NO175480B - Analogous Process for Preparing Therapeutically Active Benzopyridopiperidine, Benzopyridopiperidylidene and Benzopyridopiperazine Compounds - Google Patents

Description

The background of the invention

The present invention relates to analogue methods for the production of therapeutically active benzopyridopiperidine, piperazine and piperidylidene compounds.

The following literature describes oxygen or sulfur in the bridgehead of the three-ring portion of the molecule: Canadian Patent Application No. 780,443, Irish Patent Publication No. 17764 published April 5, 1964, European Patent Application No. 81816337.6 published March 10, 1982, Belgian Patent Application No. 638,971 published April 21, 1964, Belgian Patent Application No. 644,121 published August 20, 1964 and US Patent Nos. 4,609,664 issued September 2, 1986, 3,966,944 issued June 29, 1976, 3,803,153 issued April 9, 1974 and 3,325,501 issued June 13, 1967.

None of the literature references describe similar substitution on the piperidylidene, piperidine or piperazine nitrogen atom as that indicated below.

Derivatives of benzo[5,6]cyclo-heptapyridine are described in: EP-A-270,818,

Chemical Abstracts, vol. 197, 1987, p. 602, summary no. 23239 and

Journal of Medicinal Chemistry, 1972, vol. 15,

pp. 750-754.

EP-A-270,818 was published after the priority date of the present application.

Summary of the invention

In the present invention, an analogous method for the preparation of therapeutically active compounds with the general formula is provided

or a pharmaceutically acceptable salt or solvate thereof, wherein: one of a and d is nitrogen or -NO, and the remaining a, b, c and d groups are CH;

R<3> and R<4> can be the same or different and are independent of

each other H or halogen;

R<5>, R6, R<7> and R<8> are independently H or C₁-C₁ alkyl;

T is carbon or nitrogen, the dotted line associated with T being a possible double bond when T is

carbon;

m and n are whole numbers 0, 1, 2 or 3, so that the sum of m + n

is equal to 0-3;

when m + n is 1, X is -0- or -S(0)e-, where e is 0, 1 or 2; when m + n is 0, X can be any of the substituents for m + n equal to 1, and X can also be a direct

bonding;

when m + n is 3, then X is a direct bond;

each Ra is H;

Z is =0,

R is H, C 1 -C 4 alkyl or

where Y is N or NO.

The analogy method is characterized by: A. a compound of formula II is reacted with a for bond of formula III, where L is a suitable leaving group and the other symbols have the meanings given above, or B. a compound of formula XXX is reacted with a compound of formula XXXII or XXIX, whereby a compound of formula I is obtained if R<c> is Z (C)R

where the symbols have the meanings indicated above.

In a preferred embodiment of the invention, the following, particularly preferred compounds are prepared: l-acetyl-4-(10H-[1]-benzothiopyrano[3,2-b]pyridin-10-ylidene)piperidine, l-acetyl-4-( 8-Chloro-5,11-dihydro-[1]-benzoxepino-[4,3-b]pyridin-ll-ylidene)piperidine, l-acetyl-4-(10H-[1]-benzopyrano[3,2- b]pyridin-10-ylidene)piperidine, 4-(10H-[1]-benzopyrano[3,2-b]pyridin-10-ylidene)-1-piperidinecarboxaldehyde, l-acetyl-4-(5H-benzopyrano[2,3-b]pyridine-5 -ylidene) - piperidine, l-acetyl-4-(5,6,7,12-tetrahydrobenzo[6,7]cycloocta-[1, 2-b]pyridin-12-ylidene) piperidine, I- methoxyacetyl-4- (5,6,7,12-tetrahydrobenzo[6,7]-cycloocta[1,2-b]pyridin-12-ylidene)piperidine, II-(1-acetyl-4-piperidinylidene)-8-chloro-5, 11-dihydro-[1]-benzothiepino[4,3-b]pyridine, 11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4,3- b]pyridine-1,6-dioxide, 11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridine-6,6- dioxide,

11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridine-6-oxide,

11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridine-6,6-trioxide,

1-acetyl-4-(9H-indeno[2,1-b]pyridin-9-yl)piperazine or

1-(4-pyridinylcarbonyl)-4-(5,6,7,12-tetrahydrobenzocycloocta[1,2-b]pyridin-12-ylidene)-piperidine-N'-oxide.

The compounds produced according to the present invention can be administered in a pharmaceutical preparation comprising a compound of structural formula I together with a pharmaceutically acceptable carrier for the treatment of asthma, allergy and/or inflammation in a mammal in need of such treatment, comprising the administration of a compound of formula I to the mammal in a sufficient quantity to treat respectively allergy, asthma and/or inflammation.

Detailed description

The following expression is used here as defined below unless otherwise stated:

halogen - is fluorine, chlorine, bromine or iodine.

Certain compounds produced according to the invention can exist in different isomeric and conformational forms. The invention encompasses the preparation of all such isomers and conformers, both in pure form and in mixture, including racemic mixtures.

The compounds of formula I produced according to the invention can be present in unsolvated as well as 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 the purposes of the invention.

As indicated above, the pyridine and benzene rings of formula I may contain one or two substituents R 3 and R 4 . In compounds where there is more than one such substituent, they may be the same or different. The compounds with combinations of such substituents are thus within the scope of the invention. The lines drawn into the rings from the R<3->R<8->groups also indicate that such groups can be attached in any of the available positions.

Numbering of the compounds produced according to the invention varies with the size of the central ring. However, numbering of piperidine, piperidylidene or piperazine remains consistent with the nitrogen atom at the bottom designated 1', the carbon atom on the left designated 2', and the numberings increase clockwise. The carbon atoms to the left and right of the nitrogen atom at the bottom are thus respectively 2' and 6'.

Certain compounds produced according to the invention will be acidic in nature, e.g. those compounds which have a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminium, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines, such as ammonia, alkylamines, hydroxyalkylamines, N-methylglucamine and the like.

Certain basic compounds prepared according to the invention also form pharmaceutically acceptable salts, e.g. acid addition salts. For example, the pyrido or pyrazino nitrogen atoms can form salts with strong acids, while compounds with basic substituents, such as amino groups, also form salts with weak acids. Examples of suitable acids for salt formation are hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, methanesulfonic acid and other mineral and carboxylic acids that are well known to those skilled in the art. in the field of technology. The salts are prepared by bringing the free base form into contact with a sufficient amount of the desired acid to give a salt in the usual way. 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 free base forms differ somewhat from their respective salt forms with regard to certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention.

All such acid and base salts (eg, pyridinyl nitrogen salts) are intended to be pharmaceutically acceptable salts prepared within the scope of the invention, and all acid and base salts are considered to be equivalent to the free forms of the corresponding compounds.

The following methods can be used to prepare compounds of general structural formula I.

A. A compound of general formula II can be reacted with compound III with, and sometimes without, the presence of base, thereby obtaining 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 can e.g. 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), 1-(3-dimethylaminopropyl-3-ethylcarbodiimide (DEC) and N,N'-carbonyldiimidazole (CDI). The exiting group can

also be alkoxy, and then the compounds of formula I can be prepared by boiling a compound of formula II together with an excess of a compound of formula III under reflux cooling.

Compounds of general formula II can be prepared by cleaving the group COOR<b> from the corresponding carbamates IV, e.g. via acid hydrolysis (e.g. HC1) or base hydrolysis (e.g. KOH):

where R<b> is a group which does not prevent the cleavage reaction, e.g. Rb is optionally substituted alkyl, such as ethyl, or 2,2,2-trichloroethyl.

Depending on the type of R<b>, as determined by those skilled in the art, compound IV may alternatively be treated with an organometallic reagent (eg CH3Li), a reductive reagent (eg Zn in acid) etc, thereby obtaining compounds with formula II.

Compound IV can be prepared from the N-alkyl compound, shown as formula V below, in the manner described in US Patent Nos. 4,282,233 and 4,335,036.

There are a large number of other methods for converting compound V to compound II. For example, treatment of compound V with BrCN via von Braun reaction conditions would give nitrile VI, as shown below. Subsequent hydrolysis of the nitrile under either aqueous, basic or acidic conditions would give compound II. This method is preferred when there is substitution on the piperidine ring.

B. Preparation of piperazine analogs

Compounds of the piperazine type, where T is N in formula I, are best prepared via alkylation of an appropriately substituted piperazine compound XXX with compound XXXII, containing the appropriate 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, typically in a temperature range from ambient temperature to reflux temperature, whereby compound XXXIII is obtained.

In this reaction, R<c> is H, CO 2 R<b>, C(Z)R or alkyl. The preparation of the tricyclic ring structure, where L is Cl, is analogous to the method in US Patent No. 3,409,621. When R<c> is C(Z)R, compounds according to the invention are prepared. When R<c> is H, alkyl or C02R<b>, the compounds are converted into compounds according to the invention by methods previously described here.

An alternative route to the production of compound XXXIII is by reductive amination of the azaketone XXIX with the appropriately substituted piperazine.

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 3 µm molecular sieves. The Schiff base intermediate can be reduced using several different reducing agents, such as NaCNBH3, or catalytic hydrogenation, e.g. hydrogen or Pd/C.

When R<c> is C(Z)R, compounds of formula I are prepared. When R<c> is H, CO 2 Rb or alkyl, the prepared compounds are converted into compounds of formula I as previously described.

In the above methods, it is sometimes desirable and/or necessary to protect certain R and R3 to R<8> groups during the reactions. Common protecting groups can be used. For example, the groups indicated in column 1 of the following table may 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 by standard procedures.

The compounds of the invention have antagonistic properties for platelet activating factor ("PAF"). PAF is an important biochemical mediator of such processes as platelet aggregation, smooth muscle contraction (especially in lung tissue), vascular permeability and neutrophil activation. Recent evidence places PAF as an underlying factor involved in airway hyperreactivity. The compounds produced according to the invention can therefore always be used when PAF is a factor in the disease or disease state. This includes allergic diseases, such as asthma, respiratory distress syndrome in adults, urticaria and also inflammatory diseases, such as rheumatoid arthritis and osteoarthritis.

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 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 test mimics clinical use of PAF antagonists to provide data simulating clinical use of the compounds described herein.

A. PAF antagonism assay

In vitro analvse:

Production of platelet-rich plasma (PRP):

Human blood (50 ml) was taken from healthy male blood donors and placed in an anticoagulant solution (5 ml) containing sodium citrate (3.8%) and dextrose (2%). Blood was centrifuged at 110 x g for 15 min, and supernatant PRP was carefully transferred to a polypropylene tube. Platelet-poor plasma (PPP) was prepared by centrifuging PRP at 12,000 x g for 2 min in a "Beckman Microfuge B". PRP was used within 3 hours after the blood sample was taken.

Platelet aggregates in ons analysis:

When an aggregating 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 assays were performed using a dual-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"<8> M. Incubations were continued until the increase in light transmission reached a maximum (usually about 2 min). Values for inhibition were calculated by comparing the maximum 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 inhibitor concentration (IC50) 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 in Table I.

As PAF is a known bronchoconstrictive agent in mammals, PAF antagonism can be evaluated by measuring inhibition by the compounds of the invention in PAF-induced bronchoconstriction in guinea pigs.

B. PAF-induced bronchospasm in guinea pigs

In vivo analysis

Non-sensitized guinea pigs were fasted overnight and on the following morning were anesthetized with 0.9 ml/kg i.p. of dialurethane (0.1 g/ml diallylbarbituric acid, 0.4 g/ml ethyl urea and 0.4 g/ml urethane). The trachea was cannulated and the animals were ventilated using a Harvard rodent respirator at 55 bpm 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 measure of intratracheal pressure, which was recorded on a Harvard polygraph. The jugular vein was cannulated for the 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 inflation pressure occurring within 5 min of challenge was measured. Test compounds were administered either orally (2 h before PAF as a suspension in 0.4% methyl cellulose vehicle) or intravenously (10 min before PAF as a solution in dimethyl sulfoxide).

The compounds produced according to the invention also have antihistamine properties which can be determined by means of test method C below. Test Method C, "Prevention of Histamine-Induced Lethality", demonstrates basic antihistamine activity of representative compounds of structural formula I. Protection against histamine lethality is indicative of strong antihistamine properties.

Test procedures D, E and F show the extent of CNS activity induced by the compounds of the invention. The presence of strong CNS activity indicates a high probability of sedative action caused by the compounds, a typical unwanted side effect of anti-histamines. Accordingly, a low level of CNS activity is preferred under most circumstances.

C. Antihistamine activity assay

Prevention of histamine-induced mortality in guinea pigs

The compounds can also be evaluated for antihistamine activity by their ability to protect female albino guinea pigs (250-350 g) against death induced by the intravenous injection of histamine dihydrochloride at 1.1 mg/kg, which is approximately twice the LD99 . Doses of the antagonists are administered orally to separate groups of fasted animals 1 hour before the histamine challenge, and protection against death is recorded for 30 min after histamine administration. ED50 values were determined for each drug using probit analysis.

CNS activity assays

D. Antagonism of physostigmine mortality

The physostigmine-induced lethality test is an indication of CNS activity, and the described test is a modification of the technique reported by Collier et al., Br. J. Pharmac, 32, pp. 295-310 (1968). Physostigmine salicylate

(1.0 mg/kg s.c.) produces 100% mortality when administered to mice grouped at 10 per plastic cage (11 x 26 x 13 cm). Test agents were administered orally 30 min before physostigmine.

The number of survivors was counted 20 min after physostigmine administration.

E. Antagonism of vinegar vrevridninq

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, pp. 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-minute period starting 3 minutes after acetic acid treatment. A twist was defined as a sequence of back bending, pelvic rotation and back 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. Neurophysiol. , 9, pp. 231-239

(1946) used. One hour after oral administration of the test drug or vehicle, mice were administered a 13 mA, 60 cycle a.c. electroconvulsive shock (ECS) for 0.2 seconds via corneal electrodes. This shock strength produces tonic convulsions defined as hindlimb extension in at least 95% of vehicle-treated mice.

Of the above-mentioned test procedures for measuring CNS activity, the physostigmine-induced lethality test is believed to be a major index of non-sedating properties as it mainly reflects central anticholinergic potency which is believed to contribute to sedative action.

In Table I below, PAF antagonism data are presented for previously known compounds and for the compounds produced according to the present invention.

As seen from the data in Table I, the compounds of structural formula I exhibit PAF antagonistic activity. Accordingly, these compounds can be used when clinically appropriate.

For the preparation of pharmaceutical preparations from the compounds prepared by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, capsules with powder and suppositories. The powders and tablets can include from approx. 5 to approx. 70% active ingredient on a weight/weight basis. Suitable solid supports are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, capsules with powder 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 and cocoa 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 suitable size and allowed to cool and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions. As an example, water or water-propylene glycol solutions for parenteral injection can be mentioned.

Liquid form preparations may also include solutions for intranasal administration.

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

Also included are solid form preparations which are intended to be converted just before use into liquid form preparations either for oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds produced according to the invention can also be delivered transdermally. The transdermal preparations can take the form of creams, lotions, aerosols and/or emulsions, and can be included in a transdermal patch of the matrix or reservoir type, as is common in the art for this purpose.

Preferably, the compound is administered orally.

Preferably, the pharmaceutical preparation is in unit dose form. In this form, the preparation is divided into unit doses that contain appropriate amounts of the active ingredient, e.g. an effective amount to achieve the desired purpose.

The amount of active compound in a unit dose of preparation can be varied or regulated from approx. 0.01 mg to 2000 mg, preferably from approx. 1 mg to 100 mg, depending on the specific application. An appropriate dosage can be determined by comparing the activity of the compound with the activity of a known PAF antagonist.

The actual dosage used may vary, depending on the needs of the patient and the severity of the condition being treated. Determining the correct dosage for a specific situation is within the skill of the art. 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 the sake of convenience, the total daily dosage can be divided and, if desired, administered in portions during the day.

The amount and frequency of administration of the compounds prepared according to the invention and the pharmaceutically acceptable salts thereof will be regulated in accordance with the judgment of the attending physician who considers such factors as age, the patient's condition and size, as well as the severity of the symptoms being treated. A typical recommended dosage schedule for oral administration is from 10 mg to 2000 mg/day, preferably 10-750 mg/day, in 2-4 divided doses to achieve relief of symptoms. The dosage ranges for the treatment of allergy and inflammation are generally considered to be the same. Accordingly, ranges for oral dosage will be similar, ranges for injectable dosage will be similar, etc.

The following examples illustrate the present invention in more detail.

Manufacturing example 1

A. 1-Methyl-4-(10H-rylbenzopyranor3.2-bl-10-hydroxy-pyridinyl)piperidine

1.3 g (6.1 mmol) of benzo[b]thiopyrano[2,3-b]-pyridin-10-one was slurried in 30 ml of dry tetrahydrofuran ("THF") at room temperature under an argon atmosphere. N-methyl-4-piperidinyl-magnesium chloride (1.2 eq.). 4.8 ml of 1.5 M reagent in THF) was added, forming a dark solution. It was stirred at room temperature for 1 hour.

The reaction was quenched with concentrated NH 4 Cl and extracted with ethyl acetate. The organic portions were washed with brine and dried over Na 2 SO 4 . The solvent was removed and the resulting liquid was chromatographed (5%->10% CH 3 OH/NH 3 in CH 2 Cl 2 ) to give a yellowish solid crystallizable from pentane (0.80 g).

B. 1-methyl-4-(10H-r11benzothiopyranof3,2-blpyridin-10-ylidene) piperidine

The title compound from Part A above (780 mg) in H 2 SO 4 (85%, 20 mL) was heated to 105°C in an oil bath for 20 min. The reaction mixture was poured into ice water and basified with NaOH (25%). It was extracted with CH 2 Cl 2 , and the combined organic portions were washed with brine. It was dried over Na 2 SO 4 to give a yellowish glass (408 mg).

It was purified by flash chromatography over 10% T

15% CH3OH in CH2Cl2 to give a yellowish glassy solid (290 mg). C. l- cvan- 4-( 10H- f 11benzothiopyrano f 3, 2- blpyridine- 10- ylidene) piperidine

The title compound from Part B above (291 mg) was added to a solution of cyanobromide (158 mg, 1.5 eq.) in dry benzene (8.5 mL) at room temperature and stirred for 3 hours.

The solvent was removed under high vacuum to give a solid which was flash chromatographed (5% CH 3 OH in CH 2 Cl 2 ) to give the title compound as a yellowish solid (220 mg, mp 192-193°C).

D. 1-aminocarbonyl-4-(10H-f11benzothiopyranoT3.2-blpyridin-10-ylidene)piperidine and

4-(10H-r11benzothiopyranor3,2-b]pyridin-10-ylidene)-piperidine

A mixture of the title compound from Part C above (210 mg) and 29% aqueous HCl (20 mL) was refluxed for 24 hours. The reaction mixture was poured onto ice and basified with 25% aqueous NaOH. The mixture was extracted with CH 2 Cl 2 (2 x 200 mL) and the combined organic portions were washed with brine. It was dried over Na 2 SO 4 , filtered and the solvent removed to give

a glassy, solid substance.

It was chromatographed on SiO 2 (230-400 mesh), eluting with 10% T 15% CH 3 OH in CH 2 Cl 2 , to give the title compound in two fractions, fraction 1 containing the N-H compound IA as a yellowish solid (146 mg, sm. mp 162-163°C), and fraction 2 which contained the aminocarbonyl-substituted compound IB as an off-white solid (32 mg, mp 185-187°C).

Manufacturing example 2

A. 1-methyl-4-(10H-f11benzothiopyranof3,2-blpyridin-10-ylidene) piperidine

1-Methyl-4-(10H-[1]benzopyrano[3,2-b]pyridin-10-ylidene)piperidine was prepared as described in US Patent No. 3,803,153. B. 1-cyano-4-(10H-f11benzopyranoT3,2-blpyridin-10-ylidene) piperidine

A solution of cyanobromide (22.9 g, 0.196 M) was stirred in dry benzene (300 mL) at room temperature, and a solution of the title compound from part A above was added (54.5 g, 0.196 M) in benzene (300 mL ).

The resulting solution was filtered after

3 hours and concentrated to dryness, whereby a grey-white solid was obtained (44.0 g, m.p. 172-175°C).

The product was recrystallized from acetonitrile to give the title compound.

C. 4-(10H-rylbenzopyranor3.2-blpyridine-10-vlidene)-piperidine

A mixture of the title compound from Part B above (44.0 g, 0.152 M), glacial acetic acid (1140 mL), concentrated HCl (115 mL), and H 2 O (760 mL) was refluxed for 20 h. Excess acetic acid and H 2 O were removed under reduced pressure, cooled and basified with Na 2 CO 3 . It was extracted with chloroform and dried over Na 2 SO 4 . It was concentrated to dryness and chromatographed on silica gel using acetonitrile to give the title compound (27.0 g, m.p. 158-160°C).

Manufacturing example 3

A. 3-(3-phenylpropyl)pyridine

A mixture of 2-phenylethyl-3-pyridinyl ketone (19.5 g, 0.092 M), NaOH (8.0 g), hydrazine hydrate (8 mL, 85% in H 2 O), and diethylene glycol (125 mL) was heated to 240 °C for 4 hours.

It was extracted with benzene (1x), then with diethyl ether (1x). The combined organic extracts were washed with H 2 O (3x), the solvent removed and distilled to give the title compound (15.8 g, b.p. 130-131°C at 2 mm Hg).

B. 3-(3-phenylpropyl)pyridine-N-oxide

Cold H 2 O 2 (101 mL, 30%) was added to a cold solution of the title compound from Part A above (166 g, 0.84 M) in CH 3 CO 2 H (252 mL).

It was heated to 60°C for 24 hours and poured into ice water. It was basified with NH 4 OH and the total volume was brought to 2.0 L. The product separated as an oil which solidified on cooling. It was filtered, and the filtrate was dissolved in CHCl 3 .

The solvent was removed and the product crystallized from benzene/hexane to give the title compound (63.0 g, m.p. 34-35°C).

C. 2-cyano-3-(phenyl-n-propyl)pyridine

Dimethyl sulfate (76 g, 0.6 M) was added to the title compound from Part B above (171.5 g) and it was stirred on a steam bath for 3 hours. H 2 O (200 ml) was added and the solution was cooled, then the solution was added dropwise to a solution of NaCN (92 g) in H 2 O (260 ml) at 0°C under a 3-atmosphere. The solution was allowed to remain at 0°C for 4 hours, and then the mixture was stirred for 12 hours at room temperature while maintaining the reaction under an N 2 atmosphere. The resulting brownish solution was extracted with CHCl 3 . The combined organic portions were concentrated and purified via distillation. The title compound was crystallized from the correct fractions using benzene/petroleum ether (34.0 g, mp 50-52°C).

D. 12H- benzorbl- 5. 6. 7, 12- tetrahydrochrocvclocttar 2, 3- blpyridin- 12- one

The title compound from Part C above (5.0 g) was stirred with polyphosphoric acid (250 g) while heating to 240°C, and then the heat was reduced to 220°C and held there for 2 hours.

The reaction mixture was poured into ice water and made basic with NaOH. It was extracted with diethyl ether and the solvent removed to give the title compound in crude form (4.0 g, m.p. 141-145°C) which can be recrystallized from 2-butanone to give the title compound as a white solid substance (m.p. 153-155°C).

E. 1- methyl- 4-(5, 6, 7, 12- tetrahydrobenzof 6, 71cycloocta-T1, 2-bl- 12- hydroxypyridinyl) piperidine

Sodium (2.7 g, 0.12 M) was dissolved in NH 3 (200 mL) and stirred for 20 min. The title compound from part D above (13 g, 0.058 M) in THF (105 mL) was slowly added and it was stirred for 5 min. A solution of 4-chloro-1-methylpiperidine (7.8 g, 0.058 M) in THF (25 mL) was added and stirring was continued.

NH 4 Cl (5.0 g) and NH 3 (75 mL) were added and stirring was continued for an additional 2 h.

The mixture was concentrated to dryness and then partitioned between water and benzene. It was extracted with additional benzene. The solvent was removed, leaving a viscous, golden brown residue.

The golden brown residue was triturated with petroleum ether and isopropyl ether. The solution was cooled and the liquid decanted from the precipitate to give the title compound as a white solid (5 g, m.p. 122-124°C).

F. 1-methyl-4-(5,6,7,12-tetrahydrobenzof6,71cycloocta-T1,2-blpyridin-12-ylidene)piperidine

The title compound from Part E above (1.413 g) was mixed with CH 3 CO 2 H (12 mL), acetyl chloride (7 mL) and acetic anhydride (3.5 mL) and heated to 100°C under an N 2 atmosphere.

After 3 hours, the mixture was concentrated under vacuum, and the residue was poured into NaOH (1 N). It was extracted with CH 2 Cl 2 (3x). The organic portions were combined, dried over MgSO 4 , filtered and rotary evaporated to dryness.

It was purified by flash chromatography (5% CH3OH/NH3

in CH 2 Cl 2 ) to give the title compound which can be crystallized from pentane (1.014 g).

G. 1-(1.1,1-trichloroethoxycarbonyl)-4-(5,6,7,12-tetrahydrobenzof6,7"lcyclooctal"1,2-b1pyridin-12-ylidene)-piperidine

The title compound from Part F above (1.008 g,

3.31 mmol) was mixed with (CH3CH2)3N (0.70 mL) and dry toluene

(30 ml) at 90°C under an argon atmosphere. 2,2,2-trichloroethylcarbonyl chloride (1.80 ml) was added dropwise over 20 min. The temperature was kept at 90°C for 1.67 hours, then it was cooled to room temperature and poured into aqueous NaOH (1 N).

The reaction mixture was extracted with CH 2 Cl 2 (3x), the organic portions were combined, and dried over MgSO 4 .

It was filtered and rotary evaporated to dryness.

It was purified by flash chromatography (CH 3 OH 2% in CH 2 Cl 2 ) and the correct fractions were pooled to give the title compound.

H. 4-(5,6,7,12-tetrahydrobenzocycloocta\1,2-blpyridin-12-ylidene)piperidine

The title compound from part G above and glacial acetic acid

(20 mL) was mixed under a N 2 atmosphere at 90-90°C with zinc dust (2.12 g).

After 3 hours, the reaction mixture was cooled to room temperature, filtered and rotary evaporated to dryness. The residue was basified with NaOH (1 N) and extracted with CH 2 Cl 2 (4x). The organic portions were combined, dried over MgSO 4 , filtered and rotary evaporated to dryness. It was purified by flash chromatography (5% T 7% CH 3 OH/NH 3 in CH 2 Cl 2 ) and the correct fractions were collected to give the title compound as a glass (603 mg).

Manufacturing example 4

A. 2-cyano-3-(bromomethyl)pyridine

2-cyano-3-methylpyridine (11.8 g), N-bromosuccinimide ("NBS") (26.8 g, 1.0 eq.) and aza(bis)isobutyronitrile ("ABIN")

(180 mg) was mixed in dry CCl 4 (300 mL). The mixture was boiled under reflux.

The mixture was poured into water, basified with NaOH and extracted with CH 2 Cl 2 . The organic portion was washed with water, dried, filtered and concentrated to give a liquid. The product was chromatographed and eluted with diethyl ether/hexane (30%). The correct fractions were combined to give the monobromo compound (5.01 g) as a yellowish solid.

B. 2-cyano-3-(3-chlorophenoxymethyl)pyridine

A solution of the title compound from Part A above (0.71 g, 3.6 mmol), Nal (54 mg, 0.1 eq.) and Cs 2 CO 3 (1.17 g, 1.0 eq.) in dry acetone (17 ml, dried over MgSO 4 ) was stirred at room temperature for 5 min, and then 3-chlorophenol (463 mg) was added via syringe.

It was boiled under reflux over an oil bath for 4.5 hours.

It was filtered and the filtrate was washed with dry acetone. The filtrate was concentrated, slurried in diethyl ether and filtered again, whereby a brown solid was obtained which is the title compound in impure form. It was triturated with pentane and reslurried in diisopropyl ether (40 mL) with activated charcoal and heated on a steam bath.

It was filtered and the solvent was evaporated to give the title compound which crystallized as a white solid (640 mg, m.p. 70-72°C).

C. 8-chloro-5,11-dihydrol"11benzoxepinor4,3- blpvridin-ll-one

The title compound from Part B above (6.1 g) in CF 3 -SO 3 H (60 mL) was stirred at room temperature for 3 hours. After completion, the reaction was quenched with H 2 O and concentrated HCl (30%) and stirring was continued for 0.5 h.

It was heated to 35°C for 0.5 hour. It was basified with NaOH (25%) and extracted with CH 2 Cl 2 (2x). It was washed with saline (2x), filtered and dried over Na2-S<0>4.

The resulting semi-solid (6.35 g) was triturated with diisopropyl ether, and the isomers were separated via flash chromatography (3% EtOAc in hexanes). The appropriate fractions were combined to give the title compound as a solid (4.902 g, m.p. 139.5-140.5°C), and the 10-chloro compound as a solid (462 mg, m.p. p. 100-100.5°C).

D. 1- methyl- 4-( 8- chloro- 11- hydroxy- 5, 11- dihydro TIIbenz-oxepinor4, 3- blpyridinyl) piperidine

To a solution of the title compound from Part C above (3.47 g) in dry tetrahydrofuran ("THF") (37 mL) was slowly added the Grignard reagent (11.9 mL, 1.2 M) and it was stirred at room temperature for 0.5 hours.

The reaction was quenched with ice and NH4Cl. The solution was extracted with CH 2 Cl 2 (2x), dried, filtered and concentrated to give the title compound. The product was chromatographed on silica gel (5% T 7.5% CH 3 OH/NH 3 in CH 2 Cl 2 ) to give the title compound as a glass (2.56 g).

E. 1-methyl-4-(8-chloro-5,11-dihydro[11benzoxepin[4,3-blpyridin-ll-ylidene)piperidine

The title compound from Part D above (934 mg) in CF 3 SO 3 H (20 mL) was stirred at room temperature for 15 min. The temperature was raised to 45°C in an oil bath and held there for 1.25 hours. It was cooled to room temperature and the mixture was poured into ice water. It was basified with dilute NaOH and extracted with CH 2 Cl 2 (2x). It was then washed with brine (1x) and dried over Na 2 SO 4 to give the title compound as a brown glass.

It was purified by mixing with activated carbon in ethyl acetate, then filtered and the solvent removed to give a tan solid.

It was recrystallized from ethyl acetate and diisopropyl ether, whereby the title compound was obtained as an off-white solid (540 mg, m.p. 168-170°C).

F. 1-ethoxycarbonyl-4-(8-chloro-5.11-dihydroIIIbenzoxe-pino r 4,3-blpyridin-ll-ylidene) piperidine

The title compound from Part E above (474 mg,

1.45 mmol) was dissolved in toluene (10 mL), and (CH 3 CH 2 ) 3 N

(0.656 mL) was added. The reaction mixture was heated and maintained at 80-85°C, and C1CO2CH2CH3 (1.242 mL) was slowly added. The reaction mixture was maintained at 80-85°C while stirring for 3 hours.

The reaction was quenched with H 2 O and the reaction mixture was extracted with ethyl acetate (2 x 100 mL). It was washed with brine, separated and dried over Na 2 SO 4 . The solvent was removed and it was purified via flash chromatography, eluting with ethyl acetate in hexane (40 T 60%), to give the title compound as an off-white solid which can be purified by trituration with pentane and diisopropyl ether (428 mg, m.p. 118-120°C).

G. 4-(8-chloro-5.11-dihydrori~lbenzoxepinor4,3-blpyridin-11-ylidene) piperidine

The title compound from Part F above (333.8 mg) was dissolved in CH 3 CH 2 OH (5 mL) and 14% aqueous KOH was added. It was boiled under reflux and argon atmosphere for 19 hours.

The reaction was quenched with H 2 O and extracted with CH 2 Cl 2 (3 x 100 mL). It was washed with brine (1 x 100 mL), dried over Na 2 SO 4 and filtered. The solvent was removed to give a glassy off-white solid.

It was recrystallized with ethyl acetate/diisopropyl ether, whereby the title compound was obtained as a white powder (161.5 mg, m.p. 166-176°C).

Manufacturing example 5

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

The starting material, 1,2,6-trimethyl-4-piperidinol, can be prepared by the method described in Rrchi Kem, volume 27, pp. 189-192 (1955). To a cooled (ice bath) solution of 1,2,6-trimethyl-4-piperidinol (12.2 g, 85.3 mmol) in 120 mL of dry benzene was slowly added thionyl chloride (17 mL, 233 mmol). The dark reaction mixture was 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 the solvent removed to give an impure brown liquid which was distilled (2-4 mm Hg, 62-64°C), giving the title compound (8.0 g).

B. 2,6-Dimethyl-4-(10H-f11benzothiopyranof3,2-blpyridin-10-ylidene)piperidine

The chloride, 1,2,6-trimethyl-4-chloropiperidine (4.2 mg,

26 mmol), was slowly dropped into a solution of dry THF

(18 mL) containing Mg (633 mg, 26.3 mM). The Grignaird reagent was formed after heating for 6 hours at 70°C.

The Grignard reagent was added to the appropriate ketone in Preparative Example 1 and converted to the final intermediate as described therein, whereby the title compound was prepared.

Manufacturing example 6

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 and maintained at 85°C during the addition. The temperature in the mixture was allowed to fall <*>to approx. 35°C.

After partial removal of 185 ml of acetic acid via distillation under vacuum, it was washed with NaHSO 4 solution and then neutralized with 10% NaOH solution to a pH of approx. 7. The product was extracted with CH 2 Cl 2 to give the title compound as a white solid (142 g).

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

Dimethyl sulfate (42.0 g, 0.33 mol) was slowly added to a mechanically stirred solid of 41.0 g (0.33 mol) 3,5-dimethylpyridinium-N-oxide. The mixture was heated on a steam bath for 1 hour. Vacuum was applied while cooling to afford the title compound as a brownish solid.

C. 2-cyano-3,5-dimethylpyridine

A solution of sodium cyanide (49.0 g, 0.999 mol, 3.0 eq.) in 135 mL of water was cooled to 0°C (air-free), and 1-methoxy-3,5-dimethyl-pyridinium methyl sulfate (83, 0 g, 0.33 mol) in 100 ml of water (air-free) was added dropwise over 1 1/4 hours while keeping the temperature below 3°C. The mixture was filtered and washed with water to give 40 g of the title compound which can be recrystallized from isopropyl ether and pentane (4:1)

(m.p. 61-62°C).

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

A solution of 2-cyano-3,5-dimethylpyridine (20.3 g, 0.153 mol) in 100 ml of acetic acid and 20 ml of concentrated sulfuric acid was stirred for 10 min. t-butanol (20 mL) was added over a further 15 min. The solution was heated to 75°C and held there for 30 min. It was cooled to room temperature and made basic with 25% NaOH. The product was extracted (3x) with ethyl acetate (600 ml). The organic portions were combined and washed (1x) with saline. It was dried (Na 2 SO 4 ), filtered and concentrated under vacuum to give the title compound as a yellowish oil (31.26 g).

E. N-(1,1-dimethylmethyl)-3-f3-(4-fluorophenyl)propyl-5-methyl-2-pyridine-carboxamide

A solution of N-(1,1-dimethylethyl)-3-methyl-2-pyridinecarboxamide in dry THF was cooled to -40°C, and 2 equiv. n-butyllithium was added. A large excess of sodium bromide was added and it was stirred for 15 min. 1 eq. 4-fluorophenethyl chloride was added and it was stirred for 2.5 hours while warming to -5°C. The reaction was quenched with water and the product extracted twice with ethyl acetate and then washed with saline (2x). The organic phase was dried over Na 2 SO 4 , filtered and the solvent removed to give the title compound.

F. 3-f3-(4-fluorophenyl)propyl1-5-methyl-2-pyridine-carbonitrile

The title compound from part E above in POCl3 was heated to 110°C under an argon atmosphere for several hours. The reaction mixture was poured onto ice and basified with 50% NaOH solution. The mixture was extracted with ethyl acetate (3x) and washed with water. It was washed with brine and dried over Na 2 SO 4 . The solvent was removed and the residue passed through a coarse SiO 2 column (60-200 mesh) to give the title compound as a white solid.

G. 3- methyl- 10- fluoro- 5, 6, 7, 12- tetrahydrobenzo T 6, 71cyclo-octa f 1, 2- blpyridin- 12- one

The title compound from part F was cyclized in polyphosphoric acid at 240°C for several 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 the title compound.

H. 4-(3-methyl-10-fluoro-5,6,7,12-tetrahydrobenzocycloocta f1.2-blpyridin-12-ylidene) piperidine

The carbonyl compound from part G above can be converted to the title compound as described in preparation example 3 above.

Manufacturing example 7

A. 2-cyano-3-(bromomethyl)pyridine

The title compound was prepared as described in Preparation Example 4, Part A.

B. 2-cyano-3-(3-chlorophenylthiomethyl)pyridine

To a stirred, cloudy solution of sodium methoxide (14.7 g, 0.27 mol) in methanol (450 mL), kept in a water bath, was added a solution of 3-chlorothiophenol (39.5 g, 0.27 mol) in methanol (95 mL) added. To the resulting solution was added a solution of the title compound from Part A above (48.9 g, 0.25 mol) in methanol (195 mL), and the reaction mixture was stirred at room temperature for 1 hour.

The reaction mixture was concentrated under reduced pressure, 500 ml of ether was added to the residue, stirred and filtered to remove sodium bromide. The ether was evaporated under reduced pressure to give the title compound as an amber oil which can be used without further purification in the following cyclization procedure (Part C).

C. 8- chloro- 5, 11- dihydro f 11benzothiepino f 4. 3- blpyridin- 11-one

A solution of the title compound from Part B above (49.7 g, 0.19 mol) in CF 3 SO 3 H (500 mL) was stirred for 3.5 h

at 95°C. The reaction mixture was allowed to cool to below 60°C and was poured onto crushed ice (1500 ml). The mixture was stirred for 0.5 hour, and sufficient aqueous sodium hydroxide (220 mL of 50% solution) to raise the pH to 9 was added.

The aqueous solution was extracted with ethyl acetate (1x), saturated with sodium chloride and re-extracted (2x) with ethyl acetate. The combined extracts were washed with brine (3x), filtered and dried over anhydrous MgSO 4 . The solvent was removed under reduced pressure and the remaining material chromatographed on silica gel, eluting with ethyl acetate-hexanes (3:2) to give the title ketone as a golden brown solid, m.p. 186-187°C.

D. 1- methyl- 4-( 8- chloro- 11- hydroxy- 5, 11- dihydro T11benzo- thiepinor4, 3- blpyridinyl) piperidine

While cooling in an ice-water bath, a suspension of the title ketone from part C above (13.4 g, 51.2 mmol) in dry tetrahydrofuran (= THF, 52 mL) was added to a stirred solution (55 mL of about 1 M) in THF of The Grignard reagent derived from 1-methyl-4-chloropiperidine. The resulting mixture was stirred for 1 hour at room temperature.

The reaction was quenched by cooling the mixture to 10°C in an ice water bath and saturated aqueous ammonium chloride solution (50 mL) was added. Methylene chloride (100 mL) was added and the mixture was stirred for a few minutes. The mixture was filtered through "Celite" and the filter cake washed with methylene chloride. The original filtrate and washings were combined, the methylene chloride phase was separated, and the water phase was extracted (2x) with additional methylene chloride. The extracts were combined, washed with saline (2 x 75 ml) and dried over anhydrous sodium sulfate. It was filtered, the filtrate was stripped under reduced pressure and the residue chromatographed on silica gel eluting with methylene chloride-methanol-ammonium hydroxide (90:9:0.5) to give the title compound as an off-white to pale pink solid with m.p. . 158.5-159.5°C.

E. 1-methyl-4-(8-chloro-5,11-dihydrorylbenzothiepinor4>3-blpyridin-11-ylidene)piperidine

A solution of the title compound from Part D above (5.04 g, 13.9 mmol) was heated in CF 3 SO 3 H at 45°C for 10.5 hours. The reaction solution was cooled to room temperature and poured into a stirred ice-water mixture. It was further cooled in an ice water bath and aqueous sodium hydroxide (130 ml of a 50% solution) was added with stirring. The solution was extracted with methylene chloride (3x), the combined extracts washed first with water (2x) and then with brine (1x), dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The remaining glass was purified by chromatography on silica gel, elution with methylene chloride-methanol-ammonium hydroxide (90:9:0.25) and trituration of the thereby isolated solid in acetonitrile. After filtration, the title compound was obtained as a light golden brown solid containing 0.08 mol of methylene chloride, m.p. 175-177°C.

F. 1-ethoxycarbonyl-4-(8-chloro-5,11-dihydro philbenzo-thiepino[4.3-blpyridin-ll-ylidene) piperidine

To a stirred solution of the title compound from Part D above (1.44 g, 4.2 mmol) and triethylamine (966 mg, 9.5 mmol) in dry toluene (27 mL) maintained at 80 °C was added dropwise ethyl chloroformate (2.78 g, 25.6 mmol). After 1 hour, more triethylamine (480 mg, 4.7 mmol) was added and heating was continued at 80°C for another 1 hour.

The reaction mixture was cooled to 50°C, ethyl acetate (15 ml) was added, washed first with water (2 x) and then with brine (1 x) and dried over anhydrous magnesium sulfate. It was filtered, the filtrate evaporated under reduced pressure and purified by chromatography of the remaining solid on silica gel. It was first eluted with ethyl acetate-hexanes (9:1), then the partially purified material was rechromatographed with ethyl acetate-hexanes (1:1), whereby the title compound was obtained as a grey-white solid with m.p. 154-157°C.

G. 4-(8-Chloro-5,11-dihydrol)benzothiepinor4,3-bl pyridin-11-ylidene)piperidine

A solution of the title compound from Part F above (720 mg, 1.87 mmol) and potassium hydroxide (2.0 g, 35.6 mmol) in ethanol (20 mL) and water (2 mL) was refluxed for 21 .5 hours in an inert gas atmosphere.

It was cooled to room temperature, diluted with methylene chloride (20 ml) and washed first with water (4x) and then with saline (1x). The solution was dried over anhydrous sodium sulfate, filtered and the filtrate evaporated under reduced pressure to give the title compound as an off-white solid, m.p. 206.5-215°C.

Example 1

1-Acetyl-4-(10H- rylbenzothiopyranor3,2-blpyridin-1O-ylidene)-piperidine

The title compound from Preparative Example 1, Part D (131 mg) was dissolved in dry CH 2 Cl 2 (6 mL) and pyridine (57 µl) in CH 2 Cl 2 (1 mL) was added. It was cooled in an ice bath under an argon atmosphere and CH 3 C(O)Cl (50 µl) in CH 2 Cl 2 (2 ml) was added dropwise. The reaction mixture was stirred while warming to room temperature during 30 min.

The reaction mixture was diluted with CH 2 Cl 2 and quenched with dilute NaOH (0.5 N, 50 mL). The organic layer was separated and extracted with CH 2 Cl 2

(1x). The organic layer was washed with saline (1x),

dried over Na 2 SO 4 , filtered and the solvent removed. It was then azeotropically distilled with toluene (1x), whereby a glassy solid (145 mg) was obtained which can be triturated with ethyl acetate and pentane.

It was purified by flash chromatography and eluted with

5% CH 3 OH in CH 2 Cl 2 to give the title compound as a white glassy solid (140 mg).

Similarly, 1-acetyl-2,6-dimethyl-4-(10H-[1]-benzothiopyrano[3,2-b]pyridin-10-ylidene)piperidine was prepared from the title compound in Preparative Example 5, Part B.

Example 2

4-(10H-TIIbenzopyranoT3,2-b]pyridin-10-ylidene)-1- piperidinecarboxaldehyde

The title compound from Preparative Example 2, Part C (13.1 g), in ethyl formate (400 ml) was refluxed on a steam bath for 12 hours.

Excess ethyl formate was removed under vacuum to give a brown oil.

The resulting brown oil was triturated with ethyl acetate to give the title compound as a crystalline solid which can be recrystallized from ethyl acetate

(7.5 g, m.p. 142-145°C.)

Example 3

1-acetvl-4-(10H-T11benzopyranof3.2-blpyridin-10-ylidene)-piperidine

The title compound from Preparative Example 2, Part C (304 mg) was dissolved in dry CH 2 Cl 2 (10 mL) and pyridine (0.456 mL).

It was cooled in an ice bath under an argon atmosphere, and acetic anhydride (0.505 mL in CH2Cl2 (2 mL)) was slowly added. The reaction mixture was stirred while warming to room temperature over 30 min to give the title compound in crude form.

It was purified via flash chromatography eluting with 0% T 3% CH 3 OH in CHCl 3 . The appropriate fractions were combined after removal of the solvent and the solid was triturated with pentane (2x) to give the title compound as a white solid (178 mg, mp 124-126°C).

Example 4

1-acetvl-4-(5,6,7,12-tetrahydrobenzor6,71cvkloctari,2-blpyridin-12-vlidene)piperidine

The title compound from Preparative Example 3, part H (302 mg, 1.04 mmol) was dissolved in dry CH 2 Cl 2 (10 mL) at 0°C under an N 2 atmosphere. Acetic anhydride (110 µl) was added dropwise.

After 4.5 hours, the reaction was stopped by pouring into aqueous NaOH (1 N). It was extracted with CH 2 Cl 2 (3x). The organic portions were combined, dried over MgSO 4 , filtered and rotary evaporated to dryness to give the title compound as a glass (331 mg).

Similarly, 1-acetyl-4-(3-methyl-10-fluoro-5,6,7,12-tetrahydrobenzo[6,7]cycloocta[1,2-b]pyridin-12-ylidene)piperidine was prepared from the title compound from Preparation Example 6, Part G.

Example 5

l- acetvl- 4- 8- chloro- 5 . ll- dihydrorom benzoxepinor4. 3-bl pyridin-ll-ylidene) piperidine

The title compound from Preparative Example 4, Part G (113 mg) was dissolved in CH 2 Cl 2 (4 mL). Pyridine (58.4 µl) was added and the reaction mixture was cooled. Acetyl chloride (51.4 µl) was added and it was stirred under an argon atmosphere.

less than 1 hour.

The reaction mixture was poured into water and extracted with CH 2 Cl 2 . The combined organic portions were washed with brine and dried over Na 2 SO 4 .

The solvent was removed to give the title compound as an off-white glass.

The resulting compound was purified by flash chromatography eluting with 5% CH 3 OH in CH 2 Cl 2 to give the title compound as a white glass (110 mg).

Example 6

l-Methoxacetyl-4-(5,6,7,12-tetrahydrobenzor6,71cycloocta-fl,2-b1pyridin-12-ylidene)piperidine

The title compound from Preparation Example 3, Part Hr and pyridine was dissolved in dry CH 2 Cl 2 at 0°C under an argon atmosphere. 1.1 equiv. of methoxyacetyl chloride was added dropwise and it was slowly warmed to room temperature. After 1.5 hours, the mixture was taken up in CH 2 Cl 2 and washed with brine. It was dried over Na2SO4, filtered and concentrated under vacuum, whereby a residue was obtained which can be purified via flash chromatography.

Example 7

1-acetyl-4-(8-chloro-5,11-dihydrof11benzothiepinoT4,3-blpyridin-ll-ylidene)piperidine

To a stirred solution of the title compound from Preparative Example 7, Part G (470 mg, 1.43 mmol), and pyridine (225 mg, 2.84 mmol) in methylene chloride (21 mL), maintained at 10°C, was added acetyl chloride (220 mg, 2.83 mmol), and the resulting solution was stirred at 10°C for 45 min.

Ice water (20 mL) was added and the mixture was basified with 2.5 M aqueous sodium hydroxide. The layers were separated and the aqueous layer was extracted with methylene chloride (2x). The extracts were combined, washed with saline (1x), dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure. The remaining glass was chromatographed on silica gel, it was eluted with methylene chloride-methanol-ammonium hydroxide (90:9:0.25), the resulting yellow powder was triturated with hexanes and filtered to give the title compound as a very pale yellow hemihydrate , sm.p. 80-83.5°C (dec.).

Example 8

1-Acetyl-4-(8-chloro-5,11-dihydro TIIbenzothiepino\A.3-bl pyridin-ll-ylidene)piperidine-6-oxide

Solid 3-chloroperoxybenzoic acid (59.4 mg of 80-85%, 0.293 mmol) was added to a stirred, cold (-50°C) solution of the title compound from Example 7 above (109 mg, 0.293 mmol) in methylene chloride (7 mL) , and the resulting solution was stirred at -50°C for 1 hour.

The cold solution was sequentially washed with 1.1 M aqueous sodium bicarbonate (1x), water (2x) and saline (1x). It was dried over anhydrous magnesium sulfate, filtered and the solvent evaporated from the filtrate under reduced pressure. The residue was triturated with ether and filtered to give the 1/4 hydrate of the title compound as a white solid, m.p. 209-211°C (dec.).

Example 9

(a) 1-Acetyl-4-(8-chloro-5,11-dihydro["1"1benzothiepino-f4,3-blpyridin-11-ylidene)piperidine-6,6-oxide

(b) l- acetyl- 4-( 8- chloro- 5, ll- dihydrorylbenzothiepino-T4, 3- blpyridin- ll- ylidene) piperidine- 1, 6, 6- trioxide (c) 1- acetyl- 4-( 8 - chloro- 5, 11- dihydrorylbenzothiepino- f 4,3-blpyridin-ll-ylidene)piperidine-l,6-dioxide

(a) Solid 3-chloroperoxybenzoic acid (98.3 mg of 80-85%, K 0.48 mmol) was added to a stirred, cold (-50°C) solution of the title compound from Example 7 (202 mg, 0.546 mmol) in methylene chloride (6 ml). It was stirred for 1 hour at -50°C, a second amount of 3-chloroperoxybenzoic acid (98.3 mg, K 0.48 mmol) was added and stirred for a further 1 hour at -50°C. A third

portion of 3-chloroperoxybenzoic acid (9.4 mg, K 0.046 mmol) was added, and the reaction mixture was allowed to warm to room temperature. At room temperature it was stirred for 1 hour, a fourth amount of the oxidizing agent (9.4 mg, K 0.046 mmol) was added and stirred for a final 1 hour period.

The reaction mixture was washed first with 1.1 M aqueous sodium bicarbonate (1x) and then with saline (1x). It was dried over anhydrous magnesium sulphate, filtered and the solvent evaporated from the filtrate under reduced pressure. The residue was chromatographed on silica gel, eluting with methylene chloride-methanol-ammonium hydroxide (98:5:0.25), whereby fractions corresponding to the title compounds or (a), (b) and (c). The fractions enriched with compound (a) were again chromatographed on silica gel eluting with methylene chloride-methanol-ammonium hydroxide (99:1:0.13), whereby the title sulfone was obtained as a 3/4 hydrate, m.p. 225-228°C (dec. ). (b) The solid recovered from the chromatography fractions containing compound (b) was triturated, it was filtered, and the solid was crystallized from methanol-isopropyl ether. The crystalline product was triturated with ether and filtered to give the 3/4 hydrate of the title sulfone N-oxide as a white solid, m.p. 238-240°C (dec.). (c) The solid recovered from the chromatography fractions containing compound (c) was triturated in ether and filtered to give the title sulfoxide N-oxide as a tan solid, m.p. 180-184°C (dec.). Example 10 1-(4-Pyridinylcarbonyl)-4-(5,6,7,12-tetrahydrobenzocycloocta-T1,2-blpyridin-12-ylidene)piperidine-N'-oxide

To a mixture of 4.50 g (15.5 mmol) 4-(5,6,7,12-tetrahydrobenzocycloocta[1,2-b]pyridin-12-ylidene)piperidine, 2.19 g (15.7 mmol ) isonicotinic acid N-oxide and 2.33 g (17.2 mmol) of 1-hydroxybenzotriazole hydrate in 30 ml of dry methylene chloride at -15°C and under a nitrogen atmosphere, a solution of 3.26 g was added dropwise over 25 min (16.9 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 60 ml of dry methylene chloride. The reaction mixture was slowly allowed to warm to room temperature. After 3 hours, the mixture was poured into a solution of 10% aqueous sodium dihydrogen phosphate and extracted with methylene chloride (3x). The combined organic portions were dried over MgSO 4 , filtered and concentrated under vacuum to give a product which was purified via flash chromatography to 1-(4-pyridinylcarbonyl)-4-(5,6,7,12-tetrahydrobenzocycloocta[l ,2-b]pyridin-12-ylidene)piperidine-N-oxide.

Example 11

1-acetyl-4-(9H-indenor2>1-blpyridin-9-yl)piperazine

Intermediate compound XIV can be reduced with a reducing agent such as NaBH4 to give the corresponding alcohol. This can be converted to the corresponding 9-methylsulfonylindeno[2,1-b]pyridine.

A mixture of 68 mg (0.28 mmol) 9-methylsulfonyl-9H-indeno[2,1-b]pyridine, 76 mg K2CO3 (0.55 mmol) and 59 mg (0.46 mmol) N-acetyl-piperazine in 10 ml of acetonitrile was heated at about 40°C under a nitrogen atmosphere for 4 hours. The mixture was poured into water and extracted 3x with EtOAc. The organic layers were combined, washed with brine, dried over MgSO 4 , filtered and concentrated under vacuum. The residue was purified via flash chromatography (2-3% MeOH/NH3 in CH2Cl2) to give 52 mg (65%) of the title compound as an off-white solid.

Claims (2)

1. Analogy method for the preparation of therapeutically active compounds of the general formula or a pharmaceutically acceptable salt or solvate thereof, where: one of a and d is nitrogen or -NO, and the remaining a, b, c and d groups are CH; R<3> and R<4> may be the same or different and are independent of each H or halogen; R<5>, R<6>, R<7> and R<8> are independently H or C₁-C₁-alkyl; T is carbon or nitrogen, as the dotted line attached to T is any double bond when T is carbon; m and n are whole numbers 0, 1, 2 or 3, so that the sum of m + n is equal to 0-3; when j + n is 1, X is -0- or -S(0)e-, where e is 0, 1 or 2; when m + n is 0, X can be any of the substituents for m + n equal to 1, and X can also be a direct bond; when m + n is 3, then X is a direct bond; each Ra is H; Z is =O, R is H, C₁-C₁ alkyl or where Y is N or NO; characterized in that: A. a compound of formula II is reacted with a compound of formula III, where L is a suitable leaving group and the other symbols have the meanings given above, or B. a compound of formula XXX is reacted with a compound of formula XXXII or XXIX, whereby a compound of formula I is obtained if R<c> is Z(C)Rwhere the symbols have the meanings indicated above. 2. Method according to claim 1 for the production of: l-acetyl-4-(10H-[1]-benzothiopyrano[3,2-b]pyridin-10-ylidene)piperidine, l-acetyl-4-(8-chloro- 5,11-dihydro-[1]-benzoxepino-[4,3-b]pyridin-ll-ylidene)piperidine, l-acetyl-4-(10H-[1]benzopyrano[3,2-b]pyridine- 10-ylidene)piperidine, 4-(10H-[1]-benzopyrano[3,2-b]pyridin-10-ylidene)-1-piperidinecarboxaldehyde, l-acetyl-4-(5H-benzopyrano[2,3-b]pyridine-5 -ylidene)-piperidine, l-acetyl-4-(5,6,7,12-tetrahydrobenzo[6,7]cycloocta-[1,2-b]pyridin-12-ylidene)piperidine, I-methoxyacetyl-4- (5,6,7,12-tetrahydrobenzo[6,7]-cycloocta[1,2-b]pyridin-12-ylidene)piperidine, II-(1-acetyl-4-piperidinylidene)-8-chloro-5, 11-dihydro-[1]-benzothiepino[4,3-b]pyridine, 11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4,3- b]pyridine-1,6-dioxide, 11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridine-6,6-dioxide, 11-(1-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridine-6-oxide, 11-(l-acetyl-4-piperidinylidene)-8-chloro-5,11-dihydro-[1]-benzothiepino[4,3-b]pyridine-6,6-trioxide, l-acetyl-4-(9H -indeno[2,1-b]pyridin-9-yl)piperazine or 1-(4-pyridinylcarbonyl)-4-(5,6,7,12-tetrahydrobenzocycloocta[1,2-b]pyridin-12-ylidene)-piperidin -N'-oxide, characterized in that corresponding starting compounds are used.