NO173062B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE BENZO (5,6) CYCLOHEPTAPYRIDINES - Google Patents

Description

The present invention relates to an analogue method for the production of therapeutically active benzo[5,6]-cycloheptapyridines.

In the U.S. patent documents no. 3 326 924, 3 717 647 and

4,282,233, European Patent Application No. 0042544 and Villani et al., Journal of Medicinal Chemistry, vol. 15, No. 7, pp. 750-754 (1972) and Arzn. Forch 36, 1311-1314 (1986) certain 11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines are described as antihistamines. In the U.S. patent document no. 4 355 036 certain N-substituted piperidylidene compounds are described.

The compounds produced according to the present invention have the general formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein: R<1> is hydrogen or lower alkyl;

R3 and R<4> may be the same or different and are independently H or halogen, or R3 and R<4> may together form an unsaturated C5-C7 fused ring;

R6 and R<8> are H, -CF3 or lower alkyl;

R<9> is absent or is O" or -CH3;

X is N or C, since C may contain a possible double bond to carbon atom 11;

the dotted line between carbon atoms 5 and 6 is a possible double bond, so when a double bond is present, A and B are H, and when no double bond is present between carbon atoms 5 and 6, A is H2, lower alkyl and H, H and -OH, or =O, and B is H2;

Z is 0 or S; and

R is H, phenyl, lower alkyl, lower alkylthio, lower alkylamino, lower alkenyl, or lower oxyalkyl;

where the substituents have the following more detailed definitions: lower alkyl (including the alkyl parts in lower alkoxy) are straight or branched carbon chains and contain from 1 to 6 carbon atoms,

lower alkenyl are straight or branched carbon chains with at least one carbon-to-carbon double bond and containing from 2 to 6 carbon atoms, and

halogen is fluorine, chlorine, bromine or iodine.

Preferably one or both of R3 and R<4> is halogen, e.g. chlorine or fluorine. The most preferred meaning for R<3 >and/or R4 is a halogen located on carbon atom 8 and/or 9, as shown in the following numbered ring structure:

R<6>, R<8>, A and B are preferably H. X is preferably a single- or double-bonded carbon atom. The bond between positions 5 and 6 is preferably a single bond. The bond between the piperidyl ring and the cycloheptyl ring is preferably a double bond.

Particularly preferred compounds: 8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine,

8-chloro-11-(1-methoxyacetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine,

8-chloro-11-(1-propionyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine,

8-fluoro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine,

9-fluoro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine,

8-bromo-11-[1-acetyl-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine,

8,9-difluoro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine,

11-(1-acetyl-4-piperidyl)-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]pyridine,

3,8-dichloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine,

8-chloro-11-(1-acetyl-4-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine and

8-chloro-11-(1-acetyl-4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine-N-oxide.

The compounds with the general formula I are prepared according to the invention by an analogous method which is characterized by: a) that a compound of formula II is reacted with a compound of formula III where R<1>, R<3>, R<4>, R<6>, R8, R<9>, A, B, X, Z and R are as defined above and L is a suitable leaving group, or b) direct conversion of an N-alkyl compound with formula V with a compound of formula III where R<1>, R<3>, R4, R6, R<8>, R<9>, A, B, X, Z, R and L are as defined above, and alkyl is a straight or branched carbon chain which contains from 1 to 20 carbon atoms, c) that methyl isocyanate is added dropwise under nitro genatmosphere to a mixture of and triethylamine in dry THF at -10 °C, whereby it is obtained d) that a mixture of and methyl iodide in toluene is heated, whereby it is obtained e) that a mixture of

m-chloroperoxybenzoic acid is added in dry CH2C12 at -10 °C below

nitrogen atmosphere, whereby it is obtained

f) that a mixture of N-acetylpiperazine and triethylamine in dry THF is boiled under reflux cooling and under a nitrogen atmosphere, whereby it is obtained g) that it is reacted with whereby it is obtained

which is acetylated with acetic anhydride to the corresponding compound of formula I,

h) that

traded with which it is obtained

which is acetylated with acetic anhydride to the corresponding compound of formula I, and

i) that

traded with by which it is obtained

which is acetylated with acetic anhydride to the corresponding compound of formula I, after which, if desired, a compound obtained is converted into a pharmaceutically acceptable salt or solvate thereof.

Certain compounds of formula I may exist in different isomers as well as conformational forms. The invention encompasses all such isomers, both in pure form and in mixture, including racemic mixtures.

The compounds of formula I can exist in both unsolvated and solvated forms, including hydrated forms, e.g. hemihydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for purposes of the invention.

Certain basic compounds of formula I form pharmaceutically acceptable salts, e.g. acid addition salts and quaternary ammonium salts. For example, pyrido-

or the pyrazino nitrogen atoms form salts with strong acids, while compounds with basic substituents,

such as amino groups, also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric,

sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art in the field of technology. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to prepare a salt in the conventional manner. The free base forms can be regenerated by treating the salt with a suitable dilute aqueous base solution, such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The quaternary ammonium salts are prepared using conventional methods, e.g. reaction between a tertiary amino group in a compound of formula I with a quaternized compound, such as an alkyl iodide etc. The free base forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes according to the invention.

All such base and quaternary salts are intended to be pharmaceutically acceptable salts within the scope of the invention, and all base salts are considered equivalent to the free forms of the corresponding compounds.

The following analogous procedures can be used to prepare compounds of the general formula I.

A. A compound of general formula II is reacted with compound III in the presence of base to prepare compounds of general structural formula I. Representative examples of suitable bases are pyridine and triethylamine. L denotes a suitable leaving group. A compound of formula III may be an acyl halide (e.g. L = halogen) or acyl anhydride (e.g. L is

If the leaving group is hydroxy, alter-

natively a coupling reagent is used to form compound I. Examples of coupling agents include N,N'-dicyclohexylcarbodiimide (DCC) and N,N'-carbonyldiimidazole (CDI). The leaving group may also be alkoxy, in which case the compounds of formula I may be prepared by refluxing a compound of formula II with an excess of a compound of formula III.

If compound III is a compound R-CH2-L, can

L can be any group that is easy to remove, such as halogen, p-toluenesulfonyloxy, methylsulfonyloxy, trifluoromethylsulfonyloxy, etc.

Compounds of general formula II can be prepared

by cleaving the group COOR<a> from the corresponding carbamates IV, e.g. via acid hydrolysis (e.g. HC1) or base hydrolysis (e.g. KOH):

where Ra is a group that does not prevent the cleavage reaction, e.g. R a is an optionally substituted alkyl, such as ethyl.

Depending on the properties of Ra, as determined by one skilled in the art, compound IV may alternatively be treated with organometallic reagent (e.g. CH3LD, a reducing reagent (e.g. Zn in acid) etc) so that compounds of formula II is formed.

Compound IV can be prepared from the N-alkyl compound, shown as formula V below, in the manner described in U.S. Pat. patents 4 282 233 and 4 335 036.

V

It will also be apparent to those skilled in the art that there are other methods for converting compound V to compound II. For example, treatment of compound V with BrCN via von Braun's reaction conditions would give nitrile IVa. Subsequent hydrolysis of the nitrile either under aqueous basic or acidic conditions would give compound II. This method is preferred when there is substitution on the piperidine or piperazine ring.

B. The compounds of formula I

can be made by an alternative method using direct conversion of the N-alkyl compound V with an appropriate compound of formula III, such as an acyl halide or acyl anhydride. Preferably, the reaction is carried out in the presence of a suitable nucleophile (eg Lii etc.) and solvent (eg toluene, dioxane or xylenes). A suitable base may be added and heating may be required. A temperature range of 50-150°C (preferably 100-120°C) is typically used.

Compound V is prepared as described in part A above.

Preparation of compounds with a double bond

Compounds of formula Ia, where X is a carbon atom with a double bond to carbon 11, can be prepared from compound Va as described above. Compounds of formula Va may be prepared by the methods described generally in U.S. Pat. patent document 3 326 924, or can alternatively be produced by a ring closure reaction where the desired cyclohexane ring is formed by treating compound VI with a super acid. Suitable superacids for this purpose include e.g. HF/BF3, CF3SO3H ("triflic" acid), CH3SO3H/BF3 etc. The reaction can be carried out in the absence of, or with, an inert co-solvent, such as CH2Cl2. The temperature and reaction time vary with the acid used. With HF/BF3 as the super acid system, the temperature can e.g. is regulated to minimize side reactions, such as HF addition to the exocyclic double bond. For this purpose, the temperature is generally in the range from approx. +5°C to +50°C. With CF3SO3H as a superacid system, the reaction can be carried out at elevated temperatures, e.g. from approx. 25°C to approx. 150°C, and at lower temperatures, but it then takes longer to complete the turnover.

In general, the superacid is used in excess, preferably in amounts from approx. 1.5 to approx. 30 equivalents.

A ketone compound of formula VI can be formed by hydrolysis of VII, e.g. such as by reacting a Grignard intermediate of formula VII with an aqueous acid (eg aqueous HCl). Ia in formula VII is chlorine, bromine or iodine.

The Grignard intermediate VII is formed by reacting the cyano compound VIII with an appropriate Grignard reagent IX prepared from 1-alkyl-4-halopiperidine. The reaction is generally carried out in an inert solvent, such as ether, toluene or tetrahydrofuran, under usual Grignard conditions, e.g. temperature from approx. 0°C to approx. 75°C. Alternatively, other organometallic derivatives of the 1-alkyl-4-halopiperidine can be used.

The cyano compound of formula VIII is prepared by converting the tertiary butylamine of formula X with a suitable dehydrating agent, such as POCl3, SOCl2f<p>2°5' toluenesulfonyl chloride in pyridine, oxalyl chloride in pyridine, etc. This reaction can be carried out in the absence of or together with a co-solvent such as xylene.

The dehydrating agent, such as POCl3, is used in equivalent amounts or more, and preferably amounts from approx. 2 to approx. 15 equivalents. Any suitable temperature and any suitable time can be used to carry out the reaction, but generally heat is added to accelerate the reaction. Preferably, the reaction is carried out at or near reflux temperature.

The tertiary butyl amide of formula X can be prepared by reacting a compound of formula Xla and Xlb in the presence of base, where G is chlorine, bromine or iodine.

The compound of formula XI can be formed by hydrolysis of the corresponding nitrile where the appropriate cyanomethylpyridine, such as 2-cyano-3-methylpyridine, is reacted with a tertiary butyl compound in acid, such as concentrated sulfuric acid or concentrated sulfuric acid in glacial acetic acid. Suitable tertiary butyl compounds include, but are not limited to, t-butyl alcohol, t-butyl chloride, t-butyl bromide, t-butyl iodide, isobutylene, or any other compound which under hydrolytic conditions forms t-butylcarboxamides with cyano compounds. The reaction temperature will vary, depending on the reactants, but generally the reaction is carried out in the range from approx. 50°C to approx. 100°C with t-butyl alcohol. The reaction can be carried out with inert solvents, but is usually carried out without solvents.

An alternative method for the formation of compounds of general structural formula Ia comprises direct cyclization of compound XII as shown below.

Cyclization to form the cycloheptene ring is performed with a strong acid (eg, "triflic", polyphosphoric acid, HF/BF3) and can be performed in an inert solvent, such as ether, toluene, or THF. Temperature and time may vary with the acid used, as described under method A above.

Compounds of formula XII can

is prepared by treating a compound of formula VI with an appropriate acyl halide or acyl anhydride of formula III. Most preferably, this reaction is carried out in the presence of a good nucleophile, such as Lii, in a suitable solvent, such as toluene, dioxane or xylene, and at a temperature in the range from 50-150°C, preferably 100-120°C.

A second method for preparing compounds of formula XII comprises reacting an unsubstituted piperidylidene compound of formula XIV with an appropriate acyl halide or acyl anhydride of formula III in the presence of a base, such as pyridine or triethylamine. If L = OH in compound III, then alternatively the coupling of compound XIV with compound III may require the use of a conventional coupling agent, such as DCC or CDI.

Compounds of formula XIV are prepared from corresponding carbamates of formula XV via acid hydrolysis, e.g. using aqueous hydrochloric acid, or base hydrolysis using e.g. potassium hydroxide. Alternatively, some compounds can be prepared by treating the carbamate, formula XV, with an organometallic reagent, such as methyl lithium or a reducing reagent, such as zinc in acid, etc., depending on the properties of the Ra<-> group. If e.g. Ra is a simple alkyl group, C02R<a> can be split by alkaline hydrolysis at 100°C.

The carbamate compounds of formula XV can be prepared from the appropriate alkyl compound of formula VI by treatment with a chloroformate, preferably in an inert solvent, such as toluene, while heating to about 80°C. Other alternative methods are available for the conversion of XIII to XII as previously described (eg von Braun's reaction conditions).

Compounds of formula VI can be prepared as described under method A above.

Preparation of piperazine analogues

Compounds of the piperazine type Ib, where X is N in formula I, are best prepared via alkylation of the appropriately substituted piperazine compound XVI with compound XVII containing the appropriately substituted halide (such as Cl, Br, I) or other similar leaving group (tosyloxy or mesyloxy) . The reaction is usually carried out in an inert solvent, such as THF or toluene, optionally with a base, such as triethylamine or potassium carbonate, usually in a temperature range from ambient temperature to reflux temperature, to prepare compound XVIII.

R<c> in this reaction is H, CC^R<3>/ C(Z)R or alkyl. The preparation of compound XVII, where L is Cl, is analogous to the procedure described in U.S. Pat. patent no. 3 409 621. Those skilled in the art can prepare other derivatives of XVII (eg where L is Br, I, mesyloxy, tosyloxy). When R<c>is C(Z)R, the compounds of general formula I are included. When R<c>is H, alkyl or C02R<a>, these are converted into compounds according to formula I by methods previously described here.

An alternative route for the preparation of compound XVIII is by reductive amination of the aza-ketone XIX with the appropriately substituted piperazine XVI.

The reaction is usually carried out in a polar solvent, such as methanol or ethanol, possibly in the presence of a dehydrating agent, such as 3Å molecular sieves. The intermediate Schiff base can be reduced to compound XVIII using a variety of reducing agents, such as NaCNBH 3 , or catalytic hydrogenation, e.g. hydrogen over Pd/C.

When R<c> is C(Z)R, the compounds of the general formula I are included. When R<c> is H, C02R<a> or alkyl, these are converted to compounds according to formula I as previously described.

Preparation of compounds with a single bond

Compounds of formula Ic, where X is a carbon atom with a single bond to carbon atom 11, can be prepared by the following methods.

A. Compounds of formula VI can be converted to the corresponding alcohol compound XX by using a suitable reducing agent. The reduction can be carried out with a number of different reducing agents (eg NaBH 4 or LiAlH 2 ) in an inert solvent, such as THF or ether.

Compound XX can be cyclized to compound XXI via a number of different methods. For example, the cyclization can be carried out under similar conditions to those described for the cyclization of compound VI to compound V using e.g. PPA or "triflic" acid.

The alkyl can then be converted into compounds according to the present invention using previously described methods.

B. Alternatively, compounds according to the invention can

is prepared from XII by methods similar to those described above, to reduce compound XII to compound XXII and to cyclize compound XXII to compound Ic.

In formula XXIII, the double bond can be catalytically hydrogenated to compound XXIV using a variety of different catalysts, such as Pt, Rh, Ru or Pd, on various supports as described in U.S. Pat. patent documents no.

3,419,565, 3,326,924 and 3,357,986.

Alternatively, the double bond can be isomerized to the bridgehead using a super acid, such as "triflic" acid at high temperature (eg 150-200°C) to produce compound XXV. Subsequent catalytic hydrogenation, preferably using Rh or Ru, will then give compound XXIV.

When R<c> is C(Z)R, the compounds of formula XXIV are compounds of the general formula I. When R<c> is H, alkyl or CO2R<a>, the compounds are converted into compounds of the general formula I as before described.

C. A third method for the preparation of the present compounds is by the use of the suitably substituted Grignard reagent XXVI (or other equivalent metallized reagent M, e.g. organolithium etc). Compound XXVI can be reacted with compound XVII, where L is a leaving group (e.g. chloride), whereby the desired compound XXI is obtained.

These reactions are usually carried out in an inert solvent, such as ether. toluene or THF, in a temperature range of approx. *78 to approx. +50°C.

Alternatively, the metallizing substituent and the leaving substituent can be exchanged and reacted under the same conditions, whereby the same compound XXI is obtained.

Compound XXI can be converted into compounds according to the invention as previously described. Further details regarding these methods are described in U.S. Pat. patent documents no. 3 419 565, 3 326 924, 3 357 986 and in Org. Chem. 50, p. 339 (1985).

D. Alternatively, compounds of formulas XXVI and XXVII, the preparation of which is described in U.S. Pat. patent documents no. 3 419 565, 3 326 924 and 3 357 986, are used to provide compound XXI. This can be accomplished by reductive removal of the alcohol under a number of different conditions, e.g. the procedures described in J.A.C.S. 104, p. 4976 (1982) and in J. Org. Chem. 50, p. 339

(1985).

Compound XXI can be converted into compounds according to the present invention as previously described.

Substitution of the bridgehead

The following method can be used to prepare compounds with structural formula I substituted in one or more of the bridgehead carbon atoms. For the compounds XXX-XXXIII which are substituted in one bridgehead carbon atom, the substitution group shown may have a bond drawn into the cycloheptane ring through the bridgehead, and not to a particular bridgehead carbon atom. This is used to indicate that the bonds of the substitution group to a particular bridgehead carbon atom are a function of the parent compound. If e.g. the methoxy group in compound XXXI below is bound to bridgehead carbon 5, the carbonyl group on the bridgehead in compound XXXIII will also be on carbon 5. Both isomers substituted in position 5 and/or 6 are meanwhile intended to be

within the scope of the invention.

By substituting an isomer of the precursor compound, a compound having the substitution on the other bridgehead carbon atoms than that shown in the drawing can be synthesized.

The bridgehead of compound XXVIII, which is described in U.S. Pat. patent document no. 3 326 924, is first brominated with a suitable brominating agent, such as N-bromosuccinimide (NBS) in the presence of an initiator, such as azobisisobutyryl nitrile (ABIN), benzoyl peroxide, etc. in an inert solvent, such as CCl 4 , benzene, or a similar solvent. Heat or light may be required to initiate the reaction. The bromine atom on the bridgehead can then be removed with base, whereby the olein compound XXIX is formed. Examples of suitable bases for removal include diazabicycloundecane (DBU), diazabicyclononane (DBN) and diazabicyclooctane (DABCO). Removal is usually carried out in an inert solvent at reflux temperature. Examples of suitable inert solvents include CH 2 Cl 2 , CCl 4 , toluene, tetrahydrofuran (THF), dioxane and CHCl 3 , with CHCl 3 being preferred.

Alternatively, compound XXVIII can be boiled under reflux in the presence of an oxidizing agent, whereby compound XXIX is obtained. Representative examples of oxidizing agents suitable for oxidizing compound XXVIII include 2,3-dichloro-5,6-dicyano-1,4-quinone (DDQ) and SeCl 2 .

Compound XXIX can be converted to compound XXX by adding excess powdered AgNO 3 in methanol, followed by addition of excess Br 2 , which bromoetherates the unsubstituted bridgehead carbon atom. The bridgehead bromine atom is then removed with excess base, such as DBU, whereby a compound of formula XXX is obtained. The reaction can be carried out in an inert solvent, such as CHCl3, at reflux temperature. The resulting isomeric mixture can be separated by column chromatography or another suitable method.

A compound of formula XXXI is prepared by treating the 5-substituted or 6-substituted isomer of formula XXX with a Grignard reagent XXVI or similar metal-containing reagent in an inert solvent, such as ether, benzene or tetrahydrofuran (THF). Compound XXVI is prepared in a known manner from magnesium and the 4-chloro-N-substituted piperidine. The reaction solution can be boiled under reflux if necessary, after which the reaction can be quenched with NH4Cl, whereby compound XXXI is formed.

A compound of formula XXXI may be hydrolysed with any strong aqueous acid, e.g. 80-95% H2SO4 or HC1, which has a pH lower than 1, at a temperature not higher than room temperature, for no longer than one hour, whereby an intermediate compound of formula XXXII is prepared.

After complete hydrolysis, compound XXXII can be dehydrated with CF3SO3H ("triflic" acid) or a similar acid to give compound XXXIII. Examples of other acids for dehydration of compound XXXII at carbon atom 11 include e.g. HF/BF3, CH3SO3H/BF3 etc. The reaction can be carried out in the absence of, or with, an inert co-solvent, such as CH2CI2. The temperature and reaction time vary with the acid used. When "triflic" acid is used as the super acid system, the temperature can be regulated to minimize side reactions. For example, compound XXXII with a carbonyl group on carbon atom 5 is best dehydrated when the temperature is kept in the range from approx. 40°C to approx. 80°C, preferably approx. 75°C. Alternatively, dehydration of a compound with a carbonyl group on carbon atom 6 is best carried out at elevated temperatures, such as from approx. 100-130°C.

Compound XXXIII can then be converted into compounds according to formula I as previously described.

Ketone XXX can be reduced to the corresponding alcohol XXXIV using a number of different reducing agents (e.g. NaBH4 in MeOH, LiAlH4 in ether). The alcohol can then be converted into a suitable leaving group (L), such as halide (e.g. Cl, Br, I) or other derivative (e.g. tosyloxy), whereby compound XXXV is obtained. For example, the chloride of XXXV (L = Cl) can be obtained from the alcohol by using SOCl2 in an inert solvent, such as toluene.

Alkylation of the appropriately substituted piperazine compound XVI with XXXV then gives XXXVI. The reaction is usually carried out in an inert solvent, such as THF or toluene, optionally with a base, such as triethylamine or potassium carbonate, usually at ambient temperature to reflux temperature.

Compound XXXVI can then be hydrolysed with any strong aqueous acid, e.g. 80-95% H2SO4 or HCl, whereby the desired keto compound XXXVII is obtained.

The bridgehead carbonyl group in compound XXXVIII or XXXIII can be reduced to a hydroxy group by treating compound XXXVIII with a suitable reducing agent, such as NaBH4 in CH3 or LiAlH4 in ether, whereby a compound of formula XXXIX is obtained.

Compounds XXXIX, XXXVII or XXXII can be used to produce other substitutions in the bridgehead using available methods.

When R<c> is C(Z)R, these compounds are according to general formula I. When R<c> is H, C02R<a> or alkyl, these compounds are converted into compounds according to formula I as previously described.

In the above methods, it is sometimes desirable and/or necessary to protect certain R<1->, R<3-> and R<4->

groups etc. during the reactions. Conventional protecting groups can be used. For example, the groups listed in column 1 of the table below can be protected as indicated in column 2 of the table:

Other protecting groups well known in the art may also be used. After the reaction or reactions, the protecting groups can be removed using standard procedures.

The compounds of formula I have platelet activating factor ("PAF") antagonistic properties. The compounds of formula I can therefore be used when PAF is a factor in the disease or abnormal condition. This includes allergic diseases, such as asthma, respiratory distress syndrome in adults, urticaria and inflammatory diseases, such as rheumatoid arthritis and osteoarthritis. For example, PAF is an important mediator of such processes as platelet aggregation, contraction of smooth muscle (especially in lung tissue), vascular permeability and neutrophil activation. Recent evidence implicates PAF as an underlying factor involved in airway hyperreactivity.

The PAF antagonistic properties of these compounds can be demonstrated using standard pharmacological test procedures as described below. These test procedures are standard tests used to determine PAF antagonistic activity and to evaluate the utility of the compounds in counteracting the biological effects of PAF. The in vitro assay is a simple screening test, while the in vivo assay mimics clinical use of PAF antagonists to generate data simulating clinical use of the compounds described herein.

A. PAF antagonism test

In vitro test:

Preparation of platelet-rich plasma (PRP): 50 ml of human blood was collected from healthy male donors in 5 ml of an anticoagulant solution containing 3.8% sodium citrate and 2% dextrose. The blood was centrifuged at 110 x g for 15 min. and the supernatant PRP transferred to a polypropylene tube. Platelet-poor plasma (PPP) was prepared by centrifugation of PRP at 12,000 x g for 2 min. in a Beckman "Micro-fuge B". PRP was used within 3 hours of the blood sample

was taken.

Platelet Aggregation Test: When an aggregation agent such as PAF is added to PRP, platelets aggregate. An aggregometer quantifies this aggregation by measuring light transmission (infrared) through PRP and comparing with PPP. The aggregation tests were performed using a two-channel aggregometer (model 440). PRP (0.45 ml) in aggregometer cuvettes was continuously stirred (37°C). Solutions of test compounds or vehicle were added to PRP, and after incubation for 2 min. 10-15 µl aliquots of PAF solution were added to achieve a final concentration of 1-5 x 10~^M. Incubations were continued until the increase in light transmission reached a maximum (usually about 2 min.). Values for inhibition were calculated by comparing maximal aggregation obtained in the absence and presence of the compound. For each experiment, a standard PAF antagonist, such as alprazolam, was used as a positive internal control. The inhibitory concentration (IC5q) is the concentration of compound in micromoles at which 50% of aggregation is inhibited, as measured by the light transmission through each sample of PRP compared to PPP. The test results are shown below i

tables IA, IB and IC.

PAF is also a known bronchoconstrictor in mammals. PAF antagonism can thus be evaluated by measuring inhibition by the compounds of formula I of PAF-induced bronchoconstriction in guinea pigs.

B. PAF-induced bronchospasm in guinea pigs

In vivo test

Non-sensitized guinea pigs were fasted overnight and the following morning were anesthetized with 0.9 ml/kg i.p. dialurethan (0.1 g/ml diallybarbituric acid, 0.4 g/ml ethylurea and 0.4 g/ml urethane). A cannula was inserted into the trachea, and the animals were ventilated using a Harvard rodent respirator at 55 beats/min. with a stroke volume of 4 ml. A side arm of the tracheal cannula was connected to a Harvard pressure transducer to obtain a continuous measurement of the pressure in the trachea, which was measured on a Harvard polygraph. A cannula was inserted into the jugular vein for administration of compounds. The animals were challenged i.v. with PAF (0.4 ug/kg in isotonic saline containing 0.25% BSA), and the peak increase in inspiratory pressure that occurred within 5 min. after challenge, was registered. The test compounds were administered either orally (2 hours before PAF as a suspension in 0.4% methyl cellulose vehicle) or intravenously (10 min before PAF as a solution in dimethylsulfoxide).

The compound 8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine in a dose of 1 mg/kg gave intravenous inhibited PAF-induced bronchospasm by 75% as measured by this method. Likewise, the compound 8-fluoro-11-(1-acetyl-4-piper-idylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine inhibited PAF-induced bronchospasm by 99% when administered at 3 mg/kg (i.v.). The compound 9-fluoro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridine inhibited PAF-induced bronchospasm by 97% when it was administered at 3 mg/kg (i.v.).

The compounds of formula I also have antihistamine properties which can be determined by test method C below. Test method C, "prevention of histamine-induced lethality", shows basic antihistamine activity of representative compounds of structural formula I. Protection against histamine lethality indicates strong antihistamine properties.

Test methods D, E and F show the extent of CNS activity induced by the compounds of formula I. The presence of strong CNS activity indicates a high probability of sedation caused by the compounds, a typical unwanted side effect of antihistamines. Accordingly, in most circumstances a low level of CNS activity is preferred.

C. Antihistamine activity test

Prevention of histamine-induced mortality in guinea pigs

Some of the compounds shown below in Table I were also evaluated for antihistaminic activity through their ability to protect female albino guinea pigs (250-350 g) from death induced by intravenous injection of histamine dihydrochloride at 1.1 mg/kg, which is approximately twice the LD99. Doses of the antagonists were administered orally to separate groups of fasted animals one hour before the histamine challenge, and protection against death measured for 30 min. after histamine. ED5Q values were determined for each drug by probit analysis.

CNS activity tests

D. Antagonism of physostigmine lethality

The physostigmine-induced lethality test provides an indication of CNS activity, and the described test is a modification of techniques reported by Collier et al., Br. J. Pharmac, 32, 295-310 (1968). Physostigmine salicylate (1.0 mg/kg s.c.) causes 100% mortality when administered to mice grouped with 10 per plastic cage (11 x 26 x 13 cm). The test agents were administered orally for 30 min. before physostigmine. The number of survivors was counted 20 min. after physostigmine administration.

E. Antagonism by Acetic Acid Twist The acetic acid twist test is a second test that can be used to determine CNS activity, and is essentially that described by Hendershot and Forsaith, J. Pharmac. Exp. Ther., 125, 237-240 (1959), except that acetic acid was used instead of phenylquinone to induce torsion. Mice were injected with 0.6% aqueous acetic acid at 10 mg/kg i.p. 15 min. after oral administration of the test drug. The number of writhes for each animal was counted during a 10 min period starting 3 min. after acetic acid treatment. A twist was defined as a sequence of back arching, pelvic rotation and rear foot extension.

F. Antagonism by electroconvulsive shock (ECS) The ECS test is a third test that can be used to determine CNS activity. For the ECS test, a modification of the method of Toman et al., J. Neuro-physiol., 9, 231-239 (1946) was used. One hour after oral administration of the test drug or vehicle, mice were given a 13 mA, 60 cycle a.c. electroconvulsive shock (ECS) for 0.2 sec. via corneal electrodes. This shock strength produces tonic convulsion, defined as extension of the hind feet, in at least 95% of vehicle-treated mice.

Among the above-mentioned test procedures for measuring CNS activity, the physostigmine-induced lethality test is believed to be a major index of non-sedating characteristics, as it mainly reflects central anti-cholinergic potency believed to contribute to sedative activity.

Representative results from these test procedures with compounds according to the invention are reproduced below in Tables IA, IB and IC.

As seen from the data in Tables IA, IB and IC and from the test results of the PAF-induced bronchospasm inhibition, the compounds of structural formula I exhibit PAF antagonist and antihistamine properties to varying degrees, i.e. certain compounds have strong PAF antagonist activity , but has weaker antihistamine activity. Other compounds are strong antihistamines but weaker PAF antagonists. Several of the compounds are both strong PAF antagonists and powerful antihistamines. Accordingly, it is within the scope of use to use each of these compounds when clinically appropriate. If e.g. a strong PAF antagonist is required, but weaker antihistamine activity is required, such a compound may be chosen by the doctor. If possibly both strong PAF antagonism and antihistamine activity are required, another compound of formula I will be used by the doctor.

In order to prepare pharmaceutical preparations from the compounds of general formula I, inert, pharmaceutically acceptable carriers may be either solid or liquid. Preparations in solid form include powders, tablets, dispersible granules, capsules, powder-containing capsules and suppositories. The powders and tablets can consist of from approx. 5 to approx. 70% active ingredient. Suitable solid supports are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, powdered capsules and capsules can be used as solid dosage forms suitable for oral administration.

For the production of suppositories, a low-melting wax, such as a mixture of fatty acid glycerides or coconut butter, is first melted, and the active ingredient is homogeneously dispersed in this by stirring. The molten homogeneous mixture is then poured into molds of the appropriate size to cool and thereby turn into solid form.

Preparations in liquid form include solutions, suspensions and emulsions. As an example, water or water/propylene glycol solutions for parenteral injection can be mentioned.

Preparations in liquid form can also include solvents

nings for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be present in combination with a pharmaceutically acceptable carrier, such as an inert, compressed gas.

Preparations in solid form can also be used which are intended to be converted shortly before use into preparations in liquid form, either for oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of formula I can also be delivered transdermally. The transdermal preparations may take the form of creams, lotions, aerosols and/or emulsions and may be included in a transdermal patch of the matrix or reservoir type, which is common in the art for this purpose.

The compound is preferably administered orally.

The pharmaceutical preparation is preferably available in single-dose form. In this form, the preparation is divided into single doses containing appropriate amounts of the active ingredient, e.g. an effective amount to achieve the desired purpose.

The amount of active compound in a single dose of preparation can be varied or regulated from approx. 0.1 mg to 1000 mg, preferably from approx. 1 mg to 100 mg, depending on the specific application. The appropriate dosage can be determined by comparing the activity of the compound with that of a known antihistamine compound, such as 8-chloro-6,11-dihydro-11-(1-ethoxycarbonyl-4-piperidylidene)-5H-benzo[5,6] -cyclohepta[1,2-b]pyridine which is described in U.S. Pat. patent document no. 4 282 233.

The actual dosage used can be varied, depending on the patient's needs and the severity of the condition being treated. Determining the correct dosage for a specific situation lies within the experience one has in the area. In general, treatment is started with smaller dosages that are less than the optimal dose of the compound. The dosage is then increased in small increments until the optimal effect under the circumstances is reached. For convenience, the same daily dosage can be divided and administered in portions during the day if desired.

The amount and frequency of administration of the compounds of formula I and the pharmaceutically acceptable salts thereof will be regulated in accordance with the judgment of the doctor concerned, taking into account such factors as the patient's age, condition and size, as well as the severity of the treated symptom. A typical recommended dosage schedule is oral administration from 10 mg to 1500 mg/day, preferably 10-750 mg/day, in 2-4 divided doses to achieve relief of symptoms. The compounds are non-toxic when administered within this dosage range.

The following examples are intended to illustrate the present invention.

Manufacturing example 1

A. N-(1,1-dimethylethyl)-3-methyl-2-pyridine-carboxamide

400 g of 2-cyano-3-methyl-pyridine was suspended in 800 ml of t-butanol and heated to 70°C. 400 ml of sulfuric acid was added dropwise over 45 minutes. The temperature was maintained at 75°C until the reaction was complete and for a further 30 min. The mixture was diluted with 400 ml of water, 600 ml of toluene was added, and the pH was adjusted to 10 with concentrated aqueous ammonia. The temperature was kept at 50-55°C during the preparation. The toluene phase was separated, and the aqueous layer was re-extracted. The toluene phases were pooled and washed with water. The toluene was removed to give the title compound, N-(1,1-dimethylethyl)-3-methyl-2-pyridine-carboxamide, as an oil, from which the solid product was crystallized. (Yield: 97%, determined using an internal standard sample by gas chromatography). B. 3-[2-(3-chlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridinecarboxamide 31.5 g of the title compound from preparation example IA, N-(1,1-dimethylethyl)- 3-methyl-2-pyridine-carboxamide, was dissolved in 600 ml of tetrahydrofuran, and the resulting solution was cooled to -5-40°C. Two equivalents of n-butyl lithium in hexane were added, while the temperature was maintained at -5-40°C. The solution changed to deep purple red. 1.6 g of sodium bromide was added and the mixture was stirred. A solution of 26.5 g (0.174 mol) of m-chlorobenzyl chloride in 125 ml of tetrahydrofuran was added, while the temperature was maintained at -40°C. The reaction mixture was stirred until the reaction was complete as determined by thin layer chromatography. Water was added to the reaction mixture until the color had disappeared. The reaction mixture was extracted with ethyl acetate, washed with water and concentrated to a residue which is the title compound. (Yield: 92% as shown by chromatography). C. 3-[2-(3-chlorophenyl)ethyl]-2-pyridine-carbonitrile

A solution of 175 g (0.554 mol) of the title compound from Preparative Example IB, 3-[2-(3-chlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine-carboxamide, was heated in 525 ml ( 863 g, 5.63 mol) phosphorus oxychloride, and it was refluxed for 3 hours. Completion of the reaction was determined by thin-layer chromatography. All excess phosphorus oxychloride was removed by distillation under reduced pressure, and the reaction was quenched in a mixture of water and isopropanol. The pH was brought to 5-7 by the addition of 50% aqueous sodium hydroxide solution, while the temperature was kept below 30°C. The crystalline slurry of crude product was filtered and washed with water. The crude product was purified by slurping the wet cake in hot isopropanol and cooling to 0-5°C. The product was filtered, washed with hexane and dried at a temperature below 50°C to give the title compound. (Yield: 118 g (HPLC purity:

95.7%), m.p. 72-73°C, 89.4% of the theoretical).

D. 1-(methyl-4-piperidinyl)-[3-(2-(3-chlorophenyl)ethyl)-2-pyridinylmethanone hydrochloride

118 g (0.487 mol) of the title compound from Preparation Example 1C was dissolved in 1.2 L of dry tetrahydrofuran, and 395 ml (2.48 mol/l, 0.585 mol, 1.2 equivalents) of N-methyl-piperidyl- magnesium chloride within 15 min. The temperature was maintained at 40-50°C by cooling with water, if necessary for 30 min. Completion of the reaction was determined by thin-layer chromatography. The reaction was quenched by reducing the pH to below 2 with 2N HCl, and the resulting solution was stirred at 25°C for one hour. Most of the tetrahydrofuran was removed by distillation, and the resulting solution was adjusted to pH 3.5 by addition of aqueous sodium hydroxide. It was cooled to 0-5°C, and the crystalline hydrochloride salt product was filtered off. It was washed with ice-cold water and dried to constant weight at 60°C to give the title compound. (Yield: 168.2 g (HPLC purity: 94%), mp 183-185°C, 89% of theory). E. 8-Chloro-ll-(1-methyl-4-piperidylidene)-6,ll-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine 59 g (0.15 mol) of the title compound from Preparation Example ID above was dissolved in 120 ml (120 g,

6.0 mol) of hydrofluoric acid at -s-35°C, and 44.3 g (0.66 mol) of boron trifluoride were added over the course of one hour. The completeness of the reaction was determined by thin-layer chromatography. The reaction was quenched using ice, water and potassium hydroxide which brought the solution to a final pH of 10. The product was extracted with toluene and washed with water and brine. The toluene solution was concentrated to a residue and dissolved in hot hexane. The insoluble substances were removed by filtration, and the filtrate was concentrated, whereby the title compound was obtained as an off-white powder.

(Yield: 45.7 g (HPLC purity: 95%), 92% of theory).

Alternate step E: 8-chloro-11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine

177 g (0.49 mol) of the title compound from Preparation Example ID above was reacted in 480 ml (814.1 g,

5.31 mol) of trifluoromethanesulfonic acid at 90-95°C for 18 hours under nitrogen. The completeness of the reaction was determined by thin-layer chromatography. The reaction mixture was cooled, and the reaction was quenched with ice water, and the pH was adjusted to 6 with barium carbonate. The product was extracted

with methylene chloride and concentrated under reduced pressure to approx. 1 1. It was washed with water, and the product was extracted into 1N HCl which was treated with 30 g of activated carbon, and it was filtered through celite. The pH of the filtrate was adjusted to 10 with aqueous sodium hydroxide (50%), the product was extracted into methylene chloride, and it was removed under reduced pressure to give a residue. The residue was dissolved in hot hexane and filtered to remove insolubles. The filtrate was concentrated to give the title compound as a beige powder. (Yield: 126 g (HPLC purity: 80%), 65% of theory).

F. 8-chloro-ll-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine

45.6 g (0.141 mol) of the title compound from Preparation Example 1E above was dissolved in 320 ml of toluene at 80°C, and to this was gradually added 40.4 ml (45.9 g, 0.423 mol) of ethyl chloroformate. After the addition was complete, the temperature was maintained at 80°C for one hour, then 2.7 ml (2.00 g, 0.016 mol) of diisopropylethylamine and another 4.1 ml (4.65 g, 0.0429 mol) of ethyl chloroformate were added . The completion of the reaction was monitored by means of thin layer chromatography. After completion, the reaction mixture was cooled to ambient temperature and the toluene solution was washed with water. The organic layer was concentrated to a residue, and it was dissolved in 320 ml of hot acetonitrile. The solution was decolored with 14 g of activated charcoal. The activated carbon was removed by filtration, and the filtrate was concentrated to a crystalline slurry. The mixture

was cooled to 0-5°C, and the product was isolated by filtration. It was washed with cold acetonitrile, and the product was dried at below 70°C, whereby the title compound was obtained.

(Yield: 42.4 g (HPLC purity: 97.4%), 80% of theory).

G. 8-chloro-ll-(4-piperidylidene)-6,ll-dihydro-5H-benzo-[5,6]cyclohepta[1,2-b]pyridine

39 g (0.101 mol) of the title compound from Preparation Example 1E, 8-chloro-11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b] pyridine, was hydrolyzed with 50 g of KOH in 305 ml of ethanol and 270 ml of water at reflux temperature under an argon atmosphere for 64 hours. The ethanol was partially distilled off, and the residue was diluted with brine, and it was extracted with 3 x ethyl acetate. The combined organic phases were washed with water and dried with Na 2 SC- 4 . The solvent was removed to give a solid which can be recrystallized from toluene to give the title compound as a white solid. (Yield: 24.5 g, 77%, m.p. 154-155°C).

H. By replacing in Step IB above the meta-chlorobenzyl chloride with an appropriately substituted aryl or alkyl halide, which is listed in Table II below, and using essentially the same procedures as Steps C-G, the products listed in Table II were prepared by using the method according to manufacturing example 1 above. Reaction times were determined by TLC or HPLC. In some cases, it was necessary to purify the product by means of chromatography.

Manufacturing example 2

Preparation of 9-fluoro-ll-(4-piperidylidene)-6,ll-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine

A. N-(1,1-dimethylethyl)-3-[2-(4-fluorophenyl)ethyl]-2-pyridine-carboxamide

A solution of 38.4 g (0.2 mol) N-(1,1-dimethyl-ethyl)-3-methyl-2-pyridine-carboxamide in 250 ml of dry THF was cooled to -s-40°C, and 185 ml (0.44 mol) of N-butyllithium was added. 1.9 g (18 mmol) of sodium bromide were added and stirred for 15 min. 31.8 g (0.22 mol) of 4-fluorobenzyl chloride was added and stirred for 2.5 hours, while heating to -s-5°C. The reaction was quenched with water, and the product was extracted twice with ethyl acetate, then washed with brine (2x). The organic phase was dried over Na2SO4, filtered and the solvent removed to give the title compound. (60.0 g, yield: 99%, m.p. 59-61°C).

B. 3-[2-(4-fluorophenyl)ethyl]-2-pyridine-carbonitrile

60.0 g (0.2 mol) of the title compound from Preparative Example 2A above was heated in 200 mL of POCl 3 to 110°C under an argon atmosphere for 3.5 hours. The reaction mixture was poured onto ice and basified with 50% NaOH solution. The mixture was extracted with 3 x ethyl acetate and washed with water. It was washed with saline solution and

dried over Na2SC>4. The solvent was removed and the residue was passed through a column of coarse SiO 2 (60-

200 mesh), whereby the title compound was obtained as a white solid (40 g, yield: 88%, m.p. 48-49°C).

C. 9-fluoro-5,6-dihydro-(1H)-benzo[5,6]cyclohepta[1,2-b]-pyridin-ll-one

31.5 g (139 mmol) of the title compound from Preparation Example 2B above was cyclized in 1.24 kg of polyphosphoric acid at 200°C for 5.5 hours. It was poured onto ice and made basic with NaOH solution (50%). The product was extracted with chloroform (3x) and washed with brine. The organic phase was dried with Na 2 SO 4 , filtered and the solvent removed to give 20.4 g of the title compound (yield: 64%, m.p. 78-81°C after recrystallization from diisopropyl ether). D. 9-fluoro-11-(1-methyl-4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol

10.0 g (44 mmol) of the title compound from Preparative Example 2C above was dissolved in 100 mL of THF and slowly added to a cooled (-s-40°C) solution of the Grignard reagent prepared from 57.9 mL (88 mmol) of N-methyl-4-chloro-piperidine in 70 ml THF. The mixture was stirred for approx. one

hour while it was heated to 0°C. The reaction was quenched with NH 4 Cl solution and extracted with ethyl acetate (2x). The organic phase was washed with brine and dried over Na2SO4, filtered and the solvent was removed. The residue was purified by flash chromatography and eluted with 5% methanol in CHCl 3 , whereby 10.1 g of the title compound was obtained as white, granular crystals. (Yield: 70%, m.p. 126-127°C after recrystallization from diisopropyl ether).

E. 9- fluoro- 11-(l- methyl- 4- piperidylene)- 6, ll- dihydro- 5H-benzo[ 5, 6] cyclohepta[ 1, 2- b3pyridine

7.3 g (22.3 mmol) of the title compound from Preparative Example 2D above was added to 146 ml of a 1:1 mixture of cooled H 2 SO 4 and CF 3 SO 3 H. The reaction mixture was stirred for half an hour at ice bath temperature and then at room temperature for 1.5 hours. The reaction mixture was poured onto ice and basified with 50% NaOH solution. The product was extracted with ethyl acetate (3x) and washed with brine. The organic phase was dried over Na 2 SC 4 , filtered and the solvent removed to give an impure oil. The oil was treated with charcoal and recrystallized from ethyl acetate and isopropyl ether to give 5.6 g of the title compound. (Yield : 82%, m.p. 134.5-135.5°C). F. 9-fluoro-11-(1-ethoxycarbonyl-4-piperidylidene)-6, 11- dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine

A solution of 5.0 g (16.2 mmol) of the title compound from Preparation Example 2E above and 2.6 g (26 mmol) of triethylamine in 60 ml of dry toluene was stirred at 80°C under an argon atmosphere, and 9.8 g ( 90 mmol) of ethyl chloroformate was added via a syringe. The reaction mixture was stirred at this temperature for 30 min. and at room temperature for one hour. The reaction mixture was filtered and the solvent removed. The residue was passed through a coarse SiO 2 column (60-200 mesh) and eluted with CHCl 3 to give 4.5 g of the title compound as a white solid. (Yield: 76%, m.p. 112-114°C after trituration with pentane).

G. 9- fluoro- 11-(4- piperidylidene)- 6, ll- dihydro- 5H- benzo-[ 5, 6] cyclohepta[ 1, 2-b] pyridine

3.83 g (10.4 mmol) of the title compound from Preparative Example 2F above was refluxed with 4.6 g KOH in 50 ml ethanol/I 2 O (1:1) for 4 hours under an argon atmosphere. The reaction mixture was poured into one

brine and extracted with ethyl acetate (2x), dried over Na 2 SO 4 and filtered. The solvent was removed to give 2.86 g of the title compound (yield: 90%, mp 138-140°C).

H. Using the appropriately substituted benzyl halide listed in Table III in place of 4-fluorobenzyl chloride in Step 2A above, the desired products shown in the second column of Table III were prepared using essentially the same procedure as described in Steps 2A -2G. Workup time was determined either by TLC or HPLC. In some cases, it was necessary to purify the product by means of chromatography.

Manufacturing example 3

A. 6, 11- dihydro- 11-(1- methyl- 4-piperidylidene)- 5H- benzo-[ 5, 6] cyclohepta[ 1, 2- c 3pyridine

The compound 5,6-dihydro-11H-benzo[5,6]cyclohepta-[1,2-c]pyridin-11-one can be prepared by following the procedures described in U.S. Pat. Patent Document No. 3,419,565. This ketone can be converted to the title compound using the methods previously described in Preparation Example 2, steps D and E.

B. 11-(1-cyano-4-piperidylidene)-6,11-dihydro-5H-benzo-[5,6]cyclohepta[1,2-c]pyridine

To a solution of 400 mg (1.35 mmol) 11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta-[1,2-c]pyridine in 5 .0 ml of benzene, a solution of 168 mg (1.59 mmol) of cyanogen bromide in 4 ml of benzene was added dropwise at room temperature and under an argon atmosphere. After 30 min. the mixture was poured into water and extracted once with EtOAc. The organic layer was isolated, washed once with brine, dried over Na 2 SO 4 , filtered and concentrated under vacuum. The residue was purified by flash chromatography [2 1/2% MeOH in CH2Cl2] to give 150 mg (37%) of the title compound as a solid: m.p. 212-214°C.

C. 11-(4- piperidylidene)- 6, 11- dihydro- 5H- benzo[ 5, 6] cyclohepta[ 1, 2- c3pyridine

A mixture of 140 mg (0.46 mmol) of 11-(1-cyano-4-piper-idylidene)-6,11-dihydro-5H-benzo[5,63 cyclohepta[1,2-c 3 pyridine in 20 ml 30% aqueous HC1 was boiled under reflux for approx. 22.5 hours. The mixture was poured into ice water, basified with 25% aqueous NaOH and extracted twice with CH 2 Cl 2 . The combined organics were dried over Na2SO4, filtered and concentrated under vacuum. The product was purified by flash chromatography [5% MeOH saturated with NH 3 in CH 2 Cl 2 3 to give 95 mg (75%) of the title compound as a glass.

Manufacturing example 4

A. 8-chloro-llH-benzo[5,6]cyclohepta[1,2-b]pyridine-ll-one

A mixture of 25.99 g (0.107 mol) of 8-chloro-5,6-dihydro-1H-benzo[5,6]cyclohepta[1,2-b3pyridin-11-one, 21.35 g (0.120 mol) recrystallized N-Bromosuccinimide and 167 mg (0.102 mmol) of azobisisobutyryl nitrile in 400 ml of carbon tetrachloride were refluxed under an argon atmosphere for 1.25 h. The solution was cooled slowly to 50°C and the resulting precipitate was filtered off.

The precipitate was boiled under reflux with

20 mL (0.134 mol) of 1,8-diazabicyclo[5,4,0-3undec-7-ene ("DBU") in 400 mL of CH 2 Cl 2 for one hour. It was washed three times with water, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product was crystallized from CH2Cl2/toluene, whereby 8.93 g of the title compound was obtained as colorless needles (yield: 35%).

B. 8-chloro-ll-(1-methyl-4-piperidinyl)-llH-benzo[5,6]-

cyclohepta[1,2-b]pyridine-ll-ol

To a mixture of 22 ml of 0.5 M Grignard reagent of 11.0 mmol of N-methyl-4-chloropiperidiene in THF at t45°C and under a nitrogen atmosphere, within 15 min. added dropwise a solution of 1.06 g (4.39 mmol) of 8-chloro-11H-benzo-[5,6]cyclohepta[1,2-b]pyridin-11-one in 23 ml of dry THF. After 2 hours 40 min. the reaction mixture was poured into water and extracted three times with EtOAc. The organics were combined, washed twice with brine, dried over MgSO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography [10% MeOH in CH 2 Cl 2 ] to give 970 mg (65%) of the title compound as a glass.

C. 8-chloro-ll-(1-methyl-4-piperidylidene)-llH-benzo[5,6]-cyclohepta[1,2-b3 pyridine

A mixture of 847 mg (2.48 mmol) of 8-chloro-11-(1-methyl-4-piperidinyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol in 5 ml of concentrated sulfuric acid and 5 ml of trifluoromethanesulfonic acid were heated at 70°C for 4 hours 10 minutes. The mixture was cooled to room temperature, poured into ice-cold 30% aqueous KOH and extracted three times with CH 2 Cl 2 . The organics were combined, washed once with water, dried over MgSO 4 , filtered and concentrated in vacuo to give 755 mg (94%) of the title compound as a glass.

D. 8- chloro- ll-[ 1-( 2, 2, 2- trichloroethoxycarbonyl)- 4- piper-idylidene- llH- benzo[ 5, 6] cyclohepta[ 1, 2- b 3 pyridine

To a mixture of 755 mg (2.34 mmol) of 8-chloro-11-(1-methyl-4-piperidylidene)-HH-benzo[5,6]cyclohepta[1,2-b]pyridine and 1.5 ml triethylamine in 25 ml of dry toluene, 650 μl (4.72 mmol) of 2,2,2-trichloroethyl chloroformate were added at room temperature and under a nitrogen atmosphere. The mixture was then heated to 90°C. Further amounts of the chloroformate (500 µl and 300 µl) and triethylamine (1.0 ml each time) were added to the mixture after respectively. 2 hours and 3 hours 40 min. After a total reaction time of 5 hours, the mixture was poured into water and extracted three times with CH 2 Cl 2 . The combined organics were dried over MgSO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography [1 1/2% MeOH in CH 2 Cl 2 ] to give 639 mg (56%) of the title compound as a glass.

E. 8-chloro-ll-(4-piperidylidene)-llH-benzo[5,6]cyclohepta[1,2-b]pyridine

A mixture of 210 mg (0.434 mmol) of 8-chloro-11-[1-(2,2,2-trichloroethoxycarbonyl)-4-piperidylidene)-HH-benzo-[5,6]cyclohepta[1,2-b] pyridine and 526 mg (8.05 mmol) of zinc dust in 4 ml of acetic acid were heated to 60-70°C. After 2 hours 20 min. a further 547 mg (8.37 mmol) of zinc dust was added. After another 30 min. the mixture was basified with 10% aqueous NaOH and extracted four times with CH 2 Cl 2 . The combined organics were washed once with water, dried over MgSG 4 , filtered and concentrated under vacuum. The residue was purified by flash chromatography [5-6% MeOH/NH3 in CHCl3] to give 71 mg (53%) of the title compound as a glass. Preparation example 5 A. 5-methoxy-8-chloro-llH-benzo[5,6]cyclohepta[1,2-b]pyridin-ll-one B. 6-methoxy-8-chloro-llH-benzo[5,6 ] cyclohepta[ 1, 2-b] pyri your- ll- on

5.10 mL (99 mmol) of Br2 was added to a mixture of 8.15 g (33.7 mmol) of 8-chloro-11H-benzo[5,6]cyclohepta[1,2-b]-pyridine-11- on and 23.19 g (137 mmol) of powdered AgN03 i

300 ml of dry methanol at room temperature under an argon atmosphere. After 8 hours, an additional 5.90 g (34.7 mmol) of AgNC>3 was added, followed by an additional 1.7 ml (33.0 mmol) of Br2» After half an hour, the mixture was poured into water and extracted (4 x ) with CH2CT2. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated under vacuum, whereby a mixture of the impure bromoethers was obtained.

The crude product was dissolved in 200 ml of CH2C12 at room temperature and placed under an argon atmosphere. 20 ml (134 mmol) of DBU were added and boiled under reflux for 1.3 hours. An additional 10 mL (67 mmol) of DBU was added and the mixture was refluxed for an additional hour. The mixture was poured into water and extracted three times with CH 2 Cl 2 . The organic phases were combined, washed with water and dried over magnesium sulfate. It was filtered and concentrated under vacuum. The two isomeric vinyl ethers, title compounds A and B, were separated by flash chromatography [40%-75% ethyl acetate in hexane] and recrystallized from ethyl acetate hexanes to give 1.51 g of title compound A (14.3%, m.p. 156-158°C) and 3.68 g of title compound B (35%, m.p. 161-162°C).

C. 5-Methoxy-8-chloro-11-(1-methyl-4- piperidinyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol

A 1.5 M Grignard solution of 150 mL (22.5 mmol) of N-methyl-4-chloropiperidine in THF was added dropwise over a 7 minute period to 5.00 g (18.4 mmol) of 5-methoxy- 8-Chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one in 70 ml of THF at 0°C and under an argon atmosphere. The reaction was stopped after 30 min. with a saturated solution of NH4Cl (pH 8) and extracted three times with CHCl3. The organic portions were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. It was purified by flash chromatography (CH 3 OH 5% in CH 2 Cl 2 ) to give 3.60 g (53%) of the title compound as a solid. The solid can be recrystallized from isopropyl ether, whereby a white powder is obtained (m.p. 168-170°C).

D. 8- Chloro- ll-(1- methyl- 4- piperidylidene)- 6, ll- dihydro- 5H-benzo[ 5, 6] cyclohepta[ 1, 2- b 3 pyridine- 5-one

4.26 g of 5-methoxy-8-chloro-11-(1-methyl-4-piperidinyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol was dissolved in 6 ml CH3OH at 0°C under an argon atmosphere. A cooled solution of 92% aqueous H 2 SO 4 (54 mL) was slowly added. The mixture was allowed to warm to room temperature for 35 min. The solution was poured onto ice, basified with aqueous NaOH (25%) and extracted with methylene chloride (3x). The organic parts were combined, washed with salt solution and dried over sodium sulfate. It was filtered and concentrated under vacuum. The residue was triturated with isopropyl ether to give an intermediate, 8-chloro-11-hydroxy-11-(1-methyl-4-piperidinyl)-6,11-dihydro-5H-benzo-[5,6]cyclohepta[1 ,2-b]pyridin-5-one as a white solid (3.58 g, 92%, mp 170-174°C as HCl salt).

3.58 g (10.0 mmol) of the intermediate compound was dissolved in 50 ml of trifluoromethanesulfonic acid and heated to 45°C under an argon atmosphere for 3 hours. The mixture was completely

onto ice, basified with aqueous NaOH (25% w/v) and extracted with CHCl3 (3x). The organic portions were combined, washed with brine and dried over sodium sulfate. It was filtered and concentrated under vacuum. It was chromatographed on silica gel (5% CH 3 OH in CH 2 Cl 2 ) to give the title compound as an off-white solid (1.703 g, 50%, 58% based on recovered starting material). An analytical sample was prepared by recrystallization of the product with ethyl acetate-isopropyl ether (m.p. 162-163°C).

E. Ethyl- 4-(8-chloro-5-ethoxycarbonyloxy-IIH-benzo[5,63-cyclohepta[1,2-b]pyridin-11-ylidene)-1- piperidinecarboxylate

617 mg (1.82 mmol) of 8-chloro-11-(1-methyl-4-piperidyl-idene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine -5-one and 0.50 ml (3.58 mmol) of triethylamine were dissolved in 12 ml of toluene at 80°C under an argon atmosphere. Within 2 min. 0.87 ml (9.10 mmol) of ethyl chloroformate was added dropwise. After 25 min. the mixture was cooled to room temperature, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (1% CH 3 OH in CH 2 Cl 2 ) to give 834 mg (98%) of the title compound as a glass. F. 8-chloro-ll-(4-piperidylidene)-6,ll-dihydro-5H-benzo-[5,6]cyclohepta[1,2-b]pyridin-5-one 897 mg (1.91 mmol) ethyl 4-(8-chloro-5-ethoxycarbonyloxy-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene-1-piperidine carboxylate and 20 ml (13% w/v) aqueous KOH in 15 mL of ethanol was mixed and refluxed under argon for 25 hours. The mixture was poured into water and extracted three times with CHCl 3 . The organics were combined, washed with brine, dried over sodium sulfate , filtered and concentrated under vacuum.The residue was purified by flash chromatography (2% CH3OH saturated with NH3 in CH2Cl2) and triturated with isopropyl ether to give 417 mg (67%) of the title compound as a white solid, m .p. 194-196°C (decomposition). G. 5- hydroxy- 8- chloro- 11-( 4- piperidylidene)- 6, 11- dihydro- 5H-benzo[ 5, 6] cyclohepta[ 1, 2- b 3 pyridine

400 mg (1.23 mmol) of 8-chloro-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-5-one was blan-

it in 20 ml of CH3OH at 0°C under an argon atmosphere, and three portions of NaBH4 (total 231 mg, 6.10 mmol) were added. After 30 min. the mixture was poured into water and extracted three times with ethyl acetate. The organic parts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The solid was triturated with isopropyl ether/ethyl acetate to give 351 mg (87%) of the title compound as a white solid.

Manufacturing example 6

8- chloro- 11-(( Z)- 2, 5- dimethyl- 4- piperidylidene)- 6, 11- dihydro-5H- benzo[ 5, 6] cyclohepta[ 1, 2- b 3 pyridine

A. 1,2,6-trimethyl-4-chloropiperidine

The starting material, 1,2,6-trimethyl-4-piperidinol, can be prepared by the method described in Archi Kem, volume 27, pages 189-192 (1955). To a cooled (ice bath) solution of 12.2 g (85.3 mmol) of 1,2,6-trimethyl-4-piperidinol in 120 ml of dry benzene was slowly added 17 ml (233 mmol) of thionyl chloride. The dark reaction mixture was then heated to 70°C for 20 min. The reaction mixture was cooled and then slurried in water, followed by filtration. The filtrate was extracted once with diethyl ether. The aqueous layer was separated and then basified with 30% NaOH solution. The product was then extracted twice with CH 2 Cl 2 / washed once with brine, dried (Na 2 SO 4 ), filtered and solvent removed to give an impure brown liquid which was distilled (2-4 mm Hg, 62-64°C) to give 8.0 g (58% yield) of the title compound was obtained.

B. 8-chloro-II-(1,2,6-trimethyl-4-piperidinyl)-6,11-dihydro-5H-ben2o[5,6]cyclohepta[1,2-b]pyridin-II-ol

4.2 g (26 mmol) of the chloride, 1,2,6-trimethyl-4-chloropiperidine, was slowly dropped into 18 mL of a solution of dry THF containing 633 mg (26.3 mmol) of Mg. The Grignard reagent was then formed after heating for 6 hours at 70°C.

To a cooled (ice bath), stirred solution of 6.3 g

(26 mmol) of 8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta-[1,2-b]pyridin-11-one in 50 ml of THF, the above-mentioned Grignard reagent was added. The reaction mixture was allowed to stand under stirring for one hour at this temperature, and the reaction was then quenched with NH 4 Cl solution. The product was extracted three times with EtOAc, washed once with brine, dried (Na 2 SO 4 ), filtered and solvent removed to give an impure brown material which was chromatographed to give 5.1 g (53% yield) of the title compound as a yellowish glass.

C. 8-chloro-ll-(1-methyl-(Z)-2,6-dimethyl-4-piperidylidene)-6,ll-dihydro-5H-benzo[5,6 3cyclohepta[1,2-b3pyridine

A mixture of 5.0 g (14.1 mmol) of 8-chloro-11-(1,2,6-trimethyl-4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta-[ 1,2-b]pyridin-11-ol in 100 ml of 85% H 2 SO 4 was heated in an oil bath (60-65°C) for 3 hours. The reaction mixture was cooled and diluted with water, after which it was basified with 25% aqueous NaOH solution. The crude product was extracted with CH 2 Cl 2 , washed with solvent, dried (Na 2 SO 4 ), filtered and solvent removed. Purification and separation of the E and Z isomers via chromatography (2%-»5% MeOH saturated with NH 3 in CH 2 Cl 2 ) afforded 300 mg (6%) of the title compound.

D. 8-chloro-ll-(1-cyano-(Z)-2,6-dimethyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b] pyridine

A solution of 300 mg (0.85 mmol) of 8-chloro-11-(1-methyl-(Z)-2,6-dimethyl-4-piperidylidene-6,11-dihydro-5H-benzo-[5,6 ]cyclohepta[1,2-b]pyridine in 4.5 mL benzene was slowly added dropwise to a stirred solution of 133 mg (1.2 mmol) BrCN in 4.5 mL benzene at room temperature, which was stirred for 2.5 h under argon. The reaction mixture was slurried between water and EtOAc. The EtOAc layer was washed with brine and dried (NaSO4). After filtration, the solvent was removed and the crude material was chromatographed (3% MeOH in CH2Cl2) to give 251 mg (81% yield) of the title compound.

E. 8-Chloro-ll-((Z)-2,6-dimethyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine

A mixture of 200 mg (0.55 mmol) of 8-chloro-11-(1-cyano-(Z)-2,6-dimethyl-4-piperidylidene-6,11-dihydro-5H-benzo[5,6] -cyclohepta[1,2-b]pyridine in 20 mL of 80% HCl was refluxed for 7 h. The mixture was cooled and then basified with 25% NaOH. The product was extracted twice with CH 2 Cl 2 , separated, washed once with brine, dried (NaSO 4 ), filtered and solvent removed to give 174 mg (93% yield) of the title compound as a white glass.

F. Following a similar set of procedures as in steps D and E above, 8-chloro-11-(1-methyl-(E)-2,6-dimethyl-4-piperidylidene)-6,11-dihydro -5H-benzo[5,6]cyclo-heptaphl,2-b]pyridine converted to 8-chloro-11-((E)-2,6-dimethyl-4-piperidylidene-6,11-dihydro-5H-benzo [5,6]cyclohepta-[1,2-b]pyridine.

Manufacturing example 7

8- chloro- ll-(4- piperidylidene)- 6, ll- dihydro- 3- methyl- 5H- benzo-[ 5, 6] cyclohepta[ 1, 2- b] pyridine

A. 3, 5-dimethylpyridinium-N-oxide

A solution of 285 ml (1.31 mol) of 35% peracetic acid was slowly added to a stirred solution of 149 g (1.39 mol) of 3,5-dimethylpyridine, during which the temperature rose to 85°C and was held at this temperature during the addition. After the temperature in the mixture dropped to approx. 35°C, the reaction mixture was stored at 5°C overnight.

After partial removal of 185 ml of acetic acid via distillation under vacuum, the reaction mixture was washed with NaHSO 4 solution and then neutralized with 10% NaOH solution to a pH of approx. 7. The product was extracted with CH2Cl2 to give the title compound as a white

solid (yield: 142 g, 83%).

B. 1- methoxy- 3, 5- dimethylpyridinium methyl sulfate

42.0 g (0.33 mol) of dimethyl sulfate was slowly added to a mechanically stirred solid of 41.0 g (0.33 mol) of 3,5-dimethylpyridinium-N-oxide. The mixture was then heated on a steam bath for one hour. A vacuum was then applied while cooling, whereby a brownish solid of the title compound was obtained in quantitative yield.

C. 2-cyano-3,5-dimethylpyridine

To a cooled (0°C) solution of 49.0 g (0.999 mol, 3.0 equivalents) of sodium cyanide in 135 ml of water (air-free) was added dropwise 83.0 g (0.33 mol) of l-methoxy-3, 5-dimethylpyridinium methylsulfate in 100 ml of water (air-free) for 1 1/4 hours, the temperature being kept below 3°C. The reaction mixture was stored at approx. 3°C overnight. The mixture was filtered and washed with water to give 40 g of the title compound (yield: 91%). An analytical sample was recrystallized from isopropyl ether and pentane (4:1), whereby a m.p. at 61-62°C.

D. N-(1, 1- dimethylethyl)- 3, 5- dimethyl- 2- pyridine- carboxamide

To a stirred solution of 20.3 g (0.153 mol) of 2-cyano-3,5-dimethylpyridine in 100 ml of acetic acid, 20 ml of concentrated sulfuric acid was added within 10 min. (the temperature rose to 35°C), followed by 20 ml of t-butanol during a further 15 min. The solution was heated at 75°C for 30 min., after which it was cooled to room temperature and basified with 25% NaOH. The product was extracted three times with 600 mL EtOAc which was combined and washed once with brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give 31.26 g (98%) of the title compound as a yellowish oil.

E. 8-chloro-ll-(4-piperidylidene)-6,11-dihydro-3-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridine

By replacing in step IB above N-(1,1-dimethyl-ethyl)-3,5-dimethyl-2-pyridine-carboxamide with N-(1,1-di-methylethyl)-3-methyl-2- pyridine-carboxamide and using mainly the same methods as in steps B-G, 8-chloro-11-(4-piperidylidene)-6,11-dihydro-3-methyl-5H-benzo-[5,6]cyclohepta[1 ,2-b]pyridine. The reaction times were determined by TLC or HPLC.

Manufacturing example 8

11-(4-piperidyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine

A. (1-methyl-4-piperidinyl)[3-(2-phenylethyl)-2-pyridin-yljmethanol

To a mixture of 5.0 g (16.2 mmol) (1-methyl-4-piperidinyl)[3-(2-phenylethyl)-2-pyridinyl]methanone (which can be prepared in the same way as described in preparation example 1, steps A-D) in 70 ml of ethanol, 0.8 g (21.1 mmol) of sodium borohydride was added in portions. The next day, the solution was concentrated under vacuum to give a slurry which was dissolved in water and extracted with CHCl 3 . The combined organics were dried over MgSO 4 , filtered and concentrated in vacuo to give a liquid which was distilled (bp 190-195°C, 1 mm Hg) to give 4.4 g (87%) of the title compound as a viscous oil.

B. 11-(1-methyl-4-piperidyl)-6,11-dihydro-5H-benzo[5,63-

cyclohepta[1,2-b]pyridine

A mixture of 3.5 g (11.3 mmol) 4-(1-methylpiperidyl)-2-[3-(2-phenylethyl)pyridyl]methanol and 200 g of polyphosphoric acid was heated between 160 and 170°C in 13 hours. The mixture was cooled to room temperature, poured into water, made basic with aqueous NaOH and extracted with ether. The combined organics were concentrated in vacuo and the product recrystallized from isopropyl ether to give the title compound as a white solid: m.p. 111-114°C. C. In a similar manner to that described in Example 1, steps F-G, 11-(1-methyl-4-piperidyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2 -b]pyridine be converted to 11-(4-piperidyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine. Example 1 8-chloro-ll-(1-methoxyacetyl-4-piperidylidene)-6,ll-dihydro-5H- benzo[5,6]cyclohepta[1,2-b]pyridine

3.00 g (9.7 mmol) of the title compound from Preparation Example 1G above, 8-chloro-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b ]pyridine and 1.2 ml (14.8 mmol) of pyridine were dissolved in 20 ml of dry methylene chloride at 0°C under an argon atmosphere. 1.1 ml (12.0 mmol) of methoxyacetyl chloride was added dropwise and it was slowly warmed to room temperature. After 1.5 hours, the mixture was taken up in methylene chloride and washed with saline. It was dried over Na2SC>4, filtered and concentrated under vacuum, whereby a residue was obtained, and it was purified via flash chromatography. The product was triturated with pentane and recrystallized from ethyl acetate/pentane to give 1.89 g (yield: 66%) of the title compound as a white solid, m.p. 104-106°C.

Example 2

8- or 9- substituted- 11-( l- substituted- 4- piperidylidene)-6, 11- dihydro- 5H- benzo[ 5, 6] cyclohepta[ 1, 2-b] pyridine compound

By inserting the acid halide and the amine specified in respectively first and second column in table IV below instead of respectively the methoxyacetyl chloride and the compound according to preparation example 1G, in the method described in example 1 above, the product compounds indicated in the third column of table IV were prepared. Workup times were determined by monitoring the reaction by TLC. Reaction times and

-temperatures vary slightly. In some cases, it was not necessary to purify the product by chromatography. Example 3 8-chloro-II-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H- benzo[5,6]cyclohepta[1,2-b]pyridine

An alternative method for the preparation of the title compound consists in dissolving 3.02 g (9.72 mmol) of the title compound from preparation example 1G and 3.9 ml (48.1 mmol) of pyridine in 40 ml of dry methylene chloride at 0°C under an argon atmosphere, and add 4.5 ml (47.7 mmol) of acetic anhydride dropwise. The reaction mixture was slowly warmed to room temperature. After 2 hours, the mixture was taken up in methylene chloride, washed with water twice and with brine. The mixture was dried over sodium sulfate, filtered and concentrated under vacuum to give a product which was recrystallized from acetone and pentane to give 2.41 g (yield: 70%) of the title compound as a white solid, m.p. . 155-157°C.

Example 4

8- or 9- substituted- 11-(1- substituted-4- piperidylidene)-6, 11- dihydro- 5H- benzo[ 5, 6] cyclohepta[ 1, 2-b] pyridine compounds

By replacing or the acetic anhydride and the compound from preparation example 1G with the acid anhydride and the amine specified in respectively first and second column of Table V below, in the method described in Example 3 above, the product compounds indicated in the third column of Table V were prepared. Workup times were determined by monitoring the reaction by TLC. Reaction times and temperatures varied slightly. In some cases, it was not necessary to purify the product by chromatography.

Example 5 8-Chloro-II-(1-acetyl-(Z)-2,6-dimethyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b] pyridine

To a solution of 50 mg (0.147 mmol) of 8-chloro-11-(1-acetyl-(Z)-2,6-dimethyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6] cyclohepta[1,2-b]pyridine and 24 mg (0.19 mmol) of N,N-dimethylaminopyridine in 2.6 ml of dry CH2Cl2, 60 μl (0.63 mmol) of acetic anhydride was added. The reaction mixture was stirred for 16 hours. The reaction was quenched with water and then dilute Na 2 CO 3 solution. The product was extracted with CH2Cl2 and washed with brine, dried (Na2SC>4), filtered and solvent removed to give a crude product which was isolated from preparative TLC plates (eluted with 5% MeOH in CHCl3) to give 42 mg (75% yield) of the title compound.

Using a similar procedure, 8-chloro-11-(1-acetyl-(E)-2,6-dimethyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1 ,2-b]pyridine prepared.

Example 6

8-chloro-II-[1-(ethoxycarbonylmethyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine

3.0 g (9.7 mmol) of the title compound from Preparation Example 1G was dissolved in 2.0 ml (14.3 mmol) of triethylamine, 20 ml of toluene and 10 ml of tetrahydrofuran at room temperature under an argon atmosphere. 1.30 ml (11.7 mmol) of ethyl bromoacetate was added dropwise. After 1.5 hours, the mixture was filtered and concentrated under vacuum. The residue was purified via flash chromatography. The product was triturated with pentane and recrystallized from isopropyl ether to give 2.5 g (yield: 65%) of the title compound as a white solid, m.p. 80-82°C.

Example 7

To obtain the product compounds listed in column 3 of Table VI below, the respective halide and amine from VI were used in the procedure of Example 6. The completion time of the reaction was determined by monitoring the reaction by TLC. The reaction time and temperature varied slightly. In some cases it was not necessary to purify the product by chromatography.

Example 8 8-chloro-II-[1-(t-butoxycarbonylaminoacetyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine 1.84 g ( 10.5 mmol) N-t-butoxycarbonylglycine, 2.80 g (14.6 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DEC), 1.98 g (14.7 mmol) 1-hydroxybenzotriazole- hydrate (HOBT) was dissolved in 2.0 ml (14.3 mmol) of triethylamine (Et 3 N) and 30 ml of dry methylene chloride at 0°C and under an argon atmosphere. A solution of 3.0 g (9.7 mmol) of the title compound from Preparation Example 1G in 15 ml of dry methylene chloride was added dropwise. After 1.5 hours, the mixture was taken up in methylene chloride and washed with water and then with saline. It was dried over sodium sulfate, filtered and concentrated under vacuum to give an oil which was purified by flash chromatography (5% MeOH in CHCl3). The purified product was recrystallized from ethyl acetate and pentane to give 4.15 g (yield: 91%) of the title compound as a white solid, m.p. 209-211°C. Example 9 8-chloro-II-(1-aminoacetyl-4-piperidylidene)-6,II-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine 2.50 g (5.34 mmol ) of the title compound from Example 8 was mixed with a saturated hydrogen chloride solution in 35 ml of dioxane, and it was stirred at room temperature under an argon atmosphere overnight. The mixture was concentrated under vacuum and the resulting gummy product was triturated with ethanol and diethyl ether to give 2.28 g (yield: 93%) of the title compound as a white solid. Example 10 8-chloro-II-(1-formyl-4-piperidylidene)-6,II-dihydro-5H-benzo-[5,6]cyclohepta[1,2-b]pyridine 5.0 g (16.1 mmol) of the title compound from Preparation Example 1G was dissolved in 100 ml of ethyl formate, and the mixture was boiled under reflux for 4 hours. The mixture was concentrated under vacuum and the product was triturated with hexane to give 2.2 g (40% yield) of the title compound as a white solid, m.p. 147-149°C. Example 11 8-chloro-II-(1-methylaminocarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine

To a mixture of 2.03 g (6.53 mmol) of 8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2- b]pyridine and 1.0 ml of triethylamine in 30 ml of dry THF, at +10°C and under a nitrogen atmosphere, were added dropwise over the course of 10 min. added 0.40 ml (6.78 mmol) of methyl isocyanate. The mixture was slowly warmed to room temperature. After 4 hours it was poured into water and extracted three times with CH 2 Cl 2 . The organics were combined, dried over MgSO4, filtered and concentrated in vacuo to give a product which was recrystallized from CH2Cl2/-ethyl acetate/hexanes to give 1.70 g (71%) of the title compound as white crystals , sm.p. 194.5-196°C.

Example 12

5- hydroxy- 8- chloro- 11-(1- acetyl- 4- piperidylidene)- 6, 11- dihydro-5H- benzo[ 5, 6] cyclohepta[ 1, 2-b] pyridine

To a mixture of 32.6 mg (0.10 mmol) of 5-hydroxy-8-chloro-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2- b]pyridine and 9.7 ul (0.12 mmol) of pyridine in a solution of 2 ml of methanol and 1 ml of CH2Cl2, at 0°C and under a nitrogen atmosphere, 11.3 ul (0.12 mmol) were added acetic anhydride. After 30 min. the mixture was poured into water, which was then adjusted to a pH of approx. 9 with aqueous sodium hydroxide. The mixture was extracted twice with CH 2 Cl 2 . The organics were combined, washed once with brine, dried over Na 2 SC 4 , filtered and concentrated in vacuo to give 31.2 mg (85%) of the title compound as a glass.

Example 13

N- methyl- 8- chloro- ll-(l- acetyl- 4-piperidylidene)- 6, 11- dihydro-5H- benzo[ 5, 6] cyclohepta[ 1, 2-b] pyridine- iodide

A mixture of 500 mg (1.42 mmol) of 8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta-[1,2-b] pyridine and 175 µl (2.81 mmol) of methyl iodide in 30 ml of toluene were heated at 100°C for approx. 19 hours. The reaction mixture was cooled to room temperature and the solvent decanted off. The remaining residue was recrystallized twice from CB₂C₂/isopropylether/hexanes to give 432 mg (61%) of the title compound as tan crystals: m.p. 245-247°C.

Example 14

8- chloro- 11-(1- acetyl- 4- piperidylidene)- 6, 11- dihydro- 5H- benzo-[ 5, 6] cyclohepta[ 1, 2- b] pyridine- N- oxide

To a mixture of 711 mg (2.01 mmol) of 8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b] pyridine in 30 ml of dry CH2Cl2, 246 mg (1.60 mmol) of m-chloro-peroxybenzoic acid were added at +10°C and under a nitrogen atmosphere. After 95 min. the mixture was taken up in CH 2 Cl 2 and washed once with 10% aqueous sodium bisulfite, and once with 10% aqueous sodium hydroxide. It was dried over magnesium sulfate, filtered and concentrated under vacuum. The product was purified via flash chromatography (5-8% MeOH in CH 2 Cl 2 ) and recrystallized from ethyl acetate/hexanes to give 175 mg (26%) of the title compound as a hemiethyl acetate solid: m.p. 90.5-93°C.

In a similar manner, 8,9-difluoro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridine was converted to 8 ,9-difluoro-11-(1-acetyl-4-piperidyl-idene)-6,11-dihydro-5H'-benzo[5,6]cyclohepta[1,2-b]pyridine-N-oxide.

Example 15

8- chloro- ll-(l- acetyl- 4- piperazinyl)- 6, ll- dihydro- 5H- benzo-[ 5, 6] cyclohepta[ 1, 2- b] pyridine

A mixture of 1.98 g (7.50 mmol) of 8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 1.16 g (9, 05 mmol) of N-acetylpiperazine and 2.0 ml of triethylamine in 20 ml of dry THF were refluxed under a nitrogen atmosphere for 16 hours. It was then poured into 5% aqueous sodium hydroxide and extracted three times with methylene chloride. The combined organics were dried over MgSO 4 , filtered and concentrated in vacuo to give a product which was purified by flash chromatography (5% CH 3 OH in CHCl 3 ) to give 1.71 g (64%) of the title compound as a glass.

Example 16

Using the appropriately substituted piperazine listed in Table VII in place of N-acetylpiperazine, the desired products were prepared under essentially the same conditions as described above. Workup time was determined by TLC.

Example 17 8-chloro-II-[1-acetyl-4-piperidinyl]-IIH-benzo[5,6]cyclohepta-[1,2-b]pyridine

A mixture of 1.17 g (3.32 mmol) of 8-chloro-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]- pyridine in 4 ml of trifluoromethanesulfonic acid was heated between 180 and 200°C for three days under a nitrogen atmosphere. The mixture was cooled to room temperature, poured into 10% aqueous sodium hydroxide and extracted three times with CH 2 Cl 2 . The organic portions were combined, dried over MgSO 4 , filtered and concentrated in vacuo. The residue was purified via flash chromatography [5% MeOH in CH 2 Cl 2 ] to give 534 mg (46%) of the title compound as a glass.

The following are examples of pharmaceutical dosage forms containing a compound according to the invention. As used herein, the term "active compound" is used to denote the compound 8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1 ,2-b]-pyridine. The scope of the invention in its pharmaceutical preparation aspect should not be limited by the examples given, as any other compound of structural formula I may be incorporated into the pharmaceutical preparation examples.

Examples of pharmaceutical dosage form Example A

Product in Wednesday method

Components no. 1 and 2 were mixed in a suitable mixer for 10-15 min. The mixture was granulated with component No. 3. The moist granules were ground through a coarse sieve (eg 2.54 cm) as needed. The moist granules were dried. If necessary, the dried granules were sieved and mixed with component no. 4, and it was mixed for 10-15 min. Component no. 5 was added, and it was mixed for 1-3 min. The mixture was compressed to the appropriate size and weight on a suitable tableting machine.

Example B

Capsules

Production method

Components no. 1, 2 and 3 were mixed in a suitable mixer for 10-15 min. Component no. 4 was added, and it was mixed for 1-3 min. The mixture was filled into suitable two-piece capsules of hard gelatin on a suitable encapsulation machine.

Claims (2)

1. Analogous process for the preparation of therapeutically active benzo[5,6]cycloheptapyridines of the general formula I or a pharmaceutically acceptable salt or solvate thereof, where: R<1> is hydrogen or lower alkyl; R<3> and R4 can be the same or different and are independently of each other H or halogen, or R3 and R4 can together form an unsaturated C5-C7 fused ring; R<6> and R<8> are H, -CF3 or lower alkyl; R<9> is absent or is O" or -CH3; X is N or C, where C may contain a possible double bond to carbon atom 11; the dotted line between carbon atoms 5 and 6 is a possible double bond, so that when a double bond is present, A and B are H, and when no double bond is present between carbon atoms 5 and 6, A is H2, lower alkyl and H, H and -OH, or =0, and B is H2; Z is 0 or S; and R is H, phenyl, lower alkyl, lower alkylthio, lower alkylamino, lower alkenyl or lower alkoxyleveralkyl, where the substituents have the following further definitions: lower alkyl (including the alkyl parts of lower alkoxy) are straight or branched carbon chains and contain from 1 to 6 carbon atoms, lower alkenyl are straight or branched carbon chains with at least one carbon-to-carbon double bond and which contain from 2 to 6 carbon atoms, and halogen is fluorine, chlorine, bromine or iodine, characterized by: a) that a compound of formula II is reacted with a compound of formula III where R<1>, R3, R<4>, R<6>, R<8>, R<9>, A, B, X, Z and R are as defined above and L is a suitable leaving group, or b) direct conversion of an N-alkyl compound of <1> formula V with a compound of formula III wherein R<1>, R<3>, R4, R6, R<8>, R<9>, A, B, X, Z, R and L are as defined above, and alkyl is a straight or branched carbon chain containing from 1 to 20 carbon atoms, c) that methyl isocyanate is added dropwise under nitro genatmosphere to a mixture of and triethylamine in dry THF at -10 °C, whereby it is obtained d) that a mixture of and methyl iodide in toluene is heated, whereby it is obtained e) that a mixture of in dry CH2C12 is added m-chloroperoxybenzoic acid at -10 °C under a nitrogen atmosphere, whereby it is obtained f) that a mixture of N-acetylpiperazine and triethylamine in dry THF are boiled under reflux and under a nitrogen atmosphere, whereby it is obtained g) that is reacted with whereby it is obtained that is acetylated with acetic anhydride to the corresponding compound of formula I, h) that traded with which it is obtained which is acetylated with acetic anhydride to the corresponding compound of formula I, and i) that is reacted with whereby it is obtained which is acetylated with acetic anhydride to the corresponding compound of formula I, after which, if desired, a compound obtained is converted into a pharmaceutically acceptable salt or solvate thereof. 2. Process according to claim 1 for the preparation of the following compounds: 8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2- b]pyridine, 8-chloro-11-(1-methoxyacetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 8-chloro-11- (1-propionyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 8-fluoro-11-(1-acetyl-4-piperidylidene)- 6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 9-fluoro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[ 5,6]cyclohepta[1,2-b]pyridine, 8-bromo-11-[1-acetyl-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2- b]pyridine, 8,9-difluoro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 8-chloro- 11-(1-acetyl-4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine-N-oxide, 3,8-dichloro-11-(1 -acetyl-4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 11-(1-acetyl-4-piperidyl)-6,11-dihydro- 5H-benzo[5,6]-cyclohepta[1,2-b]pyridine or 8-chloro-ll- (1-acetyl-4-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, characterized in that similarly substituted starting compounds are used.