WO1994009009A1

WO1994009009A1 - 3,3-disubstituted tri- and tetracyclic indolin-2-ones useful for the treatment of cognitive disorders

Info

Publication number: WO1994009009A1
Application number: PCT/US1993/009476
Authority: WO
Inventors: Richard Alan Earl; Melvyn John Myers
Original assignee: The Du Pont Merck Pharmaceutical Company
Priority date: 1992-10-13
Filing date: 1993-10-12
Publication date: 1994-04-28
Also published as: IL107251A0; ZA937604B; MX9306337A; JPH08502293A; AU6242294A; CA2146000A1; EP0664810A1

Abstract

Compounds of formula (I) have been shown to enhance the release of the neurotransmitter acetylcholine, and thus may be useful as chemical intermediates and as pharmacological agents in the treatment of diseases of man, such as in Alheimer's Disease and other conditions involving learning and cognition, where subnormal levels of this neurochemical are found. The compounds of this invention have the structure shown in formula (I).

Description

TITLE

3,3-Disubstituted Tri- and Tetracyclic Indolin-2-ones Useful for the Treatment of Cognitive Disorders.

Field of the Invention

This invention relates to 3,3-disubstituted tri- and tetracyclic indolin-2-ones, to pharmaceutical compositions thereof, and methods of use in mammals to treat cognitive disorders, neurological dysfunction, and/or mood disturbances such as, but not limited to degenerative nervous system diseases. Additionally, these compounds can be used as reagents in studies on the biochemical mechanism of neurotransmitter diseases.

Background Including Prior Art

Increasingly there is a need for effective

treatments for nervous systems disorders and

neurological deficiencies. Many of these diseases correlate with increasing age due mainly to degenerative changes in the nervous system. Although in early stages of some diseases, certain systems are rather

specifically affected (e.g., cholinergic systems in Alzheimer's Disease and Myasthenia Gravis, the

dopaminergic system in Parkinson's Disease, etc.) multiple neurotransmitter systems deficiencies

(acetylcholine, dopamine, norepinephrine, serotonin) are generally found at later stages of diseases such as senile dementia, multi-infarct dementia, Huntington's Disease, mental retardation, etc. This explains the generally observed multiple symptomology that includes cognitive, neurological and effective/psychotic

components (see Gottfries, Psychopharmacol., 86, 245 (1985)). Deficits in the synthesis and release of acetylcholine in the brain are generally thought to be related to cognitive impairment (see Francis, et al., New England J. Med., 7 , 313 (1985)) whereas neurological deficits (e.g. Parkinsonian symptoms) and mood/mental changes may be related to impairment of dopaminergic and serotonergic systems, respectively. Other neurological deficits (e.g., Myasthenia Gravis) are related to cholinergic deficiencies in the peripheral nervous system.

Treatment strategies employed previously encompass vasoactive drugs like vincamine and pentoxifylline;

metabolic enhancers like ergoloid mesylates, piracetam, and naftidrofuryl; neurotransmitter precursors like L-DOPA, choline, 5-hydroxytryptamine; transmitter

metabolizing enzyme inhibitors such as physostigmine; neuropeptides like adrenocorticotropic hormone and vasopressin-related peptides. Except for L-DOPA

treatment for Parkinson's Disease and cholinesterase inhibitor treatment for Myasthenia Gravis, these treatment strategies have generally failed to enhance the residual function of the affected systems by enhancing the stimulus-induced release of

neurotransmitters . Theoretically, such an enhancement would improve the signal-to-noise ratio during chemical transmission for information, thereby reducing deficits in processes related to cognition, neurological function and mood regulation.

European Patent Application 311,010 discloses that α,α-disubstituted aromatics or heteroaromatics of the formula :

or a salt thereof, are useful as cognition enhancers.

U.S. Patent No. 4,760,083 to Myers, et al.

discloses that indolines of the following formula are useful for treatment of cognitive deficiencies:

The references claim the necessity of two heteroaryl groups for activity.

European Patent Application No. 0 415 102 Al by Effland, et al. describes an invention related to the formula:

U.S. Patent No. 3,595,866 to D. E. Butler describes an invention of the formula:

European Patent Application No. 0 347 698 Al wherein Ting, et al. describes a compound of formula:

Patent WO 91/01/306 1991 discloses oxindole

derivatives of formula:

useful for treating senile dementia, i. e. improving brain functions and activating and protecting brain metabolism. This reference only discloses imides and does not suggest alkyl or aryl substituted amides.

Summary of the Invention

Presently it has been found that certain 3,3-disubstituted tri- and tetracyclic indolin-2-ones enhance the stimulus-induced release of neurotransmitters, specifically acetylcholine in nervous tissue, and thus improve processes involved in learning and memorization of an avoidance task.

According to the present invention, there are provided compounds of formula:

or pharmaceutically acceptable salts thereof,

wherein:

X is a single bond, O, S, SO, SO₂, CH₂, CH₂CH₂, CH=CH, C=O, C(R⁷)(OR⁶), CH(OR⁶), -CONR⁶-, -NR⁶CO-, -CH₂-NR⁶-, -NR⁶-CH₂-, NR⁶, -C(R⁷)=N-, -CH(R⁷)-N(R⁶)-, or -CR⁷-, -CH- when a is a single bond and b is a double bond; a and b are each single or double bonds, provided that a is a single bond when b is a double bond, and that b is a single bond when a is double bond, and that b is a double bond when

X is -CH- or -CR⁷- and when a is a single bond;

R¹ is 2-, 3- or 4-pyridyl, or 4-pyrimidinyl;

R² is -(CH₂)_m-W,

wherein m = 1-4,

and W is selected from the group:

(a) 2-, 3- or 4-pyridyl,

(b) 2-, 4-, or 5-pyrimidinyl,

(c) 2-pyrazinyl,

(d) 3- or 4-pyridazinyl,

(e) 3- or 4-pyrazolyl,

(f) 2- or 3-furyl,

(g) 2- or 3-tetrahydrofuranyl,

(h) 2- or 3-thienyl, (i) 3-indolyl,

(j) aryl unsubstituted or substituted with 1-3 R⁵,

(k) 2-fluoro-4-pyridyl, or

R² is -(CH₂)_n-Y,

wherein n = 1-6,

and Y is selected from the group:

-CH=CHCO₂R⁷, -CH=CHCOR⁷, -CH=CHR⁷, -CH=C(R⁷)₂, -CH=CH₂, -C≡CCO₂R⁷, -C=CCOR⁷, -C=CR⁷, or -C≡CH, F, Cl, Br, OR⁶, N(R⁶)₂, CO₂H, CO₂R⁷, CONHR⁷,

NHCHO, CONHR⁶, CON(R⁷)₂, CN, -OCOR⁷, COR⁷, CHO, SR⁷, SOR⁷, SO₂R⁷ or NO₂;

R³ and R⁴ are each independently selected from the group:

H, alkyl of 1-6 carbons, alkenyl of 2-6 carbons, alkynyl of 2-6 carbons; cycloalkyl of 3-7 carbons, cycloalkylalkyl of 3-10 carbons, aryl unsubstituted or substituted with 1-3 R5, alkaryl of 1-10 carbons, provided that when a is a single bond R³ is =O, =CH₂, =CH(R⁷), =C(R⁷)₂, or (CH₃)₂, and

provided that when a and b are each a single bond, then R³ and R⁴ are each independently selected from the group: =O, =CH₂, =CH(R⁷), =C(R⁷)₂,

(CH₃)₂ ; or

R³ and R⁴, taken together may form a saturated or unsaturated carbocyclic or heterocyclic ring, unsubstituted or substituted with 1-2 R⁵ substituents;

R⁵ is selected from the group:

H, alkyl of 1-6 carbons, aryl unsubstituted or substituted with 1-3 R⁸, alkaryl of 1-10 carbons, F, Cl, Br, I, OR⁶, NHR⁶, N(R⁶)₂,

CO₂H, CO₂R⁷, CONHR⁷, CON(R⁷)₂, CN, COR⁷, CHO, SR⁷, SOR⁷, SO₂R⁷, NO₂ or -CH=CH-CH=CH- which attaches to an adjacent carbon atom forming a fused ring;

R⁶ is independently selected at each occurrence

from the group:

H, alkyl of 1-6 carbons, aryl unsubstituted or substituted with 1-3 R⁸, alkaryl of 1-10 carbons, -SO₂-R⁷, and -COR⁷; R⁷ is independently selected at each occurrence

from the group:

alkyl of 1-6 carbons, aryl unsubstituted or substituted with 1-3 R⁸, and alkaryl of 1-10 carbons;

R⁸ is independently selected at each occurrence

from the group:

OR⁹, NHR⁹, N(R⁹)₂, CO₂H, CO₂R⁹, CONHR⁹,

CON(R⁹)₂, CN, COR⁹, CHO, SR⁹, SOR⁹, SO₂R⁹, and NO₂; and

R⁹ is independently selected at each occurrence

from the group:

H, alkyl of 1-6 carbons and aryl.

Preferred Embodiments

Preferred compounds of this invention are those of Formula I wherein, together or independently:

X is a single bond, O, S, SO, SO₂, CH₂, CH₂CH₂,

CH=CH, C=O, NR⁶; a is a single or a double bond; b is a single bond;

R¹ is 2-, 3- or 4-pyridyl, or 4-ρyrimidinyl;

R² is - (CH₂) _m-W, wherein m = 1-4, and

W is selected from the group:

2-, 3- or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, or 2-pyrazinyl; or

R² is -(CH₂)_n-Yr

wherein n is 1 to 6, and

Y is selected from the group:

CO₂R⁷, CN, COR⁷, CHO, -OCOR⁷; R³ and R⁴ are each independently selected from the group:

H, alkyl of 1-6 carbon atoms or -CH=CH-CH=CH- to form a fused ring; and R⁵ is selected from the group:

H, alkyl of 1-6 carbons, phenyl unsubstituted or substituted with 1-3 R⁸, F, Cl, Br, I, NO₂ or -CH=CH-CH=CH- which attaches to an adjacent carbon forming a fused ring.

More preferred compounds of this invention are those preferred compounds wherein:

X is O, S, SO, SO₂, CH₂, CH₂CH₂, C=O; R² is -(CH₂)_m-W,

wherein m = 1, and

W is selected from the group:

2-, 3- or 4-pyridyl, and 4-pyrimidinyl; or R² is -(CH₂)_n-Y,

where n = 3-4, and

Y is selected from the group:

CO₂R⁷, CN, and -OCOR⁷;

R³ and R⁴ are each H, or R³ and R⁴ join together forming a fused ring consisting of -CH=CH-

CH=CH-; and

R⁵ is selected from the group: H, Cl, Br, I, NO₂ or -CH=CH-CH=CH- which attaches to an adjacent carbon atom forming a fused ring.

Specifically preferred are those compounds of Formula I which are:

(a) 2,2-Bis(4-pyridinylmethyl)-pyrrolo[3,2,1- kl]phenothiazin-l(2H)-one;

(b) 1,1-Bis(4-pyridinylmethyl)-5,6-dihydro-4H- pyrollo[3,2,1-ij]quinolin-2(1H)-one;

(c) 2,2-Bis(4-pyridinylmethyl)-6,7-dihydro- indolo[1,7-ab][1]benzapin-1(2H)-one;

(d) 2,2-Bis(4-pyridinylmethyl)-pyrrolo[3.2.1- kl]phenoxazin-1(2H)-one; (e) 2,3-Dihydro-6,6-bis(4-pyridinylmethyl)- pyrrolo[1,2,3-de]-1,4-benzothiazin-5(6H)-one;

(f) 1,2-Dihydro-2-(4-pyridinylmethyl)-2- (pentanenitrile)-pyrrolo[3.2.1-kl]phenoxazin-1(2H)- one, hydrobromide.

It should be recognized that the above-identified groups of compounds are preferred embodiments of this invention, but that their description herein is in no way intended to limit the overall scope of this

invention.

This invention also provides pharmaceutical compositions comprising a suitable pharmaceutical carrier and an amount of one or more of the above-described compounds effective to treat cognitive or neurological dysfunction. Still further, this invention relates to a method of treating cognitive or neurological dysfunction in a mammal comprising

administering to the mammal a therapeutically effective amount of one or more of the above-described compounds.

Detailed Description of the Invention

The compounds herein described may have asymmetric centers. All chiral, enantiomeric, diastereomeric, and racemic forms are included in the present invention.

Thus, the compounds of Formula (I) may be provided in the form of an individual stereoisomer, a non-racemic

stereoisomer mixture, or a racemic mixture.

Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds

described herein, and all such stable isomers are

contemplated in the present invention.

When any variable occurs more than one time in any constituent or in Formula (I), or any other formula herein, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are

permissible only if such combinations result in stable compounds.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic

hydrocarbon groups having the specified number of carbon atoms. As used herein "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; and "biycloalkyl" is intended to include saturated bicyclic ring groups such as [3.3.0]bicyclooctane,

[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),

[2.2.2]bicyclooctane, and so forth. "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like; and

"alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like. "Cycloalkyl-alkyl" is intended to include cycloalkyl attached to alkyl. "Halo" as used herein refers to fluoro, chloro, bromo, and iodo; and

"counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.

As used herein, "aryl" or "aromatic residue" is intended to mean phenyl or naphthyl; "carbocyclic" is intended to mean any stable 5- to 7- membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic, for example, indanyl or

tetrahydronaphthyl (tetralin).

As used herein, the term "heterocycle" is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from 1 to 3 heteroatoms selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined

heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of such

heterocycles include, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl or

benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl,

tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, pyrazinyl, quinazzoyl, phthalazinyl, naphthyridinyl or octahydroisoquinolinyl.

The term "substituted", as used herein, means that one or more hydrogen atom(s) on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.

By "stable compound" or "stable structure" is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

As used herein, "pharmaceuticall acceptable salts" refer to derivatives of the disclosed compounds that are modified by making acid or base salts. Examples include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids.

Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences. 17th ed.,

Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

As used herein, the term "therapeutically effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human subject that is being sought by a clinician or researcher.

Synthesis

The compounds of the present invention may be

prepared according to the following schemes and

examples, using appropriate materials and are further exemplified by the following specific examples. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare those compounds.

Scheme 1 shows one process for the preparation of compounds of the present invention. In this scheme a compound of formula 2 is reacted in an inert solvent with chloroacetyl chloride to provide a compound of formula 3. The solvent is preferably an aromatic hydrocarbon such as benzene or toluene or a

halohydrocarbon such as methylene chloride, 1,2-dichloroethane or chloroform. The reaction temperature is not critical and generally ranges from about 20°C to about 120°C. Preferably, the reaction temperature is the reflux temperature of the solvent. Next, fusion of a compound of formula 3 with anhydrous aluminum chloride at a temperature within a few degrees of the melting point of the compound of formula 3, but using a

temperature no greater than about 200°C, affords a compound of formula 4. This reaction is disclosed in the following references which are herein incorporated by reference: Chem. Ber. 47, 2120 (1914), J. Chem. Soc. 1697 (1954), Tetrahedron 24, 6093 (1968) and J. Med. Chem. 15, 762 (1972). See also, the references listed in Table I. Next, the anion of a compound of formula 4 is generated by treatment with a base, in an appropriate aprotic solvent and at a suitable temperature. The resulting anion is then alkylated with an appropriate alkyl halide (R¹CH₂-Hal) to give a compound of formula 5. This process can then be repeated by treatment of a compound of formula 5 with a base, followed by addition of a second alkylating agent (R²-Hal) to produce a compound of Formula I.

The temperature and duration of the alkylation reaction are not critical, and may be varied over a wide range from room temperature for 24 hours to 80°C for 3 hours. Preferred conditions are room temperature, and a duration of 2-3 hours. Equivalent amounts of the reagents can be used, but it is preferable to use the haloalkylating in a slight excess This method is disclosed by Myers and Nickolson, in US Patents

4,876,259 and 4,760,083, which are herein incorporated by reference.

Scheme 1

Suitable bases for generating the anion of a compound of formula 4 and 5 include, but are not limited to, sodamide, lithium diisopropylamide (LDA), sodium hydride, potassium tert-butoxide, sodium alkoxide, potassium alkoxide, potassium hydride, lithium 2, 2, 6, 6- tetramethylpiperidine, butyl lithium, sec-butyl lithium, tert--utyl lithium, and lithium- sodium-, or potassium hexamethyldisilazide. The reaction can be conducted in an aprotic solvent, generally in an ether, such as but not limited to, tetrahydrofuran (THF), dioxane, glyme, diglyme, or diethyl ether. Additionally, the reaction can be run in dimethylformamide or dimethylacetamide. However, if the compounds are soluble in a nonpolar solvent, the reaction can be carried out in a hydrocarbon solvent such as hexanes, heptane, cyclohexane, methylcyclohexane, benzene or toluene. Depending on the strength of the base, the reactions can be conducted at a temperature from about -78°C to solvent reflux temperature. Instead of running the reaction sequentially, one may at times, add two equivalents of base to the compounds of formula 4, followed by two to three equivalents of the alkylating agent. Alternatively, phase-transfer catalysis

conditions may be used, employing a solvent such as benzene, toluene, xylene, dichloromethane, dichloroethane, or chloroform in conjunction with a quaternary ammonium salt or a quaternary phosphonium salt in the presence of an aqueous base, such as sodium hydroxide or potassium hydroxide. This procedure is described by Bryant and Huhn, in US Patent 4,806,651 and in J.

Heterocyclic Chem, 20, 771 (1983), which is herein incorporated by reference.

When the alkylation reaction is complete as evidenced by thin layer chromatography, excess anion is decomposed with saturated ammonium chloride solution, and the reaction is taken through an acid- base cycle to remove neutral starting materials. Purification of the basic product generally involves conventional

purification techniques such as flash chromatography followed by recrystallization if necessary. The pure base (one spot on thin layer chromatography and

analytical HPLC) may be collected as an oil, gum, or amorphous solid; or recrystallized from an appropriate solvent system; or further purified by chromatographic, sublimation, or distillation processes. The compounds may exist as the "free base" or as an acid addition salt formed from pharmaceutically acceptable acids.

Additionally, compounds of formula I may exist as racemates, diastereomeric mixtures, or their optically pure isomers.

Compounds of formula 5 may also be prepared

according to Scheme 2. This procedure is particularly useful when R² is not the same as -CH₂-R¹ because 5 may be obtained uncontaminated by 4 or the dialkylated product. This procedure is fully described by Bryant and Huhn, US Patent 4,806,651, which is herein

incorporated by reference.

Scheme 2

In addition to the Friedel-Crafts cycloalkylation illustrated by Scheme 1, compounds of the formula 4 may also be prepared by the general "azasulfonium ion" rearrangement methods of Gassman U.S. Patents 3,897,451 (1975), 3,996,264 (1976), and 3,972,894 (1976) which are herein incorporated by reference; see also J. Am. Chem. Soc., 96, 5512 (1974), Synthesis 534 (1981). This route is shown in Scheme 3.

Scheme 3

Other representative compounds of this invention can be synthesized by converting one Y group to another. For example, a compound of formula I which is an ester (Y = CO₂R⁷) may be converted to the corresponding alcohol (Y = CH₂OH) of formula I which can be further converted to an ether (Y = OR⁶) or the "reverse ester" (Y = CH₂OCOR⁷). For such a case, the ester can be saponified to give the acid (Y = CO₂H) which can be reduced to the alcohol. Alternatively, the ester can be directly reduced to the alcohol, which can be

subsequently acylated with an acid halide or anhydride, or by coupling the alcohol to an acid using

dicyclohexylcarbodiimide, carbonyl diimidazole, or some other coupling agent.

A nitrile can be oxidized to the corresponding amide using the procedure described by Noller, Org. Syn. Coll. Vol. II, p 586. The same amide can be prepared from the corresponding ester by saponification,

activation of carboxyl, and reaction with ammonia or ammonia derivatives. By substituting primary or secondary amines for ammonia, other compounds of this invention may be prepared.

The compounds listed in Tables I and II may be used as starting materials for the preparation of compounds of this invention. The listed compounds are either commercially available or disclosed in the literature. These lists are not comprehensive, and are intended to illustrate the invention, not to limit it. All

references in Tables are incorporated by reference.

P28 D NH s O H =O H H US 4,087,527

* s indicates single bond

St = structure

commercial = commercially available

Examples

Analytical data were recorded for the compounds described below using the following general procedures. Proton NMR spectra were recorded on a Varian FT-NMR spectrometer (200 MHz or 300 MHz); chemical shifts were recorded in ppm (3) from an internal tetramethylsilane standard in deuterochloroform or

deuterodimethylsulfoxide and coupling constants (J) are reported in Hz. Mass spectra (MS) or high resolution mass spectra (HRMS) were recorded on Finnegan MAT 8230 spectrometer or Hewlett Packard 5988A model

spectrometer. Melting points are uncorrected. Boiling points are uncorrected.

Reagents were purchased from commercial sources and, where necessary, purified prior to use according to, the general procedures outlined by D. D. Perrin and W. L. F. Armarego, Purification of Laboratory Chemicals, 3rd ed., (New York: Pergamon Press, 1988) .

Chromatography was performed on silica gel using the solvent systems indicated below. For mixed solvent systems, the volume ratios are given. Parts and percentages are by weight unless otherwise specified. Common abbreviations include: THF (tetrahydrofuran), TBDMS (t-butyl-dimethylsilyl), DMF (dimethylformamide), Hz (hertz) TLC (thin layer chromatography).All

temperatures are given in degrees centigrade (°C).

The following examples and preparations are for illustrative purposes only and are not to be construed as limiting the invention. Preparation 1

Pyrrolo[3,2,1-kl]phenoxazin-1,2-dione To a solution of phenoxazine (21.05 g, 0.115 mole) in dichloroethane (125 ml) was added oxalyl chloride

(1.05 eq., 0.121 mole, 15.3 g, 10.52 ml) with stirring. The solution was heated to 50°C for one hour, then cooled to room temperature. A solution of aluminum chloride in nitrobenzene (1M, 1 eq., 0.115 mole, 115 ml) was added via addition funnel at room temperature. The solution was stirred for 6 hours, cooled with an ice bath, and quenched with 1N HCl and water. More

dichloroethane was added, and the organic solution was washed sequentially with water, aq. NaHCO₃ and brine, and dried over magnesium sulfate. The dichloroethane was removed via rotary evaporation, and 1000 ml of hexane was added to the resulting dark nitrobenzene solution to give dark violet crystals. The solid was filtered, and dried under vacuum to provide 19.95 g (0.084 mol, 73% yield) of the title compound, mp 218-9 °C. MS (NH₃/CI) m/e 238 (M+H). Anal. Calcd for C₁₄H7NO₃: C, 70.89; H, 2.97; N, 5.90. Found: C, 70.62; H, 2.89; N, 5.82.

Preparation 2

1.2-Dihydro-2-(4-methenylpyridinyl)pyrrolo[3,2,1- kl]phenoxazin-1(2H)-one

To a mixture of the compound from Preparation 1 (2.38 g, 0.010 mole) in acetic anhydride (20 ml) was added acetic acid (2 ml) and 4-picoline (1.75 eq.,

0.0175 mole, 1.63 g, 1.7 ml). The mixture was heated to 110 °C, and held at this temperature for 45 min., at which time a red precipitate had formed. The reaction mixture was cooled to room temperature, and poured over ice. The solid was collected and washed with water.

The material was dried under vacuum overnight to obtain 2.94 g (0.0094 mole, 94% yield) of the title compound, mp 240-5°C. MS (NH₃/CI) m/e 313 (M+H).

Preparation 3

1,2-Dihydry-2-(4-pyridinylmethyl)pyrrolo[3,2,1- kl]phenoxazin-1(2H)-one

The product from Preparation 2 (3.0 g, 9.6 mmol) was weighed into a Parr™ shaker bottle, tetrahydrofuran (150 ml) was added, along with 160 mg of 20% Pd(OH)₂ on carbon and 200 mg 10% Pd/C. The mixture was shaken under 55 psi of hydrogen for 4 hours, at which time the red color had faded. The reaction mixture was filtered to remove catalyst, and the solvent was removed by rotary evaporation. The residue was purified via column chromatography (silica gel, 5% methanol in ethyl acetate), and the solid was recrystallized from ethyl acetate to give 1.902 g (6.1 mmol, 64% yield) of the title compound, mp 180-2 °C. ¹H-NMR (300 MHz, CDCl₃) 3 3.04 (dd, 1 H, J = 9, 14 Hz), 3.45 (dd, 1 H, J = 5, 14 Hz), 3.88 (dd, 1 H, J = 5, 9 Hz), 6.43 (d, 1 H, J = 7 Hz), 6.70 (d, 1 H, J = 8 Hz), 6.83 (d, 1 H, J = 8 Hz), 6.88 (m, 1 H), 7.00 (m, 2 H), 7.13 (d, 2 H, J = 6 Hz), 8.25 (dd, 1 H, J = 3, 7 Hz), 8.51 (d, 2 H, J = 6 Hz). MS (NH₃/CI) m/e 315 (M+H) . Anal. Calcd for C₂₀H₁₄N₂O₂: C, 76.42; H, 4.49; N, 8.91. Found: C, 76.23; H, 4.42, N; 8.81.

Example 193

2 , 2-Bis(4-Pyridinylmethyl)-pyrrolo[3,2.1-kl]phenoxazin- 1(2H)-one.

To a solution of pyrro!o[3.2.1-kl]phenoxazin-1(2H)-one (486 mg, 2.18 mmol) in toluene (25 ml) was added 4- picolyl chloride hydrochloride (2.2 eq., 4.8 mmol, 787 mg) and benzyltriethylammonium chloride (0.087 eq., 0.19 mmol, 43 mg). While the mixture was stirred at room temperature, 50% aq. sodium hydroxide was added

dropwise. The mixture was heated to 60°C for 2 hours, at which time TLC showed that all starting materials had been consumed. Water was added, and the dark brown reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with water, then brine, and the solution was dried over magnesium

sulfate. After removal of solvent, the residue was purified via column chromatography (silica gel, 5% methanol in ethyl acetate), and the solid was

recrystallized from dichloromethane/hexane to give 471 mg (1.16 mmol, 53% yield) of the title compound, mp 199-200°C. MS (NH₃/CI) m/e 406 (M+H). ¹H-NMR (300 MHz, CDCI₃) 9 3.12 (d, 2 H, J = 13 Hz), 3.38 (d, 2 H, J = 13 Hz), 6.60 (d, 1 H, J = 8 Hz), 6.76 (m, 1 H), 6.82 (d, 1 H, J = 8 Hz), 6.86 (d, 4 H, J = 6 Hz), 6.90- 6.98 (m, 3 H), 8.12 (m, 1 H), 8.34 (d, 4 H, J = 6 Hz). Anal. Cald for C₂₆H₁₉N₃O₂ : C, 77.02; H, 4.72; N, 10.36. Found: C, 76.81; H, 4.62; N, 10.28.

In a similar manner, the following compounds were prepared:

2,3-Dihydro-6,6-bis(4-pyridinylmethyl)-pyrrolo[1,2,3-de]-1,4-benzothiazin-5(6H)-one (Ex. 49): mp 160-161 °C, MS (NH₃/CI) m/e 374 (M+H), ¹H-NMR (300 MHz, CDCI₃) 9 2.44 (t, 2 H), 3.11 (d, 2 H, J = 12.9 Hz), 3.32 (d, 2 H, J = 12.8 Hz), 3.56 (t, 2 H), 6.79 (d, 4 H, J = 1.5 Hz), 6.91 (m, 3 H) , 8.31 (d, 4 H, J = 1.5 Hz). Anal. Calcd for :C₂₂H₁₉N₃OS: C, 70.75; H, 5.13; N, 11.25. Found: C, 70.32; H, 5.01; N, 11.04.

1,1-Bis(4-pyridinylmethyl)-5,6-dihydro-4H-pyrollo[3,2,1-ij]quinolin-2(1H)-one (Ex. 1): mp 140-1°C, MS (CH₄/CI) m/e 356 (M+H), 384 (M+29), ¹H-NMR (300 MHz, CDCI₃) 9 1.45 (quin, 2 H, J = 6 Hz), 2.42 (t, 2 H, J = 6 Hz), 3.11 (d, 2 H, J = 13 Hz), 3.26 (t, 2 H, J = 6 Hz), 3.33 (d, 2 H, J = 13 Hz), 6.82 (d, 4 H, J = 6 Hz), 6.86 (d, 1 H, J = 7 Hz), 6.94 (t, 1 H, J = 7 Hz), 7.07 (d, 1 H, J = 7 Hz), 8.28 (d, 4 H, J = 6 Hz) . Anal.

Calcd for C₂₃H₂₁N₃O: C, 77.72; H, 5.96; N, 11.82.

Found: C, 77.65; H, 5.79; N, 11.77.

2,2-Bis(4-pyridinylmethyl)-pyrrolo[3,2,1-kl]phenothiazin-l(2H)-one (Ex. 169) : mp 190-1°C, MS (CH₄/CI) m/e 422 (M+H), 450 (M+29), ¹H-NMR (300 MHz, CDCI₃) 9 3.10 (d, 2 H, J = 13 Hz), 3.38 (d, 2 H, J = 13 Hz), 6.69 (d, 1 H, J = 7 Hz), 6.77- 7.08 (m, 5 H), 6.86 (d, 4 H, J = 6 Hz), 8.34 (d, 4 H, J = 6 Hz), 8.58 (d, 1 H, J = 8 Hz) . Anal. Calcd for C₂₆H₁₉N₃OS: C, 74.09; H, 4.54; N, 9.97. Found: C, 73.87; H, 4.34; N, 9.82.

C,H,N.

2,2-Bis(4-pyridinylmethyl)-6,7-dihydro-indolo[1,7-ab] [1]benzapin-1(2H)-one dihydrochloride (Ex. 217) : mp 274-6°C, MS (CH4/CI) m/e 418 (M+H), 446 (M+29), HRMS: m/e calcd 417.1841, m/e found 417.1836. Anal. Calcd for C₂₈H₂₃N₃O●2HCl●H₂O: C, 66.14; H, 5.35; N, 8.26.

Found: C, 66.14; H, 5.23; N, 8.15.

Example 200

1,2-Dihydro-2-(4-pyridinylmethyl)-2-(pentanenitrile)- pvrrolo[3.2.1-kl]phenoxazin-1(2H)-one. hydrobromide To a slurry of sodium hydride (60% in oil, 176 mg, 4.4 mmol) in THF at room temperature was added the compound from Preparation 3 (2.2 mmol, 692 mg), followed by 5-bromovaleronitrile (5 eq., 11 mmol, 1.78 g) . One drop of ethanol was added, and the mixture was stirred at room temperature for 3 days. Methanol was added to decompose excess sodium hydride, and the solvents were removed by rotary evaporation. The residue was

partitioned between ethyl acetate and water, then the product was extracted into 1N HCl. The aqueous layer was basified, and the product was extracted into dichloromethane. Subsequent purification by column chromatography provided an oil, 475 mg, 55% yield. MS (NH₃/CI) m/e 396 (M+H). ¹H-NMR (300 MHz, CDCI₃) ∂ 1.25 (m, 2 H), 1.61 (m, 2 H), 1.88 (m, 1 H), 2.13 (m, 1 H), 2.25 (m, 2 H), 2.99 (d, 1 H, J = 13 Hz), 3.20 (d, 1 H, J = 13 Hz), 6.68 (d, 1 H, J = 8 Hz), 6.78 (d, 1 H, J = 8 Hz), 6.84 (d, 2 H, J = 6 Hz), 6.86 (m, 1 H), 6.98 (m, 3 H), 8.19 (dd, 1 H, J = 2, 7 Hz), 8.31 (d, 2 H, J = 6 Hz). The compound was converted into a salt with hydrobromic acid, mp 239-45 °C. Anal. Calcd for

C₂₅H₂₁N₃O₂●2HBr●0.25H₂O: C, 62.44; H, 4.72; N, 8.74. Found: C, 62.61; H, 4.58; N, 8.64.

By using the methods illustrated in the above examples, compounds in Tables III, IV and V can be prepared.

Biochemical Test Procedure

Neurotransmitter release assay: The neurotransmitter release activities of the compounds in this invention were determined as reported in Drug Development

Research. 19, 285-300 (1990) and is a modification of the procedure described by Mulder, et al., Brain Res.. 70, 372 (1974). These publications are herein

incorporated by reference.

Male Wistar rats (Charles River) weighing 175-200 grams were used . The rats were housed for at least seven days before the experiment in animal facility under 12/12 hour light/dark cycle. Deionized water and

standard rat chow (Purina) were available ad libitum.

Rats were decapitated and brains were removed immediately. Slices (0.3 mm thick) from the parietal cortex were prepared manually using a recessed Lucite guide. Slices were subsequently cut into 0.25 × 0.25 mm squares with a Mcllwain tissue chopper.

Cerebral cortical slices (approximately 100 mg wet weight) were incubated in 10 ml Krebs-Ringer medium (KR) containing NaCl (116 mM), KCl (3 mM), CaCl₂ (1.3 mM), MgCl₂ (1.2 mM) , KH₂PO₄ (1.2 mM), Na₂SO₄ (1.2 mM), NaHCO₃ (25 mM) and glucose (11.0 mM) to which 10 mCi ³H-choline (specific activity approximately 80 uCi/mM; Du Pont-NEN) and 10 nmol unlabeled choline had been added to give a final concentration of 1 mM. The brain preparations were incubated for 30 minutes at 37°C under a steady flow of 95% 02/5% CO₂. Under these conditions, part of the radioactive choline taken up by the preparation was converted into radioactive acetylcholine (ACh) by the cholinergic nerve endings stored in synaptic vesicles, and released upon depolarization by high potassium ion (K⁺) containing media.

After labeling of the ACh stores, the slices were washed three times with non-radioactive KR medium and transferred to a superfusion apparatus to measure the drug effects on ACh release. The superfusion apparatus consisted of 10 thermostated glass columns of 5

diameters that were provided with GF/F glass fiber filters to support the slices (approximately 10 mg tissue/column). Superfusion was carried out in KR-medium (0.3 ml/min.) containing 10 mM hemicholinium-3 (HC-3). The HC-3 prevents the reuptake of choline formed during the superfusion from phospholipids and released ACh, which would be converted into unlabeled ACh and released in preference to the pre-formed labeled ACh. The medium was delivered by a 25-channel peristaltic pump (Ismartec by Brinkman) and warmed to 37°C in a thermostated stainless steel coil before entering the superfusion column. Each column was provided with a 4-way slider value (Beckmann Instruments) which allowed rapid change of low to high K⁺/KR-medium, and with two 10-channel 3-way values that were used to change from drug-free to drug-containing low and high K⁺/KR-medium.

After 15 min. of washout of non-specifically bound radioactivity, collection of 4 min. fractions was initiated. After three 4 min. collections, the original medium was changed to a KR-medium in which the KCl concentration has been increased to 25 mM (high K+ -KR medium; S1). Depolarization-induced stimulation of release by high K+/KR-medium lasted 4 min. Drug free low and high K+/KR-media were then substituted by drug- and vehicle-containing low- and high-K+/KR medium, and superfusion was continued for three 4 min. collections with low K+/KR-medium, one 4 min. collection with high K+/KR-medium (S2), and two 4 min. collections with low-K+/KR-medium.

Drug was added to the media by 100-fold dilutions of appropriate concentrations of the drug (in 0.9% saline) with either low- or high-K+/KR-medium .

All superfusion fractions were collected in liquid scintillation counting vials. After superfusion, the slices were removed from the superfusion columns and extracted with 1.0 ml of 0.1N HCl. Liquiscint (NEN) scintillation cocktail (12 ml) was added to superfusion fractions and extracts, and the samples were counted in a Packard Tricarb Liquid Scintillation Counter. No corrections were made for quenching.

The ratio of S2/S1 (as compared to controls where no drug was present during S2) was a measure of the ability of the drug to enhance or depress stimulus-induced acetylcholine release. Per cent acetylcholine (ACh) enhanced release caused by 10 mM of drug using this assay are shown in Table 5.

Table 5

% Ach release

Ex. No. at 10 mM

1 188

49 368

169 262

193 218

200 313

217 325

Utility

The foregoing test results suggest that the

compounds of this invention have utility in the

treatment of cognitive disorders and/or neurological function deficits and or mood and mental disturbances in patients suffering from nervous system disorders like Alzheimer's Disease, Parkinson's Disease, senile

dementia, multi-infarct dementia, Huntington's disease, mental retardation, Myasthenia Gravis, etc. The above-described in vitro assay is recognized as aiding in the identification of drugs useful in the treatment of cognitive disorders and/or neurological function

deficits and or mood and mental disturbances in patients suffering from nervous system disorders like Alzheimer's Disease, Parkinson 's Disease, senile dementia, multi-infarct dementia, Huntington's disease, mental

retardation, Myasthenia Gravis, etc. Cook et al., Drug Development Research, 19, 301-304 (1990), Nickolson et al., Druσ Development Research. 19, 285-300 (1990) and DeNoble et al., Pharmacology Biochemistry & Behavior. 36, 957-961 (1990), all have shown via the above-described in vitro assay that the drug DuP 996, which has the chemical name 3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one (linopirdine), is useful in the treatment of cognition dysfunction.

Formulations

Compounds of this invention can be administered to treat said deficiencies by means that produces contact of the active agent with the agent's site of action in the body of a mammal. The compounds can be administered by any conventional means available for use in

conjunction with pharmaceuticals either as individual therapeutic agent or in combination of therapeutic agents. They can be administered alone, but are

generally administered with a pharmaceutical carrier selected on the basis of the chosen route of

administration and standard pharmaceutical practice.

The dosage administered will vary depending on the use and known factors such as pharmacodynamic character of the particular agent, and its mode and route of administration; the recipient's age, weight, and health; nature and extent of symptoms; kind of concurrent treatment; frequency of treatment; and desired effect. For use in the treatment of said diseases or conditions, the compounds of this invention can be orally

administered daily at a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divided doses one to four times a day, or in sustained release formulation was effective in obtaining the desired pharmacological effect.

Dosage forms (compositions) suitable for

administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.

The active ingredient can be administered orally is solid dosage forms, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups, and/or suspensions. The compounds of this invention can also be administered parenterally in sterile liquid dose formulations .

Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as but not limited to lactose, starch, magnesium stearate, steric acid, or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of time. Compressed tablets can be sugar- coated or film-coated to mask any unpleasant taste, or used to protect the active ingredients from the

atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract .

Liquid dose forms for oral administration can contain coloring of flavoring agents to increase patient acceptance.

In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for

parenteral solutions. Solutions for parenteral

administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, butter substances. Antioxidizing agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Also used are citric acid and its salts, and EDTA. In addition, parenteral

solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences", A. Osol, a standard reference in the field.

Useful pharmaceutical dosage-forms for

administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of units capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean, cottonseed oil, or olive oil is

prepared and injected by means of a positive

displacement was pumped into gelatin to form soft gelatin capsules containing 100 mg of the active

ingredient. The capsules were washed and dried.

Tablets

A large number of tablets are prepared by

conventional procedures so that the dosage unit was 100 mg active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of

microcrystalline cellulose, 11 mg of starch, and 98.8 mg lactose. Appropriate coatings may be applied to increase palatability or delayed adsorption.

The compounds of this invention may also be used as reagents or standards in the biochemical study of neurological function, dysfunction, and disease.

Claims

What is claimed is:

1. A compound of formula:

or pharmaceutically acceptable salts thereof,

wherein: X is a single bond, O, S, SO, SO₂, CH₂, CH₂CH₂,

CH=CH, C=O, C(R⁷)(OR⁶), CH(OR⁶), -CONR⁶-, -NR⁶CO-, -CH₂-NR⁶-, -NR⁶-CH₂-, NR⁶, -C(R⁷)=N-, -CH(R⁷)-N(R⁶)-, or -CR⁷-, -CH- when a is a single bond and b is a double bond; a and b are each single or double bonds, provided that a is a single bond when b is a double bond, and that b is a single bond when a is double bond, and that b is a double bond when X is -CH- or -CR⁷- and when a is a single bond;

R¹ is 2-, 3- or 4-pyridyl, or 4-pyrimidinyl; R² is -(CH₂)_m-W,

wherein m = 1-4,

and W is selected from the group:

(a) 2-, 3- or 4-pyridyl,

(b) 2-, 4-, or 5-pyrimidinyl,

(c) 2-pyrazinyl,

(d) 3- or 4-pyridazinyl, (e) 3- or 4-pyrazolyl,

(f) 2- or 3-furyl,

(g) 2- or 3-tetrahydrofuranyl, (h) 2- or 3-thienyl,

(i) 3-indolyl,

(j) aryl unsubstituted or substituted with 1-3 R⁵,

(k) 2-fluoro-4-pyridyl, or

R² is -(CH₂)_n-Y,

wherein n = 1-6,

and Y is selected from the group:

-CH=CHCO₂R⁷, -CH=CHCOR⁷, -CH=CHR⁷, -CH=C(R⁷)₂, -CH=CH₂, -C≡CCO₂R⁷, -C=CCOR⁷, -C≡CR⁷, or -C=CH, F, Cl, Br, OR⁶, N(R⁶)₂, CO₂H, CO₂R⁷, CONHR⁷, NHCHO, CONHR⁶, CON(R⁷)₂, CN, -OCOR⁷, COR⁷,

CHO, SR⁷, SOR⁷, SO₂R⁷ or NO₂;

R³ and R⁴ are each independently selected from the group:

H, alkyl of 1-6 carbons, alkenyl of 2-6 carbons, alkynyl of 2-6 carbons; cycloalkyl of 3-7 carbons, cycloalkylalkyl of 3-10 carbons, aryl unsubstituted or substituted with 1-3 R⁵, alkaryl of 1-10 carbons, provided that when a is a single bond R³ is =O, =CH₂, =CH(R⁷),

=C(R⁷)₂, or (CH₃)₂, and

provided that when a and b are each a single bond, then R³ and R⁴ are each independently selected from the group: =O, =CH₂, =CH(R⁷), =C(R⁷)₂, (CH₃)₂ ; or

R⁵ is selected from the group:

H, alkyl of 1-6 carbons, aryl unsubstituted or substituted with 1-3 R⁸, alkaryl of 1-10 carbons, F, Cl, Br, I, OR⁶, NHR⁶, N(R⁶)₂, CO₂H, CO₂R⁷, CONHR⁷, CON(R⁷)₂, CN, COR⁷, CHO, SR⁷, SOR⁷, SO₂R⁷, NO₂ or -CH=CH-CH=CH- which attaches to an adjacent carbon atom forming a fused ring;

R⁶ is independently selected at each occurrence

from the group:

H, alkyl of 1-6 carbons, aryl unsubstituted or substituted with 1-3 R⁸, alkaryl of 1-10 carbons, -SO₂-R⁷, and -COR⁷;

R⁷ is independently selected at each occurrence

from the group:

R⁸ is independently selected at each occurrence

from the group:

OR⁹, NHR⁹, N(R⁹)₂, CO₂H, CO₂R⁹, CONHR⁹,

CON(R⁹)₂, CN, COR⁹, CHO, SR⁹, SOR⁹, SO₂R⁹, and NO₂; and R⁹ is independently selected at each occurrence

from the group:

H, alkyl of 1-6 carbons and aryl.

A compound of Claim 1 wherein:

X is a single bond, O, S, SO, SO₂, CH₂, CH₂CH₂,

CH=CH, C=O, NR⁶; a is a single or a double bond; b is a single bond;

R¹ is 2-, 3- or 4-pyridyl, or 4-pyrimidinyl; R² is -(CH₂)_m-W,

wherein m = 1-4, and

W is selected from the group:

2-, 3- or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, or 2-pyrazinyl; or

R² is -(CH₂)_n-Y,

wherein n is 1 to 6, and

Y is selected from the group:

CO₂R⁷, CN, COR⁷, CHO, -OCOR⁷;

R³ and R⁴ are each independently selected from the group:

H, alkyl of 1-6 carbon atoms or -CH=CH-CH=CH- to form a fused ring; and

R⁵ is selected from the group:

3. A compound of Claim 2 wherein: X is O, S, SO, SO₂, CH₂, CH₂CH₂, C=O;

R² is -(CH₂)_m-W,

wherein m = 1, and

W is selected from the group:

2-, 3- or 4-pyridyl, and 4-pyrimidinyl; or

R² is -(CH₂)_n-Y,

where n = 3-4, and

Y is selected from the group:

CO₂R⁷, CN, and -OCOR⁷;

R³ and R⁴ are each H, or R³ and R⁴ join together forming a fused ring consisting of -CH=CH- CH=CH-; and R⁵ is selected from the group:

H, Cl, Br, I, NO₂ or -CH=CH-CH=CH- which attaches to an adjacent carbon atom forming a fused ring. 4. The compounds of Claim 1 which are:

(a) 2,2-Bis(4-pyridinylmethyl)-pyrrolo[3,2,1- kl]phenothiazin-1(2H)-one;

(b) 1,1-Bis(4-pyridinylmethyl)-5,6-dihydro-4H- pyrollo[3,2,1-ij]quinolin-2(IH)-one;

(c) 2,2-Bis(4-pyridinylmethyl)-6,7-dihydroindolo[l,7-ab][1]benzapin-l(2H)-one;

(d) 2,2-Bis(4-pyridinylmethyl)-pyrrolo[3.2.1- kl]phenoxazin-1(2H)-one; (e) 2,3-Dihydro-6,6-bis(4-pyridinylmethyl)- pyrrolo[1,2,3-de]-1,

4-benzothiazin-5(6H)-one;

(f) 1,2-Dihydro-2-(4-pyridinylmethyl)-2- (pentanenitrile)-pyrrolo[3.2.1-kl]phenoxazin-1(2H) one, hydrobromide.

5. A pharmaceutical composition comprising a

pharmaceutically suitable carrier and a

therapeutically effective amount of a compound of Claim 1.

A pharmaceutical composition comprising a

pharmaceutically suitable carrier and a

therapeutically effective amount of a compound of Claim 2.

A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of Claim 3.

8. A pharmaceutical composition comprising a

pharmaceutically suitable carrier and a therapeutically effective amount of a compound of Claim 4.

9. A method of treating a neurolgical disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Claim 1.

10. A method of treating a neurolgical disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Claim 2.

11. A method of treating a neurolgical disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Claim 3.

12. A method of treating a neurolgical disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Claim 4.