WO1997022342A1 - Novel method - Google Patents

Novel method Download PDF

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Publication number
WO1997022342A1
WO1997022342A1 PCT/DK1996/000520 DK9600520W WO9722342A1 WO 1997022342 A1 WO1997022342 A1 WO 1997022342A1 DK 9600520 W DK9600520 W DK 9600520W WO 9722342 A1 WO9722342 A1 WO 9722342A1
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Prior art keywords
mixture
added
mmol
evaporated
ethyl
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PCT/DK1996/000520
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French (fr)
Inventor
Uffe Bang Olsen
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Novo Nordisk A/S
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Priority to AU11383/97A priority Critical patent/AU1138397A/en
Publication of WO1997022342A1 publication Critical patent/WO1997022342A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • the present invention relates to the use of compounds of the general formula I for reducing blood glucose and/or inhibit the secretion, circula- tion or effect of insulin antagonizing peptides like CGRP or amylin .
  • the compound can be used in the treatment of patients suffering from NIDDM (no ⁇ -insulin-dependent diabetes mellitus) in order to improve the glucose tolerance.
  • NIDDM no ⁇ -insulin-dependent diabetes mellitus
  • the present invention also embraces pharmaceutical compositions comprising those compounds and methods of using the compounds and their pharmaceutical compositions.
  • 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, 1 995) where circulating plasma levels of CGRP are markedly increased .
  • inhibi ⁇ tion 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
  • N-substituted azahetero- cyclic 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.
  • N-substi- tuted azacyc c carboxylic acids are claimed as GABA uptake inhibitors
  • EP 221 572 claims that 1 -aryloxyalkylpyr ⁇ d ⁇ ne-3-carboxyl ⁇ c acids are inhibitors of GABA uptake.
  • WO 951 861 5 describes a method of treating neurogenic in- flamation by means of the compounds claimed in WO 9220658.
  • 905,692 are disclosed for having antihistaminic, spasmolytic, anti- inflammatory, sedative and ganglion-blocking activity.
  • the compounds of the present invention essentially differ from the compounds in US Patent No. 2,976,286, US Patent No. 2,965,639 and British Patent No 905,692 by the ammo acid moiety
  • One object of the invention is to provide compounds which can effec- tively be used in the treatment of insulin resistance in NIDDM or aging.
  • R 1 and R 2 independently are hydrogen, halogen, trifluoromethyl, C ⁇ -alky! or C ⁇ -alkoxy;
  • X is -O-;
  • R 4 and R 5 each represents hydrogen or may when m is 2 together repre ⁇ sent a bond;
  • R ⁇ is OH or C ⁇ -alkoxy;
  • p is 0 or 1 ;
  • q is 0 or 1 ;
  • s is 0, 1 or 2;
  • r is 2, 3 or 4;
  • m is 1 or 2;
  • n is 1 when m is 1 or n is 0 when m is 2; or a pharmaceutically accept ⁇ able salt thereof, for the manufacture of a pharmaceutical composition for reducing blood glucose and/or inhibit the release and/or activity of CGRP, e.g. in the treatment of insulin resistance related to NIDDM or aging.
  • 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 fractional crystallization of suitable salts.
  • the compounds of formula I exist as the individual geometric or optical isomers.
  • the compounds according to the invention may optionally exist as pharmaceutically acceptable acid addition salts or - when the carboxylic acid group is not esterified - as pharmaceutically acceptable metal salts or - optionally alkylated - ammonium salts.
  • salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate or similar pharma ⁇ ceutically acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 6_ ⁇ , 2 ( 1 977) which are hereby incorporated by reference.
  • C ⁇ g -alkyl refers to a straight or branched, saturated hydrocarbon chain having 1 -6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert. butyl, n- pentyl, neopentyl, n-hexyl and 2,2-dimethylpropyt.
  • halogen means fluorine, chlorine, bromine and iodine.
  • the term "patient” includes any mammal which could benefit from treatment of insulin resistance related to NIDDM or aging.
  • the term particularly refers to a human patient, but is not intended to be so Iimited.
  • the compounds of general formula I improves the glucose tolerance in diabetic ob/ob mice and that this may result from the reduced release of CGRP from peripheral nervous end- ings.
  • 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 general formula I may be prepared by using the methods taught in WO 9220658 which are hereby incorporated by reference.
  • the compounds of general formula I may be prepared by the following method:
  • This alkylation reaction may be carried out in a solvent such as acetone, dibutylether, 2-butanone, tetrahydrofuran or toluene in the presence of a base e.g. potassium carbonate and a catalyst, e.g.
  • esters have been prepared in which R ⁇ is alkoxy
  • compounds of formula I wherein R 6 is alkoxy are prepared by hydrolysis of the ester group, preferably at room temperature in a mixture of a ⁇ aqueous alkali metal hydroxide solution and an alcohol such as methanol or ethanol for about 0.5 to 6 h.
  • This reduction is carried out in a solvent such as methanol in the presence of a catalyst eg. palladium on carbon at a pressure of eg. 1 to 10 atm. and reaction time about 0.5 to 1 8 h.
  • esters have been prepared in which R ⁇ is alkoxy
  • compounds of formula I wherein R ⁇ is OH are 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 about 0.5 to 6 h.
  • the carboxylic acid group can for example be esterifi- ed. Introduction and removal of such groups is described in "Protective Groups in Organic Chemistry” J.F.W. McOrnie ed. (New York, 1 973).
  • mice 16 weeks of age, where injected glucose (2g/kg) subcutaneously.
  • blood glucose was determined in tail venous blood by the glucose oxidase method.
  • glucose oxidase method was determined in the end of the study.
  • Immuno- reactive CGRP was determined in plasma by radio-immuno-assay. Two groups of animals were used. The one group was vehicle treated, where- as the other group received a compound of formula I via drinking water
  • dosages suitable for oral administration 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 pharmaceutically acceptable acid addition salt form or where possible as a metal or a lower alkylammonium 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 compound of formula I or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutical carrier or diluent.
  • the compositions containing the compounds of this invention may be prepared by conventional 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.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid .
  • liquid carriers examples include syrup, peanut oil, olive oil and water.
  • 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.
  • 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.
  • 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.
  • the compounds of this invention are dispensed in unit dosage form comprising 50-200 mg of active ingredient in or together with a pharmaceutically 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 tech ⁇ niques contains
  • Core Active compound (as free compound 100 mg or salt thereof)
  • the route of administration may be any route which effectively trans ⁇ ports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intra ⁇ nasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred
  • oral or parenteral e.g. rectal, transdermal, subcutaneous, intra ⁇ nasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred
  • the mixture was then allowed to cool to room temperature and a solution of potassium carbonate ( 1 .4 g) in water ( 1 00 ml) was added .
  • the phases were separated and the organic phase was washed successively with water, an aqueous sodium acetate solution (pH 5) and an aqueous citric acid solution (pH 5) .
  • the organic phase was then extracted with a 5% aqueous citric acid solution (50 ml) .
  • the acidic (pH 1 ) aqueous extract was washed with toluene (2x50 ml) and then a 4 N sodium hydroxide solution was added until pH 6-7.
  • Phenothiazme (3.8 g, 1 9 mmol) was added to a suspension of sodium hydride (0.92 g, 23 mmol, 60% oil dispersion) in dry dibutylether (25 ml under an atmosphere of nitrogen. The mixture was heated at 1 35°C for 1 h and then cooled to approximately 100°C. 2-(2-((tetrahydro-2- pyranyl)oxy)ethoxy)ethylchloride (8 g, 38 mmol) was added in one portion and the mixture was heated overnight at 1 10°C. The reaction mixture was poured into water (250 ml) and extracted with dichloromethane (3x50 ml) and diethyl ether (50 ml) .
  • the acidic aqueous phases are combined and washed with ethyl acetate ( 1 5 ml) . All the organic phases were discarded and to the acidic aqueous phase was added ethyl acetate (50 ml) and water (50 ml) . A 4 N sodium hydroxide solution was added until pH 8.5 and the phases were separated . The aqueous phase was extracted with ethyl acetate ( 1 5 ml) and the combined organic phases were washed with brine and dried over sodium sulphate.
  • Example 3 The acid prepared in Example 3 (0.2 g, 0.5 mmol) was dissolved in methanol ( 10 ml) and stirred under an atmosphere of hydrogen for 1 6 h at room temperatue in the presence of 10% palladium on carbon catalyst (50% aqueous paste). The mixture was filtered and the solvent was evaporated in vacuo to give an oily residue, which was re-evaporated from acetone and then crystallized from acetone ( 10 ml). This afforded 0.1 3 g (65 %) of the title compound.
  • the oily residue was dissolved in acetone (25 ml) and ethyl (R)-3-piperidinecarboxylate (3.3 g, 21 .0 mmol) and potassium carbonate (3.5 g, 25.0 mmol) were added. The mixture was stirred at room tem- perature for 1 20 h . The mixture was filtered and the solvent was evapor ⁇ ated in vacuo. The oily residue was submitted to column chromatogra ⁇ phy on silica gel ( 100 g) using a mixture of ethyl acetate and n-heptane (2:3) as eluent.
  • Example 5 The acid prepared in Example 5 (0.5 g, 1 .1 mmol) was dissolved in methanol ( 1 5 ml) and stirred under an atmosphere of hydrogen for 8 h at room temperature in the presence of 10 % palladium on carbon catalyst (50 % aqueous paste) . The mixture was filtered and the solvent was evaporated in vacuo to give an oily residue which was re-evaporated from acetone and then crystallised from a mixture of acetone and ethyl acetate. This afforded 0.3 g (60%) of the title compound as an amor ⁇ phous solid.
  • the oily residue was dissolved in a mixture of ethyl acetate (50 ml) and water (50 ml) .
  • a 34% aqueous tartaric acid solution was added until pH 4.
  • the phases were separated and the aqueous phase was extracted with ethyl acetate (25 ml) .
  • the combined organic phases were extracted with a 34% aqueous tartaric acid solution (2x5 ml) and the organic extracts were discarded.
  • the acidic aqueous phases were combined, diluted three times with water and ethyl acetate (40 ml) was added.
  • a 4 N sodium hydroxide solution was added until pH 7 and the phases were separated .
  • the oily residue was dissolved in ethyl acetate ( 1 50 ml).
  • a 34% aqueous tartaric acid solution (100 ml) was added and pH was adjusted to 2.5 with a 4 M aqueous sodium hydroxide solution.
  • the phases were separated and the organic phase was washed with a 2.5% aqueous solution of sodium bicarbonate ( 100 ml) and a 5% aqueous sodium bicarbonate solution (25 ml) .
  • the combined aqueous phases were extracted with ethyl acetate ( 100 ml) .
  • the combined organic phases were dried over magnesium sulphate.
  • Example 3 in dioxane (25 ml) was hydrogenated at 10 atm. for 1 6 h at room temperature in the presence of 10% palladium on carbon catalyst (50% aqueous paste). The mixture was filtered and the solvent was eva ⁇ porated in vacuo to give an oily residue, which was re-evaporated from carbontetrachloride. This afforded 2.2 g 2-(2-( 10, 1 1 -dihydro-5H-di- benzo[a,d]cyclohepten-5-yl)ethoxy)ethanol as an oil.
  • the reac ⁇ tion mixture was stirred at room temperature for 1 6 h The mixture was placed on an ice-bath and a concentrated aqueous hydrochloric acid solution (0.37 ml) was added. The volatiles were evaporated in vacuo, the residue suspended in dichloromethane and the solid removed by filtration. The solvent was evaporated from the filtrate in vacuo to give a residue which was re-evaporated with dichloromethane to give 0.30 g of the title compound as an amorphous solid.
  • the phases were separ ⁇ ated and the organic phase was extracted with a 34% aqueous tartaric acid solution (3x1 5 ml).
  • the three aqueous tartaric extracts were com ⁇ bined and icewater ( 1 50 ml) and ethyl acetate ( 100 ml) was added .
  • a 1 2 N aqueous sodium hydroxide solution was added until pH 4 and the phases were separated.
  • the organic phase was washed with a 5% sodium bicarbonate solution and brine and dried over magnesium sui- phate.

Abstract

The present invention relates to the use of compounds of general formula (I) for reducing blood glucose and/or inhibit the secretion, circulation or effect of insulin antagonizing peptides like CGRP or amylin. Hence the compound can be used in the treatment of insulin resistance related to NIDDM (non-insulin-dependent diabetes mellitus) or aging.

Description

Novel Method
Field of the Invention
The present invention relates to the use of compounds of the general formula I for reducing blood glucose and/or inhibit the secretion, circula- tion or effect of insulin antagonizing peptides like CGRP or amylin . Hence the compound can be used in the treatment of patients suffering from NIDDM (noπ-insulin-dependent diabetes mellitus) in order to improve the glucose tolerance. The present invention also embraces pharmaceutical compositions comprising those compounds and methods of using the compounds and their pharmaceutical compositions.
Background of the Invention
The potent effects of CGRP on skeletal muscle glycogen synthase 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 phosphorylatad glucose away from glycogen storage and into the glycolytic and oxidative path- ways (Rosetti et al. Am. J. Physiol. 264. E1 -E1 0, 1 993) . 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, 1 995) where circulating plasma levels of CGRP are markedly increased . Hence inhibi¬ tion 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 231 996 some derivatives of N-(4,4-dιsubstιtuted-3- butenyUazaheterocyc c carboxylic acids are claimed as inhibitors of
GABA uptake. In EP 342635 and EP 374801 , N-substituted azahetero- cyclic 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. In WO 9107389 and WO 9220658, N-substi- tuted azacyc c carboxylic acids are claimed as GABA uptake inhibitors
EP 221 572 claims that 1 -aryloxyalkylpyrιdιne-3-carboxylιc acids are inhibitors of GABA uptake.
Further, WO 951 861 5 describes a method of treating neurogenic in- flamation by means of the compounds claimed in WO 9220658. WO
951 8793 discloses N-substituted azaheterocychc carboxylic acids and esters thereof, methods for their preparation, compositions containing them and their use in treatment of hyperalgesic and/or inflammatory conditions.
In addition to the above cited references, US Patent No 2,976,286 and British Patent No. 905,692 discloses 10-
(dιalkylamιnoethoxyethyl)phenothιazιnes and US Patent No. 2,965,639 discloses 5-(dιalkylamιnoethoxyethyl)- 10, 1 1 -dιhydrodιbenzo[b,f]azepιnes The compounds of US Patent No 2,965,639 and British Patent No.
905,692 are disclosed for having antihistaminic, spasmolytic, anti- inflammatory, sedative and ganglion-blocking activity. The compounds of the present invention essentially differ from the compounds in US Patent No. 2,976,286, US Patent No. 2,965,639 and British Patent No 905,692 by the ammo acid moiety
One object of the invention is to provide compounds which can effec- tively be used in the treatment of insulin resistance in NIDDM or aging.
Description of the Invention
It has surprisingly been found that compounds of the general formula I below can be used in the treatment of insulin resistance related to NIDDM or aging.
Accordingly, the present invention relates to the use of compounds of the general formula I
Figure imgf000005_0001
wherein
R1 and R2 independently are hydrogen, halogen, trifluoromethyl, C^-alky! or C β-alkoxy; Y is > N-CH2-, > CH-CH2- or > C - CH- when s is 0, 1 or 2 or Y is > CH-CH = N- or > C = N- when s is 0 wherein only the under¬ scored atom participates in the ring system; X is -O-;
Z is -O-, -S-, -CH2-, -CH2CH2-, -CH = CH-CH2-, -CH2-CH = CH-, - CH2CH2CH2-, -CH = CH- or -O-CH2-;
R4 and R5 each represents hydrogen or may when m is 2 together repre¬ sent a bond; Rβ is OH or C^-alkoxy; p is 0 or 1 ; q is 0 or 1 ; s is 0, 1 or 2; r is 2, 3 or 4; m is 1 or 2; n is 1 when m is 1 or n is 0 when m is 2; or a pharmaceutically accept¬ able salt thereof, for the manufacture of a pharmaceutical composition for reducing blood glucose and/or inhibit the release and/or activity of CGRP, e.g. in the treatment of insulin resistance related to NIDDM or aging.
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 fractional 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 pharmaceutically 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 pharma¬ ceutically acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 6_δ, 2 ( 1 977) which are hereby incorporated by reference.
The term "C^g-alkyl" as used herein, alone or in combination, refers to a straight or branched, saturated hydrocarbon chain having 1 -6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert. butyl, n- pentyl, neopentyl, n-hexyl and 2,2-dimethylpropyt.
The term "C^g-alkoxy" and "C 8-alkoxy" as used herein, alone or in combination, refers to a monovalent substituent comprising a
Figure imgf000007_0001
group or C^g-alkyl group respectively, linked through an ether oxygen having its free valence bond from the ether oxygen, e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy.
The term "halogen" means fluorine, chlorine, bromine and iodine.
As used herein, the term "patient" includes any mammal which could benefit from treatment of insulin resistance related to NIDDM or aging. The term particularly refers to a human patient, but is not intended to be so Iimited.
Illustrative examples of compounds encompassed by the present inven¬ tion include:
(R)-N-(2-(2-( 1 0, 1 1 -Dihydro-5H-dibenz[b,f]azepin-5-yl)ethoxy)ethyl)-3- piperidinecarboxylic acid;
N-(2-(2-{ 10, 1 1 -Dihydro-5H-dibenz[b,f]azepin-5-yl)ethoxy)ethyl)-1 ,2,5,6- tetrahydro-3-pyridinecarboxylic acid;
N-(2-(2-( 1 0, 1 1 -Dihydro-5H-dibenz[b,f]azepin-5-yl)ethoxy)ethyl)-3-pyrro- lidineacetic acid;
(R)-N-(2-(2-(3,7-Dichloro-10, 1 1 -dihydro-5H-dibenz[b,f]azepin-5-yl)- ethoxy)ethyl)-3-piperidinecarboxylic acid;
(R)-N-(2-((3-( 10, 1 1 -Dihydro-5H-dibenz[b,f]azepin-5-yl)-1 -propyl)oxy)- ethyl) 3-pιperιdιnecarboxylιc acid;
(R)-N-(2-(2-(5,6,7, 1 2-Tetrahydrodιbenz[b,g]azocιn-1 2-yl)ethoxy)ethyl)-3- pipeπdinecarboxylic acid;
(R)-N-(2-(2-(6, 1 1 -Dιhydro-5H-dιbenz[b,e]azepιn-5-yi)ethoxy)ethyl)-3-pιpe- πdinecarboxylic acid;
(R)-N-(2-(2-(5,6, 1 1 , 1 2-Tetrahydrodιbenz[b,f]azocιn-1 2-yl)ethoxy)ethyl)~3- pipeπdinecarboxylic acid;
(R}-N-(2-(2-( 10H-Phenothιazιn-10-yl)ethoxy)ethyl)-3-pιperιdιnecarboxylιc acid;
(R)-N-(2-(2-(2-Chloro-1 OH-phenothιazιn-10-yl)ethoxy)ethyl)-3-pιperιdιne- carboxyhc acid;
(S)-N-(2-(2-(2-(Trιfluoromethyl)-10H-phenothιazιn-10-yl)ethoxy)ethyl)-3- pipeπdinecarboxylic acid;
(R)-N-(2-(2-( 10H-Phenoxazιn- 10-yl)ethoxy)ethyl)-3-pιperιdιnecarboxylιc acid;
(R)-N-(2-(2-( 10, 1 1 -Dιhydro-5H-dιbenzo[a,d]cyclohepten-5-ylιdene)etho- xy)ethyl)-3-pιperιdιnecarboxylιc acid;
(R)-N-(2-(2-(10, 1 1 -Dιhydro-5H-dιbenzo[a,d]cyclohepten-5-yl)ethoxy)- ethyl)-3-pιperιdιnecarboxylιc acid;
N-(2-(2-( 10, 1 1 -Dιhydro-5H-dιbenzo[a,d]cyclohepten-5-yl)ethoxy)- ethyl)-1 , 2,5,6-tetrahydro-3-pyrιdinecarboxylιc acid; (R)-N-(3-(2-(10,11-Dihydro-5H-dibenzola,d]cyclohepten-5-ylidene)- ethoxy)-1-propyl)-3-piperidinecarboxylicacid;
(R)-N-(3-(2-(10,11-Dihydro-5H-dibeπzo[a,d]cyclohepten-5-yl)ethoxy)- -1 -propyl)-3-piperidinecarboxylic acid;
(R)-N-(3-(2-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)ethoxy)-1-propyl)-3- piperidinecarboxylic acid;
(R)-N-(2-(( 10,11 -Dihydro-5H-dibenzo[a, d]cyclohepten-5-ylidene)metho- xy)ethyl)-3-piperidinecarboxylic acid;
(R)-N-(2-(({10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)amino)- oxy)ethyl)-3-piperidinecarboxylic acid;
(R)-N-(2-{((( 10,11 -Dihydro-5H-dibenzo[a, d]cyclohepten-5-yl)methylene)- amino)oxy)ethyl)-3-piperidinecarboxylicacid;
(R)-1-(2-(2-(5H-Dibenz[b,f]azepin-5-yl)ethoxy)ethyl)-3-piperidinecarboxylic acid;
(R)-1-(2-(2-(2,8-Dibromo-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)etho- xy)ethyl)-3-piperidinecarboxylic acid;
(R)-1-(2-(2-(10,11-Dihydro-3-fluoro-5H-dibenz[b,f]azepin-5-yl)ethoxy)- ethyl)-3-piperidinecarboxylic acid;
(R)-1-(2-(2-(2,8-Difluoro-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)ethoxy)- ethyl)-3-piperidinecarboxylic acid;
(R)-1-(2-(2-(3-Chloro-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl}ethoxy)- ethyl)-3-piperidinecarboxylic acid; E/Z-(R)-1 -(2-{2-(3-Chloro-10, 1 1 -dihydro-5H-dibenzo[a,d]cyclohepten-5- ylidene)ethoxy)ethyl)-3-piperidiπecarboxy lie acid;
(R)- 1 -(2-(((3-Chloro-10, 1 1 -dihydro-5H-dibeπzo(a,d]cyclohepten-5- ylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid;
(R)- 1 -(2-(((3,7-Dichloro-10, 1 1 -dihydro-5H-dibenzo[a,d]cyclohepten-5- ylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid;
or a pharmaceutically acceptable salt thereof.
It has been demonstrated that the compounds of general formula I improves the glucose tolerance in diabetic ob/ob mice and that this may result from the reduced release of CGRP from peripheral nervous end- ings. 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 general formula I may be prepared by using the methods taught in WO 9220658 which are hereby incorporated by reference.
The compounds of general formula I may be prepared by the following method:
Method A:
Figure imgf000011_0001
A compound of formula II wherein R\ R2, X, Y, Z, p, q, r and s are as defined above and W is a suitable leaving group such as halogen, p- toluene sulphonate or mesylate, is allowed to react with an azaheteroc- yclic compound of formula III wherein R\ R5, R6, m and n are as defined above. This alkylation reaction may be carried out in a solvent such as acetone, dibutylether, 2-butanone, tetrahydrofuran 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 1 20 h. If esters have been prepared in which Rβ is alkoxy, compounds of formula I wherein R6 is alkoxy, compounds of formula I wherein Rβ is OH are prepared by hydrolysis of the ester group, preferably at room temperature in a mixture of aπ aqueous alkali metal hydroxide solution and an alcohol such as methanol or ethanol for about 0.5 to 6 h.
Compounds of formula I, in which R4 and R5 does not represent a bond; Z does not represent -S-, -CH = CH-, -CH = CH-CH2- or CH2-CH = CH-; and
Y represents > CH-CH2-, are prepared by method B:
Figure imgf000012_0001
IV
A compound of formula IV wherein R1 , R2, R4, R5, R6, r, s, p, q, m, n and Z are as defined above, except that R4 and R5 must not represent a bond and Z must not be -S-, -CH = CH-, -CH = CH-CH2- or -CH2-CH = CH-, is hydrogenated to give I in which R4, R5 and Z are as defined above. This reduction is carried out in a solvent such as methanol in the presence of a catalyst eg. palladium on carbon at a pressure of eg. 1 to 10 atm. and reaction time about 0.5 to 1 8 h.
If esters have been prepared in which Rθ is alkoxy, compounds of formula I wherein Rθ is OH are 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 about 0.5 to 6 h.
Compounds of formula II and III are prepared by methods familiar to those skilled in the art.
Under certain circumstances it is necessary to protect the intermediates used in the above methods e.g. a compound of formula III with suitable protecting groups. The carboxylic acid group can for example be esterifi- ed. Introduction and removal of such groups is described in "Protective Groups in Organic Chemistry" J.F.W. McOrnie ed. (New York, 1 973).
Pharmacological Methods
The reduction of plasma levels of CGRP in diabetic mice treated with a compound of the general formula I is described in the following.
ob/ob female mice, 16 weeks of age, where injected glucose (2g/kg) subcutaneously. 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. Immuno- reactive CGRP was determined in plasma by radio-immuno-assay. Two groups of animals were used. The one group was vehicle treated, where- as the other group received a compound of formula I via drinking water
( 1 00 mg/l) for five days before the test.
For the above indications the dosage will vary depending on the com¬ pound of general 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, prefer¬ ably from about 1 mg to about 500 mg of compounds of formula I, conveniently given from 1 to 5 times daily, optionally in sustained release form. Usually, dosage forms suitable for oral administration 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 pharmaceutically acceptable acid addition salt form or where possible as a metal or a lower alkylammonium 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 compound of formula I or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutical carrier or diluent. The compositions containing the compounds of this invention may be prepared by conventional 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 pharmaceutically 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 tech¬ niques contains
Core Active compound (as free compound 100 mg or salt thereof)
Colloidal silicon dioxide (Areosif) 1 .5 mg
Cellulose, microcryst. (Avicef) 70 mg
Modified cellulose gum (Ac-Di-Sof) 7.5 mg Magnesium stearate
Coating
HPMC approx 9 mg
"Mywacet 9-40 T approx. 0.9 mg
"Acylated monoglyceπde used as plasticizer for film coating
The route of administration may be any route which effectively trans¬ ports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intra¬ nasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred
EXAMPLES
The process for preparing compounds of formula I is further illustrated in the following examples, which, however, are not to be construed as limiting.
Hereinafter, TLC is thin layer chromatography and THF is tetrahydrofuran, CDCI3 is deuteπo chloroform and DMSO-dθ is hexadeuteπo dimethylsulfoxide The structures of the compounds are confirmed by either elemental analysis or NMR, where peaks assigned to characteristic protons in the title compounds are presented where appropriate. NMR shifts (δ) are given in parts per million (ppm). M.p. is melting point and is given in °C. Column chromatography was carried out using the technique described by W.C. Still et al, J. Org. Chem. 1 978,
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 se.
EXAMPLE 1
(R)-N-(2-(2-( 10, 1 1 -Dihydro-5H-dibenz[b,f]azepin-5-yl)ethoxy)ethyl)-3- piperidinecarboxylic acid hydrochloride
A mixture of sodium hydride (0.40 g, 0.010 mol, 60% oil dispersion) and 10, 1 1 -dihydro-5H-dibenz[b,f]azepine ( 1 .95 g, 0.010 mol) in dry dibutylether (30 ml) was heated at reflux temperature for 3.5 h under an atmosphere of nitrogen. The reaction mixture was cooled to 1 00°C and bis-2-chloro-ethyl ether (4.7 ml) was added and the mixture was heated at reflux temperature for 1 6 h. The reaction mixture was cooled and water (50 ml) was added.
The mixture was extracted with toluene ( 100 ml) . The organic extract was dried over sodium sulphate and the solvent evaporated in vacuo to give 2.8 g of an oily residue containing 2-chloro-1 -(2-( 10, 1 1 -dihydro-5H- dibenz[b,f]azepin-5-yl)ethoxy)ethane. To this oil was added ethyl (R)-3- piperidinecarboxylate (3.0 g, 0.019 mol) and the mixture was heated at 1 50"C for 1 .5 h. The reaction mixture was allowed to cool to 80°C and toluene ( 100 ml) was added. The mixture was then allowed to cool to room temperature and a solution of potassium carbonate ( 1 .4 g) in water ( 1 00 ml) was added . The phases were separated and the organic phase was washed successively with water, an aqueous sodium acetate solution (pH 5) and an aqueous citric acid solution (pH 5) . The organic phase was then extracted with a 5% aqueous citric acid solution (50 ml) . The acidic (pH 1 ) aqueous extract was washed with toluene (2x50 ml) and then a 4 N sodium hydroxide solution was added until pH 6-7.
The aqueous mixture was extracted with toluene and the organic extract was treated with charcoal and dried over sodium sulphate. The solvent was evaporated in vacuo to give 2. 1 g (50%) of (R)-N-(2-(2-( 10, 1 1 - dιhydro-5H-dιbenz[b,f]azepιn-5-yl)ethoxy)ethyl)-3-pιperιdιnecarboxylιc acid ethyl ester as an oil. TLC: rf = 0.20 (SiO2; n-heptane/THF = 7:3) .
The above ester was dissolved in ethanol ( 1 0 ml) and a 1 2 N sodium hydroxide solution (1 .25 ml) was added. The mixture was stirred at room temperature for 4 h A concentrated hydrochloric acid solution was added until pH 1 . Dichloromethane (300 ml) was added followed by water until the solid material was dissolved . The phases were separated and the organic phase was dried over sodium sulphate. The solvent was evaporated in vacuo to give a residue, which was re-evaporated twice with acetone and then recrystallized from acetone. This afforded 1 .4 g (65 %) of the title compound
M.P. 1 85-1 86°. Calculated for C24H31CIN2O3 - 1Λ H2O: C, 66.9%; H, 7.3%; Cl, 8.2%; N, 6.5%; Found: C, 67.0%; H, 7.5 %; Cl, 8.2%; N, 6.3%.
EXAMPLE 2a
(R)-N-(2-(2-( 10H-Phenothιazιn-10-yl)ethoxy)ethyl)-3-pιperιdιnecarboxylιc acid hydrochloride
Phenothiazme (3.8 g, 1 9 mmol) was added to a suspension of sodium hydride (0.92 g, 23 mmol, 60% oil dispersion) in dry dibutylether (25 ml under an atmosphere of nitrogen. The mixture was heated at 1 35°C for 1 h and then cooled to approximately 100°C. 2-(2-((tetrahydro-2- pyranyl)oxy)ethoxy)ethylchloride (8 g, 38 mmol) was added in one portion and the mixture was heated overnight at 1 10°C. The reaction mixture was poured into water (250 ml) and extracted with dichloromethane (3x50 ml) and diethyl ether (50 ml) . The combined organic extracts were washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuo leaving an oil, which was sub¬ mitted to column chromatography using dichloromethane as eluent. Collecting the proper fractions afforded 3.9 g of crude 10-{2-(2-
((tetrahydro-2-pyranyl)oxy)ethoxy)ethyl)- 10H-phenothiazine. TLC: rf = 0.72 (SiO2; dichloromethane/methanol = 19: 1 ).
A mixture of crude 1 0-(2-(2-((tetrahydro-2-pyranyl)oxy)ethoxy)ethyl)- 10H-phenothiazine (3.8 g, 10 mmol), 2-propanol (50 ml) and a 4 M aqueous sulfuric acid solution (8 ml) was heated at 60°C for 3 h and then left overnight at room temperature. The reaction mixture was poured into a mixture of water (500 ml) and a 4 N sodium hydroxide solution ( 1 7 ml) . The mixture was extracted with diethyl ether ( 1 50 ml) and the organic extract was washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuo to give 1 .5 g of crude 2- (2-( 10H-phenothiazin-10-yl)ethoxy)ethanol. TLC: rf = 0.52 (SiO2; dichloromethane/methanol = 19: 1 ) .
A well-stirred mixture of the above alcohol (1 .5 g, 5.2 mmol), triethylamine ( 1 .8 ml) and toluene (20 ml) placed under an atmosphere of nitrogen was cooled on an ice-bath. A solution of methanesulfonyl chloride (1 .5 g, 10.4 mmol) in toluene (5 ml) was added within 1 5 minutes. Stirring was continued for 45 minutes on an ice-bath and then for 30 minutes at room temperature. Water ( 1 5 ml) was added and the mixture was stirred at room temperature for 1 5 minutes. The phases were separated and the aqueous phase was extracted with toluene (20 ml) . The combined organic extracts were washed with a 5 % sodium bicarbonate solution, brine and then dried over sodium sulphate. The solvent was evaporated in vacuo to give an oil, which was dissolved in toluene (30 ml) . To this solution was added potassium carbonate (2.5 g, 1 8.3 mmol) and ethyl (R)-3-piperidinecarboxylate tartrate (3.2 g, 10.4 mmol) and the suspension was heated at reflux temperature for 3 days. The cooled reaction mixture was filtered and the solid washed with a small portion of toluene. The solvent was evaporated from the filtrate in vacuo to give a residue, which was dissolved in a mixture of ethyl acetate (30 ml) and water (30 ml) . A 34% aqueous solution of tartaric acid was added until pH 4. The phases were separated and the aqueous phase was extracted with ethyl acetate ( 1 5 ml) . To the combined organic phases were added water (10 ml) and a 34% aqueous solution of tartaric acid (3.5 ml). The phases were separated and the organic phase was extracted with a mixture of water ( 10 ml) and a 34% aque¬ ous solution of tartaric acid (2 ml) . The acidic aqueous phases are combined and washed with ethyl acetate ( 1 5 ml) . All the organic phases were discarded and to the acidic aqueous phase was added ethyl acetate (50 ml) and water (50 ml) . A 4 N sodium hydroxide solution was added until pH 8.5 and the phases were separated . The aqueous phase was extracted with ethyl acetate ( 1 5 ml) and the combined organic phases were washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuo to give 0.8 g of (R)-N-(2-(2-(10H-phenothiazin- 10-yl)ethoxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf = 0.20 (SiO2; dichloromethane/methanol/acetic acid = 20:2: 1 ) .
The above ester (0.8 g, 1 .8 mmol) was dissolved in ethanol ( 1 5 ml) and a 4 N sodium hydroxide solution (2 ml) was added. The mixture was stirred vigorously at room temperature for 4 h. The solvent was evapor- ated in vacuo to give aπ oily residue. Dichloromethane ( 100 ml) was added and the mixture was cooled on an ice-bath. A concentrated hydrochloric acid solution ( 1 ml) was added . The mixture was stirred vigorously for a few minutes and the phases were separated. The organic phase was dried over sodium sulphate and the solvent was evaporated in vacuo. The residue was re-evaporated with dichloromethane, dissolved in dichloromethane and left overnight at 4°C. The solid formed was isolated by filtration to give 0.6 g of the title compound as a solid .
M.P. 1 88-189°C. Calculated for C22H27CIN2O3S: C, 60.7%; H, 6.3%; N, 6.4%; Found: C, 60.4%, H, 6.3%; N, 6.3%.
The following compounds were prepared by a similar procedure:
EXAMPLE 2b
(R)-N-(2-(2-( 10H-Phenoxazin-10-yl)ethoxy)ethyl)-3-piperidinecarboxylic acid hydrochloride
After an alkaline hydrolysis similar to that described above, the dichloromethane extract was dried over sodium sulphate and evaporated in vacuo. The foamy residue was heated to reflux temperature with acetone, cooled, filtered and dried to give 1 .7 g of the title compound as a solid.
M.P. 1 61 -1 64°C. Calculated for C22H28CIN2O4: C, 63.1 %; H, 6.5%; N, 6.7%; Found: C, 63.1 %; H, 6.6%; N, 6.4% . EXAMPLE 2c
(R)-N-(2-(2-(2-Chloro- 10H-pheno- thiazin-10-yl)ethoxy)ethyl)-3-piperidinecarboxylic acid hydrochloride
After an alkaline hydrolysis similar to that described above, the dichloromethane extract was dried over magnesium sulphate and evapor¬ ated in vacuo. The foamy residue was heated in acetone, cooled, filtered and dried to give 2.3 g of the title compound as an amorphous solid .
M.P. 75°C. Calculated for C22H25CIN2O3S.HCI.H2O: C, 54.2%; H, 5.8%; N, 5.8%; Found : C, 54.8%; H, 5.7%; N, 5.5% .
EXAMPLE 2d
(S)-N-(2-(2-(2-(Trifluoromethyl)-10H-phenothiazin-10-yl)ethoxy)ethyl)-3- piperidinecarboxylic acid hydrochloride
After an alkaline hydrolysis similar to that described above, the dichloromethane extract was dried over magnesium sulphate and evapor¬ ated in vacuo. The residue was re-evaporated twice with acetone and dissolved in acetone (20 ml) and left for crystallization . The solid formed was isolated by filtration and dried to give 1 .9 g of the title compound as an amorphous solid.
M.P. 1 1 5°C. Calculated for C23H2βCIF3N2O3S: C, 54.9%; H, 5.2%; N, 5.6%; Found:
C, 54.7%; H, 5.4%; N, 5.4%. λ NMR (DMSO-d6) δ 4.20 (t, 2H) .
EXAMPLE 2e (R)-1-(2-(2-(5H-Dibenz[b,f]azepin-5-yl)ethoxy)ethyl)-3-piperidiπecarboxylic acid hydrochloride
M.P. 169°C. Calculated for C24H28CIN2O3:
C, 67.2%; H, 6.8%; N, 6.5%; Cl, 8.3%; Found:
C, 66.9%; H, 6.9%; N, 6.3%; Cl, 8.1%.
EXAMPLE 2f
(R)-1-(2-(2-(2,8-Dibromo-10,11-dihydro-5H-dibenz[b,f]azepin-5- yl)ethoxy)ethyl)-3-piperidinecarboxylic acid hydrochloride
M.P. 163-164°C. Calculated for C24H29Br2CIN2O3:
C, 49.0%; H, 5.0%; N, 4.8%; Found: C, 48.8%; H, 5.2%; N, 4.6%.
EXAMPLE 2o
(R)-1 -(2-(2-(10, 11 -Dihydro-3-fluoro-5H-dibenz[b,f]azepin-5- yl)ethoxy)ethyl)-3-piperidinecarboxylic acid hydrochloride
Amorph. solid. Calculated for C24H30CIFN2O3.C3HβO:
C, 64.0%; H, 7.2%; N, 5.5%; Cl, 7.0%; Found: C, 63.5%; H, 7.1%; N, 5.7%; Cl, 7.1%.
EXAMPLE 2h
(R)-1-(2-(2-(2,8-Difluoro-10,11-dihydro-5H-dibenz[b,f]azepin-5- yl)ethoxy)ethyl)-3-piperidinecarboxylic acid hydrochloride
M.p. 153-155°C. Calculated for C24H29CIF2N2O3.1/4H2O:
C, 61.1%; H, 6.3%; N, 5.9%; Found: C, 61 .5%; H, 6.5 %; N, 5.9%.
EXAMPLE 2i
(R)-1 -(2-(2-(3-Chloro-10, 1 1 -dihydro-5H-dibenz[b,f]azepin-5- yl)ethoxy)ethyl)-3-piperidinecarboxylic acid hydrochloride
Amorph. solid. 1 H NMR (DMSO-d6) δ 3.50 (t, 2H); 3.58 (s, 2H); 3.92 (t, 2H) .
EXAMPLE 3a
(R)-N-(2-(2-( 10, 1 1 -Dihydro-5H-dibenzo[a,d]cyclohepten-5- ylidene)ethoxy)ethyl)-3-piperidinecarboxylic acid hydrochloride
A solution of 10, 1 1 -dihydro-5H-dibenzo[a,d]cyclohepten-5-one (9.4 g, 0.045 mol) in dry THF ( 100 ml) was placed under an atmosphere of nitrogen . A solution of vinylmagnesium bromide in THF ( 100 ml, 0.5 M) was added in such a rate to keep the reaction temperature at 30-35°C. When addition was complete the mixture was heated at 50-60°C for 1 .5 h. The reaction mixture was cooled on an ice-bath and a solution of ammonium chloride ( 10 g) in water (50 ml) was carefully added. Diethyl ether ( 100 ml) was added and the phases were separated . The aqueous phase was extracted with diethyl ether (100 ml) and the combined organic phases were dried over sodium sulphate. The solvent was evaporated in vacuo to give a residue which was re-evaporated twice with dichloromethane to give 1 1 .8 g of crude 5-ethenyl-10, 1 1 -dihydro- 5H-dibenzo[a,d]cyclohepten-5-ol.
The above crude alcohol (9.2 g) was dissolved in dichloromethane ( 100 ml) and the mixture was placed on an ice-bath . A solution of trimethylsilyl bromide (6.6 g, 0.043 mol) in dichloromethane (50 ml) was added dropwise within 30 minutes. When addition was complete the mixture was stirred at room temperature for 45 minutes. Icewater (50 ml) and a saturated aqueous sodium bicarbonate solution (200 ml) was added . The phases were separated and the organic phase was dried over sodium sulphate. The solvent was evaporated in vacuo to give a residue, which was re-evaporated with cyclohexane. This afforded 10.5 g of crude 5-(2-bromoethylidene)- 10, 1 1 -dihydro-5H- dibenzo[a,d]cycloheptene.
A solution of n-butyllithium in hexanes (12 ml, 2.5 M) was added dropwise to ice-cooled ethylene glycol (25 ml) under an atmosphere of nitrogen. When addition was complete the mixture was stirred at room temperature for 30 minutes. A solution of the above crude bromide (7.1 g) in cyclohexane (20 ml) was added in one portion and the hexanes were removed by vigorous stirring and a strong nitrogen flow. Then the reaction mixture was stirred at room temperature for 68 h. Water (30 ml) was added and the mixture was extracted with ethyl acetate (3x50 ml) . The combined organic extracts were dried over sodium sulphate and the solvent was evaporated in vacuo. The oily residue was submitted to column chromatography on silica gel (1 50 g) using a mixture of THF and n-heptane (3:7) as eluent. Collecting the proper fractions afforded 2.4 g of 5-(2-(2-hydroxyethoxy)ethylidene)-10, 1 1 -dihydro-5H- dibenzo[a,d]cycloheptene as an oil. TLC: rf = 0.1 8 (SIO2; THF/n-heptane = 3:7).
A solution of the above alcohol (3.7 g, 1 3.2 mmol)) in dry THF (40 ml) was placed under an atmosphere of nitrogen and placed on an ice-bath. A solution of n-butyllithium in hexanes (3.7 ml, 2.5 M) was added dropwise and the mixture was stirred for another 1 5 minutes, p- Toluenesulfonyl chloride (2.5 g, 13.2 mmol) was added in one portion and the mixture was stirred on an ice-bath for 1 h. The solvent was evaporated in vacuo keeping the bath temperature below 20°C. The residue was dissolved in acetone (25 ml) and ethyl (R)-3- piperidinecarboxylate (3.1 g, 1 9.8 mmol) and potassium carbonate (3.3 g, 24.0 mmol) were added . The mixture was stirred at room temperature for 140 h. The mixture was filtered and the solvent was evaporated in vacuo. The oiiy residue was submitted to column chromatography on silica gel (200 g) using a mixture of ethyl acetate and n-heptane ( 1 : 1 ) as eluent. Collecting the proper fractions afforded 1 .7 g of (R)-N-(2-(2- (10, 1 1 -dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)ethoxy)ethyl)-3- piperidinecarboxylic acid ethyl ester as an oil. TLC: rf = 0. 19 (SiO2; ethyl acetate/n-heptane = 1 : 1 ) .
The above ester ( 1 .7 g, 4.1 mmol) was dissolved in ethanol ( 1 5 ml) and a 4 N sodium hydroxide solution (3.5 ml) was added . The mixture was stirred vigorously at room temperature for 5 h. Dichloromethane (300 ml) was added followed by a 4 N hydrochloric acid solution until pH 1 . The mixture was stirred vigorously for a few minutes and the phases were separated . The organic phase was dried over sodium sulphate and the solvent was evaporated in vacuo. The residue was re-evaporated twice with acetone, once with ethyl acetate and once with diethyl ether to give 1 .7 g of the title compound as a solid which was recrystallized from acetone.
M.P. 1 57-1 59°C. Calculated for C25H30CINO3: C, 70.2%; H, 7.1 %; N, 3.3%; Found:
C, 70. 1 %; H, 7.1 %; N, 3.2%.
By a similar procedure as described in Example 3a the following com¬ pound has been prepared:
EXAMPLE 3b E/Z-(R)- 1 -(2-(2-(3-Chloro-10, 1 1 -dihydro-5H-dibenzo[a,d]cyclohepten-5- ylidene)ethoxy)ethyl)-3-piperidiπecarboxylic acid hydrochloride
Amorph. solid . Calculated for C25H30CI2N03.H2O:
C, 62.5%; H, 6.5%; N, 2.9%; Found:
C, 62.7%; H, 6.5%; N, 2.7%.
1H NMR (DMSO-d6) δ Minor isomer: 6.02 (t, 1 H, -CH = ); Major isomer:
6.05 (t, 1 H, -CH = ).
EXAMPLE 4
(R)-N-(2-(2-( 10, 1 1 -Dihydro-5H-dibenzo[a,d]cyclohepten-5- yl)ethoxy)ethyl)-3-piperidinecarboxylic acid hydrochloride
The acid prepared in Example 3 (0.2 g, 0.5 mmol) was dissolved in methanol ( 10 ml) and stirred under an atmosphere of hydrogen for 1 6 h at room temperatue in the presence of 10% palladium on carbon catalyst (50% aqueous paste). The mixture was filtered and the solvent was evaporated in vacuo to give an oily residue, which was re-evaporated from acetone and then crystallized from acetone ( 10 ml). This afforded 0.1 3 g (65 %) of the title compound.
M. P. 147-148°C.
' H NMR (DMSO-d6) δ 4.24 (brs, 1 H) .
EXAMPLE 5
(R)-N-(3-(2-(10, 1 1 -Dihydro-5H-dibenzo[a,d]cyclohepten-5- ylidene)ethoxy)-1 -propyl)-3-piperidinecarboxylic acid hydrochloride
A solution of n-butyllithium in hexanes (1 6.8 ml, 2.5 M) was added dropwise to ice-cooled propylene glycol (25 ml) under an atmosphere of nitrogen . When addition was complete the mixture was stirred at room temperature for 1 5 minutes. A solution of crude 5-(2-bromoethylidene)- 10, 1 1 -dihydro-5H-dibenzo[a,d]cγcloheptene ( 10. 1 g, prepared as described in Example 3a) was added in one portion and the reaction mixture was stirred at room temperature for 42 h. Water (40 ml) was added and the mixture was extracted with ethyl acetate (3x75 ml) . The combined organic extracts were washed with water ( 1 5 ml), dried over sodium sulphate and the solvent was evaporated in vacuo. The oily residue was submitted to column chromatography on silica gel (200 g) using a mixture of THF and n-heptane (3:7) as eluent. Collecting the proper fractions afforded 4.2 g of 5-(2-(3-hydroxypropyloxy)ethylidene)- 10, 1 1 -dihydro-5H-dibenzo[a,d]cycloheptene as an oil. TLC: rf = 0.1 8 (SiO2; THF/n-heptane = 3:7).
A solution of the above alcohol (4.2 g, 14.3 mmol) in dry THF (30 ml) was placed under an atmosphere of nitrogen and placed on an ice-bath. A solution of n-butyllithium in hexanes (5.7 ml, 2.5 M) was added dropwise within 1 5 minutes and the mixture was stirred for another 1 5 minutes. p-Toluenesulfonyl chloride (2.7 g, 14.0 mmol) was added in one portion and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo keeping a low bath temperature. The oily residue was dissolved in acetone (25 ml) and ethyl (R)-3-piperidinecarboxylate (3.3 g, 21 .0 mmol) and potassium carbonate (3.5 g, 25.0 mmol) were added. The mixture was stirred at room tem- perature for 1 20 h . The mixture was filtered and the solvent was evapor¬ ated in vacuo. The oily residue was submitted to column chromatogra¬ phy on silica gel ( 100 g) using a mixture of ethyl acetate and n-heptane (2:3) as eluent. Collecting the proper fractions afforded 3.0 g of (R)-N-(3- (2-( 10, 1 1 -dihydro-5H-dibenzo[a,d]cyclohepten-5-yiidene)ethoxy)- 1 - propγl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf = 0.1 9
(SiO2; ethyl acetate/n-heptane = 1 : 1 ) . The above ester (2.5 g, 5.8 mmol) was dissolved in ethanol (1 5 ml) and a 4 N sodium hydroxide solution (4.3 ml) was added . The mixture was stirred vigorously at room temperature for 5 h. A 4 N hydrochloric acid solution was added until pH 1 followed by dichloromethane (400 ml) . The mixture was stirred vigorously for a few minutes and the phases were separated . The organic phase was dried over sodium sulphate and the solvent was evaporated in vacuo. The residue was evaporated twice with acetone, once with ethyl acetate, dissolved in acetone (1 5 ml) and left for crystallization. This afforded 1 .9 g of the title compound as a solid .
M.P. 78-80°C. Calculated for C2βH32CINO3. % H2O: C, 68.6%; H, 7.4%; N, 3.1 %; Cl, 7.8%; Found: C, 68.3%; H, 7.3%; N, 3.0%; Cl, 7.8%.
EXAMPLE 6
(R)-N-(3-(2-( 10, 1 1 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)ethoxy)-1 -propyl)-3-piperidinecarboxylic acid hydrochloride
The acid prepared in Example 5 (0.5 g, 1 .1 mmol) was dissolved in methanol ( 1 5 ml) and stirred under an atmosphere of hydrogen for 8 h at room temperature in the presence of 10 % palladium on carbon catalyst (50 % aqueous paste) . The mixture was filtered and the solvent was evaporated in vacuo to give an oily residue which was re-evaporated from acetone and then crystallised from a mixture of acetone and ethyl acetate. This afforded 0.3 g (60%) of the title compound as an amor¬ phous solid.
M.P. 80-81 °C.
1H NMR (DMSO-d6) δ 4.21 (brs, 1 H) . EXAMPLE 7a
(R)-N-(2-(((10, 1 1 -Dihydro-5H-dibenzo[a,d]cyclohepten-5- ylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid hydrochloride
A mixture of 1 0, 1 1 -dihydro-5H-dibenzo[a,d]cyclohepten-5-one (9.4 g, 45 mmol) and hydroxylamine hydrochloride (6.3 g, 90 mmol) pyridine (60 ml) was heated at reflux temperature for 48 h. Another portion of hydroxylamine hydrochloride (6.3 g, 90 mmol) was added and heating at reflux temperature was continued for another 24 h. The reaction mixture was allowed to cool and the solvent was evaporated in vacuo to give an oily residue, which was dissolved in a mixture of ethyl acetate (100 ml) and a 10% aqueous citric acid solution ( 100 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (50 ml) . The combined organic phases were extracted with an aqueous citric acid solution (50 ml) . The separated organic phase was washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuo to a solid residue, which was recrystallized from cyclohexane. This afforded 5.4 g of the oxime derivative as a solid . TLC: rf = 0.61
(SiO2; dichloromethane/methanol = 19: 1 ).
To an ice-cooled mixture of the above oxime derivative (1 .0 g, 4.5 mmol), tetrabutylammonium bromide (0.1 5 g, 0.5 mmol) and 1 ,2- dibromoethane (3.8 ml) was added a 12 M sodium hydroxide solution (5 ml) . The reaction mixture was stirred vigorously for 4.5 h. A 2 M hydro¬ chloric acid solution (50 ml) and diethyl ether (25 ml) was added. The phases were separated and the aqueous phase was extracted with diethyl ether (25 ml) . The combined organic phases were washed with a 5 % sodium bicarbonate solution, brine and dried over sodium sulphate.
The solvent was evaporated in vacuo to give a residue, which was re- evaporated successively with ethanol, toluene, methanol and dichloromethane. This afforded 1 .4 g of the crude 2-(((10, 1 1 -dihydro- 5H-dibenzo[a,d]cyclohepten-5-ylidene)amino)oxy)ethylbromide as an oil. TLC: rf = 0.65 (Si02; dichloromethane).
To a solution of 2-((( 10, 1 1 -dihydro-5H-dibenzo[a,d]cyclohepten-5- ylidene)amino)oxy)ethylbromide ( 1 .4 g, 4.2 mmol) in methyl isobutylke- tone (40 ml) was added potassium carbonate (4.7 g, 34 mmol) and ethyl (R)-3-piperidinecarboxylate tartrate (2.6 g, 8.5 mmol) and the suspension was heated at reflux temperature for 3 days. The cooled reaction mixture was filtered and the solvent was evaporated from the filtrate in vacuo. The oily residue was dissolved in a mixture of ethyl acetate (50 ml) and water (50 ml) . A 34% aqueous tartaric acid solution was added until pH 4. The phases were separated and the aqueous phase was extracted with ethyl acetate (25 ml) . The combined organic phases were extracted with a 34% aqueous tartaric acid solution (2x5 ml) and the organic extracts were discarded. The acidic aqueous phases were combined, diluted three times with water and ethyl acetate (40 ml) was added. A 4 N sodium hydroxide solution was added until pH 7 and the phases were separated . The organic phase was washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuo to give 1 g of (R)-N-(2-((( 10, 1 1 -dihydro-5H-dibenzo[a,d]cyclohepten-5- ylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf = 0.39 (SiO2; dichloromethane/methanol/acetic acid = 20:2: 1 ).
The above ester ( 1 .0 g, 3.0 mmol) was dissolved in ethanol (25 ml) and a 4 N sodium hydroxide solution (3.4 ml) was added. The mixture was stirred vigorously at room temperature for 22 h. The solvent was evapor¬ ated in vacuo to give an oily residue. Dichloromethane (75 ml) was added and the mixture was cooled on an ice-bath. A concentrated hydrochloric acid solution ( 1 .6 mi) was added. The mixture was stirred vigorously for a few minutes and the phases were separated . The organic phase was dried over sodium sulphate and the solvent was evaporated in vacuo. The residue was re-evaporated three times with dichloromethane and once with acetone to give 0.95 g of the title compound as a foam.
M.P. 119°C. 1H NMR (DMSO-dg) δ 4.5-4.6 (m,2H).
By a similar procedure as described in Example 7a the following com¬ pounds have been prepared:
EXAMPLE 7b
(R)-1-(2-(((3-Chloro-10,11-dihydro-5H-dibenzo[a,djcyclohepten-5- ylidene)amino)oxy)ethyl)-3-piperidinecarboxylicacid hydrochloride
M.P.208-210°C.
'H NMR (DMSO-d6) δ 4.55 (brs, 2H, -OCH2-).
EXAMPLE 7c
(R)-1-(2-(((3,7-Dichloro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5- ylidene)amino)oxy)ethyl)-3-piperidinecarboxylicacid hydrochloride
M.P.143-144°C. Calculated for C23H2βCI3N2O3:
C, 57.1%; H, 5.2%; N, 5.8%; Found: C, 57.5%; H, 5.6%; N, 5.5%.
EXAMPLE 8
(R)-N-(2-((10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)metho- xy)- ethyl)-3-piperidinecarboxylic acid hydrochloride To a solution of
10, 1 1 -dιhydro-5H-dιbenzo[a,d]cyclohepten-5-carboxaldehyde ( 1 1 .3 g, 51 mmoi, prepared in a similar way as described in Acta Chem Scand 1 978, B33, 1 00- 103) and tetrabutylammonium bromide ( 1 .64 g, 5 1 mmol) in dichloromethane (100 ml) was added 1 ,2-dιbromoethane (62 ml) and a 1 2 M sodium hydroxide solution ( 1 00 ml) . The reaction mix¬ ture was stirred vigorously overnight and dichloromethane ( 100 ml) was added . The phases were separated and the aqueous phase was extracted with dichloromethane ( 100 ml) The combined organic phases were washed with a 0.2 M hydrochloric acid solution ( 100 ml), brine (25 ml) and dried over magnesium sulphate The solvent was evaporated in vacuo to give 14.1 g of 2-((10, 1 1 -dιhydro-5H-dιbenzo[a,d]cyclohepten- 5-ylιdene)methoxy)ethylbromιde. TLC: rf = 0 48 (SιO2; ethyl acetate/- n-heptane = 1 :4).
To a solution of 2-((10, 1 1 -dιhydro-5H-dιbenzo[a,d]cyclohepten-5-ylι- dene)methoxy)ethylbromιde ( 14.0 g, 42.5 mmol) in acetone ( 100 ml) was added potassium carbonate (23.5 g, 170 mmol), potassium iodide (0.7 g) and ethyl (R)-3-pιperιdιnecarboxylate tartrate ( 1 9.6 g, 64 mmol). The suspension was stirred at room temperature for 3 days. The reaction mixture was filtered and the solvent was evaporated from the filtrate in vacuo. The oily residue was dissolved in ethyl acetate ( 1 50 ml). A 34% aqueous tartaric acid solution (100 ml) was added and pH was adjusted to 2.5 with a 4 M aqueous sodium hydroxide solution. The phases were separated and the organic phase was washed with a 2.5% aqueous solution of sodium bicarbonate ( 100 ml) and a 5% aqueous sodium bicarbonate solution (25 ml) . The combined aqueous phases were extracted with ethyl acetate ( 100 ml) . The combined organic phases were dried over magnesium sulphate. The solvent was evaporated in vacuo to give 1 2.0 g of (R)-N-(2-(( 10, 1 1 -dιhydro-5H-dιbenzo[a,d]cyclo- hepten-5-ylιdene)methoxy)ethyl)-3-pιρeπdιnecarboxylιc acid ethyl ester as an oil. TLC: rf = 0 45 (Sι02; dichloromethane/methanol/ acetic acid = 20:2: 1 ) .
The above ester (2.0 g, 4.9 mmol) was dissolved in ethanol (20 ml) and a 4 N sodium hydroxide solution (4.9 ml) was added . The mixture was stirred at 50°C for 2 h. Water ( 10 ml) was added and ethanol was evaporated in vacuo to give an aqueous residue. A 4 M aqueous hydro¬ chloric acid solution (6.2 ml) was added followed by dichloromethane (50 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (50 ml). The combined organic phases were washed with water (10 ml) and then dried over magnesium sul¬ phate. The solvent was evaporated in vacuo and the residue dried in vacuo to give 1 .71 g of the title compound as a solid.
M.P. 1 1 1 -1 14°C (dec). Calculated for C24H28CIN03y2 H20: C, 70.6%; H, 7.2%; N, 3.3%; Cl, 4.2%; Found:
C, 70.2%; H, 7.0%; N, 3.2%; Cl, 4.5%.
EXAMPLE 9
N-(2-(2-( 10, 1 1 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)ethoxy)ethyl)-
1 ,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride
A solution of 5-(2-(2-hydroxyethoxy)ethylidene)-10, 1 1 -dihydro-5H- dibenzo[a,d]cycloheptene (2.4 g, 8.2 mmol, prepared as described in
Example 3) in dioxane (25 ml) was hydrogenated at 10 atm. for 1 6 h at room temperature in the presence of 10% palladium on carbon catalyst (50% aqueous paste). The mixture was filtered and the solvent was eva¬ porated in vacuo to give an oily residue, which was re-evaporated from carbontetrachloride. This afforded 2.2 g 2-(2-( 10, 1 1 -dihydro-5H-di- benzo[a,d]cyclohepten-5-yl)ethoxy)ethanol as an oil.
A solution of the above alcohol (2.2 g, 7.4 mmol) in dry THF (20 ml) was placed under an atmosphere of nitrogen and placed on an ice-bath. A solution of n-butyllithium in hexanes (3.0 ml, 2.5 M) was added dropwise and the mixture was stirred for another 1 5 minutes. Methanesulfonyl chloride (0.85 g, 7.4 mmol) was added in one portion and the mixture was stirred on an ice-bath for 45 minutes. The solvent was evaporated in vacuo and the residue was dissolved in acetone (25 ml). Ethyl 1 , 2, 5, 6-tetrahydro-3-pyridinecarboxylate hydrochloride ( 1 .5 g, 7.8 mmol) and potassium carbonate (2.5 g, 1 8 mmol) were added . The mixture was stirred at reflux temperature for 1 6 h. The mixture was filtered and the solvent was evaporated in vacuo. The oily residue was submitted to column chromatography on silica gel ( 1 50 g) using a mixture of ethyl acetate and n-heptane ( 1 : 1 ) as eluent. Collecting the proper fractions afforded 1 .3 g of N-(2-(2-( 10, 1 1 -dihydro-5H- dibenzo[a, d]cyclohepten-5-yl)ethoxy)ethyl)- 1 ,2,5, 6-tetrahydro-3- pyridinecarboxylic acid ethyl ester as an oil. TLC: rf = 0.14 (SiO2; ethyl acetate/n-heptane = 1 : 1 ).
The above ester (1 .3 g, 3.1 mmol) was dissolved in ethanol ( 10 ml) and a 4 N sodium hydroxide solution (2.3 ml) was added. The mixture was stirred at room temperature for 4 h. A 4 N hydrochloric acid solution was added until pH 1 . Dichloromethane (400 ml) was added and the mixture was stirred vigorously for a few minutes and the phases were separated. The organic phase was dried over sodium sulphate and the solvent was evaporated in vacuo. The residue was re-evaporated with acetone, dissolved in acetone (50 ml) and left for crystallization. This afforded
0.45 g of the title compound as a solid.
M.P. 1 54-155°C. Calculated for C25H30CINO3: C, 70.2%; H, 7.1 %; N, 3.3%; Cl, 8.3%; Found: C, 70.1 %; H, 7.2%; N, 3.1 %; Cl, 8.2%.
EXAMPLE 10 (R)-N-(2-((3-( 1 0, 1 1 -Dihydro-5H-dibenz[b,f]azepin-5-yl)-1 -propyl)oxy)- ethyl)3-piperidinecarboxylic acid hydrochloride
To a solution of 10, 1 1 -dihydro-5H-dibenz[b,f]azepine (8.1 g, 40 mmol) in dry dibutylether (60 ml) kept under an atmosphere of nitrogen, NaH (1 .6 g, 40 mmol, 60 % oil dispersion) was carefully added. The reaction mixture was heated at reflux temperature for 4 h and then allowed to cool to 80°C. 3-Bromo-1 -propyl tetrahydro-2-pyranyl ether ( 10.7 g, 48 mmol) was added and the mixture was heated at reflux temperature for 1 6 h. To the cooled reaction mixture was added water (20 ml) and the phases were separated. From the organic phase the solvent was evapor¬ ated and the residue was dissolved in a mixture of MeOH ( 1 50 ml) and a 4 N aqueous HCI solution (50 ml). The mixture was heated at reflux temperature for 15 minutes and then stirred for 1 h at RT. Water (250 ml) was added and the mixture was extracted with ethyl acetate (2 x 200 ml) . The combined organic extracts was dried (Na2SO4), filtered and the solvent evaporated in vacuo. This afforded a residue which was submitted to chromatography on silica gel (200 g) using a mixture of n-heptane and ethyl acetate (3:2) as eluent to give 5.5 g of 3-( 10, 1 1-dihydro-5H-dibenz[b,f]azepin-5-yl)-1 -propanol as an oil. TLC: rf = 0.30 (Si02; n-heptane/ethyl acetate = 1 : 1 ).
A mixture of NaH (0.40 g, 10 mmol, 60% oil dispersion), 3-( 10, 1 1 -dihy- dro-5H-dibenz[b,f]azepin-5-yl)-1 -propanol (2.5 g, 10 mmol) and dry dibutylether (25 ml) was stirred for 1 6 h at reflux temperature under a nitrogen atmosphere. The reaction mixture was allowed to cool and 2-bromoethyl tetrahydro-2-pyranyl ether (2.5 g, 1 2 mmol) was added. Then the mixture was heated to reflux temperature and kept there for 16 h. To the cooled mixture was added water (10 ml) and the phases were separated . From the organic phase the solvent was evaporated in vacuo to give a residue which was submitted to chromatography on silica gel (200 g) using a mixture of n-heptane and ethyl acetate (7:3) as eluent. This afforded 1 .5 g of the tetrahydro-2-pyranyl intermediate. TLC: rf = 0.55 (SiO2; n-heptane/ethyl acetate = 1 : 1 ) . This intermediate was dissolved in a mixture of methanol (30 ml) and a 4 N aqueous hydro- chloric acid solution (1 5 ml) and the mixture was heated at reflux tem¬ perature for 1 5 minutes. The reaction mixture was allowed to cool and methanol was evaporated in vacuo. Water was added and the mixture was extracted with ethyl acetate. The organic extract was washed with a 5 % aqueous sodium bicarbonate solution, dried over sodium sulphate and the solvent evaporated in vacuo. This afforded 0.6 g (20 %) of
2-((3-( 1 0, 1 1 -dihydro-5H-dibenz[b,f]azepin-5-yl)- 1 -propyl)oxy)- ethanol as an oil. TLC: rf = 0.33 (Si02; n-heptane/ethyl acetate = 1 : 1 ) .
A solution of the above alcohol (0.60 g, 2.0 mmol) in dry THF (1 5 ml) was placed under an atmosphere of nitrogen and then cooled on an ice-bath.
A solution of n-butyllithium in hexanes (0.88 ml, 2.5 M) was added dropwise at 10°C. When addition was complete the mixture was stirred at 10°C for 30 minutes. Methanesulfonyl chloride (0.25 g, 2.2 mmol) was added and the reaction mixture was stirred at room temperature for
90 minutes. The volatiles were evaporated in vacuo leaving a residue which was dissolved in acetone (20 ml). Ethyl (R)-3-piperi- dinecarboxylate (0.50 g, 3.0 mmol) and potassium carbonate (0.7 g, 5 mmol) were added and the suspension was stirred at room temperature for 1 6 h and the heated at reflux temperature for 7 h. The cooled reac¬ tion mixture was filtered and the solvent was evaporated in vacuo. The oily residue was submitted to column chromatography on silica gel (1 50 g) using a mixture of ethyl acetate and n-heptane (2:3) as eluent. Col¬ lecting the proper fractions afforded 0.4 g of (R)-N-(2- ((3-( 10, 1 1 -dihydro-5H-dibenz[b,f]azepin-5-yl)-1 -propyl)oxy)ethyl)-3-piperi- dinecarboxylic acid ethyl ester as an oil. The above ester (0.4 g, 0.92 mmol) was dissolved in ethanol (10 ml) and a 4 N sodium hydroxide solution (0.70 ml) was added . The mixture was stirred at room temperature for 4 h . A 4 N hydrochloric acid solution was added until pH 1 . Dichloromethane (300 ml) was added and the phases were separated. The organic phase was dried over sodium sulphate and the solvent was evaporated in vacuo. The residue was re-evaporated with acetone, dissolved in a mixture of ethyl acetate and acetone and left for crystallization. This afforded 0.1 3 g of the title compound as a solid.
M.P. 1 30-1 32°C. Calculated for C25H33CIN2O3: C, 67.5%; H, 7.5 %; N, 6.3%; Found : C, 67.3 %; H, 7.7%; N, 6.1 %.
EXAMPLE 1 1
E/Z-(R)-N-(2-((((10, 1 1 -Dihydro-5H-dibenzo[a,d]cyclohepteπ-5-yl)methyle- ne)amino)oxy)ethyl)-3-piperidinecarboxylic acid hydrochloride
A mixture of ( 10, 1 1 -dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)carboxalde- hyde (1 1 .5 g, 52 mmol, prepared similarly as described Acta Chem. Scand. B 1979, 33, 100) and hydroxylamine hydrochloride (7.2 g, 103 mmol) in 96% ethanol (50 ml) was stirred at room temperature for 2 days. A 10% aqueous citric acid solution ( 100 ml) was added together with ethyl acetate ( 100 ml) . The phases were separated and the organic phase was washed successively with a 10% aqueous citric acid solution (50 ml), an excess of a saturated sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulphate and the solvent was evaporated in vacuo to give a solid residue which was recrystallized from cyclohexane. This afforded 5.2 g of
(10, 1 1 -dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)carboxaldehydoxime as a solid. To an ice-cooled mixture of the above oxime derivative (5.4 g, 23 mmol), tetrabutylammonium bromide (0.73 g, 2.3 mmol) and 1 ,2-dibromoethane ( 19.6 ml) was added a 1 2 M sodium hydroxide solution (30 ml) . The reaction mixture was stirred vigorously for 1 .5 h. The phases were separated and the aqueous phase was extracted with a small portion of toluene. The combined organic phases were diluted with another portion of toluene (50 ml) and washed successively with an aqueous citric acid solution (pH 6), an excess of a saturated sodium bicarbonate solution and brine. The organic phase was dried over mag- nesium sulphate and the solvent was evaporated in vacuo to give an oily residue which was re-evaporated successively with methanol and dichloromethane. This afforded 7.8 g of the crude 2-(((( 10, 1 1 - dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methyle- ne)amino)oxy)ethylbromide as an oil. TLC: rf = 0.62 (Si02; dichloromethane) .
To a solution of the above crude bromide (7.0 g, 20 mmol) in acetone (100 ml) was added potassium carbonate (1 6.8 g, 122 mmol) and ethyl (R)-3-piperidinecarboxylate tartrate ( 1 2.5 g, 41 mmol) and the suspen- sion was stirred at room temperature for 2.5 days. The solvent was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate ( 100 ml) and water (100 ml) . The phases were separated and the aqueous phase was extracted with ethyl acetate (50 ml). Water ( 100 ml) was added to the combined organic extracts and pH was adjusted to 4 with a 34% aqueous tartaric acid solution. The phases were separated and the organic phase was extracted with a 34% aqueous tartaric acid solution (3x 1 8 ml) . The three combined aqueous tartaric extracts were diluted with icewater (250 ml) and ethyl acetate was added ( 1 50 ml). A 4 N aqueous sodium hydroxide solution was added until pH 7 and the phases were separated. The organic phase was washed with a saturated sodium bicarbonate solution and brine. After drying over magnesium sulphate the solvent was evaporated in vacuo to give 6 g of (R)-N-(2-(((( 1 0, 1 1 -dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylene)- amino)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf = 0.20 (SiO2; ethyl acetate/n-heptane = 1 : 1 ) .
The above ester (5.0 g, 1 2 mmol) was dissolved in ethanol ( 100 ml) and a 2 N aqueous sodium hydroxide solution (27 ml) was added . The mixture was stirred at room temperature for 1 6 h. The solvent was evaporated in vacuo to give aπ oily residue. Dichloromethane ( 1 60 ml) was added and the mixture was cooled on an ice-bath. A concentrated hydrochloric acid solution (5.5 ml) was added . The mixture was stirred vigorously for a few minutes and the phases were separated . The organic phase was dried over magnesium sulphate and the solvent was evaporated in vacuo to give 4.1 g of the title compound as a foam. The material isolated consists of an approx. 1 :5 mixture of the E/Z isomers.
M.P. 1 10°C.
1H NMR (DMSO-dg) δ Major isomer: 5.03 (d, 1 H), 7.94 (d, 1 H);
Minor isomer: 5.49 (d, 1 H), 7.57 (d, 1 H).
EXAMPLE 1 2
(R)-N-(2-(2-(5,6,7, 1 2-Tetrahydrodibenz[b,g]azocin-1 2-yl)ethoxy)ethyl)-3- piperidinecarboxylic acid hydrochloride
To a solution of 5,6,7, 1 2-tetrahydrodibenz[b,g]azocine (2.5 g, 1 2 mmol, prepared in a similar way as described in Chem. Pharm. Bull. 1 978, 26, 942-950) and 2-(2-((tetrahydro-2-pyranyl)oxy)ethoxy)ethylchloride (3.0 g, 14 mmol) in toluene (50 ml) was added a suspension of sodium amide ( 1 .50 g, 1 9 mmol, 50% wt suspension in toluene). The reaction mixture was heated at reflux temperature for 10 h. The mixture was allowed to cool to room temperature and water (52.5 ml) was carefully added. The phases were separated and the aqueous phase was extracted with toluene (50 ml). The combined organic phases were washed with water (2x1 5 ml), brine ( 1 5 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo. The oily residue was submitted to column chromatography on silica gel ( 1 50 g) using a mixture of ethyl acetate and n-heptane ( 1 :4) as eluent. Collecting the proper fractions afforded
3.0 g of crude 1 2-(2-(2-((tetrahydro-2-pyranyl)oxy)ethoxy)ethyl)-5, 6,7, 1 - 2-tetrahydrodibenz[b,g]azocine. TLC: rf = 0.1 1 (SiO2; ethyl acetate/- n-heptane = 1 :4).
To a solution of 12-(2-(2-((tetrahydro-2-pyranyl)oxy)ethoxy)ethyl)-5,6,7,-
12-tetrahydrodibenz[b,g]azocine (3.0 g, 7.8 mmol) in (30 ml) was added a 4 M aqueous sulfuric acid solution. The mixture was stirred at room temperature for 1 8 h. The reaction mixture was poured into a mixture of water ( 1 50 ml) and a 4 M aqueous sodium hydroxide solution (6.5 ml) . Ethyl acetate ( 1 00 ml) was added and pH was adjusted to 8.5 with a
5 % aqueous sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted with ethyl acetate (50 ml). The combined organic phases were washed with brine (20 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo and the residue was re-evaporated with dichloromethane. This afforded 2.1 g of crude 2-(2-(5,6,7, 1 2-tetrahydrodibenz[b,g]azociπ-1 2-yl)ethoxy)ethanol. TLC: rf = 0.39 (Si02; dichloromethane/methanol = 19: 1 ) .
A mixture of the above alcohol ( 1 .8 g, 6 mmol), triethylamine (2.5 ml) and toluene (30 ml) placed under an atmosphere of nitrogen was cooled on an ice-bath. A solution of methanesulfonyl chloride (1 .7 g, 12 mmol) in toluene (5 ml) was added dropwise. Stirring was continued for 45 minutes on an ice-bath and then the temperature was allowed to reach ambient temperature. Water (20 ml) was added and the mixture was stirred at room temperature for 1 5 minutes. The phases were separated and the aqueous phase was extracted with toluene (20 ml) . The com¬ bined organic phases were washed with a 5% aqueous sodium bicarbon- ate solution and dried over magnesium sulphate. The solvent was evaporated in vacuo to give an oil which was dissolved in toluene (30 ml) . To this solution was added potassium carbonate (2.9 g, 21 mmol) and ethyl (R)-3-piperidinecarboxylate tartrate (3.7 g, 1 2 mmol) . The suspension was heated at 100°C for 24 h and then allowed to cool to ambient temperature. The mixture was filtered and the solid washed with toluene (20 ml) . The solvent was evaporated in vacuo to give an oily residue which was submitted to column chromatography on silica gel (1 50 g) using a gradient of a mixture of ethyl acetate and n-heptane (1 :4 - 1 : 1 ) . Collecting the proper fractions afforded 1 .27 g of (R)-N-(2-(2-
(5,6,7, 1 2-tetrahydrodibenz[b,g]azocin-1 2-yl)-ethoxy)ethyl)-3- piperidinecarboxylic acid ethyl ester as an oil. TLC: rf = 0.39 (Si02; dichloromethane/ methanol/acetic acid = 20:2: 1 ) .
The above ester (1 .2 g, 2.7 mmol) was dissolved in ethanol (5 ml). A 4
N aqueous sodium hydroxide solution (2 ml) and water (3 ml) were added . The mixture was heated at 50°C with stirring for 1 h . Water (25 ml) was added and ethanol was evaporated in vacuo. The aqueous residue was extracted with diethyl ether (2x25 ml) which was discarded. Then a 4 N aqueous hydrochloric acid solution (3 ml) was added to the aqueous phase and the resulting acidic solution was extracted with dichloromethane (2x50 ml) . From the combined dichloromethane extracts the solvent was evaporated in vacuo and the residue re-evaporated with acetone. The foamy residue was trituated with diethylether to give 0.71 g of an amorphous solid which was recrystallized from 2-propanol (35 ml). After drying in vacuo 0.45 g of the title compound was obtained as a white solid .
M.P. 203.5-205.5°C. Calculated for C25H33CIN2O3: C, 67.5%; H, 7.5%; N, 6.3%; Cl, 8.0% Found:
C, 67.5%; H, 7.7%; N, 6.0%; Cl, 7.9%. EXAMPLE 1 3
(R)-N-(2-(2-(6, 1 1 -Dihydro-5H-dibeπz[b,e]azepin-5-yl)ethoxy)ethyl)-3- piperidinecarboxylic acid formate
To a solution of 6, 1 1 -dihydro-5H-dibenz[b,e]azepine (5.0 g, 26 mmol, Coll . Czechoslov. Chem. Commun. 1 958, 23, 1 330) and 2-(2-((tetrahydro-2pyranyl)oxy)ethoxy)ethylchloride (6.4 g, 30 mmol) in toluene (25 ml) placed under an atmosphere of nitrogen was added a suspension of sodium amide (5.0 g, 64 mmol, 50% wt suspension in toluene) . The reaction mixture was heated at reflux temperature for 8 h. The mixture was allowed to cool to room temperature and toluene (50 ml) was added . The phases were separated and the organic phase was washed with a 1 N aqueous hydrochloric acid solution (2x100 ml), excess of a 5 % aqueous sodium bicarbonate solution and brine (25 ml). After drying over magnesium sulphate the solvent was evaporated in vacuo. The oily residue was submitted to column chromatography on silica gel (250 g) using a mixture of ethyl acetate and n-heptane ( 1 :4) as eluent. Collecting the proper fractions afforded 2.6 g of
1 2-{2-(2-((tetrahydro-2-pyranyl)oxy)ethoxy)ethyl)-6, 1 1 - dihydro-5H-dibenz[b,e]azepine. TLC: rf = 0.41 (SiO2; ethyl acetate/π- heptane = 1 : 1 ).
To a solution of 1 2-(2-(2-((tetrahydro-2-pyranyl)oxy)ethoxy)ethyl)-6, 1 1 - dihydro-5H-dibenz[b,e]azepine (2.9 g, 7.9 mmol) in 2-propanol (30 ml) was added a 4 M aqueous sulfuric acid solution (6 ml) . The mixture was stirred at room temperature for 1 h. The reaction mixture was poured into a mixture of water (100 ml) and toluene (25 ml) . The phases were separated and the organic phase was washed with excess of a saturated aqueous sodium bicarbonate solution. The acidic aqueous phase was made alkaline with aqueous sodium hydroxide and extracted with toluene. The combined organic phases were washed with brine and dried over magnesium sulphate. The solvent was evaporated in vacuo to give 2.2 g of crude 2-(2-(6, 1 1 -dihydro-5H-dibenz[b,e]azepin-5-yl)ethoxy)- ethanol. TLC: rf = 0.17 (Si02; ethyl acetate/n-heptane = 1 : 1 ).
A mixture of the above alcohol (2.1 g, 7.4 mmol), triethylamine (2.6 ml) and toluene (30 ml) placed under an atmosphere of nitrogen was cooled on an ice-bath. A solution of methanesulfonyl chloride (2.1 g, 1 5 mmol) in toluene (5 ml) was added dropwise. Stirring was continued for 45 minutes on an ice-bath and then the temperature was allowed to reach ambient temperature. Water (20 ml) was added and the mixture was stirred at room temperature for 1 5 minutes. The phases were separated and the organic phases were washed with a 5% aqueous sodium bicar¬ bonate solution and brine and dried over magnesium sulphate. The solvent was evaporated in vacuo to give an oil which was dissolved in methyl isobutylketone (40 ml). To this solution was added potassium carbonate (3.6 g, 26 mmol) and ethyl (R)-3-piperidinecarboxylate tartrate (4.6 g, 1 5 mmol) . The suspension was heated at 40°C for 24 h and then at reflux temperature for 3 h. The reaction mixture was allowed to cool to ambient temperature and water (50 ml) was added. The phases were separated and from the organic phase the solvent was evaporated in vacuo. This afforded an oily residue which was submitted to column chromatography on silica gel (1 25 g) using a mixture of ethyl acetate and n-heptane ( 1 : 1 ) as eluent. Collecting the proper fractions afforded 1 .0 g of (R)-N-(2-(2-(6, 1 1 -dihydro-5H-dibenz[b,e]azepin-5-yl)- ethoxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf =
0.36 (SiO2; ethyl acetate).
The above ester ( 1 .0 g, 2.4 mmol) was dissolved in ethanol (25 ml) and a 2 N aqueous sodium hydroxide solution (4.7 ml) was added . The mixture was heated at 50°C with stirring for 2.5 h. The volatiles were evaporated in vacuo and dichloromethane (100 ml) was added to the residue. The mixture was cooled on an ice-bath and a concentrated aqueous hydrochloric acid solution ( 1 .2 ml) was added dropwise with vigorous stirring . The phases were separated and the organic phase was dried over magnesium sulphate. The solvent was evaporated in vacuo and the residue re-evaporated several times with acetone.
The residue was purified by column chromatography on silica gel using a mixture of dichloromethane, acetonitrile and formic acid (4:4: 1 ) as eluent. The proper fractions were collected and the solvent was evapor¬ ated in vacuo to give a residue which was re-evaporated successively with n-heptane, dioxane and dichloromethane. This afforded 0.4 g of the title compound as a waxy solid.
'H NMR (DMSO-d6) J 4.13 (m, 1 H); 4.67 (m, 1 H) .
EXAMPLE 14
(R)-N-(2-(2-(5,6, 1 1 , 1 2-Tetrahydrodibenz[b,f]azocin-12-yl)ethoxy)ethyl)-3- piperidinecarboxylic acid hydrochloride
To a solution of 2-{2-chloroethoxy)ethanol (3.9 g, 31 mmol) in dichloromethane (1 5 ml) kept at 0°C was added triethylamine (6.2 g, 61 mmol) . A solution of methanesulfonyl chloride (3.6 g, 31 mmol) in dichloromethane (1 5 ml) was carefully added keeping the temperature below 0°C. When addition was complete the reaction mixture was left overnight at room temperature and then diluted with dichloromethane ( 1 50 ml) . The organic phase was washed with a 2 N hydrochloric acid solution (75 ml) and water (75 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo to give 6.3 g of crude 2-(2-chloroethoxy)ethyl mesylate as an oil.
A suspension of 5,6, 1 1 , 1 2-tetrahydrodibenz[b,f]azocine (5.0 g, 20 mmol) in dry THF (75 ml) placed under an atmosphere of nitrogen was cooled to -68°C. A solution of n-butyl lithium in hexanes ( 19 ml, 49 mmol, 2.5 M) was added dropwise keeping the temperature below -60°C When addition was complete stirring was continued at this temperature for 30 minutes and then the reaction mixture was left overnight at room temperature The mesylate prepared above was dissolved in dry THF (50 ml) and added dropwise to the reaction mixture.
When addition was complete the mixture was stirred at room tempera¬ ture for 1 68 h. Ice was added (80 g) and the phases were separated The aqueous phase was extracted with diethyl ether (2x50 ml) The combined organic phases were washed with water (2x50 ml) and dried over magnesium sulphate The solvent was evaporated in vacuo to give a residue which was submitted to column chromatography on silica gel using a mixture of ethyl acetate and n-heptane (2 3) as eluent This afforded 2.5 g of 2-(2-(5,6, 1 1 , 1 2-tetrahydrodιbenz[b,f]azocιn-1 2-yl)etho- xy)ethylchlorιde as an oil.
A mixture of the above chloride (2.5 g, 7.9 mmol), ethyl (R)-3-pιperιdι- necarboxylate tartrate (2.4 g, 1 6 mmol) and potassium carbonate (3.3 g, 24 mmol) in methylisobutyl ketone (60 ml) was heated at reflux tempera¬ ture for 96 h . The mixture was allowed to cool and the solvent was evaporated in vacuo. The residue was dissolved in a mixture of ethyl acetate (75 ml) and water (75 ml). The phases were separated and from the organic phase the solvent was evaporated in vacuo. The oily residue was submitted to column chromatography on silica gel using dichloromethane containing 5% of a mixture of ethanol and 25% aque- ous ammonia (9:1 ) as eluent. The proper fractions were collected and the solvent was evaporated in vacuo. The residue was submitted once more to column chromatography on silica gel using dichloromethane containing 3% of a mixture of ethanol and 25 % aqueous ammonia (9: 1 ) as eluent. The proper fractions were collected and the solvent was evaporated in vacuo to give 0.85 g of (R)-N-(2-(2-(5,6, 1 1 , 1 2- tetrahydrodιbenz[b,f]azocιn-1 2-yl)ethoxy)ethyl)-3-pιperιdιnecarboxylιc acid ethyl ester as an oil The above ester (0 4 g, 0.9 mmol) was dissolved in ethanol (7 ml) and a 2 N aqueous sodium hydroxide solution ( 1 .8 ml) was added. The reac¬ tion mixture was stirred at room temperature for 1 6 h The mixture was placed on an ice-bath and a concentrated aqueous hydrochloric acid solution (0.37 ml) was added. The volatiles were evaporated in vacuo, the residue suspended in dichloromethane and the solid removed by filtration. The solvent was evaporated from the filtrate in vacuo to give a residue which was re-evaporated with dichloromethane to give 0.30 g of the title compound as an amorphous solid.
M .P. 60-80°C. Calculated for C25H33CIN2O3.1/4 CH2CI2: C, 65 1 %; H, 7.2%; N, 6.0%; Found" C, 65 2%; H, 7.1 %; N, 6.0%.
EXAMPLE 1 5
N-(2-(2-( 10, 1 1 -Dιhydro-5H-dιbenz[b,fjazepιn-5-yl)ethoxy)ethyl)- 1 , 2, 5,6- tetrahydro-3-pyrιdιnecarboxy c acid hydrochloride
To a solution of 2-(2-chloroethoxy)ethanol (15.3 g, 123 mmol) in toluene ( 100 ml) kept at 5°C was added tnethylamine (50 g, 500 mmol) . A solution of methanesulfonyl chloride (28 g, 245 mmol) in toluene (50 ml) was carefully added keeping the temperature around 5°C. When addition was complete the reaction mixture was stirred at 5°C for 45 minutes and then 75 minutes at ambient temperature Water ( 100 ml) was added and the mixture was stirred for 1 5 minutes. The phases were separated and the organic phase was washed with water, brine and dried over magnesium sulphate. The solvent was evaporated in vacuo to give crude 2-(2-chloroethoxy)ethyl mesylate as an oil.
A solution of 10, 1 1 -dιhydro-5H-dιbenz[b,f]azepιne (24 g, 1 23 mmol) in dry THF ( 100 ml) placed under an atmosphere of nitrogen was cooled to -70°C. A solution of n-butyl lithium in hexanes (49.2 ml, 1 23 mmol, 2.5 M) was added dropwise keeping the temperature below -60°C. When addition was complete stirring was continued at -70°C for 1 5 minutes and then the reaction mixture was allowed to reach ambient tempera- ture. The mesylate prepared above was dissolved in dry THF (50 ml) and added dropwise to the reaction mixture. When addition was complete the mixture was stirred at room temperature for 64 h . Water ( 100 ml) was added and the phases were separated. The aqueous phase was extracted with diethyl ether (50 ml) . The combined organic phases were washed with brine and dried over magnesium sulphate. The solvent was evaporated in vacuo to give an oily residue which was submitted to column chromatography on silica gel (300 g, Lichroprep. 40-63 μ) using a mixture of dichloromethane and n-heptane (1 :5) as eluent. This afforded 10.4 g of 2-(2-(10, 1 1-dihydro-5H-dibenz[b,f]- azepin-5-yl)ethoxy)ethylchloride as an oil. TLC: rf = 0.23 (SiO2; dichloro- methane/n-heptane = 1 : 1 ).
A mixture of the above chloride (5.0 g, 1 6.6 mmol), ethyl
1 , 2, 5, 6-tetrahydro-3-pyridinecarboxylate hydrochloride (6.3 g, 33 mmol), potassium carbonate (8.0 g, 58 mmol) and potassium iodide (0.55 g) in methylisobutyl ketone (50 ml) was heated at reflux temperature for 48 h. The reaction mixture was allowed to cool and water (50 ml) was added. The phases were separated and from the organic phase the solvent was evaporated in vacuo to give an oily residue. This residue was dissolved in a mixture of ethyl acetate (50 ml) and water (50 ml)and pH was adjusted to 4 with a 34% aqueous tartaric acid solution. The phases were separ¬ ated and the organic phase was extracted with a 34% aqueous tartaric acid solution (3x1 5 ml). The three aqueous tartaric extracts were com¬ bined and icewater ( 1 50 ml) and ethyl acetate ( 100 ml) was added . A 1 2 N aqueous sodium hydroxide solution was added until pH 4 and the phases were separated. The organic phase was washed with a 5% sodium bicarbonate solution and brine and dried over magnesium sui- phate. The solvent was evaporated in vacuo to give 6.0 g of N-(2-(2-( 10, 1 1 -dιhydro-5H-dιbenz[b,f]azepιπ-5-yD- ethoxy)ethyl)- 1 ,2, 5, 6-tetrahydro-3-pyπdιnecarboxylιc acid ethyl ester as an oil. TLC: rf = 0.47 (SιO2; dichloromethane/methanol/acetic acid = 20:2: 1 ) .
The above ester (5.0 g, 1 2 mmol) was dissolved in ethanol (250 ml) and a 2 N aqueous sodium hydroxide solution (24 ml) was added . The mixture was stirred at room temperature for 1 6 h. The solvent was evaporated in vacuo to give an oily residue. Dichloromethane (200 ml) was added and the mixture was cooled on an ice-bath. A concentrated hydrochloric acid solution (5.9 ml) was added. The mixture was stirred vigorously for a few minutes and the phases were separated. The organic phase was dried over magnesium sulphate and the solvent was evaporated in vacuo to give an oily residue which was re-evaporated with acetone. This afforded 4.8 g of the title compound as a foam.
M.P. 103°C Calculated for C24H29CIN2O3.H2O: C, 64.5 %; H, 6.5 %; N, 6.3%; Found : C, 64.9%; H, 6.9%; N, 5.9%.
1H NMR (DMSO-dg) δ 3.53 (t, 2H); 3.95 (t, 2H); 6.96 (brs, 1 H).
EXAMPLE 1 6
N-(2-(2-( 10, 1 1 -Dιhydro-5H-dιbenz[b,f]azeριn-5-yl)ethoxy)ethyl)-3-pyrrolι- dineacetic acid hydrochloride
A mixture of 2-(2-(10,1 1 -dιhydro-5H-dιbenz[b,f]azepιn-5-yl)ethoxy)ethyl- chloride ( 1 .5 g, 4.9 mmol, prepared as described in Example 1 5), methyl
3-pyrrolιdιneacetate acetate (2.0 g, 9 8 mmol), potassium carbonate (2.4 g, 1 7 mmol) and potassium iodide (0.1 6 g) in methylisobutyl ketone (30 ml) was heated at reflux temperature for 48 h. The reaction mixture was allowed to cool and water (40 ml) was added. The phases were separ¬ ated and from the organic phase the solvent was evaporated in vacuo to give an oily residue. This residue was dissolved in a mixture of ethyl acetate (25 ml) and water (25 ml) and pH was adjusted to 4 with a 34% aqueous tartaric acid solution. The phases were separated and the organic phase was discarded. Ethyl acetate (25 ml) was added to the aqueous phase and pH was adjusted to approx. 9 with a 2 M aqueous sodium hydroxide solution. The phases were separated and from the organic phase the solvent was evaporated in vacuo to give an oily residue which was submitted to column chromatography on silica gel
( 1 80 ml) using a mixture of THF and n-heptane (1 : 1 ) as eluent. Collect¬ ing the proper fraction afforded 1 .0 g of N-(2-(2 (10, 1 1 -dihydro-5H-dibenz[b,f]azepin-5-yl)ethoxy)ethyl)-3-pyrrolidine- acetic acid methyl ester as an oil.
The above ester (1 .0 g, 2.5 mmol) was dissolved in ethanol (25 ml) and a 2 N aqueous sodium hydroxide solution (4.9 ml) was added. The mixture was stirred at room temperature for 1 6 h . The solvent was evaporated in vacuo to give an oily residue. Dichloromethane ( 100 ml) was added and the mixture was cooled on an ice-bath. A concentrated hydrochloric acid solution ( 1 ml) was added dropwise. The mixture was stirred vigorously for 1 5 minutes at approx. 10°C. Magnesium sulphate was added and the mixture was stirred at ambient temperature for 30 minutes and filtered. The solvent was evaporated in vacuo to give 0.9 g of the title compound as a foam.
M.P. 1 38°C. Calculated for C24H31CIN2O3: C, 66.9%; H, 7.3%; N, 6.5%; Found: C, 66.8%; H, 7.4%; N, 6.2%. 1H NMR (DMSO-d6) 6 3.54 (t, 2H); 3.94 (t, 2H) .
EXAMPLE 1 7 (R)-N-(2-(2-(3, 7-Dichloro- 10, 1 1 -dihydro-5H-dibenz[b,f]azepin-5-yl)etho- xy)- ethyl)-3-piperidinecarboxylic acid hydrochloride
To a solution of 3, 7-dichloro-10, 1 1 -dihydro-5H-dibenz[b,f]azepine (2.0 g, 7.6 mmol, prepared as described in British Patent No. 777, 546)) in dry dimethylsulfoxide (20 ml) placed under an atmosphere of nitrogen was added sodium hydride (0.36 g as a 55 % oil dispersion, 8.3 mmol) . The reaction mixture was stirred at 70°C for 1 h and then allowed to cool to ambient temperature. 2-(2-((Tetrahydro-2-pyra- πyl)oxy)ethoxy)ethylchloride ( 1 .7 g, 8.3 mmol) was added and the mixture was stirred at room temperature for two days. The reaction mixture was poured into icewater and extracted with ethyl acetate
(2x200 ml) . The combined organic extracts were washed with water and dried over magnesium sulphate. The solvent was evaporated in vacuo to give 3.7 g of an oil which was dissolved in methanol (100 ml) . A 4 N aqueous hydrochloric acid solution (30 ml) was added and the mixture was stirred at 50°C for 1 h . The cooled reaction mixture was diluted with water (700 ml) and extracted with ethyl acetate (2x200 ml) . The combined organic extracts were washed with a saturated aqueous sodium bicarbonate solution and dried over magnesium sulphate. The solvent was evaporated in vacuo to give an oily residue which was submitted to column chromatography on silica gel ( 100 g) using a mixture of ethyl acetate and n-heptane (3:7) as eluent. Collecting the proper fractions afforded 1 .3 g of 2-(2-(3,7-dichloro-10, 1 1 -dihydro-5H- dibenz[b,f]azepin-5-yl)ethoxy)ethanol as an oil. TLC: rf = 0.32 (SiO2; ethyl acetate/n-heptane = 1 : 1 ).
To a mixture of the above alcohol ( 1 .3 g, 3.7 mmol), triethylamine ( 1 .3 ml) and dry diethyl ether (75 ml) was added dropwise a solution of methanesulfonyl chloride (0.63 g, 5.5 mmol) in dry diethyl ether (25 ml) . Stirring was continued for 1 h at room temperature. The reaction mixture was washed with water and dried over potassium carbonate. The solvent was evaporated in vacuo to give an oily residue which was dissolved in acetone (30 ml) . To this solution was added potassium carbonate ( 1 .0 g, 7.4 mmol) and ethyl (R)-3-piperidinecarboxylate ( 1 .2 g,
7.4 mmol) and the suspension was heated at reflux temperature for 1 6 h. Another portion of ethyl (R)-3-piperidinecarboxylate (0.5 g) was added and the mixture was heated at reflux temperature for 24 h. The cooled reaction mixture was filtered and from the filtrate the solvent was evaporated in vacuo. This afforded an oil which was submitted to column chromatography on silica gel ( 100 g) using a mixture of ethyl acetate and n-heptane ( 1 : 1 ) as eluent. Collecting the proper fractions gave 1 .5 g of (R)-N-(2-(2-(3,7-dichloro-10, 1 1 -dihydro-5H-dibenz[b,f]- azepin-5-yl)ethoxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf = 0.1 8 (SiO2; ethyl acetate/n-heptane = 1 : 1 ) .
The above ester (1 .5 g, 3.1 mmol) was dissolved in ethanol (20 ml) . A 4 N aqueous sodium hydroxide solution (2.3 ml) was added and the mixture was stirred at ambient temperature for 3 h. A concentrated aqueous hydrochloric acid solution (3 ml) was added until pH 1 and the mixture was extracted with dichloromethane (300 ml) . The phases were separated and the organic phase was washed with water (10 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo and the residue re-evaporated with acetone. The foamy residue was dissolved in acetone (20 ml) and left for crystallization. This afforded
1 .25 g of the title compound as a solid.
M.P. 21 3-214°C. Calculated for C24H29CI3N203: C, 57.7%; H, 5.9%; N, 5.6%; Found : C, 57.6%; H, 6.1 %; N, 5.6%.
EXAMPLE 18 (R)-N-(3-(2-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)ethoxy)-1 -propyl)-3- piperidinecarboxylic acid hydrochloride
A mixture of 5-(ethylidene)-10, 1 1 -dihydro-5H-dibenzo[a,d]cycloheptene (4.0 g, 1 8 mmol, prepared similar as described in J. Med . Chem. 1 990, 33, 3095), dibenzoyl peroxide (60 mg), N-bromosuccinimide (3.2 g, 18 mmol) and carbontetrachloride (20 ml) was heated at reflux temperature for 1 8 h. N-bromosuccinimide ( 1 .6 g, 9 mmol) was added and the mixture was heated at reflux temperature for 24 h. The mixture was allowed to cool and then filtered through silica gel (50 ml) and the gel was washed with dichloromethane ( 1 50 ml) . From the combined filtrate and washing the solvents were evaporated in vacuo to give 6.85 g of an oil . A solution of n-butyllithium (6.7 ml, 1 6.7 mmol, 2.5 M) was added dropwise to ice-cooled propylene glycol ( 100 ml) under an atmosphere of nitrogen. When addition was complete the mixture was stirred at room temperature for 90 minutes. A solution of the crude bromide prepared above (5 g) dissolved in toluene (50 ml) was added and the mixture was stirred at room temperature for 3 days. The mixture was diluted with water ( 100 ml) and the phases were separated . The aqueous phase was extracted with toluene (2 x 50 ml). The combined organic extracts were washed with water (50 ml), brine and dried over sodium sulphate. The solvent was evaporated in vacuo to give a residue which was submitted to column chromatography on silica gel (225 g) using a mixture of THF and n-heptane (3:7) as eluent. Collecting the proper fractions afforded 0.6 g of 3-(2-(5H-dibenzo[a,d]cyclohepten-5ylidene)ethoxy)-1 -propanol as an oil.
A mixture of the above alcohol (0.6 g, 2.0 mmol) and triethylamine
(0.52 g, 5.1 mmol) in toluene (10 ml) was placed on an ice-bath under an atmosphere of nitrogen. A solution of methanesulfonyl chloride (0.59 g, 4. 1 mmol) in toluene ( 1 .5 ml) was added keeping the temperature below 10°C. When addition was complete the mixture was stirred for 45 minutes at 5°C and 30 minutes below 1 5°C. Water was added (5 ml) and the mixture was stirred at ambient temperature for 1 5 minutes. The phases were separated and the aqueous phase was extracted with toluene (5 ml) . The combined organic phases were washed with a 5 % aqueous sodium bicarbonate solution, brine and dried over sodium sulphate. The solvent was evaporated in vacuo to give a residue which was dissolved in toluene ( 10 ml) . Ethyl (R)-3-piperidinecarboxylate tartrate ( 1 .25 g, 4.1 mmol) and potassium carbonate (0.98 g, 7.1 mmol) was added and the mixture was heated at reflux temperature for 1 6 h.
The mixture was allowed to cool and then filtered. The solvent was evaporated from the filtrate leaving an oil which was dissolved in ethyl acetate (20 ml) . Water (20 ml) was added and pH was adjusted to 4 with a 34 % aqueous tartaric acid solution. The phases were separated and the aqueous phase was extracted with ethyl acetate ( 10 ml) . The organic phases were combined and washed with excess of a 5 % aqueous sodium bicarbonate solution, brine and dried over sodium sulphate. The solvent was evaporated in vacuo to give an oil which was re-evaporated successively with methanol and dichloromethane. This afforded 0.77 g of an oil which was dissolved in toluene ( 1 5 ml) and extracted with a 34 % aqueous tartaric acid solution (1 5 + 7 ml). The combined aqueous extracts were washed with toluene (5 ml) and the toluene phases were discarded . The acidic aqueous phase was diluted with water (30 ml) and ethyl acetate (50 ml) was added. A 4 N aqueous sodium hydroxide solution (1 2 ml) and excess of a 5 % aqueous sodium bicarbonate solution was added , The phases were separated and the aqueous phase was extracted with ethyl acetate (30 ml) . The combined ethyl acetate extracts were washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuo to give an oil which was re-evaporated successively with methanol and dichloromethane. This afforded 0.42 g of (R)-N-(3-(2-(5H-dibenzo[a,d]-cyclohepten-5-ylidene)- ethoxy)-1 -propyl)-3-piperidinecarboxylic acid ethyl ester as an oil. The above ester (0.42 g, 1 .0 mmol) was dissolved in ethanol (5 ml) and a 1 2 N aqueous sodium hydroxide solution (0.36 ml) was added . The mixture was stirred at room temperature for 3.5 h and the solvent was evaporated in vacuo to give aπ oily residue. Dichloromethane (30 ml) was added and the mixture was cooled on an ice-bath. A concentrated hydrochloric acid solution (0.45 ml) was added dropwise and a small amount of icewater was added to dissolve the solid formed. The phases were separated and the organic phase was dried over sodium sulphate. The solvent was evaporated in vacuo to give an oily residue which was re-evaporated with dichloromethane. This afforded 0.43 g of the title compound as aπ amorphous solid.
M. P. 1 14- 1 19°C.
1H NMR (DMSO-dg) δ 3.77 (dd, 1 H); 4.08 (dd, 1 H); 5.63 (dd, 1 H); 6.90-6.97 (m, 2H) .

Claims

1 . The use of a compound of the general formula I
Figure imgf000055_0001
wherein R1 and R2 independently are hydrogen, halogen, trifluoromethyl, C1 6-alkyl or C,.6-alkoxy; Y is > N-CH2-, > CH-CH2- or > C = CH- when s is 0, 1 or 2 or Y is > CH-CH = N- or > C = N- when s is 0 wherein only the under¬ scored atom participates in the ring system; X is -O-; Z is -O-, -S-, -CH2-, -CH2CH2-, -CH = CH-CH2-, -CH2-CH = CH-, -
CH2CH2CH2-, -CH = CH- or -O-CH2-;
R4 and R5 each represents hydrogen or may when is 2 together repre¬ sent a bond; Rθ is OH or CT.g-al oxy; p is 0 or 1 ; q is 0 or 1 ; s is 0, 1 or 2; r is 2, 3 or 4; m is 1 or 2; n is 1 when m is 1 or n is 0 when m is 2; or a pharmaceutically accept¬ able salt thereof, for the manufacture of a pharmaceutical compostion for reducing blood glucose and/or inhibit the activity of CGRP.
. The use according to claim 1 wherein R1 and R2 independently are hydrogen, halogen or triflouromethyl.
3_;. The use according to claim 1 or 2 wherein Z is -O-, -S-, -CH2-, -(CH2)2-, -(CH2)3- or -CH = CH-.
,. The use according to any one of the preceding claims wherein Rθ is OH.
j The use according to any one of the preceding claims wherein m is 1 .
J3_, The use according to any one of the preceding claims wherein m is 2.
7. The use according to any one of the preceding claims wherein said composition is in a form suitable for oral administration.
8. The use according to any one of the preceding claims wherein said compound is administered as a dose in a range from about 0.5 to
1 000, preferably in the range from about 1 to 500 and especially in the range from about 50 to 200 mg/pr. day.
Ϊ The use according to any one of the preceeding claims wherein the treatment is related to insulin resistance in NIDDM.
1 0. The use according to any one of the preceeding claims wherein the treatment is related to insulin resistance in aging.
1 1 . A method for reducing blood glucose and/or inhibit the activity of
CGRP comprising administering to a patient a clinically effective amount of a compound of formula I as stated in claim 1 or a pharmaceutically acceptable salt thereof.
1 2. A method according to the previous claims wherein R1 and R2 independently are hydrogen, halogen or triflouromethyl.
1 3. A method according to any one of the preceeding method claims wherein Z is -O-, -S-, -CH2-, -(CH2)2-, -(CH2}3- or -CH = CH-.
14. A method according to any one of the preceeding method claims wherein R6 is OH.
1 5. A method according to any one of the preceeding method claims wherein m is 1 .
1 6. A method according to any one of the preceeding method claims wherein m is 2.
1 7. A method according to any one of the preceeding method claims wherein said compound is administered as a dose in a range from about 0.5 to 1000, preferably in the range from about 1 to 500 and especially in the range from about 50 to 200 mg/pr. day.
1 8. A method according to any one of the preceeding method claims wherein the treatment is related to insulin resistance in NIDDM.
1 9. A method according to any one of the preceeding method claims wherein the treatment is related to insulin resistance in aging.
20. A method for reducing blood glucose and/or inhibit the activity of CGRP which method comprises administering a clinically effective amount of a compound of formula I or a salt thereof and a pharmaceuti¬ cally acceptable composition containing such a compound, to a patient in need of such treatment.
21 . Any novel feature or combination of features described herein .
PCT/DK1996/000520 1995-12-15 1996-12-10 Novel method WO1997022342A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1036565A1 (en) * 1997-12-05 2000-09-20 Institute of Medicinal Molecular Design, Inc. Preventives/remedies for diabetes
US7417040B2 (en) 2004-03-01 2008-08-26 Bristol-Myers Squibb Company Fused tricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992020658A1 (en) * 1991-05-17 1992-11-26 Novo Nordisk A/S Novel heterocyclic carboxylic acids
WO1995018615A1 (en) * 1994-01-04 1995-07-13 Novo Nordisk A/S A method of treating neurogenic inflammation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992020658A1 (en) * 1991-05-17 1992-11-26 Novo Nordisk A/S Novel heterocyclic carboxylic acids
WO1995018615A1 (en) * 1994-01-04 1995-07-13 Novo Nordisk A/S A method of treating neurogenic inflammation

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1036565A1 (en) * 1997-12-05 2000-09-20 Institute of Medicinal Molecular Design, Inc. Preventives/remedies for diabetes
EP1036565A4 (en) * 1997-12-05 2003-04-23 Inst Med Molecular Design Inc Preventives/remedies for diabetes
US7417040B2 (en) 2004-03-01 2008-08-26 Bristol-Myers Squibb Company Fused tricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3

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