Selective serotonin receptor antagonists and therapeutic applications thereof

Abstract

Spiro[9,10-dihydroanthracene]-9,3′-pyrrolidine (SPAN) and derivatives thereof are provided as selective serotonin receptor antagonists. The compounds are selective, high affinity antagonists of 5-HT2 serotonin receptors. The compounds are useful as antidepressant and antianxiety agents.

Description

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The invention generally relates to selective serotonin receptor antagonists and methods of their use as antidepressant and antianxiety agents. In particular, the invention provides spiro[9,10-dihydroanthracene]-9,3′-pyrrolidine (SPAN) and derivatives thereof as selective high affinity antagonists of 5-HT receptors.

[0004] 2. Background of the Invention

[0005] Serotonin (5-hydroxytryptamine, or 5-HT; see Formula 1) is a product of tryptophan metabolism that mediates many diverse physiological activities. Most fundamentally, this well-characterized tryptamine derivative functions as a potent neurotransmitter by regulating G-protein coupled and ligand gated ion channel receptors at the surface of nerve and muscle cells. This activity is mediated by the binding of serotonin to several classes of cell-surface 5-HT receptors. Numerous 5-HT receptors are known and have been categorized into several families (5-HT1-5-HT7) and some are further divided into subfamilies (e.g. 5-HT2A and 5-HT2C). Many of the 5-HT receptors have been cloned and their specific functions elucidated. 1

[0006] Imbalances in serotonin activity are believed to be responsible for a variety of clinically recognized disorders. For example, many brain disorders in humans are associated with fluctuations in serotonin levels and are effectively treated with drugs that interact specifically with 5-HT receptors or that block the reuptake of serotonin into the presynaptic axon terminals, suggesting that serotonin dysregulation may be involved in these disorders. For example, serotonin receptor ligands are clinically approved as drugs for the treatment of depression, psychosis, anxiety, and certain sexual aberrations, as well as for other conditions such as migraine headaches, chemotherapy-induced nausea, high blood pressure, certain abnormal cardiovascular activities and abnormal thermoregulation.

[0007] However, most of these existing agents are relatively nonselective in that they exhibit affinities for several 5-HT receptor classes, as well as for central dopaminergic, noradrenergic, histaminergic, and/or cholinergic receptors, as well as blocking serotonin and dopamine reuptake into the nerve terminus. As a consequence of activity at nonserotonergic sites, the use of these agents may result in undesirable side effects such as tardive dyskinesia, tardive dystonia, excessive weight gain, etc. These side effects can be debilitating and may require clinical treatment in and of themselves. The possibility of the occurrence of side effects is a cause of distress to patients, and is a likely contributor to patient non-compliance with suggested drug therapy regimens.

[0008] Ligands which bind with varying degrees or selectivity to some families of 5-HT receptors are known. For example, U.S. Pat. Nos. 5,496,957 and 5,504,101 to Glennon (Mar. 5, 1996 and Apr. 2, 1996, respectively, the complete contents of which are hereby incorporated by reference) describe agents which bind to the 5-HT1Dβ receptor. And U.S. Pat. No. 5,942,536 to Fritz et al. (Aug. 24, 1999, the complete contents of which is hereby incorporated by reference) describes agents which bind to the 5-HT1f receptor. Roth et al. (1994) describe the binding affinities of 36 typical and atypical antipsychotic agents to 5-HT6 and 5-HT7 receptors, and Glennon et al. (1989) describe classes of agents which bind to 5-HT1A receptors. Finally, Glennon et al. (1994) describe the effect of different amine substitutions on phenylalkylamine and indolylalkylamine derivatives which bind to 5-HT2A and 5-HT2C serotonin receptors. There is an ongoing need for the development of alternative agents that selectively bind to specific families of 5-HT receptors with high affinity.

SUMMARY OF THE INVENTION

[0009] It is an object of this invention to provide compounds having the formula 2

[0010] In the compounds, R1 and R2 may be —H, —OH, —OCH3, halogen, aryl, alkylaryl, or substituted or unsubstituted branched or unbranched C1-C10 alkyl or alkylaryl, and may be the same or different, and X may be a) carbon with two —H substituents, b) carbon with one or two lower alkyl substituents, or c) a heteroatom or heteroatomic group selected from the group consisting of —O—; —S—; or —SO2—. In some embodiments, R1 may be —H, —CH2CH2CH2Ph, —OCH3, —CH2(CH2) 4CH3, phenyl, or —OH. In some embodiments, R2 may be —H, —CH3 or CH2Ph. In some embodiments, X may be —CH2—, —C(CH3)2—, —O— or —S—.

[0011] Specific embodiments include compounds with the following formulas: 34

[0012] The invention further provides a pharmaceutical composition comprising, a compound of formula 5

[0013] in which R1 and R2 may be —H, —OH, —OCH3, halogen, aryl, alkylaryl, or substituted or unsubstituted branched or unbranched C1-C10 alkyl or alkylaryl, and may be the same or different, and X may be a) carbon with two —H substituents, b) carbon with one or two lower alkyl substituents, or c) a heteroatom or heteroatomic group selected from the group consisting of —O—; —S—; or —SO2—. In some embodiments, R1 may be —H, —CH2CH2CH2Ph, —OCH3, —CH2(CH2)4CH3, phenyl, or —OH. In some embodiments, R2 may be —H, —CH3 or CH2Ph. In some embodiments, X may be —CH2—, —C(CH3)2—, —O— or —S—, and a pharmaceutically acceptable carrier.

[0014] The present invention also provides a method of treating a condition caused by abnormal serotonin activity in a patient in need thereof. The method includes the step of administering a compound of formula 6

[0015] in which R1 and R2 may be —H, —OH, —OCH3, halogen, aryl, alkylaryl, or substituted or unsubstituted branched or unbranched C1-C10 alkyl or alkylaryl, and may be the same or different, and X may be a) carbon with two —H substituents, b) carbon with one or two lower alkyl substituents, or c) a heteroatom or heteroatomic group selected from the group consisting of —O—; —S—; or —SO2—. In some embodiments, R1 may be —H, —CH2CH2CH2Ph, —OCH3, —CH2(CH2)4CH3, phenyl, or —OH. In some embodiments, R2 may be —H, —CH3 or CH2Ph. In some embodiments, X may be —CH2—, —C(CH3)2—, —O— or —S—. The compound is administered in a quantity sufficient to ameliorate symptoms of said condition in said patient. The condition may be for example, clinical depression or anxiety, schizophrenia, schizoaffective disorder, and various eating and sleeping disorders. The compound may be an antagonist of 5HT2 receptors, an antagonist of H1 receptors, or an antagonist of both 5HT2 receptors and H1 receptors.

[0016] The invention further provides a method of blocking a 5HT2 receptor in a patient in need thereof. The method includes the step of administering to the patient of a compound of formula 7

[0017] in which R1 and R2 may be —H, —OH, —OCH3, halogen, aryl, alkylaryl, or substituted or unsubstituted branched or unbranched C1-C10 alkyl or alkylaryl, and may be the same or different, and X may be a) carbon with two —H substituents, b) carbon with one or two lower alkyl substituents, or c) a heteroatom or heteroatomic group selected from the group consisting of —O—; —S—; or —SO2—. In some embodiments, R1 may be —H, —CH2CH2CH2Ph, —OCH3, —CH2(CH2)4CH3, phenyl, or —OH. In some embodiments, R2 may be —H, —CH3 or CH2Ph. In some embodiments, X may be —CH2—, —C(CH3)2—, —O— or —S—. The compound is administered in a quantity sufficient to block the 5HT2 receptor.

[0018] The invention further provides a method of blocking an H1 receptor in a patient in need thereof The method includes the step of administering to the patient a compound of formula 8

[0019] in which R1 and R2 may be —H, —OH, —OCH3, halogen, aryl, alkylaryl, or substituted or unsubstituted branched or unbranched C1-C10 alkyl or alkylaryl, and may be the same or different, and X may be a) carbon with two —H substituents, b) carbon with one or two lower alkyl substituents, or c) a heteroatom or heteroatomic group selected from the group consisting of —O—; —S—; or —SO2—. In some embodiments, R1 may be —H, —CH2CH2CH2Ph, —OCH3, —CH2(CH2)4CH3, phenyl, or —OH. In some embodiments, R2 may be —H, —CH3 or CH2Ph. In some embodiments, X may be —CH2—, —C(CH3)2—, —O— or —S—. The compound is administered in a quantity sufficient to block the H1 receptor.

[0020] The invention further provides a method of blocking both a 5HT2 receptor and an H1 receptor in a patient in need thereof. The method includes the step of administering to the patient a compound of formula 9

[0021] in which R1 and R2 may be —H, —OH, —OCH3, halogen, aryl, alkylaryl, or substituted or unsubstituted branched or unbranched C1-C10 alkyl or alkylaryl, and may be the same or different, and X may be a) carbon with two —H substituents, b) carbon with one or two lower alkyl substituents, or c) a heteroatom or heteroatomic group selected from the group consisting of —O—; —S—; or —SO2—. In some embodiments, R1 may be —H, —CH2CH2CH2Ph, —OCH3, —CH2(CH2)4CH3, phenyl, or —OH. In some embodiments, R2 may be —H, —CH3 or CH2Ph. In some embodiments, X may be —CH2—, —C(CH3)2—, —O— or —S—. The compound is administered in a quantity sufficient to block both the 5HT2 and the H1 receptor.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

[0022] The present invention provides certain compounds that exhibit high binding affinity for serotonin receptors 5-HT2A and 5-HT2C. Without being bound by theory, the compounds appear to act as antagonists of these receptors. By “antagonist” we mean the compounds block the action of endogenous serotonin at the receptor and prevent activation of the receptor.

[0023] Further, the compounds of the present invention are highly selective, being essentially devoid of affinity for the dopamine D2 receptors and the serotonin and norepinephrine transporters. As such, the compounds are useful for treating conditions for which it is desirable to selectively block serotonin receptor function with an antagonist. Because the compounds are highly selective for the target receptors, they cause fewer side effects than previously known serotonin receptor ligands.

[0024] A generic chemical structure of the compounds of the present invention is given in Formula 2. 10

[0025] In Formula 2:

[0026] R1 and R2 may be —H, —OH, —OCH3, halogen, aryl, alkylaryl, or substituted or unsubstituted branched or unbranched C1-C10 alkyl or alkylaryl, and may be the same or different. X may be a) carbon with two —H substituents, b) carbon with one or two lower alkyl substituents, or c) a heteroatom or heteroatomic group, examples of which include but are not limited to —O—, —S—, and —SO2—.

[0027] By “alkylaryl” we mean an aryl substituted with a C1-C4 alkyl, or a C1-C10 alkyl bridging between an aryl substituent (e.g. phenyl) and the phenyl moiety depicted in Formula 2. “Phenyl” and “benzyl” are used interchangably herein. Lower alkyl substituents include branched or unbranched C1-C4 alkyl groups such as methyl, ethyl, etc. Branched or unbranched C1-C10 alkyl or alkylaryl may be substituted, i.e. one or more of the hydrogens may be replaced with a non-hydrogen atom or chemical group, for example, with other alkyl groups such as lower alkyls, phenyl, etc.

[0028] Exemplary substituents R1, R2 and X of generic Formula 2 are as given in Table 1 where “Compound Number” refers to the number assigned to the compound in the synthesis schemes described in the Examples section.

TABLE 1
Examples of R1, R2 and X Substituents
Compound Number	R1	R2	X
[5]	—H	—H	—CH2—
[23]	—CH2CH2CH2Ph	—H	—CH2—
[17]	—OCH3	—H	—CH2—
[21]	—CH2(CH2)4CH3	—H	—CH2—
[17a]	—OH	—H	—CH2—
[25]	—Ph	—H	—CH2—
[6]	—H	—CH3	—CH2—
[7]	—H	—CH2Ph	—CH2—
[22]	—CH2CH2CH2Ph	—CH2Ph	—CH2—
[16]	—OCH3	—CH2Ph	—CH2—
[20]	—CH2(CH2)4CH3	—CH2Ph	—CH2—
[18]	—OH	—CH2Ph	—CH2—
[12]	—H	—H	—C(CH3)2—
[30]	—H	—H	—O—
[36]	—H	—H	—S—

[0029] The simplest “least substituted” compound of the present invention is spiro[9,10-dihydroanthracene]-9,3′-pyrrolidine [5] (SPAN), the formula for which is given in Formula 3. 11

[0030] In compound [5], the synthesis of which is described in Example 1, R1 and R2 are both —H and X is —CH2—. The other compounds of the invention are generally substituted with more complex chemical groups (i.e. with chemical groups composed of more atoms) and thus may be considered as derivatives or analogs of [5]. By “derivatives” or “analogs” we mean that the other compounds of the invention have the basic chemical structure of compound [5] but contain different chemical groups at one or more of positions R1, R2 and X.

[0031] The compounds of the present invention are ligands of (i.e. bind to) serotonin receptors 5-HT2 and 5-HT2A and 5-HT2C. By “high affinity” we mean that the compounds display a Ki in the range of about less than 1 to about 500 nM. In contrast, compounds with low or moderate affinities diplay Ki values in the range of about 2000 to about 10,000 nM, and about 500 to about 2000 nM, respectively. For example, compound [5] displays a Ki of 4nM for 5-HT2 receptors and a Ki of 24 nM for the structurally related 5-HT2c receptor and is therefore a high affinity ligand for both receptors.

[0032] In addition, the compounds of the present invention are selective for 5HT2 serotonin receptors 5-HT2, 5-HT2A and 5-HT2C. By “selective” we mean that the affinity of the compounds for serotonin receptors is significantly higher than for other related receptor types. For example, a compound with low selectivity typically has an affinity of about 10-fold or less higher than for other related receptor types, whereas moderately and highly selective compounds display about 10-100 fold and about 100 to 10,000 fold higher affinities, respectively. By “related receptor types” we mean other receptors implicated in the most serous side effects of typical 5HT2 antagonists, e.g. the D2 receptor, and the serotonin and norepinephrine transporters. For example, compound [5] displays a Ki of 4 nM for the 5-HT2 receptor and a Ki of 24 nM for the structurally related 5-HT2c receptor but is essentially devoid of binding activity for the dopamine D2 receptor (Ki=5040 nM), the serotonin transporter (Ki>10,000 nM) and the norepinephrine transporter (Ki>10,000 nM).

[0033] The compounds of the present invention are useful in treating a variety of disorders that result from abnormal serotonin activity. They may be used as prophylactic and/or acute-phase remedies for the relief and reversal of serotonin-regulated symptoms. In particular, disorders that result from an increased synaptic concentration of serotonin, in particular as found in depressive disorders, and that can be ameliorated by inhibition of the 5HT2 serotonin receptors. Examples of such conditions include but are not limited to clinical depression or anxiety, schizophrenia, schizoaffective disorder, and various eating and sleeping disorders.

[0034] The present invention also encompasses a pharmaceutical preparation comprising at least one compound of the present invention together with a pharmaceutically acceptable carrier. The compounds of the invention can be used either as the free base or as the pharmaceutically acceptable acid-addition salt form, for example, hydrochloride, hydrobromide, tartrate, and maleate. Such a pharmaceutical preparation may be in any of many forms suitable for administration of drugs, including but not limited to injectable dosage forms and solid dosage forms such as tablets, capsules, and the like. The compounds can be administered in the pure form or in a pharmaceutically acceptable formulation including suitable elixirs, binders, and the like, or as pharmaceutically acceptable salts or other derivatives. It should be understood that the pharmaceutically acceptable formulations and salts include liquid and solid materials conventionally utilized to prepare injectable dosage forms and solid dosage forms such as tablets and capsules. Water may be used for the preparation of injectable compositions which may also include conventional buffers and agents to render the injectable composition isotonic. Other potential additives include: colorants; surfactants (TWEEN, oleic acid, etc.); and binders or encapsulants (lactose, liposomes, etc). Solid diluents and excipients include lactose, starch, conventional disintergrating agents, coatings and the like. Preservatives such as methyl paraben or benzalkonium chloride may also be used. Depending on the formulation, it is expected that the active composition will consist of 1-99% of the composition and the vehicular “carrier” will constitute 1-99% of the composition. The pharmaceutical compositions of the present invention may include any suitable pharmaceutically acceptable additives or adjuncts to the extent that they do not hinder or interfere with the therapeutic effect desired of agent.

[0035] The invention further provides a method for treating clinical disorders resulting from aberrant serotonin activity in a patient in need of such treatment. According to the method, at least one compound of the present invention is administered to the patient in a quantity sufficient to ameliorate symptoms of such disorders.

[0036] Those of skill in the art will recognize that the exact dosage of an agent to be so-administered may vary depending on factors such as the age, gender, weight and overall health status of the individual patient, as well as on the nature of the disorder being treated. Generally, dosages in the range of from about 0.1 to about 1000 mg active agent/kg body weight/24 hr., and more preferably about 1.0 to about 500.0 mg active agent/kg body weight/24 hr., and even more preferably about 10 to about 100.0 mg active agent/kg body weight/24 hr., are effective. The level of efficacy and optimal amount of dosage for any given compound may vary from compound to compound.

[0037] The agents of the present invention may be administered by any of a wide variety of means which are well known to those of skill in the art, (including but not limited to intravenously, intramuscularly, intraperitoneallly, orally, rectally, intraocularly, and the like) or by other routes (e.g. transdermal, sublingual, aerosol, etc.). and may be in any form (e.g. liquid, solid, etc.) which is suitable for the means of administration. Further, the agents may be administered either alone or together with other medications in a treatment protocol.

[0038] Further, several of the compounds (e.g. [5], [16], [17], [30] and [36] of the present invention also display a high affinity for the histamine H1 receptor, high affinity being defined herein as displaying a Ki value of about 100 nm or less. This receptor is known to function in allergic reactions in the periphery and regulation of sleep in the central nervous system. Thus, compounds of the present invention may also be utilized to treat conditions in which it is desirable to antagonize the action of histamine at Hi receptors. Examples of such conditions include but are not limited to sleep disorders and allergic reactions.

[0039] Finally, the compounds of the present invention may be used as above for determining 5-HT2 receptor family function, for example, in a laboratory or clinical diagnostic setting.

EXAMPLES

Example 1

[0040] Synthesis of Spiro[9,10-dihydroanthracene-]9,3′-pyrrolidine [5] (SPAN)

[0041] The synthesis of SPAN was carried out as depicted in Scheme 1 and as further described below. Referring to Scheme 1, reagents and conditions were as follows: (a) POCl3, reflux, 45 min, (b) C2H5ONa, BrCH2COOC2H5, EtOH, reflux, (c) 10% Pd/C, CH3OH, HCl, (d) Borane-THF/THF; 6.0M HCl. 12

[0042] 9-Cyano-9,10-dihydroanthracene [2]

[0043] POCl3 (5.5 mL, 59 mmol) was added to crystalline 9,10-dihydroanthracene carboxamide [1] (0.54 g, 2.43 mmol) while stirring. The solution was then heated at reflux (45 min), when TLC showed complete absence of starting material. The solution was then poured into a mixture of crushed ice and NH4OH with vigorous stirring. The solution was stirred (15 min) and excess of NH4OH was added to keep the solution alkaline. The solid formed was extracted with ether (3×50 ml). The combined ether extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure to give an yellow oil which crystallized immediately. The product was purified by mplc using pet. ether: acetone (9:1) as eluent to give 0.296 g (60%) of pure 9-Cyano-9,10-dihydroanthracene as colorless crystals mp. 106-108° C. **lit. mp. 101-102° C. ICcm−1 2215. 1H NMR (CDCl3)d: 3.87-3.93 (d, J=18 Hz, 1H, CH2), 4.05-4.11 (d,J=18 Hz, 1H, CH2), 5.02 (s, 1H, CH), 7.28-7.79 (m, 8H, Ar—H). 13C NMR (CDCl3) d: 36.14, 37.60, 119.54, 125.88, 127.12, 127.60, 128.53, 128.82, 129.56, 131.34, 136.65

[0044] (9-Cyano-9,10-dihydro-anthracen-9-yl)-acetic acid ethyl ester [3]

[0045] 9-Cyano-9,10-dihydroanthracene [2] (1.25 g, 6.09 mmol) was added to sodium ethoxide prepared from Na (0.196 g, 8.53 mmol) and EtOH (10 mL) and heated at reflux (1 hr). The solution was then cooled in an ice bath and ethyl bromoacetate (1.42 g, 8.53 mmol) was added drop wise via a syringe. The resulting mixture was heated at reflux (4 h) cooled and filtered. The residue was washed with ether (25 mL). Water (25 mL) was added to the filterate and the organic layer was separated. The aqueous layer was once again extracted with ether (25 mL). The combined ether extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure to give an oil which was purified by mplc using pet. ether: EtOAc (9:1) as eluent to give 1.245 g (70%) of the product as a colorless oil, which crystallized on prolonged standing: mp 69-70° C. (EtOAc-pet. ether).1H NMR (CDCl3)d: 1.10-1.15 (t, J=7.5 Hz, CH3), 2.85 (s, 2H, CH2), 3.97-4.14 (m, 4H, CH2), 7.33-7.89 (m, 8H, Ar—H). 13C NMR (CDCl3) d: 14.53, 35.27, 46.05, 46.28, 61.63, 121.89, 127.58, 127.70, 128.93, 134.21, 135.10, 167.96

[0046] Spiro [9,10-dihydroanthracene]-9,4′-pyrrolidin-2′-one [4]

[0047] A mixture of (9-Cyano-9,10-dihydro-anthracen-9-yl)-acetic acid ethyl ester [3] (0.60 g, 2.061 mol), 10% Pd/C (0.15 g) in methanol (40 mL) and HCl (1 mL) was hydrogenated at 50 kg/cm3 (3 days). The catalyst was filtered off with celite and the solvent was evaporated under reduced pressure to give a white semisolid. Water (25 mL) was added and the solution was made basic with 10% NaOH and extracted with EtOAc (3×25 mL). The combined EtOAc extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure to give a colorless oil which crystallized immediately on standing. The solid was recrystallized from CHCl3-pet.ether to give 0.35 g (68%) of the pure amide as a white crystalline solid: mp 189-190° C. 1H NMR (CDCl3)d: 3.06 (s, 2H, CH2), 3.70 (s, 2H, CH2), 4.00-4.06 (d, J=18 Hz, 1H, CH2), 4.09-4.15 (d, J=18 Hz, 1H, CH2), 6.15 (s, 1H, NH), 7.24-7.58 (m, 8H, Ar—H). 13C NMR (CDCl3) d: 36.37, 43.20, 47.49, 55.66, 125.04, 127.50, 128.73, 136.35, 141.36, 178.40

[0048] Spiro[9,10-dihydroanthracene]-9,3′-pyrrolidine [5]

[0049] A 1.0 M solution of BH3-THF complex (7.00 ml, 7.00 mmol) was added at 0° C. to a well stirred solution of 4-Spiro-9-(9,10-dihydroanthracene)pyrrolidin-2-one [4](0.35 g, 1.40 mmol) in anhydrous THF (2 mL). The solution was brought to RT and then heated at reflux (8 h), cooled to RT and 6 M solution of HCl (4 mL) was added cautiously to the reaction mixture. The reaction mixture was then heated at reflux (1 hr), cooled to RT and the solvent was removed under reduced pressure, resulting in a white suspension. Water (20 mL) was added to it and extracted with EtOAc (20 mL). The aqueous phase was then basified using 10% NaOH and extracted with Et2O (3×25 ml). The combined Et2O extracts were washed with water and brine, dried (MgSO4) and the solvent was removed under reduced pressure to give 0.31 g (94%) the amine as colorless oil. The oil started to darken rapidly and was dissolved in anhydrous acetone and fumaric acid (0.15 g, 1.31 mmol) was added and heated. The solution on cooling gave the fumarate as pale pink powder, which remained on two recrystallizations. mp. 190.5-191.5° C. (EtOAc-CH3OH). 1H NMR (DMSO-d6)d: 2.25-2.30 (t, J=7.5 Hz, 2H, CH2), 3.21-3.26 (t, J=7.5 Hz, 2H, CH2), 3.55 (s, 2H, CH2), 4.06 (s, 2H, CH2), 6.44 (s, 1H, fumarate), 7.20-7.56 (m, 8H, Ar—H). 3C NMR (DMSO-d6) d: 36.22, 36.67, 45.18, 51.09, 54.10, 124.43, 126.69, 126.76, 128.17, 135.84, 137.08, 141.44, 168.96. Anal. Calcd. For (C17H17N.½C4H4O4): C, 77.79; H, 6.52; N, 4.77. Found. C, 77.12; H, 6.56; N, 4.78

Example 2

[0050] Synthesis of Spiro[9,10-dihydroanthracene]-9,3′-(1-methyl)-pyrrolidine [6]

[0051] The synthesis of compound [6] was carried out as depicted in Scheme 2 and as described below. Referring to Scheme 2, reagents and conditions were as follows: (a) NaCNBH3/CH3CN. 13

[0052] Spiro[9,10-dihydroanthracene]-9,3′-pyrrolidine [5] (0.23 g, 1.0 mmol) was dissolved in a mixture of anhydrous CH3CN (10 mL) and formaldehyde (37%, 0.5 mL). NaCNBH3 (0.10 g, 1.6 mmol) was added in portions over 5 min. and the reaction mixture was stirred (45 min) at room temperature. Glacial acetic acid was added dropwise until the solution tested neutral. Stirring was continued for another 45 min, glacial acetic acid being added occasionally to maintain pH. The solvent was removed under reduced pressure and 2 N NaOH (20 mL) was added and extracted with Et2O (2×25 mL). The combined Et2O extracts were then extracted with 1N HCl (3×25 mL). The acid extracts were combined and neutralized with solid NaOH and extracted with Et2O (3×25 mL). The combined Et2O extracts were washed with water, brine, dried (MgSO4) and evaporated under reduced pressure to give 0.155 g (63%) of colorless oil. The oil was dissolved in anhydrous acetone and fumaric acid (0.079 g, 0.68 mmol) was added and heated to dissolve the acid. The solution on cooling the product as a white powder: mp. 162-163° C. (EtOAc-CH3OH). 1H NMR (DMSO-d6)δ: 2.39-2.44 (t, J=7.5 Hz, 2H, CH2), 2.46 (s, 3H, CH3), 3.00-3.04 (t, J=6 Hz, 2H, CH2), 3.11 (s, 2H, CH2), 4.02 (s, 2H, CH2), 6.59 (s, 1H, fumarate), 7.18-7.62 (m, 8H, Ar—H). 13C NMR (DMSO-d6) δ: 35.77, 38.50, 42.20, 49.94, 55.85, 67.28, 125.43, 126.39, 126.56, 127.89, 134.56, 136.19, 143.03, 166.67. Anal. Calcd. For (C18H19N.C4H4O4.0.25 H2O): C, 71.42; H, 6.40; N, 3.78. Found. C, 71.68; H, 6.68; N, 3.75

Example 3

[0053] Synthesis of Spiro[9,10-dihydroanthracene]-9,3′-(1-benzyl)-pyrrolidine [7]

[0054] The synthesis of compound [7] was from [5] was carried out as depicted in Scheme 3 and as described below. Regarding Scheme 3, reagents and conditions were as follows: C6H5CH2Br, Et3N, CH2Cl2, reflux. 14

[0055] Spiro[9,10-dihydroanthracene]-9,3′-pyrrolidine [5] (0.125 g, 0.53 mmol) was dissolved in anhydrous CH2Cl2 ( 10 mL) and triethylamine was added dropwise. The reaction mixture was cooled in an ice-bath and benzyl bromide (0.113 g, 0.66 mmol) in anhydrous CH2Cl2 (5 mL) was added via syringe. The reaction mixture was warmed to room temperature and then heated at reflux (4 h). The solvent was removed under reduced pressure and water (20 mL) was added to the residue and extracted with EtOAc (3×25 mL). The combined EtOAc extracts were washed with water, brine, dried (MgSO4) and evaporated under reduced pressure to give a dark brown oil which was purified by mplc using CH2Cl2 as eluent to give 0.12 g (70%) of the amine as a colorless oil. The oil was dissolved in anhydrous acetone and fumaric acid (0.047 g, 0.40 mmol) was added and heated to dissolve the acid. The solution on cooling gave the product as a white powder: mp. 175-176° C. (EtOAc-CH3OH). 1H NMR (DMSO-d6)δ: 2.31-2.35 (t, J=6 Hz, 2H, CH2), 2.87-2.92 (t, J=7.5 Hz, 2H, CH2), 3.02 (s, 2H, CH2), 3.74 (s, 2H, CH2), 3.98 (s, 2H, CH2), 6.61 (s, 1H, fumarate), 7.14-7.66 (m, 8H, Ar—H). 13C NMR (DMSO-d6) δ: 35.56, 49.22, 53.81, 59.68, 66.15, 125.67, 126.19, 126.53, 127.28, 127.78, 128.60, 128.81, 134.40, 135.83, 143.92, 166.39. Anal. Calcd. For (C24H23N.C4H4O4): C, 76.16; H, 6.16; N, 3.17. Found. C, 76.08; H, 6.25; N, 3.21

Example 4

[0056] Synthesis of Spiro[-(10,10-dimethyl)-9,10-dihydroanthracene]-9,3′-pyrrolidine [12]

[0057] Compound 12 was synthesized as depicted in Scheme 4 and as described below. Referring to Scheme 4, reagents and conditions were as follows: (a) POCl3, reflux, 45 min, (b) C2H5ONa, BrCH2COOC2H5, EtOH, reflux, (c) 10% Pd/C, CH3OH, HCl, (d) Borane-THF/THF; 6.0M HCl. 15

[0058] 9-cyano-10,10-Dimethyl-9,10-dihydroanthracene [9]

[0059] POCl3 (25 mL, 00 mmol) was added to crystalline 10,10-Dimethyl-9,10-dihydroanthracene-9-carboxamide [8] (1.25 g, 4.9 mmol) while stirring. The solution was then heated at reflux (30 min), when TLC showed complete absence of starting material. The solution was then poured into a mixture of crushed ice and NH4OH with vigorous stirring. The solution was stirred for 15 minutes and excess of NH4OH was added to keep the solution alkaline. A solid substance separated out which was extracted with ether (3×50 ml). The combined ether extracts were washed with water, brine, dried (MgSO4) and evaporated under reduced pressure to give an light yellow oil which crystallized immediately. The product obtained was chromatographically pure and recrystallized readily from EtOH to give 1.0 g (86%) of the product as colorless prisms. mp. 91-92° C. 1H NMR (CDCl3)d: 1.54 (s, 3H, CH3), 1.79 (s, 3H, CH3), 5.32 (s, 1H, CH), 7.32-7.68 (m, 8H, Ar—H). 13C NMR (CDCl3) d: 30.22, 30.33, 36.95, 125.77, 127.43, 127.92, 129.28. Anal. Calcd. For (C17H15N): C, H, N.

[0060] (9-Cyano-10,10-dimethyl-9,10-dihydro-anthracen-9-yl)-acetic acid ethyl ester [10]

[0061] 9-cyano-10,10-Dimethyl-9,10-dihydroanthracene [9] (0.8 g, 3.42 mmol) was added to sodium ethoxide prepared from Na metal (0.110 g, 4.80 mmol) and ethanol (10 mL) and heated under reflux for one hour leading to the development of a greenish brown solution. The solution was then cooled in an ice bath and ethyl bromoacetate (0.80 g, 4.80 mmol) was added dropwise via a syringe. The resulting mixture was then heated at reflux (4 h) and filtered. The solid residue was washed with ether (25 mL). Water (25 mL) was added to the filterate and the organic layer was separated. The aqueous layer was once again extracted with ether (25 mL). The combined ether extracts were washed with water, brine, dried (MgSO4) and evaporated under reduced pressure to give an oil which was purified by medium pressure liquid chromatography using pet. ether: EtOAc (9:1) as eluent to give 0.978 g (74%) of the product as a colorless oil. 1H NMR (CDCl3)d: 0.98-1.06 (t, 3H, CH3), 1.64-1.67 (d, J=9Hz, 3H, CH3), 1.71-1.74 (d, J=9 Hz, 3H, CH3), 3.04-3.07 (d, J=9Hz, 2H, CH2), 3.86-3.94 (q, 2H, CH2), 7.29-7.77 (m, 8H, Ar—H). 13C NMR (CDCl3) d: 14.39, 33.85, 35.21, 38.37, 52.29, 61.38, 123.17, 127.53, 127.84, 128.17, 129.48, 130.97, 143.23, 167.97.

[0062] Spiro[-(10,10-dimethyl)-9,10-dihydroanthracene]-9,4′-pyrrolidin-2′-one [11]

[0063] A mixture of(9-Cyano- 10,10-dimethyl-9,10-dihydro-anthracen-9-yl)-acetic acid ethyl ester [10] (0.975 g, 3.05 mol), 10% Pd/C (0.1 g) in methanol (20 mL) and HCl (1 mL) was hydrogenat at 50 kg/cm3 (24 h). The catalyst was filtered off with celite and the solvent was evaporated under reduced pressure to give a white semisolid. Water (25 mL) was added and the solution was made basic with 10% NaOH and extracted with EtOAc (3×25 mL). The combined EtOAc extracts were washed with water, brine and dried using anhydrous MgSO4 and evaporated under reduced pressure to give a colorless oil which was purified by mplc using pet.ether: EtOAc (8:2) as eluent to give a white solid. The solid was recrystallized from CHCl3-pet.ether to give 0.4 g (40%) ofthe pure amide as colorless needles. mp 236-237° C. 1H NMR (CDC13)d: 1.68 (s, 6H, CH3), 3.07 (s, 2H, CH2), 3.97 (s, 2H, CH2), 7.32-7.56 (m, 8H, Ar—H).13C NMR (CDCl3) d: 35.17, 35.26, 37.89, 43.67, 53.34, 63.86, 126.68, 126.98, 127.70, 128.00, 141.14, 142.47, 178.04

[0064] Spiro[-(10,10-dimethyl)-9,10-dihydroanthracene]-9,3′-pyrrolidine [12]

[0065] A 1.0M solution of BH3-THF complex (7.00 ml, 7.00 mmol) was added at 0° C. to a well stirred solution of Spiro[-(10,10-dimethyl)-9,10-dihydroanthracene]-9,4′-pyrrolidin-2′-one [11] (0.15 g, 0.54 mmol) in anhydrous THF (2 mL). The solution was brought to room temperature and then heated at reflux (8 h), cooled and 6 M solution of HCl (4 mL) was added cautiously to the reaction mixture. The reaction mixture was then heated at reflux for an additional hour, cooled and the solvent was removed under reduced pressure, resulting in a white suspension. Water (20 mL) was added to it and extracted with EtOAc (20 mL). The aqueous phase was then basified using 10% NaOH and the resultant solution was extracted with Et2O (3×25 ml). The combined Et2O extracts were washed with water, brine, dried (MgSO4) and the solvent was removed under reduced pressure to give 0.129 g (90%) the amine as a colorless oil. The oil was dissolved in anhydrous acetone and fumaric acid (0.062 g, 0.538 mmol) was added and heated. The solution on cooling gave the fumarate as a white powder: mp. 207-208° C. (EtOAc-CH3OH). 1H NMR (DMSO-d6)d: 1.57 (s, 3H, CH3), 1.63 (s, 3H, CH3), 2.31-2.36 (t, J=7.5 Hz, 2H, CH2), 3.51-3.56 (t, J=7.5 Hz, 2H, CH2), 3.63 (s, 2H, CH2), 6.53 (s, 1H, fumarate), 7.27-7.64 (m, 8H, Ar—H). 13C NMR (DMSO-d6) δ: 33.77, 35.19, 37.67, 47.00, 48.70, 48.88, 63.75, 126.70, 127.17, 135.39, 140.55, 142.59, 168.28. Anal. Calcd. For (C19H21N.C4H4O4): C, 72.80; H, 6.64; N, 3.69. Found C, 72.40, 6.64, 3.65

Example 5

[0066] Synthesis of Spiro[-(3-methoxy)-9,10-dihydroanthracene]-9,3′-pyrrolidine [17]

[0067] The compound [17] was synthesized as depicted in Scheme 5 and described below. Referring to Scheme 5, reagents and conditions were as follows: (a) 2-Bromobenzaldehyde, anhydrous THF, 0° C. (b) LiAlH4/AlCl3, anhydrous Et2O, reflux (c) n-BuLi, anhydrous Et2O, n-benzyl-3-pyrrolidone (d) CH3SO3H, rt (e) 10% Pd/C, CH3OH. 16

[0068] (2-Bromo-phenyl)-(3-methoxy-phenyl)-methanol [13]

[0069] 3-Methoxyphenyl magnesium bromide (1.0 M solution in THF; 5.4 mL, 5.4 mmol) was taken in a flask under N2 and cooled (0° C.). 2-Bromobenzaldehyde (1 g, 5.4 mmol) in anhydrous THF (10 mL) was added dropwise via syringe over 5 min. The reaction mixture was stirred at this temperature for 20 min. and slowly brought to room temperature. After stirring for another 30 min. satd. NH4Cl solution (20 mL) was added and the mixture was extracted with Et2O (3×25 mL). The combined Et2O extracts were washed with water, brine, dried (MgSO4) and evaporated under reduced pressure to give a yellow oil. The oil was purified by mplc using CH2Cl2 as eluent to give 1.275 g (81%) of the alcohol as a colorless oil. 1H NMR (CDCl3)d: 2.71 (s, 1H, OH), 3.78 (s, 3H, CH3), 6.15 (s, 1H, CH), 6.80-7.58 (m, 8H, Ar—H). 3C NMR (CDCl3) d: 55.80, 75.16, 113.29, 119.90, 123.39, 128.33, 129.11, 129.71, 130.08, 133.39.

[0070] 3-(2-Bromobenzyl)-methoxy benzene [14]

[0071] LiAlH4 (0.154 g, 4.06 mmol) was suspended in anhydrous Et2O (10 mL) under a N2 atmosphere and cooled (0° C.) with stirring. Anhydrous AlCl3 (1.08 g, 8.14 mmol)was dissolved in ice-cold anhydrous Et2O (20 mL) and added dropwise to the LiAlH4 suspension. After complete addition the suspension was stirred at the same temperature (20 min.). (2-Bromo-phenyl)-(3-methoxy-phenyl)-methanol [13] (0.68 g, 2.32 mmol) was dissolved in anhydrous Et2O (10 mL) and added dropwise via syringe to the suspension. After complete addition the reaction mixture was heated at reflux (4 h), cooled (0° C.) and EtOAc was added dropwise to destroy the excess of the reagent and the mixture was added to 20% aq. H2SO4 (50 mL). Et2O (50 mL) was added and extracted. The Et2O layer was separated, washed with water, brine, dried (MgSO4) and evaporated to give a reddish yellow oil. The oil was purified by mplc using pet. ether-CH2Cl2 (9:1) as eluent to give 0.485 g (75%) of the pure product as a colorless oil. 1H NMR (CDCl3)d: 3.81 (s, 3H, CH3), 4.14 (s, 2H, CH2), 6.79-7.62 (m, 8H, Ar—H). 13C NMR (CDCl3) d: 42.34, 55.69, 112.07, 122.02, 125.48, 128.07, 128.50, 130.02, 131.66, 133.43.

[0072] 1 -Benzyl-3-[2-(3-methoxy-benzyl)-phenyl]-pyrrolidin-3-ol [15]

[0073] 3-(2-Bromobenzyl)-methoxy benzene (0.5 g, 1.80 mmol) [14] was dissolved in anhydrous Et2O (15 mL)and cooled to −78° C. under N2. n-butyl lithium (0.8 mL, 1.98 mmol, 2.5M soln. in Et2O) was added dropwise over 5 min. and stirred for 30 min. The reaction mixture was then brought to room temperature over 1 hr. The reaction mixture was cooled to −78° C. and n-benzyl-3-pyrrolidone (0.31 mL, 1.9 mmol) in anhydrous Et2O (5 mL) was added via syringe with stirring. The reaction mixture was brought to room temperature over 3 hr. Water (50 mL) was added and the organic phase was extracted. The aqueous phase was extracted with Et2O (50 mL) and the combined Et2O extracts were washed with water, brine and dried (MgSO4). Et2O was removed under reduced pressure to give a red oil which was purified by mplc using CH2Cl2:(CH3)2CO (9:1) as eluent to give 0.3 g (45%) of the aminoalcohol as a dark yellow oil. A small sample was converted into its filmarate, mp 148-149° C. (EtOAc-CH3OH). 1H NMR (DMSO-d6)d: 2.11-2.40 (m, 2H, CH2), 2.96-2.99 (d, 4H, CH2), 3.23-3.27 (d, 1H, OH), 3.67 (s, 3H, CH3), 3.89 (s, 2H, CH2), 4.27 (s, 2H, CH2), 6.58-7.42 (m, 14H, Ar—H). 13C NMR (CDCl3) d: 38.21, 52.70, 55.21, 59.71, 66.46, 80.27, 111.23, 115.17, 121.54, 125.84, 125.97, 127.38, 127.86, 128.67, 129.38, 129.58, 132.17, 134.71, 139.49, 143.93, 159.37, 160.97.

[0074] 3-Methoxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [16]

[0075] Methanesulfonic acid (5 mL) was added to 1-Benzyl-3-[2-(3-methoxy-benzyl)-phenyl]-pyrrolidin-3-ol [15] (0.5 g, 1.33 mmol) taken in a round bottom flask equipped with a stirrer under N2 at room temperature. Stirring was continued (30 min.), when TLC showed absence of starting material. Crushed ice/water was added to the reaction mixture and the solution was made basic by the addition of 10% NaOH. The alkaline reaction mixture was extracted with EtOAc (3×25 mL). The combined EtOAc extracts were washed with water, brine and dried (MgSO4). EtOAc was removed under reduced pressure to give a red oil which was purified by mplc using CH2Cl2:(CH3)2CO (9:1) as eluent to give 0.24 g (52%) of the amine as a colorless oil. The oil was converted into its oxalate salt mp. 187-188° C. (Acetone). Anal. Calcd. For (C25H25NO.C2H2O4): C, 72.79; H, 6.10; N, 3.14. Found. C, 72.75; H, 6.15; N, 3.11. 1H NMR (DMSO-d6)d: 2.52 (s, 2H, CH2), 3.27 (bs, 2H, CH2), 3.40 (s, 2H, CH2), 3.77 (s, 3H, CH3), 4.00 (s, 2H, CH2), 4.13 (s, 2H, CH2) 6.82-7.63 (m, 12H, Ar—H). 13C NMR (DMSO-d6) d: 35.60, 48.56, 52.92, 54.98, 58.54, 111.67, 112.74, 124.45, 125.75, 126.18, 127.59, 128.08, 128.42, 129.57, 135.96, 137.52, 155.71, 157.52, 162.69.

[0076] 3-Methoxy-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydro-anthracene [17]

[0077] 3-Methoxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [16] (0.23 g, 0.647 mmol) was dissolved in CH3OH (15 mL) and 10% Pd/C (0.050 g) was added under N2. A few drops of HCl were added and the reaction mixture was hydrogenated on a parr-hydrogenator at 50 psi overnight and the catalyst was filtered off using celite. The filterate was evaporated and water (15 mL) was added and basified using 10% NaOH. The basic solution was extracted with CH2Cl2 (2×25 mL) and the combined extracts were washed with water, brine and dried (MgSO4). The CH2Cl2 was removed under reduced pressure to give a yellow oil which was purified by mplc using CH2Cl2:CH3OH (9:1) as eluent to give 0.126 g (74%) of the product as a colorless oil which darkened rapidly. The oil was converted into its oxalate salt, mp. 99-101° C. (Acetone). Anal. Calcd. For (C18H19NO.C2H2O4.0.5(CH3)2CO. 0.5 H2O) : C, 65.63; H, 6.40; N, 3.56. Found. C, 65.39; H, 5.99; N, 3.31. 1H NMR (CDCl3)d: 2.32-2.38 (m, 2H, CH2), 2.97-3.02 (t, J=15 Hz, 2H, CH2), 3.18 (bs 2H, CH2), 3.83 (s, 3H, CH3), 4.05 (bs, 2H, CH2), 6.79-7.77 (m, 7H, Ar—H). 13C NMR (CDCl3) d: 36.75, 41.94, 52.78, 55.27, 65.73, 112.93, 125.87, 126.24, 126.90, 127.47, 128.01, 128.80, 129.61.

Example 6

[0078] Synthesis of 3-Hydroxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10- dihydroanthracene [18]

[0079] Compound 18 was synthesized as depicted in Scheme 6 and described below. Referring to Scheme 6, reagents and conditions were as follows: BBr3, CH2Cl2, −78° C. 17

[0080] To a solution of 3-Methoxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [16] (0.24 g, 0.675 mmol) in anhydrous CH2Cl2 (10 mL) at −78° C. was added BBr3 (2.70 mL, 2.7 mmol, 1M soln. in CH2Cl2) dropwise. The temperature was raised to ambient temperature over a period of 2 hr. and stirring was continued for 6 hr. The reaction mixture was cooled to −78° C. and CH3OH (5 mL) was added dropwise via syringe and the solvent was removed under reduced pressure. The residue was redissolved in CH3OH and satd. Solution of NaHCO3 was added and extracted with Et2O (2×25 mL). The combined Et2O extracts were washed with water, brine and dried (MgSO4). The solvent was removed under reduced pressure to give a dark yellow oil. The oil was purified by mplc using CH2Cl2:(CH3)2CO (9:1) as eluent to give 0.21 g (91%) the product as a pale yellow oil. The oil was converted into its oxalate salt mp. 133-134° C. (EtOAC—CH3OH). Anal. Calcd. For (C24H23NO.C2H2O4. 0.5H2O): C, 70.89; H, 5.94; N, 3.17. Found. C, 70.90; H, 5.88; N, 3.30. 1H NMR (DMSO-d6)d: 2.50 (bs, 2H, CH2), 3.30 (bs, 2H, CH2), 3.42 (bs, 2H, CH2), 3.91 (bs, 2H, CH2), 4.17 (bs, 2H, CH2), 6.65-7.57 (m, Ar—H, 12H). 13C NMR (DMSO-d6) d: 36.41, 49.40, 53.69, 59.25, 64.40, 113.81, 115.09, 127.08, 129.34, 130.77, 132.40, 137.05, 138.24, 142.73, 156.49, 164.15, 208.92.

Example 7

[0081] Synthesis of Spiro[-(3-hydroxy)-9,10-dihydroanthracene]-9,3′-pyrrolidine [19]

[0082] Compound [19] was synthesized as depicted in Scheme 7 and described below. Referring to Scheme 7, reagents and conditions were as follows: BBr3, CH2Cl2, −78° C. 18

[0083] Spiro[-(3-methoxy)-9,10-dihydroanthracene]-9,3′-pyrrolidine [17] (0.2 g, 0.756 mmol) was dissolved in anhydrous CH2Cl2 ( 10 mL) and cooled to −78° C. under N2. BBr3 (3.78 mL, 1.0M soln. in CH2Cl2) was added dropwise via syringe over 15 min. The reaction mixture was allowed to stir at room temperature overnight and cooled to −78° C. Anhydrous CH3OH (5 mL)was added dropwise and the solvents were evaporated under reduced pressure to give a dry solid. The solid was redissolved in anhydrous CH3OH (5 mL) and EtOAc (35 mL) was added and cooled. The product crystallized as a pale white solid, which was once again recrystallized from EtOAc-CH3OH to give 0.15 g (60%) ofthe product as its hydrobromide, mp. 150-151° C. (dec.). 1H NMR (DMSO-d6)d: 2.32-2.36 (t, J=6 Hz, 2H, CH2), 3.39 (bs, 2H, CH2), 3.71 (bs, 2H, CH2), 3.99 (bs, 2H, CH2), 6.65-7.54 (m, 7H, Ar—H), 9.28 (bs, 1H). 13C NMR (DMSO-d6) d: 35.86, 44.43, 49.37, 51.93, 112.80, 114.76, 124.76, 126.24, 126.74, 127.98, 129.50, 137.06, 138.30, 139.80, 156.04, 195.17. Anal. Calcd. For (C17H17NO.HBr.0.5H2O): C, 59.83; H, 5.61; N, 4.10. Found. C, 59.35; H, 5.48; N, 3.60.

Example 8

[0084] Synthesis of 3-n-Hexyl-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydroanthracene [21]

[0085] Compound [21] was synthesized as depicted in Scheme 8 and as described below. Referring to Scheme 8, reagents and conditions were as follows: (a) Triflic anhydride, C5H5N (b) 1-hexene, 9-BBN, PdCl2(dppf), K3PO4, anhyd. THF (c) 10% Pd/C, CH3OH, HCl. 19

[0086] 3-Trifluoromethane sulfonyl oxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [19]

[0087] To a solution of 3-Hydroxy-9,9-[spiro-3′-(-benzyl)-pyrrolidinyl]-9,10-dihydro-anthracene [16] (0.765 g, 2.241 mmol) in pyridine (5 mL) at 0° C. was added triflic anhydride (0.961 g. 0.58 mL, 3.4 mmol) dropwise via syringe under N2. The reaction mixture was gradually brought to room temperature and stirred (3 hr.). Crushed ice/water was added and the solution was extracted with Et2O (2×25 mL). The combined Et2O extracts were washed with water, brine, dried (MgSO4) and evaporated under reduced pressure to give a red oil. The oil was purified by mplc using pet. Ether:acetone (9:1) as eluent giving 0.93 g (85%) of the triflate as a reddish brown oil. 1H NMR (CDCl3)d: 2.34-2.40 (m, 2H, CH2), 2.85-2.88 (m, 2H, CH2), 2.99-3.15 (m, 2H, CH2), 3.76 (s, 2H, CH2), 4.02-4.05 (m, 2H, CH2), 7.13-7.84 (m, 12H, Ar—H). 13C NMR (CDCl3) d: 35.43, 48.73, 53.95, 59.92, 66.59, 118.58, 121.77, 126.54, 128.31, 133.85, 137.46, 142.69, 144.88, 147.18

[0088] 3-n-Hexyl-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [20]

[0089] An oven dried flask equipped with a septum inlet and condenser was flushed with N2 and charged with a soln. of 9-BBN (2.15 mL, 1.079 mmol, 0.5 M soln.), cooled to 0° C. and 1-hexene (0.133 mL, 1.079 mmol) was added via syringe. The mixture was brought to room temperature and stirred (8 hr.). To the prepared BBN soln. was added K3PO4(0.312 g, 1.471 mmol), PdCl2(dppf) (0.020 g, 5 mol %) and 3-Trifluoromethane sulfonyl oxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [19] (0.48 g, 0.980 mmol) in anhydrous THF (10 mL). The reaction mixture was heated at reflux overnight, cooled and water (20 mL) was added. The reaction mixture was then extracted with EtOAc (3×25 mL). The combined EtOAc extracts were washed with water, brine and dried (MgSO4). The solvent was removed under reduced pressure to give a dark brown oil, which was purified by mplc using pet. Ether-EtOAc (9:1) as eluent to give 0.34 g (85%) of the product as an yellow oil. The oil was converted into its oxalate, mp. 135-136° C. (EtOAc-CH3OH). 1H NMR (CDCl3)d: 0.872.34-2.40 (bm, 13H, CH2), 2.30-2.42 (bm, 2H, CH2), 2.62 (bs, 2H, CH2), 2.93 (bs, 2H, CH2), 3.13 (bs, 2H, CH2), 3.75 (bs, 2H, CH2), 4.00 (bs, 2H, CH2), 7.04-7.72 (m, 12H, Ar—H). 13C NMR (CDCl3) d: 27.19, 28.87, 35.62, 35.77, 41.37, 48.69, 54.26, 60.14, 67.07, 111.26, 123.54, 125.55, 126.06, 126.58, 127.24, 128.02, 128.37, 134.70, 134.77, 135.04, 139.33, 139.55, 140.14, 140.32, 142.28, 144.18. Anal. Calcd. For (C30H35N. C2H2O4.0.5H2O) : C, 75.56; H, 6.52; N, 2.75. Found. C, 75.04; H, 6.76; N, 2.91.

[0090] 3-n-Hexyl-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydroanthracene [21]

[0091] 3 -n-Hexyl-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [20] (0.20 g, 0.488 mmol) was dissolved in CH3OH (15 mL) and 10% Pd/C (0.050 g) was added under N2. A few drops of HCl were added and the reaction mixture was hydrogenated on a parr-hydrogenator at 50 psi overnight and the catalyst was filtered off using celite. The filterate was evaporated and water (15 mL) was added and basified using 10% NaOH. The basic solution was extracted with CH2Cl2 (2×25 mL) and the combined extracts were washed with water, brine and dried (MgSO4). The CH2Cl2 was removed under reduced pressure to give a yellow oil which was purified by mplc using CH2Cl2:CH3OH (9:1) as eluent to give 0.11 g (70%) ofthe product as a colorless oil which darkened rapidly. The oil was converted into its oxalate salt, mp. 110-111° C. (EtOAc-CH3OH). 1H NMR (CDCl3)d: 0.83-0.89 (m, 2H, CH2), 1.21-1.31 (m, 9H, CH2), 2.36-2.40 (t, J=6 Hz, 2H, CH2), 2.56-2.61 (t, J=6 Hz, 2H, CH2), 3.49 (bs, 2H, CH2), 3.74 (bs, 2H, CH2), 4.03 (bs, 2H, CH2), 7.11-7.54 (m, 7H, Ar—H). Anal. Calcd. For (C23H29N.C2H2O4.0.25 H2O): C, 72.52; H, 7.66; N, 3.38. Found. C, 72.29; H, 7.55; N, 3.15.

Example 9

[0092] Synthesis of 3-(3-Phenylpropyl)-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydroanthracene [23]

[0093] Compound [23] was synthesized as depicted in Scheme 9 and as described below. Referring to Scheme 9, reagents and conditions were as follows: (a) allyl benzene, 9-BBN, PdCl2(dppf), K3PO4, anhyd. THF (b) 10% Pd/C, CH3OH, HCl 20

[0094] 3-(3-Phenylpropyl)-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [22]

[0095] An oven dried flask equipped with a septum inlet and condenser was flushed with N2 and charged with a soln. of 9-BBN (2.15 mL, 1.079 mmol, 0.5 M soln.), cooled to 0° C. and allyl benzene (0.142 mL, 1.079 mmol) was added via syringe. The mixture was brought to room temperature and stirred (8 hr.). To the prepared BBN soln. was added K3PO4 (0.312 g, 1.471 mmol), PdCl2(dppf) (0.020 g, 5 mol %) and 3-Trifluoromethane sulfonyl oxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [19] (0.48 g, 0.980 mmol) in anhydrous THF (10 mL). The reaction mixture was heated at reflux overnight, cooled and water (20 mL) was added. The reaction mixture was then extracted with EtOAc (3×25 mL). The combined EtOAc extracts were washed with water, brine and dried (MgSO4). The solvent was removed under reduced pressure to give a dark brown oil, which was purified by mplc using pet. Ether-EtOAc (9:1) as eluent to give 0.22 g (52%) of the product as an yellow oil. The oil was converted into its oxalate, mp. 137-138° C. (EtOAc-CH3OH). 1H NMR (DMSO-d6)d: 1.55 (bs, 4H, CH2), 2.47 (s, 4H, CH2), 3.21 (s, 2H, CH2), 3.38 (s, 2H, CH2), 3.94-3.98 (d, J=12Hz, 2H, CH2), 4.07 (s, 2H, CH2). 13C NMR (CDCl3) d: 21.61, 25.82, 31.63, 35.57, 48.63, 59.90, 61.83, 70.58, 125.40, 125.96, 126.45, 127.82, 128.20, 134.73, 135.12, 137.9, 139.04,142.86, 143.77. Anal. Calcd. For(C33H33N.C2H2O4.H2O): C, 76.20; H, 6.76; N, 2.53. Found. C, 76.11; H, 6.54; N, 2.94.

[0096] 3-(3-Phenylpropyl)-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydroanthracene [23]

[0097] 3-(3-Phenylpropyl)-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl] -9,1 0-dihydroanthracene [22] (0.20 g, 0.451 mmol) was dissolved in CH3OH (15 mL) and 10% Pd/C (0.050 g) was added under N2. A few drops of HCl were added and the reaction mixture was hydrogenated on a parr-hydrogenator at 50 psi overnight and the catalyst was filtered off using celite. The filterate was evaporated and water (15 mL) was added and basified using 10% NaOH. The basic solution was extracted with CH2Cl2 (2×25 mL) and the combined extracts were washed with water, brine and dried (MgSO4). The CH2Cl2 was removed under reduced pressure to give a yellow oil which was purified by mplc using CH2Cl2:CH3OH (9:1) as eluent to give 0.071 g (45%) of the product as a colorless oil which darkened rapidly. The oil was converted into its oxalate salt, mp. 81-82° C. (EtOAc-CH3OH). 1H NMR (DMSo-d6)d: 1.57-1.71 (bd, 4H, CH2), 2.38 (s, 2H, CH2), 2.47 (s, 2H, CH2), 3.38 (s, 2H, CH2), 3.77 (s, 2H, CH2), 4.07 (s, 2H, CH2), 7.27-7.52 (bm, 7H, Ar—H). Anal. Calcd. For (C26H27N.C2H2O4.2H2O): C, 70.12; H, 6.93; N, 2.92. Found. C, 69.45; H, 6.34; N, 3.66.

Example 10

[0098] Synthesis of 3-(3-Phenyl)-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydroanthracene [25]

[0099] Compound [25] was synthesized as depicted in Scheme 10 and as described below. Referring to Scheme 10, reagents and conditions were as follows: (a) Phenyl boronic acid, [(C6H5)3P]4Pd, K2CO3, anhyd. toluene (b) 10% Pd/C, CH3OH, HCl. 21

[0100] 3-(3-Phenyl)-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [24]

[0101] An oven dried flask equipped with a septum inlet and condenser was flushed with N2 phenyl boronic acid (0.25 g, 2.043 mmol) 3-Trifluoromethane sulfonyl oxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [19] (0.48 g, 0.980 mmol) and K2CO3(0.282 g, 2.04 mmol) were added followed by anhydrous toluene (15 mL). [(C6H5)3P]4Pd (0.035 g, 3 mol %) was added immediately and the reaction mixture was heated at 90° C. for 4 hr. The reaction mixture was then cooled to room temperature and diluted with EtOAc (25 mL) and washed with satd. NaHCO3 soln., water, brine and dried (MgSO4). The solvent was removed under reduced pressure to give a dark brown oil, which was purified by mplc using pet. ether as eluent to give 0.235 g (58%) of the product as a colorless oil. The oil was converted into its oxalate, mp. 138-139° C. (EtOAc-CH3OH). 1H NMR (CDCl3)d: 2.33-2.44 (m, 2H, CH2),2.46-3.17 (m, 4H, CH2), 3.75-3.78 (d, J=9 Hz, 2H, CH2), 4.02-4.10 (m, 2H, CH2), 7.12-7.84 (m, 17H, Ar—H). 13C NMR (CDCl3) d: 35.92, 41.66, 49.79, 54.58 60.32, 67.02. Satisfactory elemental analyses could not be obtained.

[0102] 3-(3-Phenyl)-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydroanthracene [25]

[0103] 3-(3-Phenyl)-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [24] (0.25 g, 0.622 mmol) was dissolved in CH3OH (15 mL) and 10% Pd/C (0.10 g) was added under N2. A few drops of HCl were added and the reaction mixture was hydrogenated on a parr-hydrogenator at 50 psi (4 days) and the catalyst was filtered off using celite. The filterate was evaporated and water (15 mL) was added and basified using 10% NaOH. The basic solution was extracted with CH2Cl2 (2×25 mL) and the combined extracts were washed with water, brine and dried (MgSO4). The CH2Cl2 was removed under reduced pressure to give a yellow oil which was purified by mplc using CH2Cl2:CH3OH (9:1) as eluent to give 0.081 g (42%) of the product as a colorless oil which darkened rapidly. The oil was converted into its fumarate salt, mp. 129-130° C. (EtOAc-CH3OH). 1H NMR (DMSO-d6)d: 2.35-2.39 (t, J=6Hz, 2H, CH2), 3.33-3.3 (t, J=6 Hz, 2H, CH2), 3.78 (s, 2H, CH2), 4.02-4.04 (d, J=6 Hz, 2H, CH2), 6.51 (s, 2H, CH=CH), 7.27-7.71 (m, 12H, Ar—H). 13C NMR (CDCl3) d: 35.92, 46.92, 51.71, 58.88, 123.83, 126.26, 126.87, 127.54, 128.56, 135.99, 136.83, 138.86, 140.55, 141.22, 141.90. Anal. Calcd. For (C23H21N.C4H4O4.H2O) : C, 72.16; H, 6.22; N, 3.08. Found. C, 71.62; H, 6.19; N, 2.84.

Example 11

[0104] Synthesis of Spiro[xanthenyl]-9,3′-pyrrolidine [30]

[0105] Compound [30] was synthesized as depicted in Scheme 11 and as described below. Referring to Scheme 11, reagents and conditions were as follows: (a) POCl3, reflux, 45 min, (b) n-BuLi, BrCH2COOC2H5, Et2O, reflux, (c) 10% Pd/C, CH3OH, HCl, (d) Borane-THF/THF; 6.0M HCl. 22

[0106] 9H-Xanthene-9-carbonitrile [27]

[0107] POCl3 (25 mL) was added to crystalline 9H-Xanthene-9-carboxamide [26] (1.5 g, 6.65 mmol) while stirring. The solution was then heated at reflux (45 min), when TLC showed complete absence of starting material. The solution was then poured into a mixture of crushed ice and NH4OH with vigorous stirring. The solution was stirred (15 min) and excess of NH4OH was added to keep the solution alkaline. The solid formed was extracted with ether (3×50 ml). The combined ether extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure to give an yellow oil which crystallized immediately. The product was purified by mplc using pet. ether: acetone (8:2) as eluent to give 1.2 g (87%) 9H-Xanthene-9-carbonitrile as colorless needles, mp 97-98° C. (EtOH).

[0108] (9-Cyano-9H-xanthen-9-yl)-acetic acid ethyl ester [28]

[0109] 9H-Xanthene-9-carbonitrile [27] (1.0 g, 4.825 mmol) was dissolved in anhydrous Et2O and cooled in an icebath. n-Butyl lithium (1.93 mL, 6.75 mmol. 2.5M soln. in hexanes) was added dropwise over 10 min. with continuos stirring. Stirring was continued for 30 min. at the same temperature and then brought to room temperature. The reaction mixture was heated at reflux (1 hr), cooled in an icebath and ethyl bromo acetate (0.75 mL, 6.755 mmol) was added dropwise via syringe. The resulting mixture was heated at reflux (4 h) cooled and filtered. The residue was washed with ether (25 mL). Water (25 mL) was added to the filterate and the organic layer was separated. The aqueous layer was once again extracted with ether (25 mL). The combined ether extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure to give an oil which was purified by mplc using pet. ether: EtOAc (9:1) as eluent to give 0.9 g (64%) of the product as a colorless oil. 1H NMR (CDl3)d: 1.04-1.08 (t, J=7.5 Hz, CH3), 3.01 (s, 2H, CH2), 3.90-3.99 (q, 2H, CH2), 7.14-7.69 (m, 8H, Ar—H). 13C NMR (CDCl3) d: 13.54, 39.06, 48.47, 60.85, 116.88, 118.90, 119.75, 123.81, 127.34, 129.83, 150.30, 166.98.

[0110] Spiro[xanthenyl]-9,4′-pyrrolidin-2′-one [29]

[0111] A mixture of (9-Cyano-9H-xanthen-9-yl)-acetic acid ethyl ester [28] (0.50 g, 1.70 mmol), 10% Pd/C (0.15 g) in methanol (40 mL) and HCl (1 mL) was hydrogenated at 50 kg/cm3 (3 days). The catalyst was filtered off with celite and the solvent was evaporated under reduced pressure to give a white semisolid. Water (25 mL) was added and the solution was made basic with 10% NaOH and extracted with EtOAc (3×25 mL). The combined EtOAc extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure to give a colorless oil which crystallized immediately on standing. The solid was recrystallized from CHCl3-pet.ether to give 0.295 g (69%) of the pure amide as a colorless needles, mp 182-183° C. 1H NMR (CDCl3)d: 3.02 (s, 2H, CH2), 3.82 (s, 2H, CH2), 6.51 (s, 1H, NH), 7.07-7.44 (m, 8H, Ar—H). 13C NMR (CDCl3) d: 39.98, 48.50, 60.72, 116.39, 123.70, 125.77, 126.46, 128.31, 149.59, 176.10.

[0112] Spiro[xanthenyl]-9,3′-pyrrolidine [30]

[0113] A 1.0M solution of BH3-THF complex (5.0 ml, 5 mmol) was added at 0° C. to a well stirred solution of Spiro[xanthenyl]-9,4′-pyrrolidin-2′-one [29] (0.25 g, 0.99 mmol) in anhydrous THF (2 mL). The solution was brought to RT and then heated at reflux (8 h), cooled to RT and 6M solution of HCl (4 mL) was added cautiously to the reaction mixture. The reaction mixture was then heated at reflux (1 hr), cooled to RT and the solvent was removed under reduced pressure, resulting in a white suspension. Water (20 mL) was added to it and extracted with EtOAc (20 mL). The aqueous phase was then basifled using 10% NaOH and extracted with Et2O (3×25 ml). The combined Et2O extracts were washed with water and brine, dried (MgSO4) and the solvent was removed under reduced pressure to give 0.185 g (79%) the amine as colorless oil. The oil started to darken rapidly and was dissolved in anhydrous acetone and fumaric acid (0.15 g, 1.31 mmol) was added and heated. The solution on cooling gave the fumarate as pale pink powder, which remained on two recrystallizations. mp. 183-184° C. (EtOAc). 1H NMR (DMSO-d6)d: 2.26-2.31 (t, J=9 Hz, 2H, CH2), 3.41-3.45 (t, J=6 Hz, 2H, CH2), 3.64 (s, 2H, CH2), 6.54 (s, 2H, CH═CH), 7.11-7.64 (m, 8H, Ar—H). 13C NMR (DMSO-d6) d: 44.35, 59.51, 115.96, 123.73, 126.54, 127.24, 128.22, 134.87, 140.12, 141.02, 149.87, 167.74, 179.90, 186.56. Anal. Calcd. For (C17H17N.C4H4O4.0.5H2O): C, 66.28;H, 5.56; N, 3.86. Found. C, 66.41; H, 5.59; N, 3.82

Example 12

[0114] Synthesis of Spiro[thioxanthenyl]-9,3′-pyrrolidine [36]

[0115] Compound [36] was synthesized as depicted in Scheme 12, and as described below. Referring to Scheme 12, reagents and conditions were as follows: (a) NaBH4, CH3OH (b) (i) SOCl2/Et2O (ii) CuCN/C6H6 (c) n-BuLi, BrCH2COOC2H5, Et2O, reflux, (c) 10% Pd/C, CH3OH, HCl, (d) Borane-THF/THF; 6.0M HCl. 23

[0116] 9H-Thioxanthen-9-ol [32]

[0117] A suspension of thioxanthen-9-one [31] (2 g, 9.42 mmol) in anhydrous CH3OH (30 mL) was stirred under N2 and NaBH4 (1.42 g, 37.68 mmol) was added slowly in portions over 15 min. After complete addition the reaction mixture was heated at reflux (3 hr.) and cooled to room temperature. Ice-water was added and the reaction mixture was extracted with CH2Cl2 (3×50 mL). The combined CH2Cl2 extracts were washed with water, brine, dried (MgSO4). The solvent was removed under reduced pressure to give a yellow solid, which was recrystallized from pet.ether to give 1.87 g (93%) of the alcohol as pale yellow needles, mp 104-105° C.

[0118] 9H-Thioxanthene-9-carbonitrile [33]

[0119] A suspension of 9H-Thioxanthen-9-ol [32] (2.14 g, 9.98 mmol) in anhydrous Et2O (20 mL) under N2 and SOCl2 (0.8 mL, 11.48 mmol) was added with caution via syringe with stirring at 0-5° C. The alcohol dissolved before a white solid began to separate. After stirring (1 hr.) at room temperature, the solvent was removed under reduced pressure and C6H6 (10 mL) was added and solvent removed to dryness again. All manipulations were performed with rigorous exclusion of air. Anhydrous C6H6 (20 mL) and CuCN powder (1.79 g, 19.97 mmol) were added and the suspension was stirred at reflux (4 hr.).The reaction mixture was filtered while hot and the residue was washed with hot C6H6 (50 mL). The filterate was evaporated to give a crystalline residue containing thioxanthene and thioxanthen-9-one as well as the desired nitrile. One recrystallizations from hexane removed thioxanthene and one recrystallizations from 2-propanol removed most of the thioxanthen-9one to provide 1.3 g (59%) of the pure nitrile, mp. 97-98° C.

[0120] (9-Cyano-9H-thioxanthen-9-yl)-acetic acid ethyl ester [34]

[0121] 9H-thioxanthene-9-carbonitrile [33] (1.20 g, 5.37 mmol) was dissolved in anhydrous Et2O and cooled in an icebath. n-Butyl lithium (2.14 mL, 5.37 mmol, 2.5M soln. in hexanes) was added dropwise over 10 min. with continuous stirring. Stirring was continued for 30 min. at the same temperature and then brought to room temperature. The reaction mixture was heated at reflux (1 hr), cooled in an icebath and ethyl bromo acetate (0.83 mL, 7.52 mmol) was added dropwise via syringe. The resulting mixture was heated at reflux (4 h) cooled and filtered. The residue was washed with ether (25 mL). Water (25 mL) was added to the filterate and the organic layer was separated. The aqueous layer was once again extracted with ether (25 mL). The combined ether extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure to give an oil which was purified by mplc using pet. ether: EtOAc (9:1) as eluent to give 0.97 g (59%) of the product as a colorless oil. 1H NMR (CDCl3)d: 1.08-1.12 (t, J=6 Hz, CH3), 3.08 (s, 2H, CH2), 3.95-4.03 (q, 2H, CH2), 7.31-8.00 (m, 8H, Ar—H). 13C NMR (CDCl3) d: 38.49, 47.63, 60.76, 118.91, 127.00, 127.24, 127.80, 128.15, 130.73, 130.98, 167.66.

[0122] Spiro[xanthenyl]-9,4′-pyrrolidin-2′-one [35]

[0123] A mixture of(9-Cyano-9H-thioxanthen-9-yl)-acetic acidethyl ester [34] (0.50 g, 1.61 mmol), 10% Pd/C (0.15 g) in methanol (40 mL) and HCl (1 mL) was hydrogenated at 50 kg/cm3 (3 days). The catalyst was filtered off with celite and the solvent was evaporated under reduced pressure to give a white semisolid. Water (25 mL) was added and the solution was made basic with 10% NaOH and extracted with EtOAc (3×25 mL). The combined EtOAc extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure to give a colorless oil which crystallized immediatelyon standing. The solid was recrystallized from CHCl3-pet.etherto give 0.32 g (74%) of the pure amide as a white solid, mp 178-179° C. 1H NMR (CDCl3)d: 3.19 (s, 2H, CH2), 3.73 (s, 2H, CH2), 6.13 (bs, 1H, NH), 7.22-7.53 (m, 8H, Ar—H). 13C NMR (CDCl3) d: 49.60, 53.15, 124.69, 126.68, 127.61, 133.32, 137.72, 176.06.

[0124] Spiro[thioxanthenyl]-9,3′-pyrrolidine [36]

[0125] A 1.0M solution of BH3-THF complex (3.75 ml, 3.75 mmol) was added at 0° C. to a well stirred solution of spiro[thioxanthenyl]-9,4′-pyrrolidin-2′-one [35](0.2 g, 0.74 mmol) in anhydrous THF (2 mL). The solution was brought to RT and then heated at reflux (8 h), cooled to RT and 6 M solution of HCl (4 mL) was added cautiously to the reaction mixture. The reaction mixture was then heated at reflux (1 hr), cooled to RT and the solvent was removed under reduced pressure, resulting in a white suspension. Water (20 mL) was added to it and extracted with EtOAc (20 mL). The aqueous phase was then basified using 10% NaOH and extracted with Et2O (3×25 ml). The combined Et2O extracts were washed with water and brine, dried (MgSO4) and the solvent was removed under reduced pressure to give 0.092 g (49%) the amine as colorless oil. The oil started to darken rapidly and was dissolved in anhydrous acetone and converted into its oxalate, mp. 169-170° C. (EtOAc). 1H NMR (DMSO-d6)d: 2.74 (bs, 2H, CH2), 3.39 (bs, 2H, CH2), 3.79 (s, 2H, CH2), 7.36 (bs, 4H, Ar—H), 7.65 (bs, 4H, Ar—H). 13C NMR (DMSO-d6) d: 24.64, 50.02, 51.38, 124.83, 127.02, 133.32, 137.19, 163.90, 185.34. Anal. Calcd. For(C16H15NS.C2H2O4.0.25H2): C, 62.14; H, 5.07; N, 4.02. Found. C, 61.90; H, 4.92; N, 3.86

Example 13

[0126] Affinity of Compounds for 5-HT2A Serotonin Receptor

[0127] Binding assays were conducted in which the affinity of each of the compounds of interest for the 5-HT2A serotonin receptor was tested. Assays were conducted with the 5-HT2A receptor in buffer consisting of 50 mM Tris-Cl, 0.5 mM EDTA, 5 mM MgCl2, pH=7.4. The 5-HT2A affinity determinations used 3H-ketanserin as the radioligand and spiperone (Kd=0.8 nM) as the reference compound.

[0128] Binding assays were also conducted in which the affinity of selected compounds of interest for the H1 histamine receptor was tested. Assays were conducted with the H1 receptor in buffer consistion of 50 mM Tris-Cl, 0.5 mM EDTA, pH=7.4. The H1 determinations used 3H-pyrilamine as the radioligand with chlorpheniramine as the reference compound.

[0129] The results are given in Table 2.

TABLE 2
Affinity of Selected SPAN Derivatives for
5-HT2A and H1 Receptors
	5-HT2A	H1
Compound	Ki (nM)	Ki (nM)
5	3.8	8.5
23	3.5	—
17	3.7	40
21	6	1600
19	9.2	—
25	18	—
6	46	—
7	220	—
22	998	—
16	1000	74
20	2030	—
18	330	—
12	68	—
30	40	51
36	5	6

[0130] While the invention has been described in terms of its preferred embodiments, those skilled in the art will recognize that the invention can be practiced with modification within the spirit and scope of the appended claims. Accordingly, the present invention should not be limited to the embodiments as described above, but should further include all modifications and equivalents thereof within the spirit and scope of the description provided herein.

REFERENCES

[0131] Bordwell, F. G., Hughes, D. L. 1983, J. Org. Chem. 48 (13) 2216-2222.

[0132] Glennon, R. A., Dukat, M., El-Bermawy, M, Law, H, de los Angeles, J, Teitler, M, King, A and Herrick-Davis, K. 1994. J. Med. Chem. 37:1929-1935.

[0133] Glennon, R A, Naiman, N A, Peirson, M E, Smith, J D, Ismaiel, A M, Titeler, M and Lyon, R A. 1989. J. Med. Chem., 32:1921.

[0134] Roth, B L, Craigo, S C, Choudhary, A U, Monsma, F J, Shen, Y, Miltzer, H Y, Sibley, D R. 1994, J. Pharm. Exp Ther. 268: 1403.

[0135] Vaganova, T. A., Panteluva, E. V., Tananakin, A. P., Steingarts, V. D., Bilkis, I. I. 1994, Tetrahedron 50 (33) 10011-10020.

Claims

1. A compound having the formula

2. The compound of claim 1 wherein R1 is selected from the group consisting of —H, —CH2CH2CH2Ph, —OCH3, —CH2(CH2)4CH3, phenyl, and —OH.

3. The compound of claim 1 wherein R2 is selected from the group consisting of —H, —CH3 and CH2Ph.

4. The compound of claim 1 wherein X is selected from the group consisting of —CH2—, —C(CH3)2—, —O— and —S—.

5. A compound having the formula

6. A compound having the formula

6. A compound having the formula

7. A compound having the formula

8. A compound having the formula

9. A compound having the formula

10. A compound having the formula

11. A compound having the formula

12. A compound having the formula

13. A compound having the formula

14. A compound having the formula

15. A compound having the formula

16. A pharmaceutical composition comprising, a compound of formula 37wherein R1 and R2 are selected from the group consisting of —H, —OH, —OCH3, halogen, aryl, alkylaryl, and substituted or unsubstituted branched or unbranched C1-C10 alkyl or alkylaryl, and may be the same or different, and X is selected from the group consisting of a) carbon with two —H substituents, b) carbon with one or two lower alkyl substituents, and c) a heteroatom or heteroatomic group selected from the group consisting of —O—; —S—; and —SO2—, and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition of claim 16 wherein R1 is selected from the group consisting of 13 H, —CH2CH2CH2Ph, —OCH3, —CH2(CH2)4CH3 and —OH.

18. The pharmaceutical composition of claim 16 wherein R2 is selected from the group consisting of —H, —CH3 and CH2Ph.

19. The pharmaceutical composition of claim 16 wherein X is selected from the group consisting of —CH2—, —C(CH3)2—, —O— and —S—.

20. A method of treating a condition caused by abnormal serotonin activity in a patient in need thereof, comprising the step of administering a compound of formula 38wherein R1 and R2 are selected from the group consisting of —H, —OH, —OCH3, halogen, aryl, alkylaryl, and substituted or unsubstituted branched or unbranched C1-C10 alkyl or alkylaryl, and may be the same or different, and X is selected from the group consisting of a) carbon with two —H substituents, b) carbon with one or two lower alkyl substituents, and c) a heteroatom or heteroatomic group selected from the group consisting of —O—; —S—; and —SO2—, in a quantity to ameliorate symptoms of said condition in said patient.

21. The method of claim 20 wherein R1 is selected from the group consisting of —H, —CH2CH2CH2Ph, —OCH3, —CH2(CH2)4CH3 and —OH.

22. The method of claim 20 wherein R2 is selected from the group consisting of —H, —CH3 and CH2Ph.

23. The method of claim 20 wherein X is selected from the group consisting of —CH2—, —C(CH3)2—, —O— and —S—.

24. The method of claim 20 wherein said condition is selected from the group consisting of depression, anxiety, schizophrenia, schizoaffective disorder, an eating disorder, and a sleep disorder.

25. The method of claim 20 wherein said compound is an antagonist of 5HT2 serotonin receptors.

26. The method of claim 20 wherein said compound is an antagonist of both 5HT2 receptors and H1 receptors.

27. A method of blocking a 5HT2 receptor in a patient in need thereof, comprising the step of administering to said patient a compound of formula 39wherein R1 and R2 are selected from the group consisting of —H, —OH, —OCH3, halogen, aryl, alkylaryl, and substituted or unsubstituted branched or unbranched C1-C10 alkyl or alkylaryl, and may be the same or different, and X is selected from the group consisting of a) carbon with two —H substituents, b) carbon with one or two lower alkyl substituents, and c) a heteroatom or heteroatomic group selected from the group consisting of —O—; —S—; and —SO2—, in a quantity to sufficient to block said 5HT2 receptor.

28. A method of blocking an H1 receptor in a patient in need thereof, comprising the step of administering to said patient a compound of formula 40wherein R1 and R2 are selected from the group consisting of —H, —OH, —OCH3, halogen, aryl, alkylaryl, and substituted or unsubstituted branched or unbranched C1-C10 alkyl or alkylaryl, and may be the same or different, and X is selected from the group consisting of a) carbon with two —H substituents, b) carbon with one or two lower alkyl substituents, and c) a heteroatom or heteroatomic group selected from the group consisting of —O—; —S—; and —SO2—, in a quantity to sufficient to block said 5HT2 receptor.

29. A method of blocking both a 5HT2 receptor and an H1 receptor in a patient in need thereof, comprising the step of administering to said patient a compound of formula 41wherein R1 and R2 are selected from the group consisting of —H, —OH, —OCH3, halogen, aryl, alkylaryl, and substituted or unsubstituted branched or unbranched C1-C10alkyl or alkylaryl, and may be the same or different, and X is selected from the group consisting of a) carbon with two —H substituents, b) carbon with one or two lower alkyl substituents, and c) a heteroatom or heteroatomic group selected from the group consisting of —O—; —S—; and —SO2—, in a quantity to sufficient to block said 5HT2 receptor.