Field of the Invention

The present invention relates to novel N-substituted azaheterocyclic carboxylic acids and esters thereof in which a substituted alkyl chain forms part of the N- substituent or salts thereof, to methods for their preparation, to comp ositions containing them, and to their use for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibers play a pathophysiological role by eliciting neurogenic pain or inflammation. The invention also relates to the use of the present compounds for the treatment of insulin resistance in non-insulin- dependent diabetes mellitus (NIDDM) or aging, the present compounds knowing to interfere with neuropeptide containing C-fibres and hence inhibit the secretion and circulation of insulin antagonizing peptides li e CGRP or amylin.

Background of the Invention

The nervous system exerts a profound effect on the inflammatory response Antidromic stimulation of sensory nerves results in localized vasodilation and increased vascular permeability (Janecso et al. Br. J Pharmacol 1967, 31 , 138- 151) and a similar response is observed following injection of peptides known to be present in sensory nerves From this and other data it is postulated that peptides released from sensory nerve endings mediate many inflammatory responses in tissues like skin, joint, urinary tract, eye, meninges, gastro-intestinal and respiratory tracts Hence inhibition of sensory nerve peptide release and/or activity, may be useful in treatment of, for example arthritis, dermatitis, rhinitis asthma, cystitis, gingivitis, thrombo-phlelitis, glaucoma, gastro-intestinal diseases or migraine

Further, the potent effects of CGRP on skeletal muscle glycogen syπthase activity and muscle glucose metabolism, together with the notion that this peptide is released from the neuromuscular junction by nerve excitation, suggest that CGRP may play a physiological role in skeletal muscle glucose metabolism by directing the phosphorylated glucose away from glycogen storage and into the glycolytic and oxidative pathways (Rossetti et al. Am. J Physiol. 2£4, E1-E10 1993) This peptide may represent an important physiological modulator of intracellular glucose trafficking in physiological conditions, such as exercise, and may also contribute to the decreased insulin action and skeletal muscle glycogen synthase in pathophysiological conditions like NIDDM or aging-associated obesity (Melnyk et al Obesity Res 3, 337-344 1995) where circulating plasma levels of CGRP are markedly increased. Hence inhibition of release and/or activity of the neuropeptide CGRP may be useful in the treatment of insulin resistance related to type 2 diabetes or aging.

In US Patent No 4,383,999 and No 4,514,414 and in EP 236342 as well as in EP 231996 some derivatives of N-(4,4-dιsubstιtύted-3-butenyl)azaheterocyclιc carboxylic acids are claimed as inhibitors of GABA uptake. In EP 342635 and EP 374801 , N-substituted azaheterocyclic carboxylic acids in which an oxime ether group and vinyl ether group forms part of the N-substituent respectively are claimed as inhibitors of GABA uptake Further, in WO 9107389 and WO 9220658 N-substituted azacyciic carboxylic acids are claimed as GABA uptake inhibitors EP 221572 claims that 1-aryloxyalkylpyπdιne-3-carboxylιc acids are inhibitors of GABA uptake

Description of the Invention

Tne present invention relates to novel N-substituted azaheterocyclic carboxylic acids and esters thereof of formula I

wherein R and R ² independently are hydrogen, halogen, trifluoromethyl, hydroxy, Ca. ₆ -alkyl or C^-alkoxy; and

A together with the double bond represents a cyclic system selected from benzene, pyridine, pyrimidine, pyrazine, pyridazine, thiophene, pyrrole, furan, oxazole, isoxazole, imidazole, pyrazole or thiazole; and

B together with the double bond represents a cyclic system selected from pyridine, pyrimidine, pyrazine, pyridazine, thiophene, pyrrole, furan, oxazole, isoxazole, imidazole, pyrazole or thiazole; and C together with the double bond represents a bicyclic system selected from naphthalene, quinoline, isoquinoline, dihydrobenzofuran, indole, benzofuran or benzothiophene; and

Y is >N-CH ₂ -, >CH-CH ₂ - or >C=CH- wherein only the underscored atom participates in the ring system; and X is -0-, -S-, -C(R ⁶ R ⁷ )-, -CH ₂ CH ₂ -, -CH=CH-CH ₂ -, -CH ₂ -CH=CH-, -CH ₂ -(C=0)-,

-(C=0)-CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH=CH-, -N(R ⁸ )-(C=0)-, -(C=0)-N(R ⁸ )-, -0-CH ₂ -. -

CH.-0-, -S-CH ₂ -, -CH ₂ -S-, -(C=0)-, -N(R ⁹ )- or -(S=0)- wherein R ⁶ , R ⁷ , R ^e and

R ⁹ independently are hydrogen or C, _.6 -alkyl; and

r is , 2 or 3; and m is 1 or 2; and n is 1 when m is 1 and n is 0 when m is 2; and

R ³ and R ⁴ each represents hydrogen or may - when m is 2 - together represent a bond; and

R ⁵ is -OH or Ca _.6 -alkoxy; or a pharmaceutically acceptable salt thereof.

The compounds of formula I may exist as geometric and optical isomers and all isomers and mixtures thereof are included herein. Isomers may be separated by means of standard methods such as chromatographic techniques or frac¬ tional crystallization of suitable salts.

Preferably, the compounds of formula I exist as the individual geometric or optical isomers.

The compounds according to the invention may optionally exist as pharmaceuti¬ cally acceptable acid addition salts or - when the carboxylic acid group is not esterified - as pharmaceutically acceptable metal salts or - optionally alkylated - ammonium salts.

Examples of such salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate or similar pharmaceutically acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) which are hereby incorporated by reference.

The term "C.. _.6 -alkyr as used herein, alone or in combination, refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms such as e g methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, n-hexyl, 1 ,2-dιmethylpropyl, 2,2-dιmethylpropyl and 1 ,2,2-trιmethylpropyl

The term "C.. ₆ -alkoxy" as used herein, alone or in combination, refers to a straight or branched monovalent substituent comprising a C, ₆ -alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen and having 1 to 6 carbon atoms e g methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy

The term "halogen" means fluorine, chlorine, bromine or iodine

Illustrative examples of compounds encompassed by the present invention include

1-(3-(5,6-Dιhydropyrιdo[2,3-b][1]benzazepιn-11-yl)-1-p ropyl)-3- pipeπdinecarboxy c acid,

1-(3-(5,6-Dιhydropyπmιdo[4,5-b][1]benzazepιn-11-yl)-1 -propyl)-3-pιperι- dinecarboxylic acid,

1 -(3-(6, 11 -Dιhydropyrιdo[2,3-b][4, 1 ]benzoxazepιn-1 1 -yl)-1 -propyl)-3- piperidinecarboxy c acid,

1-(3-(6,11-Dιhydro[2]benzoxepιno[4 3-b]pyrιdιn-11-ylιdene)-1-propyl)-3- pipeπdinecarboxylic acid,

1-(3-(Pyrido[3,2-b][1 ,4]benzothiazin-10-yl)-1-propyl)-3-piperidinecarboxylic acid;

1-(3-(Pyrimido[5,4-b][1 ,4]benzothiazin-10-yl)-1-propyl)-3-piperidine-carboxylic acid;

1 -(3-(4,5-Dihydrobenzo[5,6]cyclohepta[1 ,2-b]thiophen-10-ylidene)-1 -propyl)-3- piperidinecarboxylic acid;

1-(3-(4,5-Dihydrocyclohepta[2,1-b:4,5-b']dithiophen-9-yli dene)-1-pro-pyl)-3- piperidinecarboxylic acid;

1 -(3-(5,6-Dihydrobenzo[5,6]cyclohepta[1 ,2-b]pyridin-11 -ylidene)-1 -propyl)-3- piperidinecarboxylic acid;

1-(3-(5,6-Dihydrobenzo[5,6]cyclohepta[1 ,2-c]pyhdin-11-ylidene)-1-propyl)-3- piperidinecarboxylic acid;

1 -(3-(5-Methyl-6-oxo-5,6-dihydro-11 H-pyrido[2,3-b][1 ,4]benzodiazepin-11 -yl)-1 - propyl)-3-piperidinecarboxylic acid;

1-(3-(5-Methyl-6-oxo-5,6-dihydro-11 H-pyrido[2,3-b][1 ,5]benzodiazepin-11-yl)-1- propyl)-3-piperidinecarboxylic acid;

1-(3-(12,13-Dihydroquino[2,3-b][f]benzazepin-5-yl)-1-prop yl)-3-piperidine- carboxylic acid;

(R)-1-(3-(12,13-Dihydro-7H-benzo[4,5]cyclohepta[1 ,2-a]naphthalen-7-ylidene)-1- propyl)-3-pιperidinecarboxylic acid;

(R)-1-(3-(12,13-Dihydro-7H-benzo[4,5]cyclohepta[1 ,2-b]naphthalen-7-ylidene)- 1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(12,13-Dihydro-7H-benzo[5,6]cyclohepta[1 ,2-a]naphthalen-7-ylidene)- 1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(4,5-Dihydrocyclohepta[2,1-b:4,5-b']dithiophen-9 -ylidene)-1-propyl)-3- piperidinecarboxylic acid;

(R)-1 -(3-(4, 10-Dihydrothieno[3,2-c][1 ]benzoxepin-10-ylidene)-1 -propyl)-3- piperidinecarboxylic acid;

(R)-1-(3-(10,11-Dihydro-5H-benzo[4,5]cyclohepta[1 ,2-b]pyridin-5-ylidene)-1- propyl)-3-piperidinecarboxyiic acid;

Z-(R)-1 -(3-( 10,11 -Dihydro-5H-benzo[4,5]cyclohepta[2, 1 -c]pyridin-5-ylidene)-1 - propyl)-3-piperidinecarboxylic acid;

E-(R)-1-(3-(10,11-Dihydro-5H-benzo[4,5]cyclohepta[2,1-c]p yridin-5-ylidene)-1- propyl)-3-piperidinecarboxylic acid;

or a pharmaceutically acceptable salt thereof.

As used herein, the term "patient" includes any mammal which could benefit from treatment of neurogenic pain or inflammation or insulin resistance in NIDDM. The term particularly refers to a human patient, but is not intended to be so limited.

It has been demonstrated that the novel compounds of formula I inhibit neurogenic inflammation which involves the release of neuropeptides from peripheral and central endings of sensory C-fibres. Experimentally this can be demonstrated in animal models of formalin induced pain or paw oedema (Wheeler and Cowan, Agents Actions 1991 , 34, 264-269) in which the novel compounds of formula I exhibit a potent inhibitory effect. Compounds of formula I may be used to treat all painful, hyperalgesic and/or inflammatory conditions in which C-fibers play a pathophysiological role by eliciting neurogenic pain or inflammation, i.e.: Acutely painful conditions exemplified by migraine, postoperative pain, burns, bruises, post-herpetic pain (Zoster) and pain as it is generally associated with acute inflammation; chronic, painful and/or inflammatory conditions exemplified by various types of neuropathy (diabetic, post-traumatic, toxic), neuralgia, rheumatoid arthritis, spondylitis, gout, inflammatory bowel disease, prostatitis, cancer pain, chronic headache, coughing, asthma, chronic pancreatitis, inflam¬ matory skin disease including psoriasis and autoimmune dermatoses, osteoporotic pain

Further, it has been demonstrated that the compounds of general formula I im- proves the glucose tolerance in diabetic ob/ob mice and that this may result from the reduced release of CGRP from peripheral nervous endings Hence the compounds of general formula I may be used in the treatment of NIDDM as well as aging-associated obesity. Experimentally this has been demonstrated by the subcutaneous administration of glucose into ob/ob mice with or without previous oral treatment with a compound of general formula I

The compounds of formula I may be prepared by the following methods

Method A:

(CH,) _r

W

(I") (ill)

A compound of formula II wherein R ¹ , R ² , X, Y, A, B and r are as defined above and W is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate may be reacted with an azaheterocyclic compound of formula III wherein R ³ , R ⁴ , R ⁵ , m and n are as defined above. This alkylation reaction may be carried out in a solvent such as acetone, dibutylether, 2-butanone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran (THF) or toluene in the presence of a base e.g. potassium carbonate and a catalyst, e.g. an alkali metal iodide at a temperature up to reflux temperature for the solvent used for e.g. 1 to 120 h. If esters have been prepared in which R ⁵ is alkoxy, compounds of formula I wherein R ⁵ is OH may be prepared by hydrolysis of the ester group, preferably at room temperature in a mixture of an aqueous alkali metal hydroxide solution and an alcohol such as methanol or ethanol, for example, for about 0.5 to 6 h.

Method B:

(IV) (III)

A compound of formula II wherein R ¹ , R ² , X, Y, C and r are as defined above and W is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate may be reacted with an azaheterocyclic compound of formula III wherein R ³ , R ⁴ , R ⁵ , m and n are as defined above. This alkylation reaction may be carried out in a solvent such as acetone, dibutylether, 2-butanone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran (THF) or toluene in the presence of a base e.g. potassium carbonate and a catalyst, e.g. an alkali metal iodide at a temperature up to reflux temperature for the solvent used for e.g. 1 to 120 h. If esters have been prepared in which R ⁵ is alkoxy, compounds of formula I wherein R ⁵ is OH may be prepared by hydrolysis of the ester group, preferably at room temperature in a mixture of an aqueous alkali metal hydroxide solution and an alcohol such as methanol or ethanol, for example, for about 0.5 to 6 h

Compounds of formula II, III and IV may readily be prepared by methods

familiar to those skilled in the art.

Under certain circumstances it may be necessary to protect the intermediates used in the above methods e.g. a compound of formula III with suitable protect- ing groups. The carboxylic acid group can, for example, be esterified. Introduc¬ tion and removal of such groups is described in "Protective Groups in Organic Chemistry" J.F.W. McOrnie ed. (New York, 1973).

Pharmacological Methods

Formalin induced pain or paw oedema

Values for in vivo inhibition of formalin induced pain or oedema for the com¬ pounds of the present invention were assessed in mice essentially by the method of Wheeler-Aceto and Cowan (Agents Action 1991 , 34, 265-269).

About 20 g NMRI female mice were injected 20 μl 1 % formalin into the left hind paw. The animals were then placed on a heated (31°C) table, and the pain response was scored. After 1 h they were killed and bled. Left and right hind paws were removed and the weight difference between the paws was used as indication of the oedema response of the formalin injected paw.

Reduced release of CGRP ob/ob female mice, 16 weeks of age, where injected glucose (2g/kg) subcu- taneously. At times hereafter blood glucose was determined in tail venous blood by the glucose oxidase method. At the end of the study the animals were decapitated and trunck blood collected. Immunoreactive CGRP was determined in plasma by radio-immuno-assay. Two groups of animals were used. The one group was vehicle treated, whereas the other group received a compound of

formula I via drinking water (100 mg/l) for five days before the test.

TABLE 1 Inhibition of formalin induced pain response at 0.1 mg/kg

Example no. % Pain inhibition

34

For the above indications the dosage will vary depending on the compound of formula I employed, on the mode of administration and on the therapy desired However, in general, satisfactory results are obtained with a dosage of from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of compounds of formula I, conveniently given from 1 to 5 times daily, optional- ly in sustained release form. Usually, dosage forms suitable for oral administra¬ tion comprise from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of the compounds of formula I admixed with a pharmaceutical carrier or diluent.

The compounds of formula I may be administered in a pharmaceutically accept¬ able acid addition salt form or where possible as a metal or a lower alkylammo- nium salt. Such salt forms exhibit approximately the same order of activity as the free base forms.

This invention also relates to pharmaceutical compositions comprising a com¬ pound of formula I or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutical carrier or diluent. The compo¬ sitions containing the compounds of this invention may be prepared by conven- tional techniques and appear in conventional forms, for example capsules, tablets, solutions or suspensions.

The pharmaceutical carrier employed may be a conventional solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water.

Similarly, the carrier or diluent may include any time delay material known to the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

If a solid carrier for oral administration is used, the preparation can be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

Generally, the compounds of this invention are dispensed in unit dosage form comprising 50-200 mg of active ingredient in or together with a pharmaceuti¬ cally acceptable carrier per unit dosage.

The dosage of the compounds according to this invention is 1-500 mg/day, e.g. about 100 mg per dose, when administered to patients, e.g. humans, as a drug.

A typical tablet which may be prepared by conventional tabletting techniques contains

Core:

Active compound (as free compound 100 mg or salt thereof)

Colloidal silicon dioxide (Areosil ^® ) 1.5 mg

Cellulose, microcryst. (Avicef) 70 mg

Modified cellulose gum (Ac-Di-Sol*) 7.5 mg

Magnesium stearate

Coating:

HPMC approx. 9 mg

^" Mywacett ^® 9-40 T approx. 0.9 mg

^" Acylated monoglyceride used as plasticizer for film coating.

The route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.

EXAMPLES

The process for preparing compounds of formula I and preparations containing them is further illustrated in the following examples, which, however, are not to be construed as limiting.

Hereinafter, TLC is thin layer chromatography, CDCI ₃ is deuterio chloroform and DMSO-d ₆ is hexadeuterio dimethylsulfoxide. The structures of the com¬ pounds are confirmed by either elemental analysis or NMR, where peaks assigned to characteristic protons in the title compounds are presented where appropriate. ¹ H NMR shifts (δ _H ) are given in parts per million (ppm). M.p. is melting point and is given in °C and is not corrected. Column chromatography was carried out using the technique described by W.C. Still et al, J. Org. Chem. (1978), 43, 2923-2925 on Merck silica gel 60 (Art. 9385). Compounds used as starting materials are either known compounds or compounds which can readily be prepared by methods known per ____.

EXAMPLE 1

(R)-1-(3-(12,13-Dihydro-7H-benzo[4,5]cyclohepta[1 ,2-a]naphthalen-7-ylidene)-1- propyl)-3-piperidinecarboxylic acid hydrochloride

A solution of cyclopropylmagnesium bromide in dry tetrahydrofuran (prepared from cyclopropyl bromide (3.8 g, 0.031 mol), magnesium turnings (0.83 g, 0.034 mol) and dry tetrahydrofuran (50 ml) under an atmosphere of nitrogen) was added dropwise to a solution of 12,13-dihydrodibenzo[4,5]cyclohepta[1,2- a]naphthalen-7-one (4.0 g, 0.016 mol; prepared as described in J. Org. Chem. 1963, 3341) in dry tetrahydrofuran (50 ml). When addition was complete the mixture was heated at 50 °C for 3 h. The reaction mixture was cooled on an ice-bath and saturated ammoniumchloride (50 ml) and water (50 ml) were carefully added. The mixture was neutralised with 5 N hydrochloric acid (25 ml) and extracted with diethyl ether (2 x 100 ml). The combined organic extracts were washed with water (100 ml), saturated ammoniumchloride (100 ml), dried (MgS0 ₄ ), filtered and the solvent was evaporated in vacuo to give 5.5 g of crude 7-cyclopropyl-12,13-dihydro-7H-benzo[4,5]cyclohepta[1 ,2-a]-7- naphthalenol.

The above crude alcohol (5.0 g) was dissolved in dichloromethane (50 ml) and a solution of trimethylsilyl bromide (2.8 g, 0.02 mol) in dichloromethane (50 ml) was added dropwise at room temperature. When addition was complete the mixture was stirred at room temperature for 1 h and water (50 ml) was added. The phases were separated and the organic phase was washed with water (50 ml) and saturated sodium bicarbonate (50 ml). The organic phase was dried (MgS0 ₄ ) and the solvent was evaporated in vacuo to give 4.7 g (78 %) of crude 7-(3-bromo-1-propylidene)-12,13-dihydro-7H-benzo[4,5]cyclohe pta[1 ,2-a]- naphthalene as an oil.

A mixture of the above crude bromide (4.2 g, 0 012 mol), (R)-3-pιperιdι- necarboxylic acid ethyl ester tartrate (7 1 g, 0.023 mol), dry potassium carbon¬ ate (9 6 g, 0.07 mol) and methyl ethyl ketone (100 ml) was heated at reflux temperature for 18 h The cooled reaction mixture was quenched with water (100 ml) and extracted with ethyl acetate (2 x 100 ml) The organic extracts were washed with water (100 ml), saturated aqueous ammoniumchloride (100 ml), dried (MgSO , filtered and the solvent evaporated in vacuo The crude product (6 1 g) was purified by column chromatography on silica gel (600 ml) using a mixture of ethyl acetate and n-heptane (1 3) as eluent This afforded 1 9 g (37 %) of (R)-1-(3-(12,13-dιhydro-7H-benzo[4,5]cyclohepta[1 ,2- a]naphthalen-7-ylιdene)-1-propyl)-3-pιpeπdιnecarboxylιc acid ethyl ester as an

TLC R _f = 0.22 (Sι0 ₂ , ethyl acetate/heptane = 1 3)

The above ethyl ester (3 87 g, 0 004 mol) was dissolved in ethanol (50 ml) A solution of sodium hydroxide (0 2 g, 0 005 mol) in water (30 ml) was added The reaction mixture was stirred for 24 h at room temperature and the solvent was removed m vacuo Water (150 ml) was added and the mixture was washed with diethyl ether (2 x 100 ml) The aqueous phase was acidified with concentrated hydrochloric acid and washed with dichloromethane (3 x 100 ml) The aqueous phase was evaporated in vacuo and the residue was suspended in a mixture of 2-propanol (10 ml) and diethyl ether (50 ml), and stirred for 60 h at room temperature The precipitate was filtered off, washed with diethyl ether and dried in vacuo to give 2 2 g of the title compound as an amorphous solid

HPLC retention time = 6 40 minutes (water/acetonitπl = 1 1 H ₃ P0

triethylamine buffer pH = 3, C-18 R _f column).

¹ H NMR (200 MHz, DMSO-d ₆ ) δ _H 1.27 - 1.68 (m, 3H), 1.81 (bd, 1H), 2.00 - 2.98 (m, 10H), 3.15 - 3.68 (m, 3H), 5.88 + 5.98 (t, 1H, "E&Z"), 7.10 - 7.32 (m, 4H), 7.39 - 7.56 (m, 3H), 7.76 (d, 1H), 7.86 (dd, 1H), 8.03 + 8.20 (d, 1H, "E&Z").

Calculated for C ₂₈ H ₂₉ N0 ₂ , HCI: C, 75.02 %; H, 6.76 %; N, 3.13 %; Found: C, 75.01 %; H, 7.08 %; N, 2.99 %.

EXAMPLE 2

(R)-1 -(3-(12, 13-Dihydro-7H-benzo[4,5]cyclohepta[1 ,2-b]naphthalen-7-ylidene)-1 - propyl)-3-piperidinecarboxylic acid hydrochloride

To an ethylmagnesium bromide solution (prepared from magnesium (1.3 g, 0.052 mol) and ethylbromide (4.3 ml, 0.058 mol) and dry tetrahydrofuran (115 ml)) cooled on an icebath, a solution of 3-chloro-1-propanol (4 4 ml, 0.052 mol) in dry tetrahydrofuran (40 ml) was added dropwise with stirring. After addition

was complete, the mixture was stirred at room temperature for 0.5 h, and magnesium (1.3 g, 0.052 mol) was added. The stirring was continued at reflux temperature for 1.5 h To the resulting mixture, a solution of 12,13-dihydro-7H- benzo[4,5]cyclohepta[1 ,2-b]naphthalen-7-one (4 5 g, 0.017 mol, prepared as described in J. Org. Chem. 21,1956, 461) in dry tetrahydrofuran (50 ml) was added dropwise, and the reaction mixture was stirred at reflux temperature for 4 5 h The cooled reaction mixture was quenched with saturated ammonium chloride (100 ml), water (100 ml) and extracted with diethyl ether (2 x 100 ml) The organic extracts were washed with water (2 x 50 ml), brine (80 ml) and dried (MgSO , filtered and the solvent was evaporated in vacuo This afforded 5.1 g (92 %) of 7-(3-hydroxy-propyl)-12,13-dihydrodibenzo-[4,5]cyclo-hepta[1 ,2- b]naphtalen-7-ol.

To a mixture of methanol (100 ml), water (50 ml), and concentrated hydro- chloric acid (10 ml), the above propanol (5 1 g, 0 016 mol) was added, and the reaction mixture was stirred at reflux temperature for 18 h. The solvent was evaporated in vacuo. the residue was dissolved in water (100 ml) and extracted with diethyl ether (2 x 100 ml) The organic extracts were washed with water (2 x 50 ml), brine (80 ml) and dried (MgSO , filtered and the solvent was evapor- ated vacuo This afforded 1.5 g (31 %) of 7-(3-hydroxy-1-propylιdene)-12,13- dιhydro-dibenzo[4,5]cyclo-hepta[1 ,2-b]naphtalene as an oil

To a mixture of the above alcohol (1 8 g, 6 0 mmol) and triethylamine (1 8 ml) in dichloromethane (100 ml), methanesulfonyl chloride (1 0 g 9 0 mmol) dissolved in dichloromethane (20 ml) was added dropwise at 10 °C The reaction mixture was stirred at room temperature for 2 h and quenched with water (50 ml) The organic phase was separated, dried (MgSO filtered and evaporated jn vacuo This afforded 2.2 g of methanesulfonic acid 3-( 1 1 ,12-

dihydro-dibenzo[4,5]cyclohepta[1 ,2-b]naphthalen-7-ylidene)-1-propyl ester as an oil.

A mixture of the above methanesulfonate (2.2 g), (R)-3-piperidinecarboxylic acid ethyl ester tartrate (3.7 g, 12.0 mmol), potassium carbonate (5.0 g, 36.0 mmol), and methyl ethyl ketone (100 ml) was heated at reflux temperature for 48 h under an atmosphere of nitrogen. The cooled reaction mixture was quenched with water (100 ml) and extracted with diethyl ether (100 ml). The organic extract was washed with water (80 ml) and brine (80 ml), dried (MgSOJ, filtered and the solvent was evaporated in vacuo. The crude product was purified by column chromatography on silica gel (400 ml) using a mixture of ethyl acetate and heptane (1 :4) as eluent. This afforded 0.3 g of (R)-1-(3- (12,13-dihydro-7H-benzo[4,5]cyclohepta[1 ,2-b]naphtalen-7-ylidene)-1-propyl)-3- piperidinecarboxylic acid ethyl ester as an oil.

The above ethyl ester (0.3 g, 0.68 mmol) was dissolved in ethanol (35 ml) and a solution of sodium hydroxide (33 mg, 0.81 mmol) in water (10 ml) was added. The reaction mixture was stirred for 20 h at room temperature and the solvent was removed in vacuo. Water (100 ml) was added and the mixture was washed with diethyl ether (100 ml). The aqueous phase was acidified (pH = 1) with concentrated hydrochloric acid and extracted with dichloromethane (3 x 100 ml). The combined organic extracts were washed with water (100 ml), dried (MgSOJ, filtered and the solvent was evaporated in vacuo. The residue was suspended in diethyl ether (10 ml) and stirred for 1 h at room temperature The precipitate was filtered off, washed with diethyl ether and dried in vacuo at 40 °C, affording 180 mg (60 %) of the title compound as an amorphous solid

Calculated for C, _R H, _Q NO,, HCI. HO:

C, 72.17%; H, 6.92%; N, 3.01%; Found: C, 72.01 %; H, 7.01 %; N, 2.75%.

By a similar procedure as described in Example 2 the following compound has been prepared using 12,13-dihydro-dibenzo[5,6]cyclohepta[1 ,2-a]naphtalen-7- one (prepared as described in J. Org. Chem. 21,1956, 461 ) instead of 12,13- dihydro-7H-benzo[4,5]cyclohepta[1 ,2-b]naphthalen-7-one.

EXAMPLE 3

(R)-1-(3-(12,13-Dihydro-7H-benzo[5,6]cyclohepta[1 ,2-a]naphthalen-7-ylidene)-1- propyl)-3-piperidinecarboxylic acid hydrochloride

Calculated for C ₂₈ H _;g N0 ₂ , HCI, 0.5 H,0: C, 73.59%; H, 6.84%; N, 3.06%; Found:

C, 73.64%; H, 7.20%; N, 2.76%.

EXAMPLE 4

(R)-1-(3-(4,5-Dihydrocyclohepta[2,1-b:4,5-b']dithiophen-9 -ylidene)-1-propyl)-3- piperidinecarboxylic acid hydrochloride

2-Bromo-3-methylthiophene (111.6 g, 0.63 mol) was dissolved in cyclohexane (1 I). Azo-bisisobutyronit le (1 g) was added, and the mixture was heated at reflux temperature. While refluxing was maintained, a mixture of N-bromo- succinimide (122.1 g, 0 71 mol) and azo-bisisobutyronitπle (10.1 g) was added in portions, as fast as foaming allowed The mixture was allowed to cool,

filtered and the solvent was evaporated in vacuo to give crude 2-bromo-3- bromomethylthiophene as an oil.

Triethyl phosphite (154 ml) was added to the above crude bromomethyl- thiophene and the mixture was heated at reflux temperature for 4 h and then allowed to cool to ambient temperature. The mixture was distilled in vacuo to give 123.5 g diethyl 2-bromo-3-thiophenylmethylphosphonate as an oil.

B.p. 125 - 135 °C (0.2 - 0.3 mBar).

Potassium iej_t-butoxide (56.1 g, 0.5 mol) was suspended in toluene (1 I) under an atmosphere of nitrogen and the mixture was cooled to 5 °C. A solution of the above phosphonate (123 g, 0.39 mol) and thiophene-3-carboxaldehyde (43.8 g, 0.39 mol) in toluene (200 ml) was added dropwise over 1 h, keeping the temperature below 10 °C. Stirring was continued at 5 °C for 0.5 h and then at ambient temperature for 16 h. The reaction mixture was poured into icewater (1.2 I), the phases were separated and the aqueous phase was extracted with toluene (0.5 I). The combined organic phases were washed with water (2 x 0.5 I), dried (MgSO and the solvent was evaporated in vacuo to give 105 g of (E)-2-bromo-3-(2-(3-thiophenyl)vinyl)thiophene as an oil.

TLC: R _t = 0.77 (Si0 ₂ : ethyl acetate/heptane = 1 :3).

The above olefin (104.5 g, 0.39 mol) was dissolved in dry diethyl ether (600 ml)

and the mixture was cooled to -65 °C. n-Butyl lithium (280 ml, 0 45 mol of a 15% solution in hexane) was added over 30 minutes. Carbon dioxide gas was then bubbled through the solution over 1 h. The mixture was allowed to warm up to ambient temperature and stirring was continued for 1 h. The mixture was poured into ice cold water (1 I) and the phases were separated. The aqueous phase was washed with diethyl ether (2 x 300 ml). Diethyl ether (500 ml) was added and the mixture was acidified to pH = 1 with 36 % hydrochloric acid The phases were separated and the aqueous phase was extracted with diethyl ether (2 x 200 ml). The combined organic extracts were washed with water (2 x 200 ml), dried (MgSO and the solvent was evaporated in vacuo to give 50.8 g (E)-3-(2-(3-thiophenyl)vinyl)thiophene-2-carboxylic acid as a solid.

TLC R _f = 0.27 (Si0 ₂ : ethyl acetate/heptane = 1 :4, containing acetic acid).

M.p. 212-214 °C.

The above carboxylic acid (50.5 g, 0.21 mol) was dissolved in tetrahydrofuran (800 ml) and under an atmosphere of nitrogen, wet 10 % Pd on activated carbon (20 g) was added. The mixture was hydrogenated at 8 atmospheres and room temperature for 21 h. A further portion of wet 10 % Pd on activated carbon (20 g) was added and the mixture was hydrogenated at 8 atmosphere and 40 °C for 20 h After cooling, the reaction mixture was filtered and the solvent was evaporated in vacuo to give the crude product (47 4 g) Recrystallisation from 96 % ethanol afforded in two crops 33 4 g 3-(2-(3- thιophenyl)ethyl)thιophene-2-carboxylιc acid as a solid

TLC R, = 0 64 (St0 ₂ ethyl acetate/heptane = 1 1 , containing acetic acid)

M.p. 162 - 166 °C.

The above saturated carboxylic acid (15.8 g, 0.066 mol) was suspended in benzene (450 ml) and phosphorus pentachloride (16.5 g, 0.079 mol) was added. The mixture was heated at reflux temperature for 10 minutes, cooled and nitrogen was bubbled through the solution for 30 minutes. The mixture was cooled to 5 °C and a solution of tin(IV) chloride (7.9 ml, 0.066 mol) in benzene (30 ml) was added at once. The mixture was heated at reflux temperature for 10 minutes and cooled to ambient temperature. Diethyl ether (100 ml) was added and the mixture was cooled to 5 °C. 5 N Hydrochloric acid (350 ml) and water (300 ml) were slowly added. The phases were separated and the aqueous phase was washed with diethyl ether (200 ml). Some black insoluble material remained in the reaction flask. This was dissolved in a mixture of acetone (300 ml) and 1 N hydrochloric acid (200 ml). The mixture was extracted with diethyl ether (200 ml) and the combined organic extracts were successively washed with 5 N hydrochloric acid, 1 N hydrochloric acid, water, and 1 N sodium hydroxide (2 x 300 ml of each). The organic phase was dried (MgSO and evaporated in vacuo. This afforded after drying, 10.70 g of 4,5- dihydrocyclohepta[2,1-b:4,5-b']dithiophen-9-one as a solid.

TLC: R, = 0.47 (Si0 ₂ : ethyl acetate/heptane = 1 :2).

M.p. 88 - 90 °C.

To a solution of ethyl magnesium bromide (prepared from magnesium turnings (2.1 g, 0.087 mol) and bromoethane (9.5 g, 0.087 mol) in tetrahydrofuran (30 ml)), 3-chloro-1 -propanol (7.3 ml, 0.087 mol) in tetrahydrofuran (30 ml) was

added with cooling (temperature below 30 °C) Stirring was continued at ambient temperature for 30 minutes, then magnesium turnings (2 1 g, 0 087 mol) and a few iodine crystals were added The Gngnard reaction was started with heating, and when all magnesium was consumed, heating at reflux temperature was continued for 1 h A solution of the above ketone (4 8 g, 0 022 mol) in tetrahydrofuran (40 ml) was added dropwise to the refluxing Gngnard solution After addition, the solution was heated at reflux temperature for further 4 5 h and stirred at ambient temperature for 16 h With stirring, the reaction mixture was poured into saturated ammonium chloride (200 ml), and stirring was continued for 30 minutes The mixture was filtered and the filtercake was washed with ethyl acetate The combined filtrates were separated and the aqueous phase was extracted with ethyl acetate (200 ml) The combined organic extracts were dried (MgSO and the solvent was evaporated in vacuo to give 9-(3-hydroxy-1-propyl)-4,5-dιhydrocyclohepta[2,1-b 4,5-b']dιthιophen-9-ol

The above crude diol was dissolved in a mixture of methanol (50 ml) and 1 N hydrochloric acid (1 ml) and the mixture was heated at reflux temperature for 2 h After cooling, the solvent was evaporated The residue was dissolved in ethyl acetate (50 ml) and the solution was washed with water (50 ml) and 5% sodium hydrogen carbonate (50 ml), dried (MgSO and the solvent was evaporated in vacuo The residue was purified by column chromatography to give 2 3 g (40% calculated from the ketone) of 3-(4,5-dιhydrocyclohepta[2,1- b 4 5-b']dιthιophen-9-ylιdene)-1-propanol as an oil

A solution of the above alcohol (2 3 g, 8 8 mmol) and tπethylamine (1 01 g 10 mmol) in dichloromethane (30 ml) was cooled to -5° C and methanesulfonyl chloride (1 05 g, 9 mmol) was added dropwise The solution was allowed to

warm up to ambient temperature and it was then stirred for 2 h. The reaction mixture was washed with water (2 x 20 ml), dried (MgSO and evaporated. The residue was dissolved in isopropyl acetate (60 ml), and lithium carbonate (8.9 g, 20 mmol) and (R)-(-) ethyl 3-piperidinecarboxylate (L)-(+) tartarate (6.2 g, 20 mmol) were added. The mixture was heated at reflux temperature for 16 h. The reaction mixture was cooled, filtered and the filtrate was evaporated in vacuo to give 6.8 g of crude (R)-1-(3-(4,5-dihydrocyclohepta[2,1-b:4,5-b']dithio- phen-9-ylidene)propyl)-3-piperidinecarboxylic acid ethyl ester as an oil, which was used without purification in the next step.

The above crude ester (6.8 g) was dissolved in ethanol (30 ml). Water (60 ml) and sodium hydroxide (4 g, 0.1 mol) were added and the mixture was heated at reflux temperature for 1 h. The mixture was cooled to ambient temperature, acidified with 6 N hydrochloric acid (33 ml) and extracted with dichloromethane (2 x 100 ml). The combined organic extracts were dried (MgSO and the solvent was evaporated in vacuo. The residue was crystallised from acetone and recrystallised from a mixture of acetonitrile and tetrahydrofuran (3:1 ) to give 2.5 g of the title compound as a solid.

M.p. 233 - 235 °C.

Calculated for C ₂₀ H ₂₃ NO ₂ S ₂ ,HCI,0.25 H ₂ 0: C, 57,96 %; H, 5.96 %; N, 3,34 %; Found: C, 57.89 %; H, 6.02 %; N, 3.22 %.

EXAMPLE 5

(R)-1 -(3-(4, 10-Dιhydrothιeno[3,2-c][1 ]benzoxepιn-10-ylιdene)-1 -propyl)-3- pipeπdinecarboxylic acid hydrochloride

2-Bromo-3-bromomethylthιophene (55 g, 0 21 mol, prepared similarly as described in example 4) was dissolved in N,N-dιmethylformamιde (350 ml) and potassium carbonate (32 5 g, 0 24 mol) was added A solution of phenol (20 1 g, 0.21 mol) in N,N-dιmethylformamιde (150 ml) was added at room tempera¬ ture with vigorous stirring, and stirring was continued for 24 h The mixture was poured into 1 N sodium hydroxide (500 ml) and extracted with ethyl acetate (500 ml) The organic phase was washed with water (4 x 500 ml), dried (MgSO and the solvent was evaporated in vacuo to give 54 9 g (95%) of 2- bromo-3-(phenoxymethyl)thιophene as an oil

TLC R, = 0 75 (Sι0 ₂ ethyl acetate/heptane = 1 4)

The above bromide (50.9 g, 0.19 mol) was dissolved in dry diethyl ether (300 ml) and the solution was cooled to -78 °C. n-Butyl lithium (80 ml, 0.22 mol, 23% solution in hexane) was added slowly, keeping the temperature below -70 °C. Dry carbon dioxide gas was then bubbled through the solution. The tempera- ture rose to -57 °C. Bubbling was continued for 2.5 h, and the temperature was then allowed to reach 0 °C. Cold water (500 ml) was added, the phases were separated and the organic phase was extracted with 1 N sodium hydroxide (3 x 150 ml). The combined aqueous phases were acidified using 5 N hydrochloric acid. The resulting precipitate was filtered off and dried, affording 35.3 g (80 %) of 3-(phenoxymethyl)-2-thiophenecarboxylic acid.

TLC: R _f = 0.20 (Si0 ₂ : ethyl acetate/heptane = 1 :4, containing formic acid). M.p. 144-146 °C.

The above carboxylic acid (34.5 g, 0.15 mol) was suspended in benzene (900 ml) and phosphorus pentachloride (36.8 g, 0.18 mol) was added The mixture was heated at reflux temperature for 10 minutes, and cooled to 30 °C. Nitrogen gas was bubbled through the mixture for 30 minutes, which was then cooled to 0 °C and a solution of tin(IV) chloride in benzene (50 ml) was added in one portion. The resulting mixture was heated at reflux temperature for 15 minutes, cooled and kept at 5 °C for 2 h. Diethyl ether (100 ml) was added followed by slow and cautious addition of 5 N hydrochloric acid (735 ml) and water (300 ml). The phases were separated, and the aqueous phase was extracted with diethyl ether (2 x 300 ml). The combined organic phases were washed with 5 N hydrochloric acid (2 x 300 ml) and water (2 x 300 ml), dried (MgSO and treated with activated carbon. Filtration and evaporation of the solvent in vacuo afforded 21.33 g (67%) of the crude product as brownish crystals

Further purification by column chromatography using a mixture of ethyl acetate and heptane (1 :4) as eluent gave 16.5 g (52 %) of 4,10-dihydrothieno[3,2- c][1]benzoxepin-10-one as a solid.

TLC: R _f = 0.29 (Si0 ₂ : ethyl acetate/heptane = 1 :4). M.p. 75-77 °C

To the above ketone (14.5 g, 0.067 mol) dissolved in tetrahydrofuran (200 ml), a solution of cyclopropyl magnesium bromide (prepared from bromocyclo- propane (21.7 ml, 0.27 mol) and magnesium turnings (6.52 g, 0.27 mol) in tetrahydrofuran (200 ml)) was added at room temperature. The mixture was stirred at room temperature for 2 h, and it was then poured into saturated ammonium chloride (800 ml). The resulting mixture was extracted with diethyl ether (2 x 300 ml). The combined organic phases were washed with saturated sodium hydrogencarbonate (300 ml), dried (MgSO and the solvent was evaporated in vacuo to give 11-cyclopropyl-4,10-dihydrothieno[3,2-c][1]benz- oxepin-10-ol as a solid.

TLC: R, = 0.29 (Si0 ₂ : ethyl acetate/heptane = 1 :4).

The above cyclopropyl carbinol (20.7 g, 0.080 mol) was dissolved in dichloro¬ methane (250 ml), and bromotrimethylsilane (11.8 ml, 0.088 mol) was added slowly with a slight increase in temperature. Stirring was continued at room temperature for 30 minutes. The reaction mixture was washed with water (2 x

300 ml) and saturated sodium hydrogencarbonate (2 x 300 ml), dried (MgSO and the solvent was evaporated in vacuo to give 22.8 g (88%) of 10-(3-bromo- 1-propylidene)-4,10-dihydrothieno[3,2-c][1]benz-oxepine as an oil.

TLC: R _f = 0.65 (Si0 ₂ : ethyl acetate/heptane = 1 :4).

The above bromide (22.8 g, 0.071 mol) was dissolved in methyl ethyl ketone (400 ml). Potassium iodide (23.5 g, 0.14 mol), potassium carbonate (58 7 g, 0.42 mol) and (R)-(-) ethyl 3-piperidinecarboxylate (L)-(+) tartarate (43.6 g, 0 14 mol) were added and the mixture was stirred vigorously for 24 h at room temperature. Ethyl acetate (400 ml) was added and the mixture was washed with water (4 x 400 ml), dried (MgSO and evaporated in vacuo The residue was purified by column chromatography, first using a mixture of ethyl acetate and heptane (1 :4) as eluent. Fractions with R _f = 0.10 were collected, evapor- ated in vacuo and then rechromatographed using a mixture of ethyl acetate and heptane (1 3) as eluent Fractions with R _f = 0 15 were collected, evapor¬ ated in vacuo. dissolved in 2 N hydrochloric acid (100 ml) and washed with diethyl ether (4 x 300 ml). The aqueous phase was adjusted to pH 12 using 50% sodium hydroxide and the alkaline mixture was extracted with diethyl ether (2 x 400 ml) The combined organic extracts were dried (MgSO and evapor¬ ation of the solvent in vacuo afforded 5.75 g (20%) of (R)-1-(3-(4,10-dιhydro- thιeno[3,2-c][1]benzoxepιn-10-ylιdene)-1-propyl)-3-pιpe� �dιnecarboxylιc acid ethyl ester as an oil

TLC R, = 0 15 (Si0 ₂ ethyl acetate/heptane = 1 3)

The above ethyl ester (5.75 g, 0.015 mol) was dissolved in 50% ethanol (250 ml), 1 N sodium hydroxide (17.4 ml, 0.017 mol) was added and the mixture was stirred at room temperature for 24 h. Water (300 ml) was added and the mixture was washed with diethyl ether (300 ml). The pH of the aqueous phase was adjusted to 2 with 1 N hydrochloric acid. Extraction with dichloromethane (3 x 300 ml), drying (MgSO and evaporation of the solvent in vacuo afforded the desired compound as a foam, which was crystallised by repeated evapor¬ ations of acetone solutions of the compound. Trituration with a mixture of diethyl ether and 2-propanol, filtration and drying afforded 1.87 g (32%) of the title compound as a solid.

M.p. 190 - 192 °C.

Calculated for C ₂₁ H ₂₃ NO ₃ S,HCI,0.25 H ₂ 0: C, 61.45 %; H, 6.02 %; N, 3.41 %; Found: C, 61.69 %; H, 6,17 %; N, 3.33 %.

EXAMPLE 6

(R)-1-(3-(10,11-Dihydro-5H-benzo[4,5]cyclohepta[1 ,2-b]pyridin-5-ylidene)-1- propyl)-3-piperidinecarboxylic acid dihydrochloride

To a solution of cyclopropylmagnesium bromide in dry tetrahydrofuran (pre¬ pared from cyclopropyl bromide (6.9 g, 0.048 mol), magnesium turnings (1 2 g, 0 049 mol) and dry tetrahydrofuran (50 ml) under an atmosphere of nitrogen) a solution of 10,11-dihydro-5H-benzo[4,5]cyclohepta[1 ,2-b]pyπdιn-5-one (5 0 g, 0 024 mol, prepared as described in Heterocyclic Chem 8, 1971 , 73) in dry tetrahydrofuran (50 ml) was added dropwise When addition was complete the mixture was stirred at room temperature for 2 h The reaction mixture was cooled on an ice-bath and saturated ammonium chloride (50 ml) and water (50 ml) were carefully added The mixture was extracted with diethyl ether (2 x 100 ml) The combined organic extracts were washed with water (100 ml), saturated ammonium chloride (100 ml), dried (MgSO , filtered and the solvent was evaporated vacuo to give crude 5-cyclopropyl-10,1 1-dιhydro-5H- benzo[4,5]cyclohepta[1 ,2-b]pyrιdιn-5-ol The crude product was purified by column chromatography on silica gel (600 ml) using a mixture of ethyl acetate and heptane (1 1 ) as eluent This afforded 2 6 g (43 %) of crude 5-cyclopropyl- 10,11-dιhydro-5H-benzo[4,5]cyclohepta[1 ,2-b]pyrιdιn-5-ol as an oil

TLC R _f = 0 17 (Sι0 ₂ ethyl acetate/heptane = 1 1)

The above alcohol (2 5 g, 0 01 mol) was dissolved in acetic acid (75 ml) and cooled on an ice bath to 15 °C To this mixture a solution of 33 % hydrobromic acid in acetic acid (10 ml) was added The mixture was stirred at 15°C for 30 minutes and water (200 ml) was added The aqueous reaction mixture was washed with diethyl ether (100 ml) and basified with 20 % sodium hydroxide The aqueous phase was extracted with diethyl ether (2 x 100 ml) and the combined organic extracts were washed with saturated sodium hydrogen- carbonate (50 ml), dried (MgSO and the solvent was evaporated vacuo affording 2 8 g (86 %) of crude 5-(3-bromo-1-propylιdene)-10,11-dιhydro-5H- benzo[4,5]cyclohepta[1 ,2-b]pyrιdιn as an oil

A mixture of the above crude bromide (2 6 g, 0 008 mol), (R)-3-pιperιdιne- carboxylic acid ethyl ester tartrate (9 8 g, 0 032 mol), potassium carbonate (6 6 g 0 048 mol), potassium iodide (0 7 g, 0 004 mol) and methyl ethyl ketone (250 ml) was heated at reflux temperature for 4 h Water (100 ml) was added to the cooled reaction mixture and the mixture was extracted with diethyl ether (2 x 100 ml) The combined organic extracts were washed with water (100 ml) saturated aqueous ammonium chloride (100 ml), dried (MgSO , filtered and the solvent evaporated in vacuo The crude product (4 3 g) was purified by column chromatography on silica gel (600 ml) using first ethyl acetate (1 L) then a mixture of ethyl acetate and triethylamine (96 4) as eluents This afforded 1 6 g (51 %) of (R)-1-(3-(10,11-dιhydro-5H-benzo[4,5]cyclohepta[1 ,2-b]pyrιdιn-5- ylιdene)1-propyl)-3-pιpeπdιnecarboxylιc acid ethyl ester as an oil

TLC: R _f = 0.19 (Si0 ₂ : ethyl acetate).

The above ester (1.0 g, 2.6 mmol) was dissolved in ethanol (50 ml) and a solution of sodium hydroxide (0.12 g, 3.1 mmol) in water (25 ml) was added. The reaction mixture was stirred for 1 week at room temperature and the solvent was removed in vacuo. Water (100 ml) was added and the mixture was washed with diethyl ether (50 ml). The aqueous phase was acidified (pH = 1 ) with concentrated hydrochloric acid and extracted with dichloromethane (2 x 50 ml). The aqueous phase was evaporated in vacuo. The residue was dissolved in 2-propanol (40 ml), filtered, and the solvent evaporated in vacuo. The residue was suspended in a mixture of acetone (15 ml) and diethyl ether (5 ml) and stirred for 60 h at room temperature. The precipitate was filtered off, washed with diethyl ether and dried in vacuo at 50°C for 48 h, to give 0.52 g (47%) of the title compound as an amorphous solid.

Calculated for C ₂₈ H ₂₉ N0 ₂ , 2 HCI, 1.75 H ₂ 0:

C, 59.17%; H, 6.80%; N, 6.00%; Found:

C, 59.43%; H, 6.99%; N, 5.59%.

EXAMPLE 7

Z-(R)-1-(3-(10,11-Dihydro-5H-benzo[4,5]cycloheρta[2,1-c] pyridin-5-ylidene)-1- propyl)-3-piperidinecarboxylic acid, dihydrochloride.

5 To a solution of cyclopropylmagnesium bromide in dry tetrahydrofuran (pre¬ pared from cyclopropyl bromide (3.5 g, 29 mmol), magnesium turnings (0.7 g, 29 mmol) and dry tetrahydrofuran (50 ml) under, an atmosphere of nitrogen) a solution of 10,11-dihydro-5H-benzo[4,5]cyclohepta[2,1-c]pyridin-5-one (3.0 g, 14.3 mmol, prepared similarly as described in J. Heterocyclic Chem. 8_, 1971 ,

10 73) in dry tetrahydrofuran (50 ml) was added dropwise. When addition was complete, the mixture was stirred at 50 °C for 1.5 h. The reaction mixture was cooled on an ice-bath and saturated ammonium chloride (15 ml) and water (50 ml) were carefully added. The mixture was extracted with diethyl ether (100 ml). The organic extract was washed with water (50 ml), saturated ammonium

15 chloride (50 ml), dried (MgSOJ, filtered and the solvent was evaporated in vacuo to give 3.7 g of crude product as an oil. Crystallisation from a mixture of ethyl acetate and heptane (4:1) afforded 1.8 g (50 %) 5-cyclopropyl-10.1 1- dihydro-5H-benzo[4,5]cyclohepta[2,1-c]pyridin-5-ol.

20 M.p. 182-184 °C

TLC: R, = 0.24 (Si0 ₂ : ethyl acetate/heptane = 4:1)

The above alcohol (1.8 g, 7.2 mmol) was dissolved in acetic acid (50 ml) and cooled in an ice bath to 10 °C. A solution of 33% hydrobromic acid in acetic acid (7 ml) was added, and the resulting mixture was stirred at 10 - 15 °C for 30 minutes Water (100 ml) was added and the mixture was neutralised with 20% sodium hydroxide and extracted with diethyl ether (2 x 100 ml). The combined organic extracts were washed with saturated sodium hydrogen- carbonate (50 ml), dried (MgSO and the solvent was evaporated vacuo to give 2 4 g (86%) of crude product Column chromatography on silica gel (600 ml) eluting with a mixture of ethyl acetate and heptane (4 1) afforded 5-(3- bromo-1-propylidene)-10,11-dihydro-5H-benzo[4,5]cyclohepta[2 ,1-c]pyπdine as an oil

TLC R _f = 0.54 (Si0 ₂ , ethyl acetate-heptane = 4;1)

A mixture of the above bromide (1 3 g, 4 1 mmol), (R)-3-pιperιdιnecarboxylιc acid ethyl ester tartrate (2 5 g, 8 3 mmol), potassium carbonate (3 4 g, 25 mmol), potassium iodide (1 4 g, 8 3 mmol), and methyl ethyl ketone (100 ml) was heated at reflux temperature for 16 h After cooling, water (100 ml) was added and the mixture was extracted with diethyl ether (2 x 100 ml) The combined organic extracts were washed with water (100 ml), saturated aque¬ ous ammonium chloride (100 ml), dried (MgSO , filtered and the solvent was evaporated _ \_\ vacuo The crude product (2 0 g) was purified by column chro¬ matography on silica gel (600 ml) using a mixture of ethyl acetate heptane and tnethyl amine (1 1 0 04) as eluent Fractions containing mixtures of E- and Z- isomers were subjected to another column chromatography on silica gel (600 ml) using a mixture of ethyl acetate heptane and tnethyl amine (1 1 0 04) as eluent This afforded 0 4 g (25%) of Z-(R)-1-(3-(10 11 -dιhydro-5H-benzo[4,5j-

cyclohepta[2, 1 -c]pyridin-5-ylidene)-1 -propyl)-3-piperidinecarboxylic acid ethyl ester and 0.15 g (10%) of E-(R)-1-(3-(10,11-dihydro-5H-benzo[4,5]cyclohep- ta[2,1-c]pyridin-5-ylidene)-1-propyl)-3-pipehdinecarboxylic acid ethyl ester as oils. (The E- and Z-assignments were based on NMR (NOESY and ROESY experiments)).

Z-isomer: TLC: R _f = 0.24 (Si0 ₂ : ethyl acetate: heptane:triethyl amine = 1 :1 :0.04).

E-isomer: TLC: R _f = 0.17 (Si0 ₂ : ethyl acetate: heptane:triethyl amine = 1 :1 :0.04).

The above Z-ester (0.40 g, 1.02 mmol) was dissolved in ethanol (25 ml) and a solution of sodium hydroxide (50 mg, 1.23 mmol) in water (10 ml) was added. The reaction mixture was stirred for 16 h at room temperature and the solvent was removed in vacuo. Water (50 ml) was added and the mixture was washed with diethyl ether (50 ml). The aqueous phase was acidified (pH = 1) with concentrated hydrochloric acid and evaporated in vacuo. The residue was dissolved in 2-propanol (15 ml), filtered, and the solvent was evaporated in vacuo. The residue was suspended in acetone (15 ml) and stirred for 4 h at room temperature. The precipitate was filtered, washed with diethyl ether and dried in vacuo at 50°C for 16 h, to give 0.20 g (49%) of the title compound as a hygroscopic amorphous solid.

'H NMR (400 MHz, DMSO-d ₆ ): δ _H 1.44 (dq, 1 H), 1.83 (m, 2H), 2.02 (d, 1 H), 2.6-3.5 (m, 13H), 6.06 (t, 1H), 7.18 (dd, 1H), 7.27 (m, 2H), 7.32 (dd, 1 H), 7.93 (d, 1 H), 8.73 (d, 1 H), 8.75 (s, 1 H).

MS(EI) (m/z): 363 (MH ⁺ , 1 %), 221 (3 %), 142 (100 %).

EXAMPLE 8

E-(R)-1-(3-(10,11-Dihydro-5H-benzo[4,5]cyclohepta[2,1-c]p yridin-5-ylidene)-1 - propyl)-3-piperidinecarboxylic acid, dihydrochlo de.

E-(R)-1-(3-(10,11-Dihydro-5H-benzo[4,5]cyclohepta[2, 1-c]pyridin-5-ylidene)-1 - propyl)-3-piperidinecarboxylic acid ethyl ester (0.15 g, 0.38 mmol, prepared as described in example 7) was dissolved in ethanol (25 ml) and a solution of sodium hydroxide (18 mg, 0.46 mmol) in water (10 ml) was added. The reac ^¬ tion mixture was stirred for 48 h at room temperature and the solvent was removed in vacuo. Water (70 ml) was added and the mixture was washed with

diethyl ether (50 ml). The organic phase was extracted with water (2 x 50 ml), and the combined aqueous phases were acidified (pH = 1 ) with 5 N hydroch¬ loric acid. The aqueous phase was evaporated in vacuo. The residue was dissolved in 2-propanol (20 ml), filtered, and the solvent was evaporated in vacuo. The residue was suspended in acetone (10 ml) and stirred for 2 h at room temperature. The precipitate was filtered and dried in vacuo at 50°C for 24 h, to give 0.04 g (24%) of the title compound as a solid.

M.p. >250 °C ¹ H NMR (400 MHz, DMSO-d ₆ ): δ _H 1.44 (dq, 1H), 1.83 (m, 2H), 2.02 (d, 1H), 2.6-3.5 (m, 13H), 6.20 (t, 1H), 7.22 - 7.38 (m, 4H), 7.68 (d, 1 H), 8.63 (d, 1 H), 8.89 (s, 1H).

MS(EI) (m/z): 363 (MH ^* . 0.1 %), 221 (5 %), 142 ^' (100 %).