MXPA99007307A

MXPA99007307A - (4-piperidinyl)-1h-2-benzopyran derivatives useful as antipsychotic agents

Info

Publication number: MXPA99007307A
Application number: MXPA/A/1999/007307A
Authority: MX
Inventors: T Strupczewski Joseph; J Bordeau Kenneth; L Pavlek Shelley
Original assignee: Hoechst Marion Roussel Inc
Priority date: 1997-02-07
Filing date: 1999-08-06
Publication date: 2000-01-01

Abstract

The present invention comprises (4-Piperidinyl)-1H-2-Benzopyran derivatives useful as antipsychotic agents, their intermediates, pharmaceutical compositions and methods of making these compounds. These compounds are useful in treating psychosis.

Description

DERIVATIVES OF (4-PIPERIDINIL.-1 H-2-BENZOPIRAN USEFUL AS ANTIPSYCHOTIC AGENTS Field of the Invention The present invention relates to intermediates for making novel compounds, novel compounds, a method for treating psychosis by administering novel compounds, and a method for making these compounds.

BACKGROUND OF THE INVENTION Psychosis is a disorder, which greatly interferes with the ability to meet the ordinary demands of life. Conceptually, it is a loss of ego limits or a great deal of damage in the reality test. Included under the term of psychosis are Schizophrenia disorder, Schizophreniform disorder, Schizoaffective disorder, Disorder Hallucinatory, Brief Psychotic Disorder, Shared Psychotic Disorder, Psychotic Disorder Due to a General Medical Condition, Psychotic Disorder Induced by Substances, and Psychotic Disorder Not Otherwise Specified, as defined by DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DISORDERS, FOURTH EDITION, Published in 1994 by the American Psychiatric Association, Washington DC USA, incorporated here by reference. Schizophrenia is a disorder of thought, which is characterized by positive symptoms (delusions, hallucinations, remarkably rare behavior) and negative symptoms (depressed affect, poverty in language, social isolation and anhendonia). The development of schizophrenia is thought to be due to an excess of dopaminergic transmission in the brain. This theory has been proposed based on the observations that typical antipsychotic drugs block dopamine D2 receptors, and drugs that increase the level of dopamine cause a psychosis that resembles the paranoid subtype of schizophrenia. Losoncyzy, M.F., et al., "The Dopamine Hypothesis of Schizophrenia," H. Y. Meltzer, ed., Psychopharmacology: The Third Generation of Progress. New York: Raven Press; 1987: 715-726. Currently, there are therapeutic treatments available to treat psychosis by administering to the patient neuroleptic drugs such as chlorpromazine, haloperidol and sulpride, for example. Of course, many of these drugs have undesirable side effects (for example, extrapyramidal symptoms) or are not as effective as desired for all patients. Therefore, there is still a need for different drug therapies.

SUMMARY OF THE INVENTION The present invention is a compound of the formula I: Formula I a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein: Ri is H, C 1-6 alkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, 5,5-dimethyl-1,1-dioxo-4-thiazolidinone, indane, C 1-6 alkylsulfonyl, trifluoroacetyl, or (CH 2) m Z (CH 2) t phenyl optionally substituted, wherein Z is O or C = 0; wherein optionally substituted represents a portion is conveniently substituted with one, two or three substituents each independently selected from H, halogen, C 1-6 alkyl, d.β alkoxy, C (= O) H, C (= O) C 1-6 alkyl, CF 3 or hydroxy; each of R 2 and R 3 are independently H, C 1-6 alkyl, -C (O) C 1-6 alkyl, CHO, or C 2-6 alkenyl; each of X and Y are independently H, hydroxy, C? -6 alkyl, halogen, acyloxy or C1-6 alkoxy, benzyloxy, or X and Y together form a diphenylmethylene ketal, cyclohexylidene ketal, methylene acetal or a carbonate group cyclical whenever X and Y are adjacently placed; and n is an integer of 1, 2 or 3; m is an integer of 0, 1, 2 or 3; and t is an integer of 0, 1, 2, or 3. The present invention also comprises a pharmaceutical composition comprising the compound of formula I and a pharmaceutically acceptable carrier; a method for treating a patient for a psychotic disorder, in particular schizophrenia, by administering to the patient a therapeutically effective amount of the compound of formula I; and a method for making the compound of formula I. An object of the present invention is to provide a novel compound useful for the treatment of a psychotic disorder. Another object of the present invention is the use of this compound to treat a medical disorder, in particular psychosis and especially schizophrenia.

Description of the Present Invention Certain terms that will have specified definitions are used herein: (1) "Aralkyl" represents an aryl or diaryl moiety connected to the rest of the molecule through an alkylene bridge. This alkylene bridge can be straight chain or branched chain and has a length of one, two, three, four, five or six carbon atoms. "Aryl" represents an aromatic radical having six atoms in a single ring system, such as phenyl, or a fused ring system such as 1 -naphthyl, 2-naphthyl, and the like. The aryl or diaryl group can optionally be substituted as described herein. Substitutions may be in the ortho, meta or para positions, as appropriate. Preferred examples of aralkyls are benzyl, phenylethyl, propylphenyl and diphenylbutyl. (2) "Optionally substituted" represents that the so-called portion is substituted as defined herein through the same or different substituents, ie, independently selected, from the group consisting of hydrogen, halogen (fluorine, chlorine, iodine or bromine), C 1-6 alkyl, C 1-6 alkoxy, C (= O) H, C (= O) C 1-6 alkyl, CF 3 or hydroxy with one, two or three substituents as appropriate for the structure. (3) "Heteroaralkyl" represents a heteroaryl connected to the rest of the molecule through an alkylene bridge. This alkylene bridge can be straight or branched chain with a length of one, two, three, four, five or six carbon atoms. The "Heteroaryl" portion refers to an aromatic portion of five or six members with one, two or three members thereof being oxygen, nitrogen, sulfur or combinations thereof. Some examples of the five-membered heteroaryls are thiophene, furan, pyrrole, imidazole, pyrazole, isothiazole, and isoxazole. Some examples of six-membered heteroaryls are pyran, pyridine, pyrazine, pyrimidine and pyridazine. The heteroaryls may also be a fused ring aromatic system having one, two or three members thereof being an oxygen, nitrogen, sulfur or combinations thereof, such as benzothiophenone, chromene, indolizine, isoindol, indole, indazole, quinoline, 2-oxo-2,3-dihydrobenzimidazil, phthalazine, quinazoline, cinoline, isochroman, chroman, 1,2-benzenedicarboximide and benzisoxazole. The heteroaryalkyl may be optionally substituted in its heteroaryl portion as described herein. (4) "Patient" represents a mammal such as a dog, cat, guinea pig, mouse, rat or human being. (5) "Treatment" or "Treating" means alleviating symptoms, eliminating the cause either on a temporary or permanent basis, or preventing or reducing the onset of symptoms of the so-called disorder. (6) "Psychotic disorder" or "Psychosis" are used interchangeably and have the meaning defined in this specification. (7) "C 1-6 alkyl", used alone or in combination with other terms represents an alkyl or (alkylene as appropriate) straight or branched chain, which has one, two three, four, five or six carbon atoms. carbon or scales thereof, for example, C? -2, C1-3, C1-4, C2-3, C2-4, etc. Some examples are methyl, ethyl, propyl, butyl, isopropyl, isobutyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl and the like. Also "C 1-6 alkoxy" may have one, two, three, four, five or six straight or branched chain carbons or scale thereof such as methoxy, ethoxy, etc. (8) "Stereoisomer" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. They include mirror image isomers (enantiomers), geometric isomers (cis / trans) and isomers of compounds with more than one chiral center that are not mirror images of one or the other (diastereoisomers). (9) "Pharmaceutically acceptable salt" represents either an acid addition salt or a basic addition salt, which is compatible with the treatment of patients for the intended use. "Pharmaceutically acceptable acid addition salt" is a non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula (I) or any of its intermediates. Some examples of inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and metal salts of such acid as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids. Examples of such acids are 2-phenoxybenzoic acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, p- toluenesulfonic, and sulfonic acids such as methanesulfonic acid and 2-hydroxyethane sulfonic acid. Said salts can exist in a hydrated or substantially anhydrous form. In general, hydrophilic organic salts of acid addition compared to their free base forms generally show higher melting points. "Pharmaceutically acceptable basic addition salts" represent non-toxic organic or inorganic basic addition salts of the compounds of Formula (I) or any of their intermediates. Examples are alkali metal or alkaline earth metal hydroxides, such as sodium, potassium, calcium, magnesium, or barium hydroxides; ammonia and organic aliphatic, alicyclic, or aromatic amines such as methylamine, trimethylamine, and picoline. (10) "Therapeutically effective amount" means an amount of the compound that is effective for the treatment of the so-called disorder. The variables X and Y of Formula I, when placed adjacently, can form a diphenylmethylene ketal, methylene acetal, cyclohexylidene ketal or cyclic carbonate group, which are respectively shown below: These groups, not including oxygens, are sometimes considered as "catechol protection groups". Its synthesis is described in Protective Groups in Organic Synthesis, second edition, by Greene, T., et al. Published by John Wiley and Sons, Inc., both incorporated herein by reference J. Med. Chem. 34: 2561-2569 (1991). It is intended that the present invention cover these and other conventional protecting groups known to those skilled in the art. The compounds of the invention can be prepared via synthetic routes described below in the schemes or other methods that may be apparent to those skilled in the art.

SCHEME A StepA2 Step A3 7a In scheme A, Y 'and X' represents Y and X as previously defined, except for the hydroxy portion, and preferably they are C 1-6 alkoxy or together they form cyclohexylidene, and most preferably they are in positions 5 and 6 of the benzopyran Step A1: The isocyanide? _ Can be made from commercially available 4- (aminomethyl) pyridine (Aldrich), which is reacted with ethyl formate to form 4 - [(N-methyl) formamide] pyridine, which is converted to an isocyanide 1_. One method to achieve the above is through the removal of water with phosgene and a tertiary amine. For example, triphenylphosphine and triethylamine are reacted with 4 - [(N-methyl) formadin] pyridine in the presence of carbon tetrachloride and dichloromethane to produce isocyanide 1_. Isocyanide 1 is condensed with benzaldehyde 2 to provide formamide 3_, which is hydrolyzed in an acid medium to ethanone 4 (see V. Scholkopf et al., Liebig 's Ann. Chem. 1976: page 969-977) . The condensation of isocyanide 1_ with benzaldehyde 2 to a vinylformamide 3_ can be achieved with an alkali metal alkoxide such as potassium t-butoxide to initiate the reaction in an ethereal solvent, preferably tetrahydrofuran. The reaction temperature can vary from 0 ° C to the boiling point of the solvent. The preferred temperature is between 0 ° C and room temperature. Step A2: Vinylformamide 3_ is converted to 4-acylpyridine 4. The reaction can be carried out in a protic solvent such as methanol using a mineral acid, preferably concentrated hydrochloric acid. The reaction temperature can vary from 0 ° C to the boiling point of the solvent but is preferred from 0 ° C to 40 ° C.

Step A3: 4-Acylpyridine 4 is reduced to alcohol 5. through the use of any suitable reducing agent, such as lithium-aluminum hydride, alkaline earth metal borohydrides and the like, sodium borohydride being the preferred reducing agent . The reaction is preferably carried out in a suitable solvent such as ethanol at a temperature range from 0 ° C to the boiling point of the solvent, at room temperature, about 22 ° C being preferred. Step A4: The reduction of the pyridine ring of the alcohol 5. to a piperidine ring to provide the piperidine 6 is achieved through the hydrogenation of the alcohol 5_ in the presence of a catalyst under acidic conditions. Examples of catalysts that can be used are those containing rhodium, palladium or platinum, of which platinum oxide is the preferred one. Acid reaction conditions can be obtained by conducting the reaction in an alkanoic acid as a solvent. Examples of alkanoic acids that can be used are acetic, propionic or butyric acids. Acetic acid being preferred. Under these conditions, the hydrogenation proceeds at a reasonable speed under a hydrogen pressure within the range of about an atmospheric pressure to 5 atmospheres of hydrogen pressure. A hydrogenation pressure of one atmosphere is preferred. Step A5: The piperidine 6_ is reacted with Lg-Pg, where Lg is a suitable leaving group such as halogen and Pg is a protecting group such as C1-6 alkylsulfonyl, trifluroacetyl, or C (= O) C1 alkyl -6. Most preferably, Pg is trifluoroacetyl, methylsulfonyl or acetyl and Lg is chloride or anhydride, which can be formed using standard acid chloride formation techniques. Scheme B shows an alternative method to obtain the intermediary 7b. useful for the production of the compounds of the present invention.

SCHEME B Step B Step B1: Ethyl isonipecotate 8 is reacted with Lg-Q and ethanol, where Lg is a suitable leaving group such as a halogen and Q is a moiety such as benzyl. The reaction takes place in the presence of an inorganic base such as potassium carbonate, preferably in the presence of a solvent such as an alcohol, such as ethyl alcohol to produce the ester 9_. Step B2: The ester 9. is reduced with a suitable reducing agent such as lithium-aluminum hydride in THF to produce the alcohol 1_. Step B3: An oxidation of alcohol 1_0 provides the aldehyde 11. The oxidation of Swern is preferred. Step B4: The epoxidation of the aldehyde 1J_ preferably in the presence of a suitable solvent provides the epoxide 12.

For example, the aldehyde 1 _ can be added to a solution of (CH 3) 3 SOI / KOt-Bu in DMSO and at about room temperature. Step B5: The substituted phenyl 1_3 is reacted with the epoxide 1_2_ to produce the intermediate 14. Different solvents and conditions may be employed when certain portions of X ', Y' and Q are employed, which will be known to those skilled in the art. technique. For example, when X 'and Y' form a cyclohexylidene ketal, a base such as nBuLi in THF can be used. Step B6: Intermediate 14 is deprotected by removing portion Q to produce piperidine 15 .. This can be achieved through the use of a hydrogenation source, preferably in the presence of a suitable catalyst and solvent. For example, when Q is benzyl, cyclohexene and a palladium catalyst in the presence of methanol is reacted with piperidine 1_5. The mixture is heated to reflux for about 1-10 hours. Step B7: Piperidine 1_5 is selectively protected at once by adding the protection compound (Pg) to the nitrogen. Any suitable protecting group can be used, which prepares the piperidine 1_5 for the cyclization step. One method is to provide as the protecting group trifluoroacetyl, C 1-6 alkyl-C (O) -, or sulfonyl of C-6 with trifluoroacetyl being preferred. The piperidine 1_5 can be reacted with appropriate anhydride such as trifluoroacetic anhydride in a suitable solvent such as dichloromethane. The addition of an acid scavenger such as triethylamine may be useful for the reaction. Trifluoroacetyl is placed in both the nitrogen and the oxygen of the initiator hydroxy group at this point. The hydroxy can be reformed through selective deprotection means, preferably through basic hydrolysis through a non-organic base such as potassium carbonate in a suitable solvent, such as methanol. This produces the unprotected hydroxy intermediate-protected with nitrogen 7b. which is now ready for the cyclization step shown in scheme C.

SCHEME C Step 05-21 Step C1: The hydroxypiperidine 7_ (which may be either 7a of Scheme A or 7b_ of Scheme B) is reacted with the amide 1_6 in a suitable non-protic inert solvent to form the formamide Y1_. Examples of suitable non-protic inert solvents are members of the halohydrocarbon group of solvents, with dichloromethane being preferred. The reaction mixture is then treated with a suitable Lewis acid catalyst. Examples of suitable Lewis acid catalysts are tri-methylated triflate I if it is boron trifluoride etherate, with boron trifluoride etherate being preferred. The cyclization can be carried out from about 0 ° C to about room temperature. The preferred starting temperature is 0 ° C, after which the reaction is allowed to warm to room temperature to provide the benzopyran 17. See, M. P DeNinno et al., Journal of Medicinal Chemisfry, volume 34, p. 256-2569 (1991), incorporated herein by reference. The formamide 1_7 produced has a portion Pg, which represents Pg of Scheme A or Pg of Scheme B. X 'and Y' represent X and Y, when both X and Y are not hydroxy and preferably are a protected form of oxygen (acyloxy, C 1-6 alkoxy, benzyloxy or X and Y together form diphenylmethylene ketal, cyclohexylidene ketal, methylene acetal or a cyclic carbonate group). Pg is preferably C (O) CF3, C (O) CH3 or S (O) 2CH3. Formamide 1_7 now represents some of the compounds of the present invention and serves as a basis for making other compounds of Formula I. In order to produce all the variables of Formula I, certain additional optional steps may be performed, which they may be referred to as unprotection steps, many of which are illustrated here. See also Protective Groups in Organic Synthesis, 2a. ed., Theodora W. Greene, et al. John Wiley and Sons, Inc., incorporated here by reference. "Optional" or "optionally" means that these steps can be used to make other compounds that fall within the scope of Formula I. Step C2: If Pg is not the desired R ^ portion then Pg can be reduced to hydrogen through the use of a suitable reducing agent such as sodium borohydride, to produce the piperidine 1_8 or if Pg is the appropriate desired portion in the Ri position, the remaining amine may be deprotected to the appropriate portion R2 / R3 (Step 04). Also, X 'and Y' can be unprotected (Step 05) .. Step C3: If you want the hydrogen to be the R-position then more steps can occur at the R2 / R3 and X / Y positions. If the hydrogen is not in the desired position R- \ compound 1_8_ can be reacted with LgRi 'to produce compound 19. For example, when the substituent to be added to the RT portion is an optionally substituted alkyl, aralkyl, an optionally substituted heteroaralkyl or - (CH2) mC (= O) (CH2) t-phenyl optionally substituted, the piperidine can be heated in an inert solvent with the selection substituent having a leaving group (Lg) such as a halide in the presence of a base to neutralize the acid released by the reaction. A suitable catalytic amount of an alkaline earth metal iodide can be added to accelerate the reaction rate when appropriate. Among the inert solvents that may be employed are aromatic hydrocarbons such as benzene, toluene and the like, as well as more polar solvents such as acetonitrile and dimethylformamide. Preferred solvents are toluene or acetonitrile. The base used in the reaction can be selected from the group of alkaline earth metal carbonates or bicarbonates, with potassium carbonate being preferred as the inorganic base. A preferred catalyst is potassium iodide in an amount of about 0.01 to about 0.10 molar equivalents of alkylating agent used. The reaction can be carried out at a suitable temperature such as within the 22 ° C scale at the boiling point of the solvent. When toluene is used as a solvent it is preferred to heat the mixture. The reaction is carried out at reflux, that is, at the boiling point of the solvent. Substituent leaving groups (Rr-Lg) which can be used to introduce the corresponding R group into the piperidine nitrogen are well known in the art, commercially available or can be made by those skilled in the art. The leaving halide group is selected from the group of chlorine, bromine and iodine. R is used to indicate the group encompassed by R ^ but does not include H. Step C4: If the desired R2 group is H and the desired R3 group is CHO, other steps can now occur with respect to the X and Y positions. other groups are desired in positions R2 and R3, the following steps may occur. Compound 1_9 can optionally be deprotected by removing the formyl group, which could provide either two hydrogens, or a hydrogen and a C1-6 alkyl group. The compound must be rented before the removal of the formyl. Subsequent mono- or di-alkylation at this point can provide R2 / R3 comprising one or two C1-6 alkyl groups. For example, the nitrogen protecting group can be removed by acid hydrolysis, preferably by heating with hydrochloric acid in ethanoi, preferably by heating with refluxing 3.0 N hydrochloric acid. The amine produced through deprotection can be monoalkylated by introducing the alkyl leaving group. This procedure can be repeated to obtain the dialkylated amine. Alternatively, a reducing agent such as LAH can be added from room temperature to the reflux temperature of the solvent to provide a mono-alkylated amine. Step C5: The oxygen protecting groups as part of X and Y (if present) represented by X 'and Y' can be split through methods well known in the art to provide X "and Y" as hydroxy. For example, when X 'and / or Y' are C6-alkoxy, the compounds 1_8 or 1_9 are heated with 48% hydrobromic acid, through the use of aluminum chloride, or split with boron tribromide. The splitting with alkoxy with boron tribromide can be carried out at lower temperatures, within the range of -78 ° C to 0 ° C in an inert solvent such as that selected from the halohydrocarbons. The preferred temperature scale is from -78 ° C to -30 ° C, and in the presence of a solvent such as dichloromethane. Step C6: If it is desired that X and Y are acyloxy (Xa and Ya), the hydroxy groups present may be acylated with R-C (= O) halogen or (RCO) 2 O, wherein R is a C 1-6 alkyl. Various starting materials are commercially available or are readily made by those skilled in the art. For example, commercially available starting materials for compound 2 comprise 2,5-dimethylbenzaldehyde (Aldrich), 5-bromo-2-ethoxybenzaldehyde (Lancaster), 2-fluoro-5-methoxy-benzaldehyde (Lancaster), 2, 5-dimethylbenzaldehyde (Aldrich), 2,5-difluorobenzaldehyde (Aldrich), and 5-bromo-2-fluorobenzaldehyde (Lancaster). The benzyloxybenzaldehyde can be made by reacting benzyl bromide or benzyl chloride with 2,5-dihydroxybenzaldehyde (Aldrich), 3,4-dihydroxybenzaldehyde (Aldrich), or 2,4-dihydroxy-benzaldehyde (Aldrich). Other commercially available starting materials represented by compound 2 comprise 3-fluoro-p-anisaldehyde (also known as 3-fluoro-4-methoxybenzaldehyde) (Aldrich), 3,4-dimethoxybenzaldehyde (Aldrich), 3-benzyloxy-4- methoxybenzaldehyde (Aldrich), 4-benzyloxy-3-methoxybenzaldehyde (Aldrich), 3-ethoxy-4-methoxybenzaldehyde (Aldrich), 3-bromo-4-methoxybenzaldehyde (Aldrich), 3-chloro-4-methoxybenzaldehyde (Aldrich), 3-4-diethoxybenzaldehyde (Pflatz &Bauer), 4-ethoxy-3-methoxy-benzaldehyde (Lancaster), 3,4-dimethylbenzaldehyde (Lancaster), 3 , 4-dichlorobenzaldehyde (Aldrich), 3,4-difluorobenzaldehyde (Aldrich), 3-chloro-4-fluorobenzyl aldehyde (Aldrich), 4-chloro-3-fluorobenzaldehyde (Lancaster), 4-benzyloxy-3-methoxybenzaldehyde (Aldrich) , 3-benzyloxy-4-methoxybenzaldehyde (Aldrich), piperonal (Aldrich), diphenylmethyleneketalbenzaldehyde (Salor), 2,4-dimethoxybenzaldehyde (Aldrich), 2-fluoro-4-methoxybenzaldehyde (Fluorochem), 4-fluoro-2-methoxybenzaldehyde (Wychem), 2,4-dimethylbenzaldehyde (Aldrich), 2,4-dichlorobenzaldehyde (Aldrich), 2,4-difluoro-benzaldehyde (Aldrich), 4-bromo-2-fluorobenzaldehyde (Lancaster) . For compound 1_6 where n = 3, aminobutyraldehyde-dimethyl (Airproducts) can be reacted with formaldehyde; wherein n = 2, 1, 1-dimethoxy-3-nitropopane (E-Merck) can be reduced to the amine and reacted with formaldehyde or alternatively the method can be used according to J. Med. Chem. (1991) vol. 34, no. 8, p. 2561-2569 starting with (H3CO) 2CH (CH2) 2Br. For compound 1_6 where n = 1, the aminoacetaldehyde dimethylacetal (Aldrich) can be formylated, for example, Chem. Pharm. Bull. 42 (8), 1655-1657 (1994). When X and Y form a cyclic carbonate, 2,3- (methylenedioxy) benzaldehyde (Aldrich) can be used as the starting material. The above steps can be combined or altered in sequence by those skilled in the art, when deemed appropriate. The use of the term "protecting group" does not represent transporting a portion containing the protective group that is not intended for therapeutic activity. The methodologies reported in the article by M. P. DeNinno et al., J. Med. Chem. 34: p. 2561-2569 (1991), incorporated herein by reference, can be used to prepare compounds with various X and Y groups, and groups R2 and R3. Some specific examples of compounds of the present invention that can be made through the above process follow. It should be understood that the compounds of the present invention are not limited to the following examples, but that the examples merely illustrate various compounds that can be made within the scope of the claims. Also, the sequence of the steps used in the following examples can be altered. The abbreviations used herein have the following meanings: THF represents tetrahydrofuran, CH2Cl2 represents methylene dichloride, TLC represents thin layer chromatography, EtOAC represents ethyl acetate, Et2NH represents diethyl amine, IR represents infrared spectrum, NMR represents nuclear magnetic resonance spectrum, CHCl3 represents chloroform, CDCL3 represents deuterochloroform, MS represents mass spectrum, HCl represents hydrochloric acid, EtOH represents ethyl alcohol, NaBH4 represents sodium borohydride, NaOH represents sodium hydroxide, mp represents melting point, C represents centigrade, MeOH represents methyl alcohol, BF3 (Et) 2 represents boron trifluoride etherate, Na2CO3 represents sodium carbonate, h represents hours, BBr3 represents boron tribromide and LAH represents lithium-aluminum hydride.

EXAMPLE 1A Intermediate: N-1,2- (2,3-dimethoxyphenyl) -1- (4-pyridinyl) vinnformamide A solution of 4- (aminomethyl) pyridine (54.1 g, 0.5 mmol) and 44.4 ml of ethyl formate it was refluxed for two hours and then allowed to stand at room temperature for 16 hours. The reaction was distilled to yield 61.6 g of N- (4-pyridylmethyl) formamide. A solution of N- (4-pyridylmethyl) formamide (27.7 g, 0.20 mmol), carbon tetrachloride (26 g, 0.17 mmol), 16.8 g of triethylamine, triphenylphosphine (52.3 g, 0.2 mmol) and 170 mL of dichloromethane was brought reflux for 3 hours. The reaction was allowed to cool, filtered and the filtrate was concentrated to a dark solid. The solid was titrated with 100 ml of ether and allowed to stand at 25 ° C overnight. Then it was filtered again. The ether was evaporated to yield an oily mixture which was filtered to provide N- (4-pyridylmethyl) isocyanide. To a stirred solution, under nitrogen, of potassium t-butoxide (39.9 g, 0.36 mmol) in 400 ml of THF, cooled to 0 ° C, N- (4-pyridylmethyl) isocyanide (20.8 g, 0.17 mmol) was added dropwise. ) dissolved in 100 ml of THF, followed by the dropwise addition of 2,3-dimethoxybenzaldehyde (28.6 g, 0.17 mmol) dissolved in 100 ml of THF. The reaction was allowed to come to room temperature, and then HOAc (20.8 g) was added dropwise. The reaction was poured into water and the aqueous mixture was extracted with CH2Cl2. The extract was washed (brine), dried (magnesium sulfate) and concentrated to provide an off white solid, which was recrystallized twice from methanol to yield 1.2 g of a white solid, m.p. 161-162 ° C. Analysis: Calculated for C16H16N2O3: 67.59% C 5.68% H 9.85% N Found: 67.50% C 5.68% H 9.73% N EXAMPLE 1B Intermediate: 2- (2,3-dimethoxy fe nií) -1 - (4-pyridinyl) ethanone To a stirred suspension of N- [2- (2,3-dimethoxyphenyl) -1- (4-pyridinyl) vinyl] formamide (45.2 g, 0.16 mmol) in 400 ml of methanol, cooled to 0 ° C, was added, dropwise, 120 ml of concentrated HCl. After completing the addition, the temperature was raised between 35-40 ° C for 2 hours. The reaction was allowed to stand at room temperature for 1 hour, and then cooled in an ice bath, 50% aqueous NaOH was added dropwise until the mixture was made basic. Water was added and the resulting white precipitate was collected to yield the desired ketone, which was removed and recrystallized twice from isopropanol to provide the title compound as a white solid, m.p. 99-101 ° C. Analysis: Calculated for C? 5H15NO3: 70.02% C 5.88% H 5.44% N Found: 69.876C 5.61% H 5.32% N EXAMPLE 1C Intermediate: 4-r2- (2,3-dimethoxyphenyl) -1-hydroxyethyl pyridine hydrochloride To a stirred solution of 2- (2,3-dimethoxyphenyl) -1- (4-pyridinyl) ethanone (2.4 g, 0.009 mmol) in 25 ml of EtOH was added, in portions, 0.005 mol of NaBH4. The reaction was stirred at room temperature for 2 hours, and then poured into water. The aqueous solution was extracted with EtOAc, and the extract was washed (water), dried (magnesium sulfate) and concentrated to provide an oil. The oil was titrated with Et2O and yielded 1.9 g of a white solid. The solid was dissolved in EtOH and ethereal HCl was added to precipitate a white hydrochloride salt. The salt was recrystallized twice from EtOH to provide the alcohol as a white solid, m.p. 204-206 ° C. Analysis: Calculated for C15H18CINO3: 60.91% C 6.13% H 4.74% N Found: 60.82% C 6'.39% H 4.68% N EXAMPLE 1D Intermediate: 4-f2- (2,3-dimethoxyphenyl) -1-hydroxyethylpiperidine Hydrogenated for 45 minutes on a Parr shaker, 4- [2- (2,3-dimethoxyphenyl) -1-hydroxyethyl] pyridine (20.0 g, 0.077 mol) in 170 ml of acetic acid on 1.5 g of PtO2. The reaction was filtered through Celite and the filtrate was combined with another operation of 21.0 g (0.08 mol). The combined filtrates were filtered under vacuum and the resulting oil was diluted with water. The aqueous solution was made basic with 50% aqueous NaOH, and the basic mixture was extracted with EtOAc. The organic extract was washed with water, dried (magnesium sulfate) and then concentrated to provide 34.3 g of an oil which solidified upon standing. The solid was removed and recrystallized twice from isopropyl ether at 5 ° C to provide the piperidine as a white solid, m.p.82-84 ° C. Analysis: Calculated for C15H23N03: 67.90% C 8.74% H 5.28% N Found: 67.92% C 8.77% H 5.21% N EXAMPLE 2A Intermediate: Trifluoroacetamine of 4-r2- (2,3-dimethoxyphenyl) -1 - (trifluoroacetyloxy) ethyne-4-piperidine To a stirred solution, under nitrogen of the piperidine alcohol of Example 1D (1.8 g, 6.8 mmol) in CH2Cl2 ( 15 ml) was added Et3N (2.8 ml, 20.4 mmol). The reaction was cooled to about 5 ° C (ice bath) and trifluoroacetic anhydride (3.1 g, 2.1 ml, 15 mmol) was added dropwise. After reacting for 1.5 hours at room temperature, the reaction was concentrated to a yellow oil. This was diluted with water and the extraction process with Et2O produced a yellow oil.

EXAMPLE 2B Intermediate: Trifluoroacetamide of 4-f2- (2,3-dimethoxyphenyl) -1-hydroxyethylpiperidine A mixture of the trifluoroacetamine compound of 4- [2- (2,3-dimethoxyphenyl) -1- (trifluoroacetyloxy) ethyl] piperidine (2.3 g , 6.0 mmole), K2CO3 (powder, 1.0 g 6.6 mmole) and 15 ml of anhydrous methanol was stirred at room temperature for 3 hours. The reaction was filtered and the filtrate was concentrated to 2.3 g of a thick yellow oil. The oil was titrated with Et2O (a white solid that resulted). The solid was filtered, and the filtrate was concentrated to provide a coarse yellow oil.

EXAMPLE 2C When Formula I is R ^ trifluoroacetyl; R2 = H; R3 = formyl; X and Y = methoxy. Cis-N-f3.4-dihydro-3- (1-trifluoroacetyl-4-piperidinyl) -5,6-dimethoxy-1H-2-benzopyran-1-ethylmet Ufo rm amide To a stirred solution, under nitrogen of trifluoroacetamide of 4- [2- (2,3-dimethoxyphenyl) -1-hydroxyethyl] -1-piperidine (19.7 g, 54 mmol), N-formylaminoacetaldehyde-dimethylacetal (8.8 g, 66 mmol) in CH2CI2 (150 mL), cooled in an ice bath, BF3 »(Et) 2 (39.4 mL, 320 mmol) was added dropwise. The reaction was stirred at room temperature for 5.5 hours, and then saturated Na 2 CO 3 was added dropwise until the foaming ceased. The organic layer was collected, washed with water, dried (K2CO3) and concentrated to provide a yellow oil. The oil was scraped with a glass rod in the presence of ether and a yellow solid was collected. Recrystallization of the sample from IPA-water (twice) yielded a pale yellow solid, m.p. 165-167 ° C. Analysis: Calculated for C2oH25F3N2? 5: 55.81% C 5.85% H 6.51% N It was found: 55.86% C 5.77% H 6.51% N 2D EXAMPLE When Formula I is Rt = H R2 = H; R3 = formyl; X and Y = methoxy. Cis-Nf-3,4-dihydro-5,6-dimethoxy-3- (4-piperidinyl) -1H-2-benzopyran-1-ylm ethyl hydrochloride! To a stirred mixture of cis-N - [- 3,4-dihydro-5,6-dimethoxy-3- (1-trifluoroacetyl-4-piperidinyl) -1H-2-benzopyran-1-ylmethyl] formamide (17.3 g, 40 mmol) in EtOH-THF (100-100 ml), NaBH 4 (1.5 g, 40 mmol) was slowly added. The reaction was stirred at room temperature, and after about 0.5 hours a solution occurred. After reacting for 6 hours, TLC (EtOH-NH 4 OH, 9: 1) indicated some unreacted starting material; therefore, an additional amount of NaBH4 (0.33 g, 8.7 mmol) was added. The reaction was allowed to proceed for a further 16 hours at room temperature and then concentrated in vacuo to a white, sticky solid. The solid was diluted with water and the standard extraction process with CH2Cl2 yielded 15.7 g of a white, waxy solid. The solid was dissolved in 100 ml of absolute EtOH and ethereal HCl was added until the solution became acidic. 50 ml of ether were added and the hydrochloride salt was collected, which was recrystallized from EtOH-Et2O and then from DMF to yield the white solid, m.p. 219-221 ° C. Ana lysis: Calculated for C18H27CIN2O4: 58.29% C 7.34% H 7.55% N Found: 57.94% C 7.35% H 7.76% N EXAMPLE 3A Intermediate: 4- [2- (2,3-dimethoxyphenyl) -1-hydroxyethyl-1-piperidine methanesulfonamide A solution of 4- [2- (2,3-dimethoxyphenyl) -1-hydroxyethyl] piperidine (10.0 g , 0.037 mmol) and Et3N (5.7 mL) in 75 mL of CH2Cl2 was cooled to 5 ° C and methanesulfonyl chloride was added dropwise. (3.6 g, 0.03 mmol) so that the temperature did not increase above 10 ° C. The reaction was allowed to stand at room temperature for 1 hour, and the reaction was concentrated in vacuo. The residue was treated with water, resulting in the formation of a white solid, which was collected to provide 10 g of the sulfonamide. The solid was recrystallized from toluene to yield the title compound, an additional recrystallization thereof, gave 0.8 g of the analytically pure product as a white solid, m.p. 112-114 ° C. Analysis: Calculated for C16H25NO5S: 55.96% C 7.34% H 4.08% N It was found: 56.05% C 7.47% H 4.27% N EXAMPLE 3B When Formula I is R ^ methylsulfonyl; R2 = H; R3 = CHO; X and Y = methoxy. C ysN-r3,4-dihydro-5,6-dimethoxy-3-1-methoxysulfonyl) -4-pyridinyl-1 H-2-benzopyran-1-ylmethamyl formamide A stirred solution, under nitrogen, methanesulfonamide of 4- [2- (2,3-dimethoxyphenyl) -1-hydroxyethyl] -1- piperidine (6.3 g, 0.018 mol) and N-formylacetaldehyde-dimethylacetal (3.0 g, 0.022 mol) in 150 ml of CH2Cl2 was cooled in an ice bath and BF3"O (Et) 2 (13.1 ml, 0.11 mol) was added dropwise. After the addition was complete, the reaction was allowed to stand at room temperature for 16 hours. Carefully add a saturated solution of Na2C0, and the organic layer was separated. The organic layer was washed with water, dried (K2CO3) and the solvent was concentrated to provide a yellow sticky solid. The solid was titrated with Et2O and 6.2 g of the slightly yellow solid was collected. The compound was recrystallized from isopropanol to yield 5.8 g (78%) of the benzopyran. Further recrystallization of a 1.5 g sample yielded the title compound as a white solid, m.p. 133-135 ° C. Analysis: Calculated for C19H28N2O6S: 55.32% C 6.84% H 6.79% N It was found: 55.05% C 6.61% H 6.60% N EXAMPLE 3C When Formula I is R? = Methylsulfonyl; R2 and R3 = H; X and Y = methoxy.

Cis-1 - (aminomet p -3,4-dihydro-5,6-dimethoxy-3- [1 - (methylsulfonyl) -4-piperidinyl-1H-2-benzopyran hydrochloride A mixture of cis-5, 6-dimethoxy-3,4-dihydro-3- (1-methylsulfonyl-4-piperidinyl) -1H-2-benzopyran-1-ylmethyl) formamide (3.8 g, 0.009 mole) and 30 ml of 6N HCl was stirred and it was refluxed for 2 hours, and then allowed to stand at room temperature for 16 hours. The reaction was diluted with water, cooled in an ice bath and made basic with aqueous NaOH. A basic solid was precipitated from the solution and this was collected to provide the desired compound. The compound was dissolved in EtOH and ethereal HCl was added to form a white hydrochloride salt. Recrystallization of the salt, first from EtOH and then from MeOH-Et20 afforded the amine hydrochloride as a white solid, m.p. 227-279 ° C. Analysis: Calculated for C18H29CIN205S: 51.36% C 6.94% H 6.65% N It was found: 51.28% C 6.72% H 6.55% N 3D EXAMPLE When Formula I is R? = methylsulfonyl; R2 and R3 = H; X and Y = hydroxy.

Cis-1- (aminomethyl) -3,4-dihydro-3- (1-methylsulfonyl-4-piperidinyl) -1H-2-benzopyran-5,6-diol hydrogen bromide This is a demethylation process and this compound was made through a similar compound as described in Example 15A starting with cis-1-aminomethyl-3,4-dihydro-5,6-dimethoxy-3- (1-methylsulfonyl-4-piperidinyl) -1H-2 -benzopyran. p.f. 278-280 ° C (decomposition). Analysis: Calculated for C16H25BrN2O5: 43.94% C 5.76% H 6.41% N It was found: 43.74% C 5.92% H 6.19% N EXAMPLE 4A When Formula I is R ^ phenethyl (aralkyl); R2 = H; R3 = formyl; X e Y = methoxy. Fumarate of cis-N-β-3,4-dihydro-5,6-dimethoxy-3- [1- (2-phenylethyl) -4-piperidinyl-1-H-2-benzopyran-1-ylmethin form amide A mixture of cis-N - [- 4,5-dihiro-5,6-dimethoxy-3- (4-piperidinyl) -1 H-2-benzopyran-1-ylmethyl] formamide (6.0 g, 0.018 mmol), K2C03 (3.0 g, 0.022 mol), (2-bromoethyl) benzene (3.9 g, 0.021 mol) and 125 ml of CH 3 CN were stirred at reflux under nitrogen for 1 hour and then at room temperature for 18 hours. The reaction was filtered and the filtrate was concentrated to provide 7.6 g of a light yellow oil. The compound was purified through preparative HPLC (Water's Associates Prep LC / System 500) using 2 columns of silica gel and 4% Et2NH-EtOAc as eluent to provide a white foam, which was dissolved in 20 ml of EtOAc and the solution was stirred at reflux. A solution of fumaric acid (0.12 g, 1.0 mmol) in 4 ml of 25% MeOH-EtOAc was added. The suspension was cooled and filtered to provide the fumarate salt. Recrystallization from CH3CN gave a white solid, m.p. 192-194 ° C. Analysis: Calculated for C30H38N2O8: 64.97% C 6.91% H 5.05% N It was found: 64.98% C 7.07% H 5.00% N EXAMPLE 4B When Formula I is R? = Phenethyl; R2 and R3 = H; X and Y = methoxy.

Cis-1- (aminomethyl) -3,4-dihydro-5,6-dimethoxy-3-H- (2-phenylethyl) -4-piperidinin-1H-2-benzopyran A mixture of cis-N- [3] hydrochloride , 4-dihydro-5,6-dimethoxy-3- [1- (2-phenylethyl) -4-piperidinyl] -1 H-2-benzopyran-1-ylmethyl] formamide (4.7 g, 10 mmol) and its Free base (2.1 g, 4.7 mmol) was dissolved in 30 mL of 3N HCl-30 mL of EtOH, and refluxed for 2 hours. The reaction was diluted with water and then stirred and cooled in an ice bath, while 50% aqueous NaOH is added dropwise. A white solid was separated from the solution and this was collected to provide the title compound. The compound was recrystallized from toluene to give a sheet as a white solid, m.p. 100-102 ° C. Analysis: Calculated for C25H34N2O3: 73.14% C 8.35% H 6.82% N Found: 72.93% C 8.56% H 6.72% N EXAMPLE 4C When Formula I is R ^ benzyl; R2 and R3 = H; X and Y = methox, cis-1- (aminomethyl) -3,4-dihydro-5,6-dimethoxy-3- (1-benzyl-4-piperidinyl) -1H-2-benzopirano difumarate This is the benzyl form of Example 4B, which has been converted to a difumarate salt. It was prepared by a procedure similar to Example 4A and 4B starting from cis-N [-3], 4-dihydro-5,6-dimethoxy-3- (benzyl-4-piperidinyl) -1H-2-benzopyran-1-ylmethyl] form amide. The compound was dissolved in 200 ml of hot EtOAc and filtered. The hot filtrate was treated with a hot solution of fumaric acid (2.05 g, 17.7 mmol) dissolved in 25 mL of 50% MeOH-EtOAc and the salt precipitated as a sticky solid. After cooling to room temperature, scraping produced a white solid, which was recrystallized from EtOH to provide a white solid. Double recrystallization from EtOH provided the difumarate salt as a white solid, m.p. 145-147 ° C. Analysis: Calculated for C32H40N2OH: 61.14% C 6.41% H 4.46% N It was found: 61.05% C 6.83% H 4.66% N EXAMPLE 4D When Formula I is R ^ phenethyl; R2 and R3 = H; X and Y = OH. Sesquihydrate cis-1- (aminomethyl) -3,4-dihydro-3- [1- (2-phenylethyl) -4-pyridinyl-1H-2-benzopyran-5,6-diol A a stirred solution of cis-1- (aminomethyl) -3,4-dihydro-5,6-dimethoxy-3- [1- (2-phenethyl) -4-piperidinyl] -1 H-2-benzopyran (2.5 g, 1.1 mmol) in 30 mL of CH 2 Cl 2, under nitrogen, cooled to -78 ° C, 1M BBr 3 in CH 2 Cl 2 (31 mL, 31 mmol) was added dropwise. After the addition was complete, the reaction was stirred at -78 ° C for 3 hours, and then at -10 ° C for 1 hour. The reaction was cooled once more at -78 ° C and added dropwise to 30 ml of methanol. The cooling bath was removed, and the solvent was concentrated under reduced pressure to produce a white solid. This solid was titrated with 30 ml of methanol, and the methane was removed in vacuo. This operation was repeated one more time and the resulting solid was titrated with EtOH and collected to provide the title compound, which was recrystallized twice from MeOH-Et2O and once from methanol to provide a white solid. This solid was dried at 110 ° C and high vacuum for 2.5 hours and yielded the catechol as a sesquihydrate dibromhydrate, m.p. 188-190 ° C. Analysis: Calculated for C23H30 2O3-l.5r.2O: 48.34% C 6.17% H 4.90% N It was found: 48.52% C 6.26% H 4.88% N EXAMPLE 4E When Formula I is R ^ phenethyl; R2 and R3 = H; X and Y = acyloxy cis-1- (aminomethyl) -5,6-diacetoxy-3,4-dihydro-3-f1 - (2-phenylethyl) -4-piperidinyl-1H-2-benzopyran A -brombromide. a stirred solution of cis-1- (aminomethyl) -3,4-dihydro-3- [1-2 (phenethyl) -4-piperidinyl] -1H-2-benzopyran-5,6-diol dibromhydrate (5.0 g 9.2 mmoles) in 40 ml of CF3CO2H under nitrogen at room temperature was added dropwise of ethyl bromide (1.5 ml, 20.3 moles) for 10 minutes. After the addition was complete, the reaction was stirred at room temperature for 90 minutes. 4 drops of water were added and the reaction was concentrated to provide 8.3 g of a beige gummy residue. The crude product was dissolved in hot IPA (25 ml) and filtered. The filtrate was stirred under nitrogen until cooled and 100 ml of Et2O was added to precipitate a white solid. The suspension was stirred for 2.5 hours under nitrogen and the solid was collected to yield 7.0 g. The compound was recrystallized twice from MeOH-Et20 to give a white solid. This was combined with two additional samples (total 8.3 g), and recrystallized from MeOH-Et20 to provide the compound that was dried at 110 ° C under high vacuum for 3 hours to yield a white solid, m.p. 190-193 ° C. Analysis: Calculated for C37H26 Br2N2O5: 51.61% C 5.77% H 4.46% N It was found: 51.70% C 5.80% H 4.42% N EXAMPLE 5 When Formula I is R ^ phenethyl; R2 = H; R3 = CH3; X and Y = hydroxy. Cis-1- (N-methylaminomethyl) -3,4-dihydro-3-ri- (2-phenylethyl) -4-piperidin-p-1H-2-benzopyran-5,6-diol dibromhydrate This is the monoalkylated form of Example 4D and can be made according to a similar procedure, starting from cis-1- (N-methylaminomethyl) -3,4-dihydro-5,6-dimethoxy-3- [1- (2-phenylethyl) - 4-piperidinyl] -1 H-2-benzopyran (3.2 g, 7.5 mmol). p.f. 208-211 ° C. Analysis: Calculated for C24H36Br2N203: 51.63% C 6.14% H 5.02% N It was found: 51.67% C 6.16% H 4.93% N EXAMPLE 6 When Formula I is R1 = phenylpropflo; R2 and R3 = H; X and Y = OH. Hemihydrate cis-1- (aminomethyl) -3,4-dihydro-3-M- (3-phenylpropyl) -4-piperidinyl) -1H-2-benzopyran-5,6-diol dibromhydrate This is the phenylpropyl form of Example 4D and was made through a similar procedure starting from cis-1 - (aminomethyl) -3,4-dihydro-5,6-dimethoxy-3- [1- (3-phenylpropyl) -4-piperidinyl) -1 H -2-benzopyran (1.6 g, 37 mmoles) pf 263-265 ° C. Analysis: Calculated for C24H34Br2N2oO3 »0.5H2O: 50.80% C 6.21% H 4.94% N Found: 50.97% C 6.33% H 4.77% N EXAMPLE 7 When Formula I is R ^ benzyl; R2 and R3 = H; X and Y = hydroxy. Cis-1 - (aminomethyl-P-3,4-dihydro-3- (1-benzyl-4-piperidinyl) -1H-2-benzopyran-5,6-diol dibromhydrate This is the benzyl form of Example 4D and is made through a similar procedure starting from cis-1 - (aminomethyl) -3,4-dihydro-5,6-dimethoxy-3- (1-benzyl-4-piperidinyl) -1H-2-benzopyran (2.2 g, 5.5 mmoles) mp 210-213 ° C. Analysis: Calculated for C22H30 Br2N2O3: 49.83% C 5.70% H 5.28% N Found: 49.86% C 5.58% H 5.15% N EXAMPLE 8 When Formula I is R ^ ethyl; R2 and R3 = CH3; X and Y = OH cis-1- (aminomethyl) -3,4-dihydro-3- (1-ethyl-4-piperidinyl) -1H-2-benzopyran-516-dol This is a procedure of demethylation (at the X and Y positions of Formula I), which is carried out similarly to the procedure described in Example 4D starting from cis-1- (aminomethyl) -3,4-dihydro-3- (1-ethyl) 4-piperidinyl) -5,6-dimethoxy-1H-2-benzopyran (2.0 g, 5.8 mmol) mp 302-304 ° C. (evolution of gas) Analysis: Calculated for C17H28 Br2N203: 43.61% C 6.03% H 5.98% N Found: 43.67% C 6.17% H 5.93% N EXAMPLE 9 When Formula I is R ^ heteroaryl-alkyl optionally substituted; R2 and R3 = H; X and Y = OH. Cis-1- (aminomethyl) -3,4-dihydro-3-y1-y3- (6-fluoro-1,2-benzisoxasol-3-ippropyl-1-4-pperidin-4-in-1H-dibromhydrate -2-benzopyran-5,6-diol N- (4-pyridylmethyl) isocyanide was made from 4-aminomethyl pyridine (Aldrich), which was reacted with ethyl formate to form N- (4-pyridylmethyl) formamide of according to the method in Liebigs Ann. Chem. 1976, 969-977 Triphenylphosphine and triethylamine were reacted with 4- [N-methylformamide) pyridine in the presence of carbon tetrachloride and dichloromethane to produce N- (4-pyridylmethyl) isocyanide . The N- (4-pyridylmethyl) isocyanide was condensed with 2,3-dimethoxybenzaldehyde (Aldrich) to form N- [2- (2,3-dimethoxyphenyl) -1- (4-pyridinyl) vinyl] formamide according to the method of Example 1A. The 2- (2,3-dimethoxyphenyl) -1- (4-pyridinyl) ethanone was made according to the method of Example 1B. The 4- [2- (2,3-dimethoxyphenyl) -1-hydroxyethyl] pyridine was made according to the method of Example 1C. The 4- [2- (2,3-dimethoxyphenyl) -1-hydroxy-ethyl] piperidine was made according to the method of Example 1D. The trifluoroacetamine of 4- [2- (2,3-dimethoxyphenyl) -1- (trifluoroacetyloxy) -ethyl] -4-piperidine was made according to the method of Example 2A. The 4- [2- (2,3-dimethoxyphenyl) -1-hydroxyethyl] piperidine was made according to the method of Example 2B. The cis-5,6-dimethoxy-3,4-dihydro-1- (N-formylaminomethyl) -3- (1-trifluoroacetyl-4-piperidinyl) -1H-2-benzopyran was made according to the method of Example 2 C. The cis-1- (N-formylaminomethyl) -3,4-dihydro-5,6-dimethoxy-3- (4-piperidinyl) -1 H-2-benzopyran was made according to the method of Example 2D. Cis-1- (N-formylaminomethyl) -3,4-dihydro-5,6-dimethoxy-3- (4-piperidinyl) -1H-2-benzopyran (6.0 g, 0.018 mol), K2CO3 (3.0 g, 0.022 mol) ) and 1-chloro-3- (6-fluoro-benzo [d] isoxasol-3-yl) -propane (6.2 g, 0.029 mol) and CH3CN (125 mL) were stirred at reflux under N2 for 6.5 hours and were left stand at room temperature for 3.5 days; the reflux was repeated for 4.0 hours. An additional 1.0 g of K2CO3 was added and refluxed for 18 hours. The reaction was cooled and filtered. The filtrate was concentrated to yield 12.1 g of a thick light brown oil and purified through silica gel columns eluting with Et2NH-EtOAc at 200 ml / min. to provide cis-N- [3,4-dihydro-5,6-dimethoxy] -3- [1 - [3- (6-fluoro-1,2-benzisoxazol-3-yl) propyl] -4-piperidinyl] -1 H-2-benzopyran-1-ylmethyl] formamide. To the above compound (5.5 g, 10.8 mmol), 3N HCl (30 mL) and absolute EtOH (30 mL) was stirred at reflux for 4.5 hours. The reaction was cooled to room temperature, diluted with 50 ml of water and cooled in an ice bath. 10 ml of 50% NaOH were added dropwise and initially a white solid was formed at a pH of 7-8; however, after further basification an oil was precipitated out of the aqueous mixture. The oil was extracted into CH2Cl2 (3 x 100 mL). The CH2Cl2 extract was washed with 50 ml of water, dried with MgSO4, and concentrated to yield 5.7 g of cis-1-aminomethyl-3,4-dihydro-5,6-dimethoxy-3- [1- [3 - (6-fluoro-1,2-benzisoxazol-3-yl) propyl] -4-piperidinyl] -1H-2-benzopyran. To a stirred solution of cis-1-aminomethyl-3,4-dihydro-5,6-dimethoxy-3- [1- [3- (6-fluoro-1,2-benzisoxazol-3-yl) propyl) -4 -piperidinyl] -1 H-2-benzopyran (2.4 g, 5.2 mmol) in 32 ml of CH2Cl2 under nitrogen and cooled to -78 ° C was added, dropwise BBr2 (2.6 ml, 27.5 mmol) in 5 ml of CH2Cl2. After the addition was complete, the reaction was stirred at -78 ° C for 3 hours and then at -20 ° C for 1 hour. The reaction was cooled to -78 ° C and 32 ml of anhydrous methanol were added dropwise. The solution was concentrated to produce a wet beige solid. The solid was titrated with 40 mL of anhydrous methanol and the volatiles were removed in vacuo to yield a sticky beige solid. This process was repeated once more and the resulting beige solid was diluted with 30 ml of absolute ethanol. The mixture was heated in a steam bath until the solution occurred and the solution was stirred under nitrogen for 18 hours. The resulting product was collected as a white solid. Two recrystallizations from MeOH-Et 2 O provided the dibromide salt. This compound was dried under high vacuum at 111 ° C for 3 hours to yield a white solid that contained about 1.5% water. p.f. 188-190 ° C. Analysis: Calculated for C25H32 Br2FN3O4: 48.64% C 5.22% H 6.81% N Found: 48.77% C 5.53% H 6.70% N EXAMPLE 10 When Formula I is R-arylalkyl substituted with methoxy; R2 = H; R3 = CH3; X and Y = OH. Cis-3,4-dihydro-3-M-l'2 - (4- (4-methoxyphenyl) etip-4-piperidinyl-1- (N-methylaminomethyl) -1H-2-benzopyran dihydrochloride -5.6-diol Lithium aluminum hydride (0.073 g, 1.9 mmol) was added to a stirred solution of cis-N- [5,6- (cyclohexylidenedioxy) -3,4-dihydro-3- [1- [2- (4-methoxyphenyl) ethyl] -4-piperidinyl] -1H-2-benzopyran-1-ylmethylformamide (0.500 g, 0.96 mmoles) in 10 ml of tetrahydrofuran at room temperature After heating under reflux for 1 hour, the reaction was The solvent was removed in vacuo to a colorless oil, this product was then added to a 5M solution of concentrated HCl in 8 ml of ethanol at room temperature. After heating under reflux for 1 hour, a white solid was precipitated from the solution.The solid was collected through filtration and dried at 80 ° C for 5 hours to produce a solid, mp 230-232 ° C. Calculated for C25H 36 CI2N204: 60.12% C 7.26% H 5.61% N It was found: 59.73% C 7.40% H 5.55% N EXAMPLE 11 When Formula I is R? = Arylalkyl substituted with methoxy; R2 and R3 = H; X and Y = OH. Cis-1 - (aminomethyl) -314-dihydro-3-yl- (2- (4-methoxyphenyl) etn-4-piperidinin-1H-2-benzopyran-5,6-dolol dihydrochloride A solution of 15% aqueous NaOH (15 mL) was added to cis-N- (5,6-cyclohexylidenedioxy) -3,4-dihydro-1- [1- [2- (4-methoxyphenyl) ethyl] 4-piperidinyl] - 1 H-2-benzopyran-1-ylmethyl) formamide (1.20 g, 0.0023 mmol) at room temperature. After stirring under reflux for 1 hour, the mixture was diluted with water and extracted into ethyl acetate. The solvent was concentrated in vacuo to yield an orange oil, 1.08 g (95%). This product was then added to a 5M solution of concentrated HCl in 20 ml of ethanol at room temperature. After stirring under reflux at 0.5 hours, a pale yellow oil was precipitated from the solution. The solid was collected and dried at 80 ° C, under vacuum, for 5 hours, m.p. 315-317 ° C. Analysis: Calculated for C24H34CI2N2? 4: 59.38% C 7.06% H 5.77% N It was found: 59.09% C 7.18% H 5.73% N EXAMPLE 12 When Formula I is R 1 = C (= O) CH 2 -phenyl substituted with fluoro; R2 and R3 = H; X and Y = H. 1-í2- (fluorophenyl) acetyl-H -3,4-dihydro-5,6-dimethoxy-1- (aminomethyl) -1H-2-benzopyran-3-ippiperidine hydrochloride A solution of cis-N- [3- [1- [2- (4-fluorophenyl) acetyl] -4-piperidinyl] -3,4-dihydro-5,6-di methoxy-1 H-2-benzopyran-1-ylmethyl] formamide (11.5 g, 0.024 moles), 60 ml of 3.0 N HCl and 60 ml of EtOH was stirred at reflux for 4.5 hours. The reaction was cooled to room temperature and diluted with 100 ml of water. The solution was cooled to 5 ° C and 50% NaOH was added to make it basic. The flask was stored at 4 ° C for 18 hours and a brown oil was separated. Most of the water was decanted and the oil was extracted in CHCl3. The CHCI3 extract was washed with water, dried with magnesium sulfate and concentrated to yield 10.5 g of an off-white gum. The product was dissolved in Et20 (500 mL) and some of the foreign material was filtered. The filtrate was treated with 1.0 M Et2O-HCl to make the solution have a pH = 1. The resulting solution was stirred for 30 minutes and the solid was collected to yield 9.4 g of a white solid. The solid was titrated with 40 ml of boiling CH3CN for about 10 minutes and allowed to cool to room temperature. The solid was filtered and dried to provide 8.3 g. Recrystallization from ethanol gave 3.89 g of a white solid. The filtrate was concentrated to about 1/3 of the volume and cooled to room temperature to yield an additional 3.1 g of the material. The two samples were combined and suspended in 100 ml of water and aqueous NaOH was added to make the mixture basic. This was extracted with CH2Cl2 and the CH2Cl2 extract was washed with water, dried with magnesium sulfate and dried to yield 6.2 g of a white foam. Purification through HPLC preparation (Waters Prep. LC2000, using 2 columns of silica gel and 0.5% NH4OH-7% MeOH-CH2CI2 as eluent) provided a white foam, which was dissolved in 25 mL of Et2O and filtered. The filtrate was treated with Et 2 O-HCl 1.0M to precipitate a white solid that was collected. Recrystallization from ethanol gave a hydrochloride salt as a white solid, m.p. 229-231 ° C. Analysis: Calculated for C25H32 CIFN204: 62.69% C 6.73% H 5.85% N It was found: 62.49% C 6.67% H 5.77% N EXAMPLE 13 When Formula I is R ^ phenethyl substituted; R2 and R3 = H; X e Y = hydrox¡. Cis-1- (amnomethyl) -3,4-dihydro-3-f1-r2- (4-fluorophenethyl) -1-4-piperidinyl) -1H-2-benzopyran-5,6-dihydrohydrate. This is a demethylation process (at the X and Y positions of Formula I) and this compound can be prepared by a similar procedure as described in Example 4D starting from cis- (aminomethyl) -3,4- dihydro-5,6-dimethoxy-3- [1- [2- (4-fluorophenethyl)] - 4-piperidinyl] -1 H-2-benzopyran (2.0 g, 4.7 mmol). p.f. 182-185 ° C. Analysis: Calculated for C23H31Br2FN2O3: 49.13% C 5.56% H 4.98% N Found: 49.28% C 5.50% H 4.95% N EXAMPLE 14 When Formula I is R 1 = arylaxy substituted with Cl; R2 and R3 = H; X and Y = OH. Cis-1- (aminomethyl) -3-H-F2- (4-chlorophenyl) etip3,4-dydrohydro-4-pyridinyl-H-1H-2-benzopyran-5,6-diol dihydrochloride A solution of 15% aqueous NaOH (15 mL) was added to cis-N- (5,6-cyclohexylidenedioxy-3- [1- [2- (4-chlorophenyl) ethyl] -4-piperidinyl] - 3,4 -dihydro-1H-2-benzopyran-1-ylmethyl) formamide (1.30 g, 0.0025 mmol) at room temperature. After stirring under reflux for 1 hour, the mixture was diluted with water and extracted with ethyl acetate. The solvent was concentrated in vacuo to yield an orange oil. This product was then added to a 5M solution of concentrated HCl in 20 ml of ethanol at room temperature. After stirring under reflux for 0.5 hours, a pale yellow solid was precipitated from the solution. The solid was collected and dried at 80 ° C for 5 hours, m.p. 325-326 ° C. Analysis: Calculated for C23H32 CI3N203: 56.39% C 6.38% H 5.72% N It was found: 56.11% C 6.39% H 5.56% N EXAMPLE 15 When Formula I is R? = Arylalkyl substituted with Cl; R2 = H; R3 = CH3; X and Y = OH.

Hemihydrate cis-3-l1-F2- (4-chlorophenyl) etip-4-piperidinip-3,4-dihydro-1- (N-methylaminomethyl) -1H-2-benzopyran-5,6-diol hydride Hydride was added of lithium-aluminum (0.072 g, 0.0019 mmol) to a stirred solution of cis-N- (5,6-cyclohexylidenedioxy) -3- [1- [2- (4-chlorophenyl) ethyl] -4-piperidinyl] -3 , 4-dihydro-1H-2-benzopyran-1-ylmethyl) formamide (0.500 g, 0.00095 mmol) at room temperature. After heating under reflux for 2 hours, the reaction was quenched for 2 hours and saturated with a solution of ammonium chloride, and diluted with ether. The organic layer was separated and the solvent removed under vacuum to yield 0.390 g (80%) of a colorless oil. This product was then added to a solution of 5M concentrated HCl in 8 ml of ethanol at room temperature. After heating under reflux for 1 hour, a white solid was precipitated in the solution. The solid was collected through filtration and dried at 80 ° C for 5 hours to yield a solid, m.p. 318-320 ° C. Analysis: Calculated for C24H32CI3N2O3-0.5 H20: 56.20% C 6.68% H 5.46% N Found: 56.03% C 6.61% H 5.48% N EXAMPLE 16 When Formula I is R ^ phenethyl substituted; R2 = H; R3 = methyl; X and Y = methoxy. Sesquifumarate of cis-3,4-dihydro-5,6-d¡methoxy-3-y1-f2- (4-fluorophenethyl) l-4-p-peridin-1 - (N-methylaminomethyl-1H) -2-benzopyran To a stirred solution of cis-N- [3- [1 -] 2- (4-fluorophenyl) acetyl] -4-piperidinyl] -3,4-dihydro-5,6-dimethoxy-1H -2-benzopyran-1-ylmethyl] formamide (7.2 g, 0.015 mol) in 250 ml of THF under nitrogen and cooled in an ice bath was added, dropwise LAH / THF (40.0 ml of a 1.0M solution) for 20 minutes After the completion of the action, the reaction was stirred at reflux for 1.5 hours, the reaction was cooled in an ice bath and 5 ml of water was added dropwise followed by 1.0M NaOH (2 ml). The mixture was filtered and the filtrate was concentrated to yield 6.6 g of a brown oil.The oil (6.4 g, 0.014 mole) was dissolved in 80 ml of ethanol and filtered, the filtrate was stirred and heated and filtered. added a hot slurry of fumaric acid (3.4 g 0.029 mole) in 20 ml of ethanol.The solution was refluxed briefly and after The mixture was stirred at room temperature under nitrogen for 20 hours. The resulting product was collected to provide 8.0 g of a beige solid. Recrystallization from ethanol gave an off white solid. An appreciable amount of solid did not dissolve during this process, therefore, it was collected to provide an additional 2.1 g of a white solid that appeared to have the same amount as the recrystallized material, which was recrystallized from ethanol to provide the sesquifumarate salt as a white solid, m.p. 118-120 ° C. Analysis: Calculated for 032H41FN2O9: 62.31% C 6.71% H 4.54% N It was found: 62.71% C 6.95% H 4.76N EXAMPLE 17 When Formula I is R ^ aralkyl substituted with F; R2 = H; R3 = CH3; X and Y = OH. Cis-314-dihydro-3-ri-r2- (4-fluorophenethyl) 1-4-piperidinyl-1- (N-methylaminomethyl) -1H-2-benzopyran-5,6-diolbibromohydrate This is a procedure of demethylation (at the X and Y positions of Formula I) and the compound can be made through a similar procedure as described in Example 5 starting with cis-1 - (N-methylamino) -3,4- dihydro-5,6-d-imethoxy-3- [1- [2- (4-fluorophenethyl)] - 4-piperidinyl] -1H-2-benzopyran. p.f. 216-218 ° C. Analysis: Calculated for C24H33Br2FN2O3: 50.02% C 5.77% H 4.86% N Found: 50.15% C 5.74% H 4.69% N EXAMPLE 18A Intermediary: 1-Benzyl-4-oxiranylpiperidine A slurry of 4-piperidinylethyl ester (6.36 moles), K2CO3 (10.98 moles) and benzyl chloride (7.63 moles) in 5 liters of ethanol was stirred at room temperature under nitrogen for forty-eight hours. The pale yellow slurry was filtered through Celite. The filtrate was concentrated to an orange oil, which was stirred with 3 liters of EtOAc and 1.5 liters of H2O for five minutes. The organic layer was isolated, washed with H2O (2x500 mL) and brine (1x500 mL), dried (MgSO4) and filtered. The filtrate was concentrated to give ethyl N-benzyl isonipecotate as an orange oil. LAH (1M solution in THF, 4.37 moles) was diluted with 4 liters of THF, the solution was cooled to 0 ° C through an IPA / dry ice bath under nitrogen. A solution of (2.95 moles) of ethyl N-benzyl isonipecotate 4 liters of THF was added over two hours. The bath was stirred and the solution was stirred for three hours before heating to reflux for eighteen hours. The heating mantle was stirred and the solution was stirred at room temperature for eighteen hours, before it was quenched at 0 ° C through the dropwise addition of: EtOAc (110 mL), H2O (164 mL), sodium hydroxide. watery to 10% (246 ml) and H2O (410 ml). The slurry was stirred at room temperature for eighteen hours and filtered, which provided N-benzyl-4-hydroxymethylpiperidine. A solution of 7.78 moles of DMSO in 3 liters of dichloromethane was added dropwise a solution of oxalyl chloride (3.54 moles) (1.77 I of a 2M solution in CH2Cl2) at -65 ° C over a period of 1.75 hours. After stirring for 25 minutes, a solution of N-benzyl-4-hydroxymethylpiperidine in CH2Cl2 (1 I) was added at -65 ° C over a period of 1.5 hours. After stirring for 20 minutes, Et3N (10.43 moles) was added in 30 minutes. The cold bath was removed and the beige slurry was stirred at room temperature for eighteen hours before adding 7.5 liters of water. This mixture was stirred for 10 minutes. The aqueous layer was isolated and extracted with Et20 (2 x 4 I, then 1 x 2 1). The organic layers were combined, washed with water (1 x 2 l) and brine (2 x 2 l), dried (MgSO 4) and filtered. The light orange filtrate was concentrated to give a crude brown oil which was purified by gravity filtration, by SiO2, eluting with heptane followed by EtOAc. The fractions were collected and concentrated to provide N-benzyl-4-piperidinyl carboxaldehyde. At room temperature, under nitrogen, a solution of KOt-Bu (95%, 2.24 moles) was added in four liters of DMSO, a solution of (CH3) 3SOI (98%, 2.24 moles) in four liters of water was added dropwise. DMSO for forty minutes. The clear yellow solution was heated at 50 ° C for 3.5 hours and then a solution of N-benzyl-4-piperidinyl-carbaldehyde (1.72 mol) in 1.5 liters of DMSO was added in 10 minutes. Heating at 50 ° C was continued for one hour, then the solution was stirred at room temperature for eighteen hours. The solution was drained to 9 liters of ice-water and extracted with heptane (6 x 2 I). The extracts were combined, washed with water (2 x 2 I), dried (MgSO4), filtered and concentrated (40 ° C / 50 torr) to a light orange oil. The oil was purified by gravity filtration through SiO2 (5 L) eluting with EtOAc (12 L). The fractions were combined and concentrated to give the title compound as a light yellow oil.

EXAMPLE 18B Intermediary: Spiro-I (1,3-benzodioxol) -2,1-cyclohexane1 A mixture of 1,2-dihydroxybenzene (2.72 moles), cyclohexanone (2.72 moles), toluene (2.3 I) and p-TsOH (0.55 g) was brought to reflux under nitrogen for eighteen hours. A total of 48 ml of water was collected with a Dean-Stark trap. After cooling, the mixture was neutralized with 5% NaOH, washed with water, dried (MgSO4) and filtered. The filtrate was concentrated to give a crude golden oil, which solidified upon standing. The crude solid was recrystallized from ether (400 ml, boiling scale 35-60 ° C) to give the ketal spirol.

EXAMPLE 19 Intermediate: 2- (1-benzyl-4-piperidinyl) -1-esopyrid, 3-benzodioxol-2, 1'-cyclohexane) -2- ethanol To a stirred solution of spiro [(1,3-benzodiozole) -2, 1'-cyclohexane] (5.5 g, 0.029 mole) in THF (40 ml) under N2 at -3 ° C was added dropwise n-butyl lithium (14 ml) of a solution of n-BuLi / hexanes 2.5 M, 0.035 moles) for 10 minutes. After the addition was complete, the reaction was stirred at room temperature for 4 hours. The reaction was cooled to -3 ° C and a solution of 1-benzyl-4-oxiranylpiperidine (5.9 g, 0.027 mol) in THF (10 mL) was added dropwise over 10 minutes. After the addition was complete, the reaction was warmed to room temperature and stirred for 17 hours. The reaction was quenched in saturated NH4CI (ca. 70 mL) and the aqueous solution was extracted with Et20 (3x75 mL). The Et20 extract was washed with aqueous NH4CI, washed with NaCl, dried with MgSO4, and concentrated to yield 12.0 g of a viscous red oil. The title compound was isolated through preparative HPLC (Waters Prep LC 2000, using 2 columns of silica gel and 5% MeOH-CH 2 Cl 2 as eluent) to produce a beige solid, which was recrystallized from ethanol for provide a white solid, which was recrystallized again from ethanol to provide a white solid, mp 120-122 ° C. Analysis: Calculated for C26H33N03 76.62% C 8.16% H 3.44% N It was found: 76.44% C 8.18% H 3.31% N EXAMPLE 20A Intermediate: 2- (4-piperidinyl-1H) -1-spiro (1,3-benzodioxol-2.1'-cyclohexane) -2-ethanol A mixture of 2- (1-benzyl-4-piperidinyl) -1-spiro ( 1, 3-benzodioxol-2,1'-cyclohexane) -2-ethanol (3.4 g, 8.3 mmol), 10% Pd / C (0.5 g), cyclohexene (13.8 g, 168.0 mmol) and methanol (72 ml) are stirred under reflux under N2 for 4 hours. The cold reaction was filtered through a pad of Celite and the filtrate was concentrated to yield a white solid, which was recrystallized from ethyl acetate to yield a white solid, m.p. 145-147 ° C. Analysis: Calculated for C19H27N1O3 71.89% C 8.57% H 4.41% N Found: 71.68% C 8.67% H 4.34% N EXAMPLE 20B A mixture of 2- (4-piperidinyl-1 H) -1-spiro (1,3-benxodioxol-2,1'-cyclohexane) -2-ethanol (141.7 g, 0.45 mol), anhydrous CH2CI2 and triethylamine (127.1 g) , 1.26 moles) were stirred under N2. The solution was cooled in ice-salt for 2 hours at approximately -2 ° C. Drop was added to trifluoroacetic anhydride (234.9 g, 1.12 moles) for 4.5 hours and the solution was stirred at room temperature for 17 hours. The reaction was concentrated to 500 g and diluted with 600 ml of water and extracted with CH2Cl2 (400 ml). The extract was washed with water, dried with K2CO3 and concentrated.

EXAMPLE 20C The compound of Example 20B was dissolved in 3.75 liters of MeOH and stirred under N2 at room temperature for 2 hours. The reaction was filtered and the concentrate was diluted with 250 ml of water and extracted with Et2O. The aqueous phase was saturated with NaCl and further extracted with Et 2 O (300 ml) (3 x 300 ml). The extract was washed with brine, dried with MgSO 4 and concentrated.

EXAMPLE 21 When the formula I is R1 = (CH2) 3C (= O) phenyl substituted with fluoro; R2 = H, R3 = formyl; X and Y = methoxy.

N- [3-f1-f4- (4-fluorophenyl) -4-oxobutyl-1-4-piperidinin-3,4-dihydro-5,6-dimethoxy-1H-2-benzopyran-1-ylmethyl-form-amide hydrochloride A mixture of N- [3, 4-dihydro-5,6-dimethoxy-3- (4-pi period ini I) - 1 H-2-benzofuran-1-ylmethyl] formamide (4.0 g, 12 mmol), 4-chloro-1,4 '-fluorobutyrophenone-4-fluorophenylbutyrophenone (3.6 g, 18.0 mmol), K2CO3 (2.5 g), Kl (60 mg) and toluene (150 ml) was stirred and refluxed for 48 hours. The reaction was filtered and the filtrate was concentrated to 8.2 g of a yellow oil. The oil was chromatographed on HPLC on silica gel, eluting with 10% MeOH / CH2Cl2. Concentration of the appropriate fractions gave a glassy oil, which was dissolved in EtOH and ethereal HCl was added to precipitate a white hydrochloride salt. P.f. 168-170 ° C. Analysis: Calculated for C28H36CIFN2O5: 62.85% C 6.78% H 5.24% N Found: 62.77% C 6.79% H 4.98% N EXAMPLE 22 When Formula I is R? = H; R3 = (C = 0) H; And they form cyclohexylidene ketal Cis-N-r5,6-cyclohexyldenodioxyl-1,3-dihydro-3- (4-piperidinyl) -1 H-2-benzopyran-1-ylmethyl) formamide A solution of N- [cis-5,6- (cyclohexylidenedioxy) -3,4-dihydro-3- (1-trifluoroacetyl-4-piperidinyl) -1H-2-benzopyran-1-methylmethylformamide (39.1 g , 0.081 mol) and 50% EtOH-THF (390 mL) was stirred at room temperature under nitrogen and NaBH4 (3.15 g, 0.083 mol) was added. The reaction was stirred at room temperature for 1 hour and concentrated to yield a white solid. The product was titrated with water, filtered and dried to yield a white solid. Vapor chromatography on silica gel, using 10% NH4OH-MeOH, provided a crude material which was recrystallized twice from toluene to give a white powder, m.p. 205-207 ° C. Analysis: Calculated for C22H30N2O4 68.37% C 7.82% H 7.25% N It was found: 68.64% C 7.69% H 7.01% IM EXAMPLE 23 When Formula I is R1 = (CH2) mZ (CH2) 2phenyl; Z = O; n = 1; R2 and R3 = H; X and Y = OH. 0.4 cis-1- (aminomethyl) -3,4-dihydro-3-ri - (2-phenoxyethyl-4-piperidine-1H-2-benzopyran-5,6-diol hydrate hydrochloride A solution of cis-1 - (aminomethyl) -5,6- (cyclohexylidenedioxy) -3,4-dihydro-3- [1- (2-phenoxyethyl) -4-piperidinyl] -1H-2-benzopyran (1.1 g, 2.3 mmoles) and a 5M concentrated HCl solution in (20 ml) of ethanol was stirred under reflux under N2 for 1 hour and white solid precipitated.The reaction was cooled in an ice bath and the resulting product was collected. The compound was recrystallized from methanol-ether and dried at 80 ° C for 4 hours to yield a white solid, mp 288-290 ° C. Analysis: Calculated for C23H32Cl2N2040.4 H20 57.71% C 6.92% H 5.85% N Se found: 57.57% C 6.97% H 5.80% N EXAMPLE 24 Where Formula I, R 1 is heteroarylalkyl, R 2 is H, R 3 is formyl, X and Y form cyclohexylidene. cis-N-r5.6- (cyclohexylidenediol) -3,4-dhydro-3-f1- (2- (thiophen-2-yl) ethyl) -4-piperid Nill-1H-2-benzofuran-1-Imetill formamide A mixture of cis- [N-5, -cyclohexylidenedioxy) -3,4-dihydro-3- (4-piperidinyl-1 H-2-benzopyran-1-ylmethyl) formamide (5.0 g, 12.9 mmol), methanesulfonic acid, 2-thiophen-2-yl-ethyl ester (2.9 g, 14.0 mmol), NaHCO3 (1.2 g) and (100 mL) of DMF was stirred at 65 ° C for 5 hours. hours. The reaction was poured into water and after extraction work-up with EtOAc an oil remained, which was solidified to a white solid. Recrystallization produced the product, while an analytical sample was observed through recrystallization from EtOAc-heptane to provide the formamide as a white solid, m.p. 142-144 ° C. Analysis: Calculated for C28H36N2O4S: 67.71% C 7.31% H 5.64% N It was found: 67.65% C 7.47% H 5.60% N EXAMPLE 25 When Formula I is R, = heteroaryalkyl; R2 and R3 = X and Y = OH.

Hydrate di-1-aminomethyl-3,4-dihydro-3-f 1- (2-thiophen-2-yl) -ethyl-4-piperidinyl-1H-2-benzopyral-5,6-diol hydrate solution of cis-N- [5,6- (cyclohexyldenodioxy) -3- [1- (2-thiophen-2-yl) ethyl) piperidi-4-yl] -3,4-dihydro-1 H-2 -benzofuran-1-yl] methyl formamide (1.4 g, 3.0 mmol) and 5M concentrated HCl in (20 mL) of EtOH was refluxed for 2 hours. The reaction was stored at 10 ° C for 16 hours, and a solid was collected. The sample was combined with a 0.2 g sample from a previous run and the combined sample was recrystallized from EtOH to yield a white solid, m.p. 185-187 ° C. Analysis: Calculated for C21H28N2O4-2HCI H2O: 52.61% C 6.73% H 5.84% N Found: 52.69% C 6.76% H 5.55% N EXAMPLE 26 When Formula I is R, = arylalkyl substituted with methyl; R2 and R3 = H; X and Y = OH. Cis-1-aminomethyl-3,4-dihydro-3-p-f2- (2-methyl phenyl) ethyl-1-4-piperidinyl-1H-2-benzopyran-5-yl-d -ol dihydrochloride A solution of cis- 1 - (aminomethyl) -5,6- (cyclohexylidenedioxy-3,4-dihydro-3- [1- [2- (2-methylphenyl) ethyl-4-piperidinyl] -1 H-2-benzopyran (1.2 g, 2.5 mmoles) and 5 M concentrated HCl in EtOH (15 mL) was refluxed for 2 hours.As the reaction proceeded, a white solid was separated from the solution.The reaction was allowed to stand at room temperature for 2 hours and the white solid was collected.The solid was dried at 80 ° C under vacuum for 4 hours to provide the product as a white hydrochloride salt, mp 312-314 ° C. Analysis: Calculated for C24H32N2O3-2H0l 61.40% C 7.30 % H 5.97% N Found: 61.00% C 7.48% H 5.82% N EXAMPLE 27 When Formula I is R-1 = trifluoroacetyl; R2 = H; R3 = (C = O) H; X and Y form cyclohexylidene ketal. cis-N-5,6- (cyclohexylidenedioxy) -3,4-dihydro-3- (1-trifluoroacetyl-4-pipridinyl) -1H-2-benzopyran-1-ylmethylp form amide solution of 4- [1-hydroxyethyl-2-spiro (1,3-benzodioxol-2,1'-cyclohexan)] - 1-piperidine (21.0 g, 0.051 mol), formylamino-acetaldehyde-dimethylacetal (8.1 g, 0.061 mol) and Anhydrous CH 2 Cl 2 (200 mL) was stirred under N 2 and cooled to -3 °. BF3 »OEt2 (37.6 ml, 0.306 moles) was added dropwise over 45 minutes, maintaining the temperature at -3 ° C. After the addition was complete, the reaction was stirred at -3 ° C for 30 minutes and then at room temperature for 19 hours. Saturated Na2CO3 was added dropwise until the foam formation ceased. The organic phase was washed with saturated Na 2 CO 3, washed with water, dried with K 2 CO 3 and concentrated to yield 22.9 g of a dark oil. The oil was titrated with Et2O to produce a solid which was collected to form a white solid. The filtrate was concentrated to produce a beige foam. The two samples were combined and chromatographed on 1.0 kg of silica gel, eluting with EtOAc to yield a white solid. A 400 mg sample was recrystallized from IPA-H20 to provide 270 mg of a villous white solid, m.p. 72-174 ° C. Analysis: Calculated for C24H29F3N2O5: 59.74% C 6.06% H 5.81% N Found: 59.52% C 6.04% H 5.80% N EXAMPLE 28 Formula I wherein R 3 is diphenyl, alkyl of 1 to 6 carbon atoms, substituted with F; X and Y form cyclohexylidene ketal; R2 is hydrogen, R3 is formyl. Hexahydrate oxalate of cis-N-r3-ri-1,4,4-bis- (4-fluorophenyl) butyl-4-pperidinyl-5,6- (cyclohexylidene dioxy) -3,4-dihydro -1H-benzopyran-1-ylmethylformamide A mixture of N- [5,6- (cyclohexylidenedioxy) -3- (piperidin-4-yl) -3,4-dihydro-1 H-2-benzopyran] formamide (2.3 g, 5.9 mmol), 4,4-bis- (4-fluorophenyl) butyl methanesulfonic acid ester (2.2 g, 6.5 mmol), NaHCO 3 (1.0 g, 11.8 mmol) in DMF (50 mL) were stirred and heated under N2 for 2 hours at 65 ° C. The reaction was stirred at room temperature for 16 hours, and then it was poured into H2O. After extraction processing with EtOAc, 3.5 g of a brown oil remained. This oil was combined with a sample from another operation and the combined sample was flash chromatographed on silica (200 g), eluting with CH 2 Cl 2 -MeOH (4%). The desired fractions were combined and concentrated to provide a white amorphous solid. The solid was dissolved in Et2O and oxalic acid (0.58 g, 6.4 mmol) was added. The reaction was briefly heated in a steam bath and a white oxalate salt was collected. The salt was recrystallized from IPA-Et20 to provide the oxalate salt of the product as a white solid, m.p. 148-150 ° C. Analysis: Calculated for C38H44F2N2O4.C2H2O4.0.5H2O: 65.82% C 6.49% H 3.83% N Found: 65.92% C 6.42% H 3.73% N EXAMPLE 29 When Formula I is R ^ diphenyl, alkyl of 1 to 6 carbon atoms substituted with F; R2 and R3 = H, X and Y = OH. Dihydrate of cis-1 - (amnomethyl) -3-f 1-1,4,4-bis- (4-fluorophenyl) butyn-4-piperidinyl-1H-2-benzopyran-5,6-diol A cis-solution -1 - (aminomethyl) -5,6- (cyclohexylidenedioxy) -3- [1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] -1H-2-benzopyran (1.0 g, 1.6 mmol ) and 5M HCl in EtOH (20 mL) was refluxed for 1 hour. The reaction was concentrated to a brown oil, and the oil was dissolved in absolute EtOH. Then ether was added to precipitate 0.8 g of a white solid. The product was combined with a 0.2 g sample from another operation, and the combined sample was recrystallized from ETOH-Et2O and then from EtOH to provide an off-white solid. The compound was dried at 80 ° C under vacuum to yield the salt as a dihydrochloride, dihydrate, m.p. 185-187 ° C. Analysis: Calculated for C31H36F2N2? 3.2HCI.2H2O: 58.95% C 6.70% H 4.44% N Found: 59.02% C 6.69% H 4.43% N EXAMPLE 30 Wherein Formula I is R1 = (CH2) mZ (CH2) t substituted phenyl; X and Y form cyclohexylidenedioxy; R2 = H and R3 = CHO. Tri-hydrate cis-N- [3- [1-r3- (4-acetyl-2-methoxyphenoxy) propyl] -4- piperidin-5,6- (cyclohexylidene dioxy) -3,4-dih Dro-1H-2-benzopyran-1-ylmethylformamide. 1 - [4- (3-Chloropropoxy) -3-methoxyphenyl-ketanone (0.14 g, 0.00057 mole), potassium carbonate (0.08 g, 0.00057 mole) were added sequentially and potassium iodide (0.02 g, 0.00010 mol) to a stirred solution of cis-N- [5,6-cyclohexylidenedioxy) -3,4-dihydro-4-piperidinyl-1H-2-benzopyran-3-ylmethyl] form amide ( 0.200 g, 0.00052 moles) in (10 ml) of N, N-dimethylformamide at room temperature. After stirring overnight at 65 ° C, the mixture was diluted with water and extracted into ethyl acetate. Purification through chromatotron (2 mm silica gel plate) eluting with 5% MeOH / DCM gave 0.250 g of a white foam. Oxalate salt formation followed by recrystallization from MeOH / ether yielded a white solid, m.p. 100-103 ° C. Analysis: Calculated for C3eH.4eN2On.3H2O: 58.68% C. 7.11% H 3.80% N It was found: 58.19% C 6.27% H 3.59% N EXAMPLE 31 Wherein Formula I is R-i = (CH2) mZ (CH2) t substituted phenyl; X and Y = OH; R2R3 = H. dihydrate cis-1 - (3-r3-r4-M- (amnomethyl) -3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran-3-yl- 1-piperidylnillpropoxyl-3-methoxypheniDetanone cis-1 - [3- [3- [4- [1 - (aminomethyl) -5,6- (cyclohexylidenedioxy) -3,4-dihydro-1H-2-benzopyran was added -3-yl] -1-p-peridinyl] -propoxy] -3-methoxyphenyl] ethanone (1.0 g, 0.0018 mol) to a solution of 5M concentrated HCl in (20 ml) of ethanol After heating under reflux for 3 hours, the solvent was concentrated in vacuo to a brown foam.The addition of ethanol solidified the material.The titration of the solid with hot ethanol yielded an off-white solid, mp 218-220 ° C. Analysis: Calculated for C27H380l2N2O6. 2H2O: 56.64% C 7.13% H 4.72% N Found: 54.94% C 6.87% H 4.63% N EXAMPLE 32 When Formula I is R1 = C (0) CH3; R3 = CHO; X and Y = methoxy. Cis-N-r3- (1-acetyl-4-piperidinyl) -3,4-dihydro-5,6-dimethoxy-H-2-benzopyran-1-ylmethine formamide A solution of 4- (2- (2 , 3-dimethoxyphenyl) -1-hydroxyethyl) piperidine (3.8 g, 0.014 mol) in 20 ml of acetic anhydride was heated between 60-65 ° C for 5 minutes. After cooling to room temperature, the reaction was diluted with water, cooled in an ice bath and 50% aqueous NaOH was added, until the reaction became basic. Extraction processing with EtOAc yielded an oil, which after purification on HPLC preparation (3% MeOH / CH2Cl2) provided 2.7 g of 4- (2,3-diemtoxyphenyl-1-hydroxyethyl) piperidin-1-acetamide as a colorless oil. To a stirred solution of 4- (2,3-dimethoxyphenyl-1-hydroxyethyl) piperidin-1-acetamide (2.4 g, 0.0078 mol), N-formylaminoacetaldehyde-dimethylacetal (1.2 g, 0.0093 mol), in 40 ml of cooled CH2Cl2. at 5 ° C, BF3 »O (Et) 2 (7.9 g, 0.047 mol) was added dropwise. After the addition was complete, the cooling bath was removed and the reaction was allowed to proceed at room temperature for 2 hours, at which time 2.0 additional equivalents of BF3 »O (Et) 2 were added. The reaction was allowed to stand at room temperature for 64 hours, and then it was poured into water. The organic layer was collected, washed with saturated Na 2 CO 3 and brine, dried (K 2 CO 3) and concentrated to yield an oil, which after titration with ether yielded a white solid. This solid was combined with another and the combined sample was recrystallized from toluene (twice) to yield the compound as a white solid, m.p. 140-142 ° C. Analysis: Calculated for C20H28N2O5: 63.81% C 7.50% H 7.44% N It was found: 63.68% C 7.46% H 7.24% N EXAMPLE 33 When Formula I is R? = H; R2 and R3 = H; X and Y = OH. 0.3 Hydrate cis-1- (aminomethyl) -3,4-dihydro-3- (4-piperidinyl) -1H-2-benzopyran-5,6-diol hydrate A solution of cis-N- [56- (cyclohexylidenedioxy) -3,4-dihydro-3- (4-piperidinyl) -1H-2-benzopyran-1-ylmethyl] form amide (0.70 g, 1.8 mmol) and 5M HCl in 15 ml of ethanol were added. stirred under reflux under N2 for 1 hour and a white solid precipitated. The reaction was cooled in an ice bath and the resulting product was collected to yield the title compound, which was recrystallized from methanol-ether and dried at 80 ° C for 4 hours to provide a white solid, m.p. 305-307 ° C. Analysis: Calculated for C15H24CI2N2O3.0.3H2O 50.50% C 6.97% H 7.86% N It was found: 50.65% C 6.93% H 7.81% N EXAMPLE 34 H - CL Formula I where X and Y = OH, R 1 = heteroarylalkyl, R 2 and R 3 = H. 1.33 Hydrate dihydrochloride of cis-1-f 3 -f 4 - (1-amino-methyl-3,4-dihydro-5,6-dihydroxy) 1H-2-benzopyran-3-ip-1-piperidininpropyl1-1,3-dihydro-benzimidazol-2-one cis-N- [5,6- (cyclohexylidene) -3,4-dihydro-3- [1 - [3- (2-Oxo-2,3-dihydro-benzimidazol-1-yl) propyl] -4-piperidinyl] -1H-2-benzopyran-1-methylmethyl formamide (0.750 g, 0.0013 mol) at a 5M solution of concentrated HCl in 15 ml of ethanol at room temperature After heating under reflux for 1 hour, a white solid was precipitated from the solution.After cooling to room temperature, the solid was collected through filtration and dried at 80 ° C for 5 hours to produce a solid, mp 219-221 ° C. Analysis: Calculated for C25H34Cl2N4O4.L 33 H2O: 54.65% C 6.73% H 10.20% N It was found: 54.29% C 6.69% H 10.06% N EXAMPLE 35 Formula I wherein X and Y = OH, Ri = heteroarylalkyl, R2 and R3 = H. Dihydrate dihydrochloride of 3-f4-r4- (cis-1- (amnomethyl) -3,4-dihydro-5, 6-dihydroxy-1H-2-benzopyran-3-yl) -piperidin-1-ipbutyl-5,5-dimethyl-1,1-dioxo-4-thiazolidinone A solution of 3- [4- [4- (cis -5,6- (cyclohexylidenedioxy) - 3,4-dihydro-1- (N-formylaminomethyl) -1 H-2-benzopyran-3-yl) -piperidin-1-yl] butyl]] - 5,5 dimethyl-1, 1-dioxo-4-thiazolidinone (1.0 g, 1.7 mmol) and 5M HCl in (15 mL) of ethanol was stirred under reflux under N2 for 3.5 hours. The cold reaction was concentrated to yield 1.2 g of a beige oil. The residue was titrated with ether and the solvent was evaporated to give a sticky solid. The product was crystallized from boiling methanol to provide a white solid. The compound was dried at 80 ° C for 4 hours to provide a white solid, m.p. 211-214 ° C. Analysis: Calculated for C24H39CI2N3O6S.2.0 H20: 47.68% C 7.17% H 6.95% N Found: 47.38% C 7.15% H 6.90% N EXAMPLE 36 Formula I wherein X and Y form cyclohexylidenedioxy, heteroarylalkyl, R 2 = H, R 3 = CHO. Di cis-N-r5,6- (cyclohexylidenedioxy) -3,4-dihydro-3-f 1 -f3- (2-oxo-2,3-dihydrobenzimidazol-1-yl) propyl 1-4-piperidinyl-1H hydrate -2-benzopyran-1-ylmethyl) 1 form amide Sequentially 1- (3-chloropropyl) -1,3-dihydrobenzimidazol-2-one (3.0 g, 0.0142 mol), potassium carbonate (1.97 g, 0.0142) moles), and potassium iodide (0.43 g, 0.0026 moles) to a stirred solution of cis-N- [5,6- (cyclohexylidenedioxy) -3,4-dihydro-4-piperidinyl-1H-2-benzopyran- 3-ylme ethyl] form amide (5.0 g, 0.0129 moles) in N, N-dimethylformamide (250 ml) at room temperature. After stirring overnight at 65 ° C, the mixture was diluted with water and extracted with ethyl acetate. Purification through flash column chromatography eluting with 5% MeOH / DCM gave 2.53 g (35%) of a pale yellow foam. Further purification of 1.0 g of this material with chromatotron (6 mm silica gel plate), eluting with 5% MeOH / DCM gave 0.640 g of a white foam. The methanol addition solidified the white solid material. Recrystallized from methanol gave a white solid. The solid was collected through filtration and dried overnight at 100 ° C to yield a white solid, m.p. 145-147 ° C. Analysis: Calculated for C32H40N4O5.2H2O: 64.41% C 7.43% H 9.39% N It was found: 64.17% C 6.94% H 9.36% N EXAMPLE 37 Formula I wherein R ^ is substituted aralkyl, R2 and R3 = H, X and Y = OH. 0.25 cis-1- (aminomethyl) -3,4-dihydro-3-f 1 - \ 2- (3-chlorophenyl) -1,4-piperidyl-1H-2-benzopyran hydrate dihydrochloride , 6-dol A solution of cis-N- [5,6- (cyclohexylidenedioxy) -3,4-dihydro-3- [1- (3-chlorophenethyl) -4-piperidinyl] -1H-2-benzopyran -1-ylmethyl] formamide (900 mg, 1.7 mmol) and a 5M solution of concentrated HCl in 12 mL of ethanol was stirred under reflux under N2 for 1 hour and a white solid precipitated. The reaction was cooled in an ice bath and the resulting product was collected. The compound was dried at 80 ° C for 4 hours to provide a white solid, m.p. 313-316 ° C. Analysis: Calculated for C23H31CI3N2O3.0.25 H20: 55.87% C 6.44% H 5.67% N Found: 55.90% C 6.17% H 5.62% N EXAMPLE 38 Formula I wherein R -? = Substituted arylalkyl, R 2 = H, R = CHO, X and Y form cyclohexylidenedioxy. Hexahydrate of cis-N-r5,6- (cyclohexylidenedioxy) -3,4-dihydro-3-ri-r2- (4-methophenol) etn-4-piperidinin-1H-2-benzoyran-1- ilmetin formamide. 2- (4-Methoxyphenyl) ethyl ester of methanesulfonic acid (3.28 g, 0.0142 mol) and potassium carbonate (1.97 g, 0.0142 mol) were sequentially added to a stirred solution of cis-N- [5,6- ( cyclohexylidenedioxy) -3,4-dihydro-4-piperidinyl-1H-2-benzopyran-3-ylmethyl] formamide (5.0 g, 0.0129 moles) in (250 ml) of N, N-dimethylformamide at room temperature. After stirring overnight at 65 ° C, the mixture was diluted with water and extracted with ethyl acetate. Purification through flash column chromatography eluting with 5% MeOH / DCM gave a yellow foam. Further purification of 0.800 g of this material through chromatotron (4 mm silica gel plate), eluting with 5% MeOH / DCM gave a white foam. Formation of the oxalate salt followed by recrystallization from methanol yielded a white solid, m.p. 131-133 ° C. Analysis: Calculated for C33H42N2O9 »0.5H2O: 63.96% C 6.99% H 4.52% N It was found 64.18% C 6.99% H 4.45% N EXAMPLE 39 Formula I wherein R-α = substituted arylalkyl, R 2 and R 3 = H, X and Y form cyclohexylidenedioxy 2,4-cis-1-aminomethyl-5,6- (cyclohexylidene-dioxy) -3,4-dihydro-3- dihydrate dihydrate ri-r4.4-bis (4-fluorophenyl) butyl-4-piperidinin-1H-2-benzopyran A solution of formamide from example 28 (0.5 g, 0.8 mmol) in THF-MeOH (5 ml-5 ml) and NaOH 15% (2.5 mi) was stirred to 50 ° C for 4 hours. The majority of the solvent was removed in vacuo, and the residue was diluted with H2O and resulted in a yellow gum. The aqueous suspension was extracted with EtOAc, and the extract was washed (H2O), dried (MgSO4) and concentrated to yield 0.6 g of a sticky solid. The solid was flash chromatographed on silica gel, eluting with a gradient of MeOH in CH 2 Cl 2 (5, 8 and 10%). The concentration of the appropriate fractions gave 0.4 g of a yellow foam. The foam was dissolved in Et2O and oxalic acid (0.13 g, 1.4 mmol) was added to provide a whitish oxalate salt. The salt was recrystallized from EtOH to yield the compound as a white solid, m.p. 153-155 ° C. Analysis: Calculated for C37H44F2N2O3.2C2H2O42.4H2O 59.54% C 6.39% H 3.37% N Found: 59.80% C 5.97% H 3.29% N EXAMPLE 40 Formula I wherein R ^ is substituted arylalkyl, X and Y = OH, R2 and R3 = H. Di cis-1- (aminomethyl) -3,4-dihydro-3-M-r3- (2- methyl-1H-indol-3-yl) propyl-4-piperidinyl-1H-2-benzopyran-5,6-diol Cis-N- [5,6- [cyclohexylidenedioxy] -3,4-dihydro was added -3- [1- [3- (2-methyl-1H-indol-3-yl) propyl] -4-piperidinyl] -1H-2-benzopyran-1-ylmethyl] formamide (0.750 g, 0.0013 moles) at a 5M solution of concentrated HCl in 15 ml of ethanol at room temperature. After stirring under reflux for 1 hour, a blue solid precipitated from the solution. The solid was collected through filtration and dried at 80 ° C for 5 hours to yield a gray solid, m.p. 265-267 ° C. Analysis: Calculated for C27H37CI2N3O3: 62.06% C 7.14% H 8.04% N Found: 61.98% C 7.42% H 7.49% N EXAMPLE 41 Formula I wherein R ^ = substituted arylalkyl, X and Y = OH, R2 and R3 = H. Cys-1- (aminomethyl) -3,4-dihydro-3-p-f2- (4-trifluoromethylphenitopyr-4-piperidinyl-1H-2-benzopyran-5-diol dihydrochloride) added cis-N- [5,6- (cyclohexylidenedioxy) -3,4-dihydro-3- [1- [2- (4-trifluoromethylphenyl) ethyl] -4-piperidinyl] -1H-2-benzopyran-1-yl methyl] formamide (0.550 g, 0.00089 mol) to a solution of 5M concentrated HCl in 10 ml of ethanol, at room temperature After stirring under reflux for 1 hour, a white solid was precipitated from the solution. collected through filtration and dried at 80 ° C for 5 hours to produce a solid, mp 299-300 ° C. Analysis: Calculated for C24H3? CI2F3N2O3: 55.07% C 5.97% H 5.35% N It was found: 54.88% C 6.21% H 5.29% N EXAMPLE 42 Formula I wherein R-t = substituted arylalkyl, R 2 = H, R 3 = CHO, X and Y form a cyclohexylidenedioxy. Hemohydrate of cis-N-l3-l1-r2- (4-chlorophenyl) ethyl-1-4-piperidin-5,6- (cyclohexylidenedioxy) -3,4-dihydro-1H-2-benzopyran- 1-methylformamide formamide Methanesulfonic acid 2- (4-chlorophenyl) ethyl ester (3.34 g, 0.0142 mol) and potassium carbonate (1.97 g, 0.0142 mmol) were added sequentially to a stirred solution of cis-N- [5 , 6- (cyclohexylidenedioxy) -3,4-dihydro-4-piperidinyl-1H-2-benzopyran-3-ylmethyl] formamide (5.0 g, 0.0129 mmole) in 250 ml of N, N-dimethylformamide at room temperature. After stirring overnight at 65 ° C, the mixture was diluted with water and extracted into ethyl acetate. Purification through flash column chromatography eluting with 5% MeOH / DCM gave 3.14 g (46% >) of a white foam. Another purification of 0.880 g of this material through chromatotron (4 mm silica gel plate) eluting with 5% MeOH / DCM gave a colorless oil. The addition of methanol solidified the material to a white solid. Double recrystallization from methanol yielded a white solid, m.p. 90-92 ° C. Analysis: Calculated for C30H37CIN2O40.5 H2O: 67.47% C 7.17% H 5.24% N Found: 67.52% C 7.43% H 5.27% N A therapeutically effective amount of the compounds of the present invention is administered to a patient in need of such therapy, i.e., a patient presenting with psychosis. Preferably, the compounds of the present invention are administered between 0.01 milligrams per kilogram per day (mg / kg / day) to 100 mg / kg / day. However, important factors, such as the species of mammal, in size, age, general health of the patient, severity of the disease, idiosyncratic responses of the patient, route of administration, and the like, may vary the dose required. Also, the route of administration can be varied depending on a number of the above factors and also including the biopharmaceutical characteristics of the compound that can be ascertained by one skilled in the art. Examples of preferred routes of administration include oral, buccal, sublingual, intravenous, intraperitoneal, inhalation, subcutaneous, rectal, topically and transdermally. See, for example, Remington's Pharmaceutical Sciences, 18a. edition, Mack Publishing, Co. (1990), incorporated herein by reference. The compounds of the present invention can be administered alone or in the form of a pharmaceutically acceptable composition, which includes pharmaceutically acceptable carriers, the proportion and nature of which is determined through the characteristics of the compound of the present invention, the route of administration and standard pharmaceutical practice. The compounds may be in the form of their pharmaceutically acceptable salt forms, such as acid addition salts or base addition salts thereof. The compounds of the present invention antagonize the effects of dopamine on the D2-type dopamine receptor as can be shown through the standard binding data or the following in vivo test.

D2L HUMAN DOPAMINE ASSAY RECEIVER UNIT The affinity of a dopamine D2 receptor compound is proportional to its antipsychotic potential (Créese et al., 1978). The dopamine D2 receptor gene was isolated from a collection of human striatal cDNA (caudate / putamen); the long slice variant (Dal Toso et al., 1989), D2 was sequenced and subcloned into an expression vector and stably transfected into Chinese Hamster Ovary Cells. A single high-expression clonal cell line was isolated and the membranes of this cell line were used for receptor binding analysis. The ability of the compounds to displace the binding of [3H] N-methyl spiroperidol (0.4 nM) to the D2L receptor was measured (Hall et al., 1990). Incubation pH regulator contained: 50 mM Tris, 120 mM NaCl; 5 mM KCl; 2 mM CaCl3; 1 mM MgCl 2; pH 7.7. For most of the assays, a 1mM stock solution of the test compound was prepared in water and the incubation pH buffer was diluted to obtain concentrations on an appropriate scale to determine the IC50 of the compound. Incubations were performed at 37 ° C in a shaking water bath for 30 minutes, and were terminated through rapid filtration through Whatman GF / B filters (pre-wetted in 0.3%) of polyethylenimine), and counted in a liquid sensing counter No specific binding was defined as that remaining in the presence of 3 μM of eticlopride. IC50 and K calculations were performed (Cheng &Prusoff, 1973) using a non-linear regression site competition analysis (GraphPad, Prism), with upper and lower limits, remaining constant at 0% and 100% inhibition , respectively. The percentage of inhibition of each drug concentration was the average of determinations in duplicate. The ligand Kd used in the calculation of K i was determined using both saturation analysis (Scatcharad, 1949), as well as kinetic analysis (association and dissociation regimes). (See Créese, I., Burt, et al., Science 192: 481-483 (1978); Dal Toso, et al., EMBO J. 8: 4025-4034 (1989); H. Hall, et al., J. Neurochem 55: 2048-2057 (1990), Cheng, Y. et al., Biochem Pharmacol 22: 3099-3108 (1973), and Scatchard, G. Ann. NY Acad. Sci. 51: 660- 672 (1949).

ASCENDING MOUSE ESSAY (CMA) This test was used to identify compounds useful in the treatment of sycosis. Costall, B. et al., Eur. J. Pharm. 50: 39.50 (1978); Protais, P., et al., Psychopharmacology 50: 1-6 (1976). Apomorphine induces the promotion to mice at low dose levels, which do not induce oral stereotyping or motor stimulation. This effect of apomorphine was antagonized through the D2 receptor antagonist. Male CD-1 mice (20-30 grams) were assigned to groups of 8 and individually placed in thick wire cages and left for one hour to adapt to the new environment. Apomorphine was injected at 1.5 mg / kg subcutaneously, which is a dose that causes rise in all subjects for thirty minutes. The test compounds were administered intraperitoneally thirty minutes before the administration of apomorphine at a dose of 20 mg / kg. For the evaluation of the ascent, three readings were taken at ten, twenty and thirty minutes after the administration of apomorphine according to the following scale: Climbing behavior Classification Mice with: the 4 legs on the floor (without ascent) 0 2 legs on the wall (rising) 1 4 legs on the wall (full ascent) 2 The ascent classifications were individually totalized (maximum classification: 6 per mouse during three readings) and the total control classification (vehicle intraperitoneally (ip) and subcutaneous apomorphine) was set at 100%. The ED50 values with 95% confidence limits calculated through a linear regression analysis of some of the compounds of the present invention, as well as a standard antipsychotic agent (clozapine) are presented in Table 1.

TABLE 1 Ph = phenyl; benzis = benzisoxazole; F = fluoro; all X and Y. positions at 5, 6 and n = 1. A [N-methyl-3H] spiroperidol [3H] NMSP test was used for the human dopamine D2 long receptors cloned to demonstrate that the compounds of the present invention they join the receiver D2. [N-methyl3H] spiroperidol was chosen as a ligand for its affinity for the D2 receptor (Hall, H. et al., J. Neuroschem 55: 2048-2057 (1990) and Leysen, JE, et al., Biochem. Pharmacol., 27: 307-328 (1977)). For most of the tests, a 100 mM supply solution of the solvent and pH regulator test compound was prepared, so that concentrations of 10"5 to 10" 8M were obtained. Cheng-Prisoff (Ki's) determinations were performed using Prism software.

TABLE 2 Long Receptor Binding Human D2 * All compounds listed are of Formula I, where n = 1 • PH = phenyl; Ac = acetyl; Ph-4 = para-substituted phenyl; Ph-2 = ortho-substituted phenyl. The compounds of the present invention can be shown to be effective in treating psychosis in humans by administering the compound to a patient suffering from psychosis, and observing the behavior thereof. These observations can be analyzed through standard tests such as the Abbreviated Hamilton Psychiatric Rating Scale, where certain classifications are given for the defined behavior. Other compounds of Formula I, preferably wherein n = 1 and X and Y are preferably 5,6-alkoxy of 1 to 6 carbon atoms, hydroxy and most preferably methoxy, in positions 5 and 6; or X and Y together form cyclohexylidene acetal are shown in Table 3.

TABLE 3

Claims

CLAIMS 1.
A compound of Formula I, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein Ri is H, alkyl of 1 to 6 carbon atoms, optionally substituted aralkyl, optionally substituted heteroaralkyl, 5,5-dimethyl-1,1-dioxo-4-thiazolidinone, indane, alkylsulfonyl, trifluoroacetyl or (CH2) mZ (CH2) t -phenyl optionally substituted, wherein Z is O or C = 0; wherein optionally substituted represents a portion that is suitably substituted with one, two or three substituents, each independently selected from H, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, C (= O) ) H, C (= O) -alkyl of 1 to 6 carbon atoms, CF3 or hydroxy; each of R2 and R3 are independently H, alkyl of 1 to 6 carbon atoms, C (O) -alkyl of 1 to 6 carbon atoms, CHO, or alkenyl of 2 to 6 carbon atoms; each of X and Y are independently H, hydroxy, alkyl of 1 to 6 carbon atoms, halogen, acyloxy or alkoxy of 1 to 6 carbon atoms, benzyloxy, or X and Y together form a diphenylmethylene ketal, methylene acetal, cyclohexylidene ketal, or a cyclic carbonate group provided that X and Y are adjacently placed; and n is an integer of 1, 2 or 3; m is an integer of 0, 1, 2, or 3; and t is an integer of 0, 1, 2, or
3. The compound according to claim 1, wherein: R-i is alkyl of 1 to 6 carbon atoms, aralkyl or heteroaralkyl; each of R2 and R3 are independently hydrogen or alkyl of 1 to 6 carbon atoms; and each of X and Y are independently hydroxy, acyloxy, or alkyl of 1 to 6 carbon atoms; and n is 1. The compound according to claim 1, wherein each of X and Y are hydroxy, alkoxy of 1 to 6 carbon atoms or acyloxy; each of X and Y are respectively in positions 5 and 6; and n is 1.
4. The compound according to claim 1, wherein n is 1.
The compound according to claim 1, wherein X and Y are each methoxy.
6. The compound according to claim 1, wherein each alkyl of 1 to 6 carbon atoms and each alkoxy of 1 to 6 carbon atoms respectively are alkyl of 1 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms.
The compound according to claim 1, wherein X and Y are each hydroxy and respectively are in positions 5 and 6.
The compound according to claim 1, wherein R ^ is aralkyl.
9. The compound according to claim 1, wherein Ri is optionally substituted heteroaralkyl.
10. The compound according to claim 1, wherein R- is phenylethyl.
11. The compound according to claim 1, wherein R: is (6-fluoro-1,2-benzisoxazol-3-yl) propyl.
The compound according to claim 1, wherein aralkyl optionally substituted in an optionally substituted benzyl, optionally substituted phenylethyl or optionally substituted phenylpropyl.
13. The compound according to claim 1, wherein the heteroaralkyl is optionally substituted 1,2-benzisoxazolyl.
14. The compound according to claim 13, wherein the heteroaralkyl is (6-fluoro-1,2-benzisoxazol-3-yl) propyl.
15. The compound according to claim 1, wherein one of X and Y are H.
16. The compound according to claim 1, wherein the compound is cis-N- [3- (1-acetyl-4 -piperidinyl) -3,4-dihydro-5,6-dimethoxy-1H-benzopyran-1-ylmethyl] formamide.
17. The compound according to claim 1, wherein the compound is 4- [2- (2,3-dimethoxyphenyl) -1-hydroxyethyl] -1-piperidine methanesulfonamide.
18. The compound according to claim 1, wherein the compound is cis-N- [3,4-dihydro-5,6-dimethoxy-3- [1- (methylsulf or nil) -4-piper i dinyl] -1H-2-benzopyran-1-ylmethyl] form amide.
19. The compound according to claim 1, wherein the compound is cis-1 - (aminomethyl) -3, 4-dihydro-5,6-dimethoxy-3- (1-methylsulfonyl-4-piperidinyl) -1H-2-benzopyran.
The compound according to claim 1, wherein the compound is cis-N- [3,4-dihydro-5,6-dimethoxy-3- [1- (2-phenylethyl) -4-piperidinyl] -1H -2-benzopyran-1-ylmethyl] formamide.
21. The compound according to claim 1, wherein the compound is cis-1- (aminomethyl) -3,4-dihydro-5,6-dimethoxy-3 - [- (2-phenylethyl) -4-piperidinyl] -1H-2-benzopyran.
22. The compound according to claim 1, wherein the compound is cis-1 - (aminomethyl) -3,4-dihydro-3- [1- (2-phenylethyl) -4-piperidinyl] -1H-2- benzopyran-5,6-diol.
23. The compound according to claim 1, wherein the compound is cis-1 - (aminomethyl) -5,6-diacetoxy-3,4-dihydro-3- [1- (2-phenylethyl) -4-piperidinyl] - 1 H-2-benzopyran.
The compound according to claim 1, wherein the compound is cis-N- [3,4-dihydro-5,6-dimethoxy-3- (1-trifluoroacetyl-4-piperidinyl) -1H-2-benzopyran -1-ylmethyl] formamide.
25. The compound according to claim 1, wherein the compound is cis-N- [3,4-dihydro-5,6-dimethoxy-3- (4-pyrifinyl) -1H-2-benzopyran- ilm ethyl] form amide.
26. The compound according to claim 1, wherein the compound is cis-N- [3- [1 - [4- (4-fluorophenyl) -4-oxobutyl] -4-piperidinyl] -3,4-dihydro -5,6-dimethoxy-1H-2-benzopyran-1-ylmethyl] formamide.
27. The compound according to claim 1, wherein the compound is cis-1- (aminomethyl) -3,4-dihydro-3- (1-ethyl-4-piperidinyl) -1H-2-benzopyran-5, 6-diol.
The compound according to claim 1, wherein the compound is cis-1- (aminomethyl) -3,4-dihydro-3- [1 - [3- (6-fluoro-1,2-benzisoxazole-3 -yl] propyl] -4-piperidinyl] -1H-2-benzopyran-5,6-diol
29. The compound according to claim 1, wherein the compound is cis-1 - (aminomethyl) -3, 4-Dihydro-3- [1- (3-phenylpropyl) -4-piperidinyl] -1H-2-benzopyran-5,6-diol
30. The compound according to claim 1, wherein the compound is cis- 1- (aminomethyl) -3,4-dihydro-5,6-dimethoxy-3- (1-benzyl-4-pipridinyl) -1H-2-benzopyran
31. The compound according to claim 1, wherein the compound is cis-1- (aminomethyl) -3- (1-benzyl-4-piperidinyl) -3,4-dihydro-1H-2-benzopyran-5,6-diol
32. The compound according to the claim 1, wherein the compound is cis-1 - (N-methylaminomethyl) -3,4-dihydro-3- [1- (2-phenylethyl) -4-piperidinyl] -1H-2-benzopyran-5,6-diol
33. The compound according to claim 1, wherein the compound is cis-1-aminomethyl-3,4-dihi. dro-3- [1 - (methylsulfonyl) -4-piperidinyl] -1H-2-benzopyran-5,6-diol.
34. The compound according to claim 1, wherein the compound is 1- [4- [cis-1 - ((aminomethyl) -3,4-dihydro-5,6-dimethoxy-1H-2-benzopyran) -3-yl] piperidin-1-yl] -2- (4-fluorophenyl) ethanone
35. The compound according to claim 1, wherein the compound is cis-1 - (aminomethyl) -3,4-dihydro. -3- [1 - [2- (4-fluorophenethyl)] - 4-piperidinyl] -1H-2-benzopyran-5,6-diol
36. The compound according to claim 1, wherein the compound is cis -3,4-dihydro-5,6-dimethoxy-2- [1 - [2- (4-fluorophenethyl)] - 4-pi per id inyl] -1- (N-methylamine) -1 H-2 -benzopyran
37. The compound according to claim 1, wherein the compound is cis-1, 3,4-dihydro-3- [1- [2- (4-fluorophenylethyl)] - 4-piperidinyl] - ( N-methylaminomethyl) -1H-2-benzopyran-5,6-diol
38. The compound according to claim 1, wherein the compound is cis-N- [3,4-dihydro-5,6- dimethoxy-3- [1 - (2-phenethyl) -4-piperidinyl] -1H-2-benzopyran-1-yl] formamide.
39. The compound according to claim 1, wherein the compound is cis-1- (aminomethyl) -3,4-dihydro-3- [1- (2-phenylethyl) -4-piperidinyl] -1H-2-benzopyran- 5,6-diol.
40. The compound according to claim 1, wherein the compound is cis-1- (aminomethyl) -3,4-dihydro-3-4- (piperidinyl) -1H-2-benzopyran-5,6-diol.
41. The compound according to claim 1, wherein the compound is cis-3,4-dihydro-3- [1- [2- (4-methoxyphenyl) ethyl] -4-piperidinyl] -1- (N- methylaminomethyl) -1H-2-benzopyran-5,6-diol.
42. The compound according to claim 1, wherein the compound is cis-1- (aminomethyl) -3,4-dihydro-3- [1 - [2- (4-methoxyphenyl) -ethyl] -4-piperidinyl ] -1H-2-benzopyran-5,6-diol.
43. The compound according to claim 1, wherein the compound is cis-1- (aminomethyl) -3- [1- [2- (4-chlorophenyl) ethyl] -3,4-dihydro-4-piperidinyl] -1H-2-benzopyran-5,6-diol.
44. The compound according to claim 1, wherein the compound is cis-3- [1- [2- (4-chlorophenyl) ethyl] -3,4-dihydro-4-piperidinyl] -1- (N- methylaminomethyl) -1H-2-benzopyran-5,6-diol.
45. The compound according to claim 1, wherein the compound is cis-3,4-dihydro-5,6-dimethoxy-3- [1- [2- (4-fluorophenylethyl)] - 4-piperidinyl] - 1- (N-methylaminomethyl) -1H-2-benzopyran.
46. The compound according to claim 1, wherein the compound is cis-3,4-dihydro-3- [1- [2- (4-fluorophenethyl)] - 4-piperidinium] - (N-methylaminomethyl) - 1H-2-benzopyran-5,6-diol.
47. The compound according to claim 1, wherein the compound is cis-1 - (aminomethyl) -5,6-diacetoxy-3,4-dihydro-3- [1- (2-phenethyl) -4-piperidinyl] - 1H-2-benzopyran.
48. The compound according to claim 1, wherein the compound is cis-3,4-dihydro-3- [1- [2- (4-fluorophenylethyl)] - 4-piperidinyl] - (N-methylaminomethyl) ) -1H-2-benzopyran-5,6-diol.
49. The compound according to claim 1, wherein the compound is cis-N- [3,4-dihydro-5,6-dimethoxy-3- [1- (2-phenylethyl) -4-piperidinyl] - 1H-2-benzopyran-1-ylmethyl] formamide.
50. The compound according to claim 1, wherein the compound is cis-1 - (aminomethyl) -3,4-dihydro-3- [1- (2-phenethyl) -4-piperidinyl] -1H-2- benzopyran-5,6-diol.
51. The compound according to claim 1, wherein the compound is cis-N- [3- [1- [4- (4-fluorophenyl) -4-oxobutyl] piperidinyl-4-yl] -3,4- dihydro-5,6-dimethoxy-1H-2-benzopyran-1-ylmethyl] formamide.
52. The compound according to claim 1, wherein the compound is cis-N- [5,6- (cyclohexylidenedioxy) -3,4-dihydro-3- (4-piperidinyl) -1H-2-benzopyran-1. -ylmethyl] form amide.
53. The compound according to claim 1, wherein the compound is cis-1 - (aminomethyl) -3,4-dihydro-3- [1- (2-phenoxyethyl) -4-piperidinyl] -1H- 2-benzopyran-5,6-diol.
54. The compound according to claim 1, wherein the compound is cis-N- [5,6- (cyclohexylidenedioxy) -3,4-dihydro-3- [1- (2- (thiophen-2-yl) ethyl) piperidin-4-yl] -1 H-2-benzopyran-1 -i I] formamide.
55. The compound according to claim 1, wherein the compound is cis-1- (aminomethyl) -3,4-dihydro-2- [1- (3-thiophen-2-yl-ethyl) -4-piperidinyl ] -1H-2-benzopyran-5,6-diol.
56. The compound according to claim 1, wherein the compound is cis-1- (aminomethyl) -3,4-dihydro-3- [1 - [2- (2-methylphenyl) -propyl] -4-piperidinyl ] -1H-2-benzopyran-5,6-diol.
57. The compound according to claim 1, wherein the compound is cis-N [5,6- (cyclohexylidenedioxy) -3,4-dihydro-3- (1-trifluoroacetyl-4-piperidinyl) -1 H- 2-benzopyran-1-ylmethyl] formamide.
58. The compound according to claim 1, wherein the compound is cis-N- [3- [1- [4,4-bis- (4-fluorophenyl) butyl] -4-pperidinyl] -5, 6- (cyclohexylidenedioxy) -3,4-dihydro-1H-2-benzopyran-1-ylmethyl] formamide.
59. The compound according to claim 1, wherein the compound is cis-1- (aminomethyl) -3- [1- [4,4-bis- (4-fluorophenyl) butyl] -4-piperidinyl] -3 , 4-dihydro-1H-2-benzopyran-5,6-diol.
60. The compound according to claim 1, wherein the compound is cis-N- [3- [1- [3- (4-acetyl-2-methoxyphenoxy) propyl] -4-piperidinyl] -5.6- (cyclohexylidenedioxy) -3,4-dihydro-1H-2-benzopyran-1-ylmethyl] formamide.
61. The compound according to claim 1, wherein the compound is cis-1- [3- [3- [4- [1- (aminomethyl) -3,4-dihydro-5,6-dihydroxy-1H- 2-benzopyran-3-yl] -1-piperidinyl] propoxy] -3-methoxyphenyl] ethanone.
62. The compound according to claim 1, wherein the compound is cis-N- [3- (1-acetyl-4-piperidinyl) -3,4-dihydro-5,6-dimethoxy-1-1H-2-benzopyran -1-ilmetl] formamide.
63. The compound according to claim 1, wherein the compound is cis-1 - (aminomethyl) -3,4-dihydro-3- (4-piperidinyl) -1H-2-benzopyran-5,6-diol.
64. The compound according to claim 1, wherein the compound is cis-1 - [3- [4- (1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran-3 -yl) -1-piperidinyl] propyl] -1,3-dihydro-benzimidazol-2-one.
65. The compound according to claim 1, wherein the compound is cis-1- [3- [4- (1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran-3). -yl) -1-piperidinyl] propyl] -1,3-dihydro-benzimidazol-2-one.
66. The compound according to claim 1, wherein the compound is cis-N- [5,6- (cyclohexylidenedioxy) -3,4-dihydro-3- [1- [3- (2-oxo-2, 3-dihydrobenzimidazol-1-yl) propyl] -4-piperidinyl] -1H-2-benzopyran-1-ylmethyl)] form amide.
67. The compound according to claim 1, wherein the compound is cis-1- (aminomethyl) -3,4-dihydro-3- [1 - [2- (3-chlorophenyl)] - 4-piperidinyl] - 1H-2-benzopyran-5,6-diol.
68. The compound according to claim 1, wherein the compound is cis-N- [5,6- (cyclohexylidenedioxy) -3,4-dihydro-3- [1- [2- (4-methoxyphenyl) ethyl] -4-piperidinyl] -1H-2-benzopyran-1-ylmethyl] formamide.
69. The compound according to claim 1, wherein the compound is cis-1-aminomethyl-5,6- (cyclohexylidenedioxy) -3,4-dihydro-3- [1- [4,4-bis (4-fluorophenyl)) butyl] -4-piperidinyl] -1H-2-benzopyran.
70. The compound according to claim 1, wherein the compound is cis-1 - (aminomethyl) -3,4-dihydro-3- [1 - [3- (2-methyl-1 H-indole-3- il) propyl] -4-piperidinyl J-1 H-2-benzopyran-5,6-diol.
71. The compound according to claim 1, wherein the compound is cis-1 - (aminomethyl) -3,4-dihydro-3- [1 - [2- (4-trifluoromethylphenyl) ethyl] -4-piperidinyl] -1H-2-benzopyran-5,6-diol.
72. The compound according to claim 1, wherein the compound is cis-N- [3- [1- [2- (4-chlorophenyl) ethyl] -4-piperidinyl] -5,6- (cyclohexylidenedioxy) - 3,4-dihydro-1H-2-benzopyran-1-ylmethyl] formamide.
73. A pharmaceutical composition comprising the compound of claim 1, and a pharmaceutically acceptable carrier.
74. A method for treating a patient for a psychotic disorder by administering to the patient a therapeutically effective amount of the compound of claim 1.
75. The method according to claim 43, wherein the psychotic disorder is schizophrenia.
76. A method for making a compound of the formula I: Formula I a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein: RT is H, alkyl of 1 to 6 carbon atoms, optionally substituted aralkyl, optionally substituted heteroaralkyl, 5,5-dimethyl-1,1-dioxo-4-thiazolidinone , indane, alkylsulfonyl, trifluoroacetyl or (CH2) mZ (CH2) t -phenyl optionally substituted, wherein Z is O or C = O; wherein optionally substituted represents a portion that is suitably substituted with one, two or three substituents, each independently selected from H, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, C (= O) ) H, C (= O) -alkyl of 1 to 6 carbon atoms, CF3 or hydroxy; each of R2 and R3 are independently H, alkyl of 1 to 6 carbon atoms, C (O) -alkyl of 1 to 6 carbon atoms, CHO, or alkenyl of 2 to 6 carbon atoms; each of X and Y are independently H, hydroxy, alkyl of 1 to 6 carbon atoms, halogen, acyloxy or alkoxy of 1 to 6 carbon atoms, benzyloxy, or X and Y together form a diphenylmethylene ketal, methylene acetal, cyclohexylidene , or a cyclic carbonate group provided that X and Y are adjacently placed; and n is an integer of 1, 2 or 3; m is an integer of 0, 1, 2, or 3; and t is an integer of 0, 1, 2, or 3. comprising the steps of: a) deprotecting compound 17, wherein X 'and Y' each are respectively X and Y, except for hydroxy and Pg is a group Suitable protector: 17 to produce compound 18; 18 b) optionally reacting compound 18, with Ri'-Lg, where Lg is a suitable leaving group and R-i 'is R-i, except for hydrogen, to produce compound 19; c) optionally mono or dialkylating the amine wherein R2 'is hydrogen and R3' is hydrogen or alkyl of 1 to 6 carbon atoms, to produce compound 20; d) optionally deprotecting compounds 18, 19 or 20, when one of X 'or Y' is alkoxy of 1 to 6 carbon atoms or benzyloxy or when X 'and Y' form a diphenylmethylene ketal, methylene acetal, cyclohexylidene ketal or a cyclic carbonate group, to produce compound 21 in wherein one of X "or Y" are hydroxy, and R2"and R3" are each hydrogen, formyl or alkyl of 1 to 6 carbon atoms; twenty-one e) optionally acylating the compound 21 when at least one of X "or Y" is hydroxy, to produce the compound 22 wherein at least Xa and Ya is acyloxy.