvent, for ex ample as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fi xed oil may be employed including synthetic mono- or diglycerides. In addition, fatly acids such as oleic acid find use in the preparation of i nj ec ta b l e s .

The compounds of general formula I may also be administered in the form of suppositories for rectal adm inistration of the drug. These composi tions can be prepared by mix ing the drug with a suitable non-i rritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

Compounds of general formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anaesthetics, preservatives and buffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingred ient thai may. be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active i n g red i en t.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

An illustration of the preparation of compounds of the present invention is given in Scheme I . Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention, as demonstrated by the following examples. 101285/2 101285/2 - 30 -I n is 0, 1 or 2; R I and R2 are Ihe same or different and represent hydrogen or straight chain or branched alkyl having 1- 6 carbon atoms; X is hydrogen, hydroxy or chloroj W is phenyl, lliienyl, or pyridyl; phenyl, lliienyl, or pyridyl, each of which may'* be mono or itsuhsli tilled with halogen, hydroxy, straight or branched chain alkyl having 1-6 carbon atoms, amino, mono or dialkylamino where each alkyl is straight or branched chain having 1-6 carbon atoms, or straight or branched chain alkoxy having 1-6 carbon atoms; Y is Oj N-R3 where R3 is hydrogen, straight or branc^ed^ chain alkyl having 1-6 carbon atoms, j phenyl, pyridyl, or phenylalkyl where the alkyl is straight or branched chain having 1-6 carbon atoms; aminoalkyl where the alkyl is a straight or branched chain having 1-6 carbon atoms, or mono or dialkyl aminoalkyl where each alkyl is a straight or branched cliain . having 1-6 carbon atoms; 101285/3 - 31 - l-imlanyl, 4-(ihio)chronianyl, 1 -( 1.2.3 , -let ra y tl ro- naphthyl); 1-indanyl, 4-(thio)chromany I. 1 -( 1 ,2,3,4-tetrahyclro- naplnliyl) each of which is monnsubsiiluted with halogen, slraiglit or branched chain · alky J having 1-6 carbon atoms, or straight or branched chain alkoxy having 1-6 carbon atoms; -COR4 or -SO2R4 where R4 is straight or branched chain or alkoxy alkyl having 1-6 carbon- atoms, phenyl,' phciiy lalky I where the alkyl is a straight or branched chain . having 1-6 carbon atoms, or phenylalkoxy where t e alkoxy is a straight or branched chain . alkoxy having 1-6 carbon atoms; C=0, CR6OR5. CR6COR5. CR6CO2R5. C ^OCORs. and CR5R6. where R5 is hydrogen, straight or branched chain alkyl having 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl where the alkyl is straight or branched chain having 1-6 carbon atoms; and R6 is hydrogen, or straight or branched chain alkyl having 1-6 carbon atoms; C 6CO R7R8 or CR6(Cll2)nNR7R8 where n is 0, 1, or 2. and R 6 and R7 are the same or different and represent hydrogen, or straight or branched chain - alkyl having 1-6 carbon atoms; and R 8 is hydrogen, straight or branched chain - alkyl having 1-6 carbon atoms, phenyl, pyridyl, or phenylaikyl where the alkyl is straight or branched chain ■' having 1-6 carbon atoms; or NR7R8 is morpholyl, piperidyl. pyrrolidyl, or N-alkyl piperazyl; CR6 R9CO2 1O where R 6 is hydrogen, or straight or branched chain . alkyl having 1-6 carbon ..atoms, and 101285/2 - 32 - R and R)0 are the same or different and represent hydrogen, straight or branched chain - alkyl having 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl where the alkyl is straight or branched chain 'having 1-6 carbon atoms; -CR6C(OH)Ri i R 12 where R\ \ and R\2 are the same or different and represent straight or* branched chain alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where the alkyl is straight or branched chain ' having 1-6 carbon atoms, and R6 is hydrogen, or straight or branched chain alkyl having 1-6 carbon atoms'; or a group of the formula: where m is 0, 1. or 2 13 is hydrogen, straight or branched chain alkyl having 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl where the alkyl is straight or branched chain having 1-6 carbon atoms; Z is methylene, oxygen, NR14 or CHCONRH where R14 is hydrogen, straight or branched chain alkyl having 1-6 carbon atoms, phenyl, pyridyl, or phenylalkykl where the alkyl is straight or branched chain " having 1-6 carbon atoms; and T is methylene or oxygen.

The invention is illustrated further by the follotfing examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures and compounds described in them.

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

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

Exam ple LLI A mixture of 2-Phenyi-5-nitro-4,6-dihydroxy-pyrimidine ( 10 g), diethylaniline (6 g) and phosphorus oxychloride ( 100 mL) was heated at reflux for 40 min. 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 the eluent to afford 2-Phenyl-5-nitro-4,6-dichloro-pyrimidine as a yellow solid. 101285/2 - 35 - Exa m ple I V A mixture of cyclohexanone (98 mg) and pyrrolidine (71 mg) and 4 A molecular sieves (500 mg) in 1 mL of benzene is allowed to stand at room temperature until enamine formation was complete (ca. 16 h). The resulting solution of enamine was cannulated into a solution of 2-Phenyl-5-nitro-4,6-dichloro-pyrimidine (270 mg) and diisopropylethyl-amine ( 129 mg) in 5 mL of methy lene chloride. After 30 min at room temperature the reaction mixture was concentrated in vacuo and treated with 3 mL of 3N HCl and 3 mL of ethanol. The reaction mixture was oonoentrated again and the residue was subjected to fl ash chromatography on silica gel wi th 20% ethyl acet ate/hex ane as the el uent to afford 2-[4-(2-Phenyl-5-nitro-6-chloro-pyrimidinyl)] -cyclohexan- l -one as a white solid. 101285/2 -36- Examnle .. Y (Compound 1) A mixture of 2-[4-(2-Pheny I-5-nitro-6-chloro-py rimidinyl)]- cyclohexan-l-one (280 mg), triethylamine (300 mg) and 10% Pd/C catalyst ( 25 mg) in 10 mL of ethanol was hydrogenated under 1 atmosphere of hydrogen at room temperature for 16 h. After filtration through Celite the I solvent was removed in vacuo and the residue was subjected to flash chromatography on silica gel with 50% ethyl acetate hexane as the eluent to afford 2-PhenyI-6,7,8,9-tetrahydro-5H-indolo[3.2-d]-pyrimidine melting at 197-198°C (Compound 1) after trituration with hexane/ether. 101285/2 -37- EXA PLE YI The following compounds were prepared essentially according to the procedure described in Example V: a) : 2-Phenyl-cyclopent(g)-5H-pyrrolo[3,2-d]-pyrimidine Compound 2). pyrimidine Compound 3), m.p. 20l-203°C. c) 2-Phenyl-8-methoxy-6,7.8,9-tetrahydro-5H-indolo[3,2-d]- pyrimidine (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°€. e ) 2-Pheny!-8-n-propyloxy-6,7,8,9-tetrahydro-5H-indolo[3,2-d]-pyrynidine (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), m.p. 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 VII To a mixture of 4-bromo-l -butene (1.0 g) and magnesium turnings ( 1.77 g) in dry tetrahydrofuran (10 mL) was added a crystal of iodine and the mixtures was stirred at room temperature until complete reaction had occurred. To this mixture was added 1 ,4-cyclohexanedione monoethylene ketal (780 mg) in tetrahydrofuran (1 mL) at 0°C. After 1 h at 0°C and 1 h at room temperature the reaction mixture was diluted with ammonium chloride solution and the product was extracted with ether. After drying over magnesium sulfate the solvent was removed in vacuo and the residue was subjected to flash chromatography with 25% ethyl actetate hexane as the eluent to afford 4-(3-Butenyl)-4-hydroxy-cyclohexanone ethylene ketal as an oil.

K*fl m p lP VIII A mixture of 4-(3-Butenyl)-4-hydroxy-cyclohexanone ethylene ketal ( 1.8 g) in methanol (40 mL) was ozonized at -70° C until a persistant blue color was obtained. The ozonide was decomposed with excess sodium borohydride at -60° C. The reaction 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 in vacuo. The residue was purified by flash chromatography with ethyl acetate as the eluent to afford 4-(3-Hydroxypropyl)-4-hydroxy-cyclohexanone ethylene ketal as an oil.

- - Air was bubbled into a solution of cuprous chloride (30 mg) and palladium dichloride (5 mg) in dimethylformamide (7.5 mL) and water (3 mL) for 2 h. 4-(3-Butenyl)-4-hydroxy-cyclohexanone ethylene ketal (300 mg) was added and the reaction was continued for 36 h. The reaction mixture was diluted with water and the product was 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 worked up as before and the residue was subjected to flash chromatography with ethyl acetate as the eluent to afford 4-(3- Hydroxybutyl)-4-hydroxy-cycIohexanone ethylene ketal as an oil.

Example X A mixture of 4-(3 -Hydroxypropy l)-4-hydroxy-cyclohexanone ethylene ketal (1.4 g) and diisopropylethylamine (3.37 mL) in methylene chloride (100 mL) at -78°C was treated with triflic anhydride (1.64 mL). After 30 min the reaction mixture was washed with water, the solvent was dried over magnesium sulfate and removed in vacuo. The residue was dissolved in 30 mL of tetrahvdrofuran and 15 mL of 3% HCl. After 5 h at room temperature the reaction mixture was diluted with water and the product was extracted with ether. After drying over magnesium sulfate the solvent was removed in vacuo to afford l-Oxaspiro[4.5]decan-8-one as an oil.

Example XI A mixture of Cyclohexane- l ,4-dione monoethylene ketal (2.0 g), N- Methyl-hydroxylamine hydrochloride ( 1.079g), sodium bicarbonate ( 1.09 g) and ethanol (20 mL) was stirred at room temperature for 18 h. The ethanol was removed in vacuo and the residue was taken up in 30 mL of toluene. After filtration, ethyl acrylate (2.2 g) was added to the filtrate and the resulting mixture was heated for 4 h at 100°C. The solvent was removed in vacuo and the resulting isoxazolo derivative was purified by flash chromatography on silica gel with 50% ethyl · acetate hexane as the eluent. This material was hydrogenated at 45 psi in 50 ml of acetic acid over 10% palladium on carbon catalyst (400 mg) at room temperature for 16 h. After filtration and removal of solvent the residue was purified by filtration through silica gel with ethyl acetate as the eluent to afford 3-Hydroxy- l -methyl- l -azaspiro[4.5 ]-decane-2,8-dione ethylene ketal as an oil.

Example XII To a mixture of 3-Hydroxy- l -methyl- l -azaspiro[4.5]decane-2,8-dione ethylene ketal ( 1.0 g), triethylamine ( 1.73 mL) and methylene chloride ( 10 mL) was added methanesulfonyl chloride (950 mg) dissolved in methylene chloride (5 mL) in a dropwise fashion at 0° C. After 30 min the reaction mixture was washed with water, the organic layer dried over magnesium sulfate and the solvent was removed in vacuo. The resulting residue was filtered through silica gel with ethyl acetate as the eluent to afford 3-Mesyloxy- 1 -methyl- l -azaspiro[4.5]decane-2,8-dione ethylene ketal as an oil.

Examole XIII A mixture of 3-Mesyloxy- l -methyl-l -azaspiro[4.5]decane-2,8-dione ethylene ketal ( 1.28 g). sodium iodide (1.8 g) and acetone (20 mL) was refluxed with stirring for 90 min. The solvent was removed in vacuo a n d 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 mL) and treated with tri-n-butyltin hydride (1.75 g) and AIBN (20 mg) and the resulting mixture was heated at 1 1 0 ° C for 1 h. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate as the eluent. The resulting product was stirred with a mixture of water (5 mL), 3N HCl (1.5 mL) and acetic acid (2 mL) for 16 h. The resulting product was extracted 3 times with methylene chloride, washed with sodium bicarbonate solution, dried over magnesium sulfate and the solvent was removed in vacuo to afford 1 -Methyl- l -azaspiro[4.5]decane-2,8-dione as an oil.

F.xamnlP XIV A mixture of l-Methyl-l-azaspiro[4.5]decane-2,8-dione (100 mg) and pyrrolidine (43 mg) and 4A molecular sieves (500 mg) in 1 mL of benzene is allowed to stand at room temperature until enamine formation was complete (ca. 16 h). The resulting solution of enamine was cannulated into a solution of 2-Pheny l-5-nitro-4,6-dichloro-pyrimidine (162 mg) and diisopropylethyl-amine (78 mg) in 3 mL of methylene chloride. After 3 h at room temperature the reaction mixture was treated with 2 mL of 3N HCl and 3 mL of water and stirring was continued for 20 min. The organic layer was separated, dried over magnesium sulfate and the solvent was removed n vacuo. The residue was subjected to flash chromatography on silica gel with ethyl acetate as the eluent to afford l-Methyl-7-[4-(2-phenyl-5-nitro-6-chloro-pyrimidinyl)]-l-azaspiro[4.5]decane-2,8-dione as a white solid. 101285/2 -43- (Compound 11) A mixture of 1 -Methyl-7-[4-(2-phenyl-5-nitro-6-chloro-pyrimidinyl)]-l -azaspiro[4.5]decane-2,8-dione (92 mg), triethylamine (60 mg) and 10% Pd/C catalyst ( 15 mg) in 5 mL of isopropanol and 1 mL of ethyl acetate was hydrogenated under 1 atmosphere of hydrogen at room temperature for 16 h. After filtration through Gelite 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 the eluent to afford -Met y 1 -2-phen.y 1-5,6,7, 9-ieirahydro-sp iro[indolo[ 3,2-dJ-pyrimi dine-2',8-pyrrolidin-5'-one] (Compound 11), m.p. 310-315°C after trituration with he x ane/et er.

EXAMPLE XVI The following compounds were prepared essentially according to the procedure described in Example XV: a) 2,-Phenyl-5,l6'.7'.9'-lelrahydro-spiro[(1.3)dioxolane-2.8'-indolo[3.2-d]-pyrimidine] (Compound 12), m.p. 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[(l,3)dioxolane-2,8,-indolo[3,2-dJ-pyriniidine] (Compound 14), m.p. 197-199°C. d) 2'-(4-Methoxypheny 0-4.5, 5',6', 7', 9'-hcxahydro-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-spirotfuran-2,8'(3H)-indolo[3,2-d]-pynmidine] (Compound 16), m.p. 208-210°C. f) 2'-(4-Fluorophenyl)-5',6',7',9'-tetrahydro-spiro[(l,3)dioxolane-2,8'-indolo[3,2-d]-pyrimidine] (Compound 17), m.p. 108-109°C. g) 5-Mcthyl-2'-phenyl-4,5,5,,6,,7'.9,-hexahydro-spiro[furan- 2,8'(3H)-indolo[3,2-d]-pyrimidine] (Compound 18). h) 4'-Methyl-2-(2-fluorophenyl)-5,6,7,9-tetrahydro-spiro[indolo[3,2-d]-pyrimidine-2',8-pyrrolidin-5'-one] (Compound 19), m.p >260OQ i) -Methyl-2-(4-methoxyphenyl)-5,6,7.9-tetrahydro-spiro[indolo[3,2-d]-pyrimidine-2',8-pyrrolidin-5'-one] (Compound 20), m.p 340-343°C. j) 2'-(2-Fluorophenyl)-5',6',7',9'-tetrahydro-spiro[(l,3)dioxolane-2,8'-indolo[3,2-d]-pyrimidine] (Compound 21), m.p. 218-220°C. k) 2'-(3-Fluorophenyl)-5',6',7',9'-tetrahydro-spiro[(l ,3)dioxolane-2,8'-indolo[3,2-d]-pyrimidine] (Compound 22), m.p. 214-216°C. 1 ) r-Methyl-2-thienyl-5,6.7,9-tetrahydro-spiro[indolo[3,2-d]-pyrimidine-2',8-pyrrolidin-5'-one] (Compound 23), m.p. 335°C(dec). m ) r-Benzyl-2-phenyl-5.6,7,9-tetrahydro-spiro[indolo[3,2-d]-pyrimidine-2',8-pyrrolidin-5'-one] (Compound 24), m.p. 296-298°C.

Example XVII A mixture of l -Benzoyl-piperidin-4-one (244 mg) and pyrrolidine (85 mg) and 4A molecular sieves (500 mg) in 2 mL of benzene is allowed to stand at room temperature until enamine formation was complete (ca. 24 h). The resulting solution of enamine was cannulated into a solution of 2-Phenyl-5-nitro-4,6-dichloro-pyrimidine(325 mg) and triethyl-amine (200 mg) in 4 mL of chloroform. After 30 min at room temperature the reaction mixture was treated with 4 mL of 2N HC1 and stirring was continued for 20 min. The organic layer was separated and dried over magnesium sulfate and the solvent was removed in vacuo. The residue was subjected to flash chromatography on silica gel with 30% ethyl acetate in hexane as the eluent to afford l -Benzoyl-3-[4-(2-phenyl-5-nitro-6-chloro-pyrimidinyl)]-piperidin-4-one as a white solid.

Fmmnle XVfif (Compound 25) A mixture of l -Benzoyl-3-(4-(2- henyl-5 -ni tro-6- c loropy rimiiiiny I) ]-p i eri rfi n-4-one (100 nig), triethy lamine (100 mg) and 10% Pd/C catalyst ( 100 nig) in 6 niL of ethanol was hydrogenated under 1 atmosphere of hydrogen at room temperature for 5 h. After filtration through Celita the solvent was removed in vacuo and the residue was subjected to flash chromatography on silica gel with 30% et l acetate in hixane as the eluent to afford 8-Benzoyl-2-pheny 1-5,6.7.9-tetrahyd ro-5H- pyrido[4.3-b]-pyrimidino[4,5-d]-pyrj-ole (Compound 25). m.p. 264-2o6°C after trituration with ether.

FYA Pf.fr YTV The following compounds were prepared essentiall according ;to the procedure described in Example XVIII: a) 2 · P en y I -5.6.7.9 · te t rahy d ro -5 H -py rano [ .3 -': ; -py ri m i d i n o [4 ,5 -d j -pyrrole: (Compound 26). ■ b) 8-Carboethox -2-(4-methoxyphenyl)-5,6,7,9-tetrahyd ro-5 H-pyrido[4.3-b]-pyrimidino[4.5-d|-pyrrole ('Compound 27). 101285/2 -47- F.xamplfe XX (Compound 28) A mixture of 2 - [4 r( 2 -(4 - Me thox y ph e ny I - 5 - n i t ro - 6-chloropyrimidinyl)]-cyclopentan-l-one (200 mg) and 10% Pd/C catalyst (100 mg) in 10 niL of ethanol was hydrogenated under 1 atmosphere of hydrogen at room temperature for 2 h. After filtration through ^elite he solvent was removed in vacuo and the residue was subjected to flash chromatography on silica gel with 20% ethyl acetate in hexane as the eluent to afford 4-Chloro-2-(4-methoxyphenyl)-cycIopent(g)-5H-pyrrolo[3,2-d]-pyrimidine (Compound 28) as a white solid.

EXAMPLE XXI The following compound was prepared essentially 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).

Examnle XXII (Compound 30) A mixture of 2,-Phenyl-6,,7',8',9'-tetrahydro-spiro[(l,3)dioxolane-2,8'(5H)-indolo[3,2-d]-pyrimidine] (200 mg), 3N sulfuric acid (1.5 mL) and methanol (1.5 mL) was 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 over magnesium sulfate, the solvent was remov ed in vacuo and the residue was crystallized froom ether/hexane to afford 2-Phenyl-5,6,7,9-tetra-hydro-8H-indolo[3,2-d]-pyrimidin-8-one (Compound 30) melting at 246-247°C. 101285/2 -49- (Compound 31) To 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 added lithium aluminum hydride (100 mg) in one portion. After 1 h at room temperature the reaction was quenched with IN NaOH, the reaction was filtered through Celite and the solvent was removed in vacuo and the residue was subjected to flash chromatography on silica gel with 10% methanol in methylene chloride as the eluent to afford 8-Hydroxy-2-phenyl-6,7,8.9-tetrahydro-5H-indolo[3.2-d]-pyrimidine (Compound 31) melting at 211-212°C.

Example XXIY The following compounds were prepared essentially 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-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) r-Methyl-2-phenyl-5,6,7,9-tetrahydro-spiro[indolo[3,2-d]-pyrimidine-2',8-pyrrolidine] (Compound 36), m.p. 187-190°C. 0 4-Chloro-8-methyl-2-phenyl-5,6.7,9-tetrahydro-5H-pyrido[4,3-b]-pyrimidino[4,5-d]-pyrrole monohydrochloride (Compound 37), m.p. 218-220 °C.

Exampls XXV 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 l-Phenyl-l,2-ethanediol (53 mg) in benzene (10 mL) was refluxed for 10 h in a Dean-Stark apparatus. The solvent was removed in vacuo and the residue was subjected to flash chromatography to afford 2-Phenyl-2'-phenyl-6\7\8\9'-tetrahydro-spiro[(l,3)dioxolane-2,8,(5H)-indolo[3.2-d)-pyrimidine] (Compound 38) as an amorphous solid. 101285/2 -52- Kxamnle XXVI (Compound 39) A mixture of . 8-Benzoyl-2-phenyl-5,6,7,9-tetrahydro-5H-pyrido[4,3-b]-pyrimidino[4,5i^d]-pyrrole (180 mg), 50% sodium hydroxide (lmL) and ethanol (1 mL) j refluxed with stirring for 4 h. The reaction mixture was neutralized with dilute HCI and the product was extracted into chloroform. After drying over magnesium sulfate the sojvent was removed in vacuo. The residue was treated with HCI in isopropanol to afford 2-Phenyl-5,6.7,9-tetrahydro- H-pyrido[4,3-b)-pyrimidino[4,5-d]-pyrrole . monohydrochloride (Compound 39). m.p. 284-287°C. 101285/2 -53- E mp XXVII (Compound 40) compound 39 A mixture of j .. (46 mg), potassium carbonate (lOOmg), allyl bromide (I81L) and dimethyl formamide (3 mL) was heated at 100°C for I h with stirring. The reaction mixture was poured onto water and the product was extracted with methylene chloride. After drying over magnesium sulfate the solvent was removed in vacuo. The residue was treated with ethanolic HCI/ ether to afford 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 XXVHI The following compounds were prepared essentially according to the procedures described in Examples I-V: a) 2-(3-Methylphenyl)-6.7.8,9-teirahydro-5H-indolo[3.2-d]-pyrimidine (Compound 41), m.p. 118- 121 °C . b ) 2-(2-Thienyl)-8-carboisoprbpoxy-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-(3-MelhoxyphenyI)-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. f ) 2-(4-Methoxyphenyl)-8-carbomethoxy-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.l99-201°C. k ) 2-(3,4-Methylenedioxyphenyl)-6,7,8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine (Compound 51). 1 ) 2-(3-Methoxy phenyl )-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)-6.7,8,9-teirahydro-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]-pyrimidinc (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-carboisopropoxy-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-methoxy phenyl )-6, 7,8,9- tetrahydro-5H-indolo[3.2-d]-pyrimidine (Compound 64), m.p. 189-191°C. y ) 2-(4-Flu0ro-3-methoxyphenyl)-6.7,8,9-tetrahyd 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). 101285/2 -56- EXAMPLE XXIX The following compounds were prepared essentially according to the procedures described in Examples VI-XVII: a) 1 '-Benzyl-2-(4-methoxyphenyl)-5.6,7,9-tetrahydro-spiro[indolo[3.2-dl-pyrimidine-2\8-pyrrolidine] (Compound 67). m.p. 101- 103°C. b) r-Benzyl-2-phenyl-5,6,7,9-tetrahydro-spiro[indolo[3;2-d]-pyrimidine-2'.8-pyrrolidine] (Compound 68). m.p. 138-139°C. c) 2'-(4-Elhoxyphenyl)-5'.6',7',9'-tetrahydro-spiro[( 1 ,3)dioxolane-2.8'-indolo[3.2-d]-pyrimidine] (Compound 69). m.p. 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) -Benzyl-2-(2-thienyl)-5.6.7.9-tetrahydro-spiro[indolo[3.2-d]-pyrimidine-2'.8-pyrrolidin-5One] (Compound 72), m.p. 290-292°C. g) r-Benzyl-2-(2-thienyl)-5.6.7.9-tetrahydro-spiro[indolo[3.2-d]-pyrimidine-2'.8-pyrrolidine] (Compound 73). m.p. 227-230°C h ) 2-(4-Methoxyphenyl)-8-(N.N-dimethylcarhamoyl^ -6.7.8.9-tetrahydro-5H-indolo[3.2-d)-pyrimidine (Compound 74), m.p. 240^242°C. i ) 2-(4-Methoxyphenyl)-8-(N,N-dimelhylaminomethyl)-6, 7,8,9-tetrahydro-5H-indolo[3.2-d|-pyrimidine (Compound 75), m.p. 81-85°C. j) 2-(4- ethoxyphenyl)-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-(acetyloxymethyl)-6.7,8.9-tetra hydro -5H-indolo[3.2-d]-pyrimidine (Compound 77), m.p. 240-242°C.

The invention and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification.

Claims (3)

101285/2 -58- WIIAT IS CLAIMED IS:

1. A compound of the formula: and pharmaceutically acceptable " salts thereof wherein: n is 0, 1 or 2; R i and R2 are the same or different and represent hydrogen or straight chain or branched alkyl having 1- 6 carbon atoms; X is hydrogen , hydroxy or chloroj W is phenyl, thienyl, or pyridyl; phenyl, thienyl, or pyridyl, each of which may'' be mono or disubstituted with halogen, hydroxy, straight or branched chain alkyl having 1-6 carbon atoms, amino, mono or dialkylamino where each alkyl is straight or branched chain having 1-6 carbon atoms, or straight or branched chain alkoxy having 1-6 carbon atoms; Y is Oj N-R3 where R3 is hydrogen, straight or branc^ed^ chain alkyl having 1-6 carbon atoms, j phenyl, pyridyl, or phenylalkyl where the alkyl is straight or branched chain ' having 1-6 carbon atoms; aminoalkyl where the alkyl is a straight or branched chain having 1-6 carbon atoms, or mono or dialkyl aminoalkyl where each alkyl is a straight or branched chain . having 1-6 carbon atoms; 101285/3 -59- 1-intlnnyl, 4-(lhio)cliromanyl, 1 -( 1.

2.

3.4-ietrahydro- napht yl); 1 - i rid any 1. 4-(thio)chromanyl, l-( 1 ,2,3.

4. -leirahydro- naphthyl) each of which is monosubstituted wilh halogen, straight or branched chain · alky I having 1-6 carbon atoms, or straight or branched chain alkoxy having 1-6 carbtfn atoms; -COR4 or -SO2R4 where R4 is straight or branched chain - or alkoxy alky 1 having 1-6 carbon atoms, phenyl, phenylalkyl where the alkyl is a straight or branched chain . having 1-6 carbon atoms, or plicnylalkoxy where the alkoxy is a straight or branched chain alkoxy having 1-6 carbon atoms; C=0. CR6OR5. CR6COR5. CR6CO2R5. CR6OCOR5, and CR5R6. where R5 is hydrogen, straight or branched chain alkyl having 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl where the alkyl is straight or branched chain having 1-6 carbon atoms; and Rg is hydrogen, or straight -or branched chain alkyl having 1-6 carbon atoms; CR6CONR7R8 or CR6(Cll2)n R7 8 where n is 0, 1, or 2, and R 6 and R7 are the same or different and represent hydrogen, or straight or branched chain -alkyl having 1-6 carbon atoms; and R8 is hydrogen, straight or. branched chain - alkyl having 1-6 carbon -atoms, phenyl, pyridyl, or phenylalkyl where the alkyl is straight or branched chain having 1-6 carbon atoms; or NR7R8 is morpholyl, piperidyl, pyrrolidyl, or N-alkyl piperazyl; CR6 R9CO2R10 where R6 is hydrogen, or straight or branched chain . alkyl having 1-6 carbon .atoms, and 101285/2 -60- Ro and Rjo are the same or different and represent hydrogen, straight or branched chain . - ■ alk t having 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl where the alky 1 is straight or branched chain .. ^having 1-6 carbon atoms; -CR6C(OH)RiiRl2 where K\\ and R\2 are the same or different and represent straight or branched chain alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where the alkyl is straight or branched chain · naving j.g carbon atoms, and R6 is hydrogen, or straight or branched chain alkyl having 1-6 carbon atoms'; or group of the formula: where m is 0, 1, or 2 Rl3 is hydrogen, straight or branched chain alkyl having 1-6 carbon atoms, phenyl, pyridyl. or phenylalkyl where the alkyl is straight or branched chain having 1-6 carbon atoms; Z is methylene, oxygen, R14 or CHCONR14 where R14 is hydrogen, straight or branched chain alkyl having 1-6 carbon atoms, phenyl, pyridyl, or phenylalkykl where the alkyl is straight or branched chain - having 1-6 carbon atoms; and T is methylene or oxygen. 101285/3 -61- A compound according lo Claim 1 which is: rein: n is 0, 1 or 2; R i and R2 are (he same or different and represent hydrogen or straight or branched chain . > alkyl having 1- 6 carbon atoms: 1*5 is , hydrogen, straight or branched chain alkyl having 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl where the alkyl is straight or branched chain . having 1-6 carbon atoms; and W is phenyl, "ihienyl, or pyridyl; or phenyl, thicnyl, or pyridyl, each of which may be mono or disubstituled with halogen, hydroxy, straight or branched ; chain alkyl having 1-6 carbon atoms, amino, mono or dialkylamino where each alkyl is straight or branched chain having 1-6 carbon atoms, or straight or branched chain - alkoxy having 1-6 carbon atoms. 101285/3 -62- 3. A compound according to Claim 1 which is: re . R l and R2 are the same or different and represent hydrogen or straight or branched chain -alkyl having 1- 6 carbon atoms; W is phenyl, thienyl, or pyridyl; or phenyl, thienyl, or pyridyl, each of which may be mono or tl i substituted with halogen, hydroxy, straight or branched chain alkyl having 1-6 carbon atoms, amino, mono or dialkylamino where each alkyl is straight or branched chain having 1-6 carbon atojns, or straight or branched chain alkoxy having 1-6 carbon atoms; and R3 is hydrogen, straight or branched chain alkyl having 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl where the alkyl is straight or branched chain 'having 1-6 carbo atoms; aminoalkyl where the alkyl is a straight or branched chain having 1-6 carbon aloms, or mono or dialkyl aminoalkyl where each alkyl is a straight or branched chain . 'having 1-6 carbon atoms; l-indanyl, 4-(thio)chromanyl. 1 -( 1 ,2,3,4-tetrahydro- naphthyl); l-indanyl, 4-(thio)chromanyl, l-( 1 ,2,3,4-ictrahydro-naphthyl) each of which is monosnbslihiled with halogen, straight or 101285/2 -63- branched chain - alkyl having 1-6 carbon atoms, or straight or branched chain ~ alkoxy having 1-6 carbon atoms; or -COR4 or -SO2R4 where R4 is straight or branched chain alkyl, having 1-6 carbon atoms, phenyl, phenylalkyl where the alkyl is a straight or branched chain having 1-6 carbon atoms, or phenylalkoxy where the alkoxy is a straight or branched chain alkoxy having 1-6 carbon atoms. compound according to Claim 1 which is: here thienyl, or pyridyl; phenyl, thienyl, or pyridyl, each of which may be mono or disubstituted with halogen, hydroxy, straight or branched chain . alkyl having 1-6 carbon atoms, amino, mono or dialkylamino where each alkyl is straight or branched chain having 1-6 carbon atoms, or straight or branched chain alkoxy having 1-6. carbon atoms; Z is methylene, oxygen, NRj4 or CHCONR14 where R14 is hydrogen. straight or branched chain - alkyl having 1-6 carbon atoms, phenyl, pyridyl, or phenylalkykl where the alkyl is straight or branched chain having 1-6 carbon atoms; T is methylene or oxygen; and U is methylene or carbonyl.

5. A compound according to Claim I, wherein Y is -NR3, X is hydrogen, n is 1, and R] and R2 are hydrogen.

6. A compound according to Claim 5, wherein R3 is benzyl or substituted benzyl.

7. A compound according to Claim 1, wherein Y is -NCOR4, X is hydrogen, n is 1, and Ri and R2 are hydrogen.

8. A compound according to Claim 7, wherein R4 is phenyl.

9. A compound according to Claim 1, wherein Y is -CR5R6, X is hydrogen, n is 0 or 1, and Ri and R2 are hydrogen.

10. A compound according to Claim 9, wherein R5 is hydrogen and Rg is branched chain lower alkyl having 1-6 carbon atoms.

11. A compound according to Claim 1, wherein Y is -CHOCOR5, X is hydrogen, n is 0 or 1, and R\ and R2 are hydrogen.

12. A compound according to Claim 11, wherein R5 is ethyl.

13. A compound according to Claim 1, wherein Y is -C=0, X is hydrogen, n is 1 and R\ and R2 are hydrogen.

14. A compound according to Claim 1, wherein Y is -CH2-, X is hydrogen, n is 0 or 1 and Rj and R2 are hydrogen.

15. A compound according to Claim 1, wherein Y is 1,3-dioxolane, X is hydrogen, n is 1 and Rj and R2 are hydrogen.

16. A compound according to claim 1, which is 2-phenyl-6,7,8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine.

17. A compound according to claim 1, which is 2-Phenyl-cyclopent(g)-5H-pyrrolo[3,2-d]-pyrimidine.

18. A compound according to claim 1, which is 2-Phenyl-cyclohept(g)- 5H-pyrrolo[3,2-d]-pyrimidine.

19. A compound according to claim 1, which is 2-Phenyl-8-methoxy- 6,7,8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine.

20. A compound according to claim 1, which is 2-Phenyl-8-benzyloxy- 6,7,8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine.

21. A compound according to claim 1, which is 2-Phenyl-8-n-propyloxy-6,7,8,9-tetrahydro-5H-indolo[3,2-d]-p rimidine.

22. A compound according to claim 1, which is 2-(4-Methoxyphenyl)-6.7,8,9-tetrahydro-5H-indolo[3.2-d]-pyrimidine.

23. A compound according to claim 1, which is 2-(2-Fluorophenyl)-6,7,8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine.

24. A compound according to 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.

26. A compound according to claim 1, which is l'-Methyl-2-phenyl-5,6,7,9-tetrahydro-spiro[indolo[3,2-d]-pyrimidine-2',8-pyrrolidin-5'-one].

27. A compound according to claim 1, which is 2'-Phenyl-5',6',7',9'-tetrahydro-spiro[(l,3)dioxolane-2,8'-indolo[3,2-d]-pyrimidine].

28. A compound according to claim 1, which is 2'-Phenyl-4,5,5'.6',7\9'-hexahydro-spiro[furan-2,8'(3H)-indolo[3,2-d]-pyrimidine].

29. A compound according to claim 1, which is 2'-(4-Methoxy-phenyl)-5',6',7',9,-tetrahydro-spiro[(1.3)dioxolane-2,8,-indolo[3,2-d]-pyrimidine].

30. A compound according to claim 1, which is 2'-(4-Methoxy-phenyl)-4,5.5',6,,7*,9'-hexahydro-spiro[furan-2,8'(3H)-indoIo[3,2-d]-pyrimidine].

31. A compound according to claim 1, which is 2'-(2-Fluorophenyl) 4,5,5'.6',7',9'-hexahydro-spirotfuran-2,8,(3H)-indolo[3,2-d]-pyrimidine].

32. A compound according to claim 1, which is 2'-(4-Fluorophenyl) 5',6',7',9'-tetrahydro-spiro[(l,3)dioxolane-2,8,-indolo[3,2-d]-pyrimidine].

33. A compound according to claim 1, which is 5-"Methyl-2'-phenyl 4.5,5'.6',7,,9'-hexahydro-spiro[furan-2,8'(3H)-indolo[3,2-d]-pyrimidine].

34. A compound according to claim 1, which is l'-Methyl-2-(2 fluorophenyl)-5,6,7,9-tetrahydro-spiro[indolo[3,2-d]-pyrimidine-2',8-pyrrolidin-5'-one].

35. A compound according to claim 1, which is l'-Methyl-2-(4-methoxyphenyl)-5,6,7,9-tetrahydro-spiro[indolo[3,2-d]-pyrimidine-2',8-pyrrolidin-5'-one].

36. A compound according to claim 1, which is 2'-(2-Fluorophenyl)-5\6\7\9'-tetrahydro-spiro[(l,3)dioxolane-2,8 ndolo[3.2-d]-pyrimidine].

37. A compound according to claim 1, which is 2'-(3-Fluorophenyl)-5',6',7\9'-tetrahydro-spiro[( 1 ,3)dioxolane-2,8'-indolo[3,2-d]-pyrimidine].

38. A compound according to claim 1, which is l'-Methyl-2-thienyl-5,6,7,9-tetrahydro-spiro[indolo[3.2-d]-pyrimidine-2',8-pyrrolidin-5'-one].

39. A compound according to claim 1, which is l'-Benzyl-2-phenyl-5,6.7,9-tetrahydro-spiro[indolo[3.2-d]-pyrimidine-2',8-pyrrolidin-5'-one].

40. A compound according to claim 1, which is 8-Benzoyl-2-phenyl-5,6,7,9-tetrahydro-5H-pyrido[4,3-b]-pyrimidinot4,5-d]-pyrrole.

41. A compound according to claim 1, which is 2-Phenyl-5,6,7,9-tetrahydro-5H-pyrano[4,3-b]-p rimidino[4,5-d]-pyrrole.

42. A compound according to claim 1, which is 8-Carboethoxy-2-(4- methoxyphcnyl)-5,6,7,9-tetrahydro-5H-pyrido[4,3-b]-pyrimidino[4,5-d]- pyrrole. 5

43. A compound according to claim 1, which is 4-Chloro-2-(4- methoxyphenyI)-cyclopcnt(g)-5H-pyrrolo[3,2-d]-pyrimidine.

44. A compound according to claim 1, which is 8-Carboethoxy-4-chloro- 2-(4-methoxyphenyl)-5,6,7,9-tetrahydro-5H-pyrido[4,3-b]-pyrimidino[4,5- 10 d]-pyrrole.

45. A compound according to claim 1, which is 2-Phenyl-5,6,7,9- tetrahydro- 8H-indoloI3,2-d]-pyrimidin-8-one. 15

46. A compound according to claim 1, which is 8-Hydroxy-2-phenyl- 6,7.8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine.

47. A compound according to claim 1, which is 8-Benzyl-2-phenyl- 5,6.7,9-tetrahydro-5H-pyrido[4,3-b]-pyrimidino[4,5-d]-pyrrole 20 monohydrochloride.

48. A compound „ according to claim 1, which is 8-Benzyl-2-(4- methoxyphenyl)-5,6,7,9-tetrahydro-5H-pyrido[4,3-b]-pyrimidino[4,5-d]- pyrrole monohydrochloride. 25

49. A compound according to claim 1, which is 8-Benzyl-2-(2- Huorophenyl)-5,6,7.9-tetrahydro-5H-pyridof4,3-b]-pyrimidino[4,5-d]- pyrrole monohydrochloride. 30

50. A compound according to claim 1, which is 8-Methyl-2-phenyl- 5,6,7,9-tetrahydro-5H-pyrido[4,3-b]-pyrimidino[4,5-d]-pyrrole monohydrochloride.

51. A compound according to claim 1, which is l'-Methyl-2-phenyl-35 5,6,7,9-tetrahydro-spiro[indolo[3,2-d]-pyrimidine-2*,8-pyrrolidine].

52. A compound according to claim 1, which is 4-ChIoro-8-methyl-2- phen l-5,6,7,9-tetrahydro-5H-pyridot4,3-b]-pyrimidino[4,5-d]-pyrrole monohydrochloride.

53. A compound according to claim 1, which is 2-Phenyl-2'-phenyl- 6',7',8'.9'-tetrahydro-spiro[(l,3)dioxolane-2,8'(5H)-indolo[3,2-d]pyrimidine].

54. A compound according to claim 1, -which is 2-Phenyl-5,6,7,9- tetrahydro-5H-pyrido[4,3-b]-pyrimidino[4,5-d] -pyrrole monohydrochloride.

55. A compound according to claim 1, which is 8-Allyl-2-phenyl-5,6,7,9- tetrahydro-5H-pyrido[4,3-b]-pyrimidino[4, 5 -d] -pyrrole monohydrochloride.

56. A compound according to 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-carboisopropoxy-6,7,8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine.

58. A compound according to claim 1. which is 2-(4-Ethoxyphenyl)-6,7,8,9-tetrahydro-5H-indoIo[3,2-d]-pyrimidine.

59. A compound according to claim 1, which is 2-(3-Methoxyphenyl)-6,7,8,9-tetrahydro-5H-indolo[3.2-d]-pyrimidine.

60. A compound according to claim 1, which is 2-(4-Methoxyphenyl)-7-methyl-6,7,8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine.

61. A compound according to claim 1, which is 2-(4-Methoxyphenyl)-8-carbomethoxy-6,7,8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine.

62. A compound according to claim 1, which is 2-(2-Fluoro-4-methoxyphenyl)-6,7,8.9-tetrahydro-5H-indolo[3,2-dj-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.

64. A compound according to claim 1, which is 2-(3-Ethoxyphenyl) 6,7,8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine.

65. A compound according to claim 1, which is 2-(3-Methoxyphenyl) cyclopent(g)-5H-pyrroIo[3,2-d]-pyrimidine.

66. A compound according to claim 1, which is 2-(3,4-Methylene dioxyphenyl)-6,7,8,9-tetrahydro-5H^indolo[3,2-d]-pyrimidine.

67. A compound according to claim 1, which is 2-(3-Methoxyphenyl) cyclohept(g)-pyrrolo[3,2-d]-5H-pyrimidine.

68. A compound according to claim 1, which is 2-(3-Hydroxyphenyl) 6,7.8,9-ietrahydro-5H-indolo[3,2-d]-pyrimidine.

69. A compound according to claim 1, which is 2-(3-Ethylphenyl)-6,7,8,9- tetrahydro-5H-indolo[3,2-d)-pyrimidine.

70. A compound according to claim 1. which is 2-(3,5-Dimethoxy-phenyl)-6,7,8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine.

71. A compound according to claim 1. which is 2-(3-FluorophenyI)-6,7.8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine.

72. 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-Flubro-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-indoIo[3.2-d]-pyrimidine.

75. A compound according to claim 1, which is 2-(3-Chlorophenyl)-6.7,8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine.

76. A compound according to claim 1, which is 2-(4-Methoxyphenyl)-8-methyl-6,7,8.9-tetrahydro-5H-indolo[3,2-d]-pyrimidine.

77. A compound according to claim 1, which is 2-(4-Methoxyphenyl)-8- carboisopropoxy-6,7,8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine.

78. A compound according to claim 1, which is 2-(3-Aminophenyl)- 6,7,8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine.

79. A compound according to claim 1, which is 2-(3-Fluoro-4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine.

80. A compound according to claim 1, which is 2-(4-Fluoro-3-methoxyphenyl)-6,7,8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine.

81. A compound according to claim 1, which is 2-(3-Fluorophenyl)-6,7,8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine.

82. A compound according to claim 1, which is l'-Benzyl-2-(4-methoxyphenyl)-5.6,7,9-tetrahydro-spiro[indolo[3,2-d]-pyrimidine-2',8-pyrrolidine].

83. A compound according to claim 1, which is l'-Benzyl-2-phenyl-5.6,7.9-tetrahydro-spiro[indolo[3,2-d]-pyrimidine-2',8-pyrrolidine].

84. A compound according to claim 1, which is 2'-(4-Ethoxyphenyl)-5,,6',7,,9'-tetrahydro-spiro[(l,3)dioxolane-2,8'-indolo[3,2-d]-pyrimidine].

85. A compound according to claim 1, which is 2-(4-Methoxyphenyl)-8-methylamino-6,7,8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine.

86. A compound according to claim 1, which is 2-(4-Methoxyphenyl)-8-dimethylamino-6,7,8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine.

87. A compound according to claim 1, which is l'-Benzyl-2-(2-thienyl)-5,6,7,9-tetrahydro-spiro[indolo[3.2-d]-pyrimidine-2',8-pyrrolidin-5'one].

88. A compound according to claim 1, which is l'-Benzyl-2-(2-thienyl)-5,6,7,9-tetrahydro-spiro[indolo[3.2-d]-pyrimidinc-2',8-pyrrolidinc]. 101285/2 - 71 - 89 · A compound according to claim 1, which is 2- (4-methoxyphenyl) -8- (N ,N-dimethylcarbamoyl) -6 , 7 , 8 , 9_tetrahydro-5H-indolo[3 , 2-d]-pyrimidine .

90. A compound according to 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 i8, 9~tetrahydro-5H-indolo[3 i2-d]-pyrimidine.

92. A compound according to claim 1, which is 2- (4-methoxyphenyl) -8-(acetyloxyniethyl ) -6 , 7.8 , 9_tetrahydro~5H-indolo[3 , 2-d]-pyrimidine . 93 · A pharmaceutical composition which comprises at least one compound according to any of the preceding claims, together with at least one non-toxic pharmaceutically acceptable carrier, adjuvant or vehicle. 9Ί . Use of a compound according to any of claims 1 to 92, for the manufacture of a medicament, substantially as described in the specification. For the Applicants, Sanford T. Colb & Co. -C: 14368 1-1147