FI92483B - Oxodibenzoxepine derivatives - Google Patents

Description

92483

Oksodibentsoksepiinijohdannaiset

Divided separated from patent application 904184.

Patent application 904184 relates to compounds of the formula oo / OR1 -0 ^^ ~ (alempl alkylene) '' i "> m '\ wherein X together with the carbon atoms to which it is attached form a benzene or thiophene ring; W and Z are independently hydrogen, halogen, lower alkyl or trifluoromethyl, R 1 is hydrogen, lower alkyl or acyl, R 2 is hydrogen, lower alkyl, cycloalkyl, aryl (lower alkyl) or acyl, m is 0 or 1 and n is an integer from 0 to 12, and, where appropriate, their optical, geometric and stereoisomers, and racemic mixtures.

Preferred embodiments are those of Compound I.

substituents in which X together with the carbon atoms to which it is attached form a benzene or thiophene ring; R 1 is hydrogen or acyl; and R 2 is alkyl, cycloalkyl or acyl.

This invention relates to compounds of formula Ia

o H

v (lower alkylene) -c = n-oh j / CÄ 30 -0 1 (I *) wherein X is as defined above, N and Z are independently hydrogen and n is 1, 2, 3 or 4.

The present invention further relates to compounds of formula II 35 2 92483 <(χ \\ (lower alkylene) B (C) #i (0) pR4

(ID

5 wherein W, X, Z and n are as defined above and R 3 is hydrogen or lower alkyl? R 4 is hydrogen, lower alkyl or lower alkoxy; m is 0 or 1; and p is 0 or 1. These compounds are useful as intermediates in the synthesis of Compound I.

Throughout the specification and appended claims, a particular chemical formula or name includes all of its optical, geometric, and stereoisomers, as well as racemic mixtures, when such isomers and mixtures are present.

15 In the above definitions, the term "lower" refers to a group of 1 to 8 carbon atoms. The term "alkyl" refers to a straight or branched chain hydrocarbon free of unsaturated bonds, e.g., methyl, ethyl, isopropyl, t-butyl, neopen-20 style, and n-hexyl; the term "cycloalkyl" refers to a monovalent substituent consisting of a saturated hydrocarbon having at least one carbocyclic ring containing from 3 to 8 carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., having free valence, etc. carbon ring carbon; the term "alkoxy" refers to a monovalent substituent consisting of an alkyl group attached via an ether oxygen and having a free valence bond from ether oxygen, e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, etc., and the term "halogen" refers to fluorine, chlorine , a member of the halogen family of bromine and iodine. The term "alkylene" refers to the divalent branched or straight chain lower alkyl group from which it is derived and whose Valens-35 linkages are from its two terminal carbons, I! 92483 3 e.g. methylene (-CH2-), ethylene (-CH2CH2-), propylene (CH2CH2CH2-), isopropylene (CH3CHCH2-), etc.

The compounds of the invention and further the compounds of formula I are prepared as follows. The subs-5 substituents W, X, Z, R 1, R 2 and R 3 and the integers m and n are as defined above, unless otherwise stated.

A compound of formula (lower alkylene) d-'oso2r5 W 1 (III) wherein R5 is alkyl is reacted with N-alkylhydroxylamine hydrochloride or N-cycloalkylhydroxylamine hydrochloride, e.g. N-methylhydroxylamine hydrochloride, N-methylhydrochloride, N-methylhydrochloride, With N-isopropylhydroxylamine hydrochloride, N-cyclohexylhydroxylamine hydrochloride, etc., with a strong base, e.g., potassium t-butoxide, sodium methoxide, etc., in a normal amination reaction to form compound I, where m is 0 and n is not 0, that is, to form compound IV

• 25 O RJ

X (lower alkylene) „-N

vjcX_M

(IV) This reaction is carried out under conventional amination reaction conditions, typically in the presence of a polar, anhydrous solvent, e.g. methanol, ethanol, propanol or a suitable mixture of these solvents, at a temperature from 0 ° C to reflux for 1 to 24 hours. Compound III, wherein X is part of a benzene ring, can be prepared> 4,92483, typically as described in U.S. Patent 4,526,891 to Martin et al.

Compound III, wherein X is part of a thiophene ring and of formula 50 x (lower alkylene) n "OSO 2 R 5 -f 2 Z (nI) 10 is prepared from a compound of lila of formula o

x (lower alkylene) bOH

15 -o Z (m.) By reaction with an alkylsulfonyl halide of formula R 5 SO 2 Hal wherein R 5 is as defined above and Hal is halogen. This reaction is carried out under normal conditions in a typical polar, basic solvent, e.g. pyridine, at a temperature of -10 to + 25 ° C for 1 to 24 hours. Compound lila can typically be prepared according to Martin et al. in J. Med. Chem 27 (1984) 372-376.

N-alkyl or N-cycloalkyl acid amides of the formula

0 0 RJ

30 (lower alkylene) n-C-N 2 v L (V) can be prepared as follows.

Compound VI of formula 35 o o

(V / V, (lower alkylene) n * c-OH

92483 is reacted with a halogenating agent, e.g., thionyl chloride, POCl 3, etc., to give a compound of formula VII (lower alkylene) -c-Hal (VII) wherein Hal is halogen. This reaction typically takes place in the presence of a suitable catalyst, e.g. N, N-dimethylformamide, in an inert solvent, e.g. methylene chloride, chloroform, etc., at a temperature of about -10 to + 20 ° C for 1 to 24 hours. Compound VI is typically prepared according to Martin et al., J. Med. Chem. 27 (1984) 15 372-376.

Compound VII is reacted with compound VIII, which is an N-alkyl or N-cycloalkylhydroxylamine salt of the formula alkyl-NHOH. HCl 20 or (VIII) cycloalkyl-NHOH. HCl wherein alkyl and cycloalkyl are as defined above, in the presence of a base, e.g. pyridine, 4-dimethylaminopyridine, etc., to form compound V. This reaction is typically performed in an ethereal solvent, e.g., tetrahydrofuran, bis (2-methoxyethyl) ether, diethyl ether, etc., at a temperature of about -0 to + 25 ° C for 1 to 24 hours. Compound VII, wherein X is part of a benzene ring, is typically prepared as described in U.S. Patent 4,515,946 to Martin et al.

The compound IX of the invention having the formula (alkyl) 35 6 92483 which is an intermediate for the preparation of compound XI (compound I wherein m is 1) is prepared by reacting compound IXa, (hydroxyphenyl) alkanoic acid ethyl ester of formula H 0 \ __ ~ 7- (lower alkylene) ncoCH 2 CH 3 (IXa) to react with compound IXb, 2- (halomethyl) benzoic acid-10 pomethyl ester of formula oe », (m>) 15 wherein Hal pn halogen . This reaction is typically performed in the presence of an acid acceptor, e.g., potassium carbonate, sodium carbonate, lithium carbonate, etc., and a catalytic amount of a promoter, i.e., an alkali metal halide, e.g., sodium iodide, potassium iodide, etc. This reaction is carried out under conventional condensation reaction conditions, typically in the presence of a suitable solvent, e.g., 2-butanone, acetone, etc., at a temperature of about 25 to 80 ° C to a reflux temperature for 1 to 48 * 25 hours.

Compound IX is typically cyclized using the method of Aultz et al., J. Med. Chem. 20 (1977) 1499-1501 or in Martin et al., J. Med. Chem. 27 (1984) 372-376 to form compound IXc of formula o

X (lower alkylene) n-C-OH

35 v Z (IXc) li 92483 7

Compound IXc is reacted with a halogenating agent, e.g., thionyl chloride, POCl 3, etc., to give compound X of the invention of formula 5 (lower alkylene) -C-Cl. This reaction typically takes place over a suitable catalyst, e.g. In the presence of N, N-dimethylformamide, and an inert solvent, e.g. methylene chloride, chloroform, etc., at a temperature of about -10 to + 20 ° C to reflux for 1 to 24 hours.

Compound X, in turn, is reacted with a solution of an amidating agent, e.g., an N-alkyl or N-cycloalkylhydroxylamine salt with a salt of the formula alkyl-NHOH. HCl or, · cycloalkyl-NHOH. HCl 20 e.g. N-methylhydroxylamine hydrochloride, N-isopropylhydroxylamine hydrochloride, N-ethylhydroxylamine hydrochloride and N-cyclohexylhydroxylamine hydrochloride, etc. in the presence of a solution of the compound in a non-aqueous, basic solvent, g2 (lower alkylene) ncN-OHH, wherein R2 is as defined above. This reaction is carried out under conventional amidation reaction conditions, typically in the presence of an anhydrous ethereal solvent, e.g., tetrahydrofuran, ether, etc., at a temperature of about 0 to 25 ° C for 1 to 24 hours.

92483 8

Compound I wherein m is 0 can be prepared as follows. An intermediate compound XII of formula ✓-N for use in the synthesis of Compound I, where m is 0. CO 2 CH 3 f y (lower alkylene) n \ qh (Xil) is prepared by reacting compound Xlla, an alcohol, (hydroxy-10-phenyl) alkanol of formula

lower alkylene) n-OH

Af 15 1.0 (XII.) 2- (halomethyl) benzoic acid methyl ester (compound IXb). This reaction is typically performed in the presence of an acid acceptor, e.g., potassium carbonate, sodium carbonate, lithium carbonate, etc., and a catalytic amount of pro-20 engine, i.e., an alkali metal halide, e.g., potassium iodide, sodium iodide, etc. This reaction is carried out under conventional condensation reaction conditions, typically in the presence of a suitable solvent such as 2-butanone, acetone, etc., at a temperature of about 10 to 80 ° C 2b * for 1 to 48 hours.

Compound XII is hydrolyzed to give compound XIII of formula AA (Q) (X 2) (lower alkylene) (or vA - ar z (xiii)) This hydrolysis is typically performed with a base such as sodium or potassium hydroxide in a suitable lower alkanol. In a 35 L solvent, e.g., methanol, ethanol, propanol, etc. 92483, etc. Typically, this reaction occurs at a temperature of about 25 to 80 ° C or at reflux for about 1 to 24 hours.

Typically, compound XIII is cyclized by a method 5 in which the hydroxy group in the side chain of the phenyl group does not react using trifluoroacetic anhydride in an inert solvent, e.g., methylene chloride, as described in U.S. Patent 4,496,580 to Martin et al., To form compound XIIIa. “N 8 ° <(lower alkylene) -oc-CF 2

VLLM

The acetylated compound XIIIa is hydrolyzed under normal hydrolysis conditions, e.g., in an aqueous solvent with a mineral acid such as hydrochloric acid, sulfuric acid, etc., at a temperature of about 50 to 80 ° C to reflux temperature for 4 to 24 hours, followed by a basic base such as ordinary base. sodium bicarbonate, etc., to form the compound XIV of the invention having the formula 0

25 · (lower alkylene) n-OH

νλΛ_ο ^ ζ (XIV)

Compound XIV is reacted with an alkylsulfonyl halide in a basic solvent such as pyridine, etc. to form compound III where n is not 0. Compound III is then reacted as described above with N-alkylhydroxylamine hydrochloride or N-cycloalkylhydroxylamine hydrochloride. potassium t-butoxide, etc., in the presence of 92483 10 to form a compound IV of the invention wherein n el is 0.

Compound XV of formula according to the invention

χ (lower alkylene) n-c «N-OH

V Z (XV) is prepared from a compound of formula XVI of formula 10 0 '(lower alkylene) -c-Cl

JLCM

v (XVI) by reaction with a reducing agent such as lithium tri-t-butoxyaluminum hydride in an ethereal solvent, e.g. diglyme, at about -80 to -70 ° C for 1-2 hours to give intermediate XVII of formula 20 ° 0 v (lower alkylene) -ch

JlDSC

(XVII)

Compound XVII, an aldehyde, is reacted with pyridine-25 * dine and hydroxylamine hydrochloride to give compound XV. This condensation reaction typically takes place in an anhydrous, basic solvent such as pyridine, etc., at a temperature ranging from the ambient ambient temperature to about 60 ° C for 1 to 30 hours. Compound XVI is typically prepared by Martin ’! et al., U.S. Patent 4,515,946.

and 92483

Compound XVIII of formula o n.

C-R5 0 o '

5 (lower alkylene) n * H

vUihK? w R »(XVIII) wherein R 5 is as defined above is prepared as follows 10.

Compound XIX of formula o

(lower) alkylene) n * OH

15 vx * '“^ Sy — 0. z (XIX) is reacted with an oxidizing agent, e.g. pyridinium chlorochromate, in a halogenated solvent such as dichloromethane, etc., under nitrogen at a temperature of 2G to about -20 ° C to ambient temperature for about 1-5 hours to form compound XlXa of formula o 25 (lower alkylene) ^ -ch V (XIX »)

Compound XlXa, where n is 0, can be prepared from compound XIX, where n is 2, by oxidation of compound XlXa, where n is 1, or can be prepared from Yoshioka et al., *: Journal of Med. Chem. 21 (1978) 633-639.

Compound XVII is reacted with hydroxylamine hydrochloride to form intermediate XX of formula 92483 12

OH

O ^

X (lower alkylene) JC'H

vyJLM

c (XX)

D

This reaction is carried out under normal conditions, typically in a basic solvent, e.g. pyridine, etc., at a temperature ranging from the ambient ambient temperature to about 60 ° C for 1 to 5 hours.

Compound XX is reacted with a reducing agent, e.g., boron trihydride, in a polar, basic solvent, e.g., pyridine, at a temperature ranging from about 0 ° C to ambient temperature for 1-5 hours to give compound XXI having formula

alkylene) n '^ * 0H

V 0 Z (m) 20

Compound XXI is reacted with an acylating agent, e.g., acetyl chloride, 2-methylpropionyl chloride, etc., in a basic solvent such as pyridine, etc. to form compound XVIII. This reaction takes place 25 ', typically under an inert gas such as nitrogen, at a temperature ranging from about -25 ° C to ambient temperature for 0.5-5 hours.

The compounds of formula I are useful as topical anti-inflammatory agents in the treatment of a variety of dermatitis, such as exogenous rashes (e.g., sunburn, photoallergic rash, urticaria, contact dermatitis, and allergic rash), endogenous rash (e.g., atopic dermatitis). , numm rash), rashes of unknown etiology (e.g., generalized exfoliative 92483 13 rash), and other skin diseases with an inflammatory component (e.g., psoriasis).

The dermatological effects of the compound were confirmed by the following methods.

5 Dermatological test methods

Phospholipase A2-induced foot swelling (PIPE)

The ability of the compounds to resist naja naja (snake venom) phospholipase A2 (PLA2) -induced tur-turf loss in male Wistar rats (100-125 g) was measured. PLA2 (3 units / 100 μΐ dH 2 O / sensor) alone or in combination with 0.1 mol / L test compound was injected into the sulplant area of the left hind paw of the rat. Immediately after injection and two hours after administration, the foot 15 was immersed in a mercury bath and the displacement of the foot was measured on a recorder via a sensor. The value was then converted to mmHg (Constants: quinacrine ED50 = 0.1 mol / L; hydrocortisone ED50 = 0.46 mol / L; Giessler, AJ et al., Agents and Action 10 (1981) 195 "Trends in 20 Inflammation Research ").

Arachidonic acid-induced swelling of the mouse ear (AAEE)

In the arachidonic acid-induced swelling of the mouse ear, the test compound is dissolved in propylene glycol-25; The 30/70 and 20 μ 20 solution in li / ethanol is applied to both ears of animals in groups of six female Swiss Webster mice, with a total of 1.0 mg of test compound applied to both ears on the inner and outer surfaces. Mice were housed in a single cage under normal conditions for one week, at which time they received ·; free food and water. The same volume (20 μΐ) of vehicle was applied to both ears of control mice. After 30 minutes, arachidonic acid (4 mg / ear) is applied to the right ear of each mouse in each group. Vehicle 35 (20 μΐ / ear) is applied to the left ear of each mouse in each group. After one hour, the mice are sacrificed and a 4 mm biopsy plug is taken from each ear and weighed. The difference between the right and left ear plugs was determined for each animal. The anti-5 inflammatory effect of the test compound is expressed as the mean percentage change in the weight of the ear biopsy plugs of the treated animals relative to the mean percentage change in the weight of the ear plugs of control animals (constant: indomethacin -90% at 1 mg / kor-10 va; Young, JM et al., Invest. Dermatol 80 (1983) 48-52).

TPA-induced ear swelling (TPAEE) In the TPA-induced ear swelling assay, TPA (12-O-tetradecanoyl phorbol-13-acetate) is dissolved in 15/30 propylene glycol / ethanol and 20 μΐ of the solution is applied to six female Swiss Webster mice. to the right ear of animals in groups comprising a total of 10 pg of TPA applied to the inner and outer surfaces of the ear. Mice were housed in a single cage under normal conditions for one week, during which time they were given free access to food and water. The test compound is dissolved in the vehicle and 20 μΐ of the solution is applied to the right ear (inner and outer surfaces) so that a total of 10 pg of the compound is applied to the ear. After about five hours, the mice are sacrificed and a 4 mm bio-25 psiaplug is taken from each ear and weighed. The difference between the right and left ear plugs was determined for each animal. The anti-inflammatory effect of the test compound is expressed as the mean percentage change in the weight of the ear biopsy plugs of the treated animals relative to the mean percentage change in the plugs of the control animals (constant: indomethacin -86% at 1 mg / ear; Young, JM et al., Invest. Dermatol. 80 (1983) 48-52).

The dermatological activities of some of the compounds of formula I as well as the control Q O A P 7 15 6 v / t compound included in the scope of U.S. Pat. No. 4,585,788 are shown in Table 1.

Table 1 5

PIPE AAEE TPAEE according to formula I.

Compound Change% 0.1 mol / l 1 mg / ear 10 pg / ear 10 2- (6,11-dihydro-11-oxo-dibenz [b, e] oxepin-2-yl) -N-hydroxy-N -methylethylamine -70-46-50 3 3- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-hydroxy-N-methylpropanamide -46-63 -71 20 N-cyclohexyl-2- (6,11-dihydro-11-oxo-dibenz [b, e] oxepin-2-yl) -N-hydroxyacetamide -85 -29-52 25 Reference compound 2- (6.11 -dihydro-11-oxodi-benz- [b, e] oxepin-2-yl-N-hydroxy-acetamide -19 +7 30

The compounds of formula I are also useful as analgesics because of their ability to relieve pain in mammals. The activity of the compounds is demonstrated by the standard 35-p-benzoquinone torsion test used to determine pain relief in mice [Proc. Soc. Exptl. Biol. Med. 95 (1957) 729].

The activity of some compounds is expressed in Table 2 as either the subcutaneous dose at which 50% of the phenyl-p-benzoquinone-induced writhing is inhibited in animals, i.e., as the ED50 value, or as the% reduction in writhing at a given dose.

16 92483

Table 2

Compound EDSO or anti-wrinkle% 2- (6,11-dihydro-11-oxo-dibenz [b, e] oxepin-2-yl) -N-ethyl-N-hydroxypropanamide ED50 = 3.6 mg / kg 3- (6,11-dihydro-11-oxo-dibenz [b, e] oxepin-2-yl) -N-cyclohexyl-N-hydroxypropanamide 76% (dose 20 mg / kg) N-cyclohexyl-2- (6,11-15-dihydro-11-oxo-dibenz [b, e] oxepin-2-yl) -N-hydroxyacetamide 68% (dose 20 mg / kg)

Propoxyphene ED50 = 3.9 mg / kg 20

Analgesic pain relief is achieved by administering to an individual in need of such treatment an effective dose of the compounds of formula I in an amount of 0.01 to 25,100 mg / kg body weight per day orally, parenterally or intravenously. The preferred dose in this range is about 10 to 50 mg / kg body weight per day. A particularly preferred effective amount is about 30 mg / kg body weight per day. It is to be understood, however, that the dosage regimen specific to each particular individual should be adjusted according to the individual need and the judgment of the person skilled in the art of administering or directing treatment. It is further to be understood that the dosages set forth herein are exemplary only and are not intended to limit the scope or use of the invention in any way.

') Effective amounts of the compounds of formula I may be administered to a patient by any of a variety of methods, for example orally in capsules or tablets, topically as ointments, solutions or ointments, gastrointestinal

II

92483 17 in the form of sterile solutions or suspensions and, in some cases, intravenous sterile solutions. The free base end products can be formulated and administered as pharmaceutically acceptable acid addition salts for stability, ease of crystallization, improved solubility, and the like.

Preferred pharmaceutically acceptable salts of the invention are those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and perchloric acid and the like, as well as organic acids such as maleic acid, tartaric acid, citric acid, acetic acid, acetic acid, acetic acid, salts formed with oxalic acid. Preferred pharmaceutically acceptable base addition salts are alkali metal salts, e.g. sodium or potassium salts, alkaline earth metal salts, e.g. calcium and magnesium salts, or complex salts, such as ammonium or substituted ammonium salts, e.g. mono-, di- or trialkylammonium salts. , di- or trihydroxyalkylammonium salts.

The compounds of formula I may be administered orally, for example, with an inert diluent or with an edible carrier. They can be enclosed in Gela capsules or compressed into tablets. For oral administration, the compounds may be incorporated into excipients and used in the form of tablets, pills, capsules, elixirs, suspensions, syrups, orodispersible tablets, chewing gums, and the like. These preparations should contain at least 0.5% of a compound of formula 30 I, the active ingredient, but may be varied depending upon the particular form and may conveniently be between about 4% to about 75% of the weight of the unit. The amount of compound in such a composition is such that a suitable dosage will be obtained. Preferred compositions and preparations are prepared so that an oral dosage form contains from about 1.0 to about 300 mg of a compound of formula I.

Tablets, pills, capsules, and the like can contain the following ingredients: a binding agent, such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose; a disintegrant such as alginic acid, Primogel ", corn starch and the like; lubricants such as magnesium stearate or Sterotex®; and a lubricant such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin, piperazine, or flavoring agents such as flavoring agents; When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil, and other unit dosage forms may contain other substances which modify the physical form of the unit dosage form, e.g., tablets or pills. The syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and flavors, in which case the various compositions used in the preparation of these various compositions may be coated with sugar, shellac or other enteric coating agents. should be pharmaceutically pure and non-toxic in the amounts used.

For parenteral administration, the active compounds of formula I may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of the aforementioned compound, but may be varied to be between about 0.5% to about 30% of the weight of the unit. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations are prepared so that a parenteral dosage unit contains about 0.5 to 100 mg of active compound.

»19 92483

The solutions and suspensions may also contain the following components: a sterile diluent such as water for injection, physiological saline, solid oils, polyethylene glycols, glycerin, pro-5 polyene glycol or other synthetic solvents; anti-bacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffering agents such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral dose can be enclosed in ampoules, disposable syringes or multidose glass or plastic bottles.

For topical administration, the active compounds of formula I may be incorporated into a solution, suspension, ointment, gel, aerosol or ointment. These preparations should contain at least 0.1% of active compound, but may be varied to be between 0.05 and 20% of the weight thereof. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferably, formulations for topical administration should contain 0.1 to 10% of active compound.

Compositions for topical administration may also contain the following components: water, solid oils, polyethylene glycols, petrolatum stearic acid, beeswax, other synthetic solvents, or mixtures thereof; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as α-tocopherol-30 acetate; chelating agents such as ethylenediaminetetra; acetic acid (EDTA); buffering agents such as acetates, citrates or phosphates; emulsifying agents such as polyoxyethylene monooleate, and coloring agents and adjuvants such as iron (III) oxide or talc. Preparations for topical administration may be enclosed in tubes, bottles or jars made of metal, glass or plastic.

Examples of compounds of the invention include: 2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-hydroxy-5-hydroxy-N-methylethylamine; 2- (6, ll-dihydro-ll-oxodibenz [b, e] oxepin-2-yl) -N-hydroxy-hydroxy-N-methylacetamide; 2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-hydroxy-hydroxy-N- (1-methylethyl) acetamide; 2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-ethyl-N-hydroxyacetamide; N-cyclohexyl-2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-hydroxyacetamide; 2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-ethyl-15-N-hydroxyethylamine; 2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-hydroxy-hydroxy-N- (2-methylethyl) ethylamine; 2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-hydroxy-hydroxy-N-methylpropanamide; 4 - {[2- (methoxycarbonyl) phenyl) methoxy} benzenepropanoic acid ethyl ester; 2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-ethyl-N-hydroxypropanamide; 3- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-hydroxy-N-methylpropanamide; 3- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) propanyl chloride; 3- (6,11-dihydro-ll-oxodibenz [b, e] oxepin-2-yl) -N-hydroxy-hydroxy-N- (1-methylethyl) propanamide; 3- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-ethyl-N-hydroxypropanamide;

• I

3- (6, ll-dihydro-ll-oxodibenz [b, e] oxepin-2-yl) -N-fal-cyclohexyl-N-hydroxypropanamide; 2 - {[4- (3-hydroxypropyl) phenoxy) methyl} benzoic acid; li 21 92483 2 - -C [4- (3-hydroxypropyl) phenoxy) methyl} benzoic acid methyl ester; 3- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) propyl trifluoroacetate; 3- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) propanol; 3- (6,11-dihydro-11-oksodibentstb, e] oxepin-2-yl) -N-hydroxy-N-methyl-l-propylamine; 4- (4,10-dihydro-10-oxothieno [3,2-c] [1] benzoxepin-8-yl) butanol methanesulfonate; 4- (4,10-dihydro-10-oxothieno [3,2-c] [1] benzoxepin-8-yl) -N-hydroxy-N-methyl-1-butylamine; N- [2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) ethyl] -N-hydroxyacetylacetamide; 2- (6,11-dihydro-11-oxodibenz [b] e] oxepin-2-yl) acetal-15-oxime; and N- [2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) methyl] -N-hydroxyacetylacetamide.

The following examples illustrate the invention and should not be construed as limiting the invention. All temperatures 20 are given in degrees Celsius.

Example 1 2- (6,11-Dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-hydroxy-N-methylethylamine

To the stirred flask were added 25.08 g of potassium t-butoxide and 18.68 g of N-methylhydroxylamine hydrochloride in 700 ml of 95% ethanol. To the mixture was added 15.02 g of finely ground 2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) ethanol methanesulfonate, and the stirred suspension was allowed to reflux for 24 hours. The suspension was concentrated to dryness and the solid residue was partitioned ;; to 500 ml of 5% sodium bicarbonate and a total of 600 ml of methylene chloride. The dried (MgSO 4) organic phase was filtered and concentrated to an oil. Thin layer analysis of the crude product (13.44 g) (silica gel, ethyl 35 acetate) showed a mixture which was separated using pre- »22 92483 parative high performance liquid chromatography (hereinafter abbreviated as HPLC; Waters Associates Prep LC / System 500; silica gel). , ethyl acetate) to give 7.24 g (57%) of pure material.

Recrystallization from methanol afforded 2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-hydroxy-N-methylethylamine, m.p. 101-102 ° C.

Analysis for C 17 H 17 NO 3;

Calculated: 72.07% C 6.05% H 4.94% N 10 Found: 71.92% C 5.87% H 4.89% N

Example 2 2- (6,11-Dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-hydroxy-N-methylacetamide

To the flask was added 11.6 g of N-methylhydroxylamine-15 hydrochloride in 250 ml of pyridine. The mixture was stirred to give a solution and the flask was cooled in an ice bath. To the stirred solution was added dropwise over several minutes a solution of 10.0 g of 2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) acetyl chloride in 400 ml of tetrahydrofuran. After the addition was complete, the flask was allowed to equilibrate to room temperature with constant stirring for 24 hours. The suspension was concentrated in half using rotary evaporation and transferred to a separatory funnel. The mixture was partitioned between 300 mL of methylene chloride and 100 mL of 10% HCl (pH of the aqueous phase below 1). The dried (MgSO 4) organic phase was filtered and concentrated to an oil using rotary evaporation. Thin layer analysis showed a mixture which was separated by preparative HPLC to give 4.76 g (45.8%) of pure material. Recrystallization from acetone gave 2- (6,11-dihydro-11-oxodibenz [b, e] -; oxepin-2-yl) -N-hydroxy-N-methylacetamide, m.p.

118 - 120 "C.

Analysis for C17H15NO4:

Calculated: 68.68% C 5.09% H 4.71% N 35 Found: 68.77% C 5.06% H 4.68% N

n 92483 23

Example 3 2- (6,11-Dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-hydroxy-N- (1-methylethyl) acetamide

To the flask was added 10.0 g of N-isopropylhydroxyl-5-amine hydrochloride in 400 ml of pyridine. The mixture was stirred to give a solution, cooled in an ice bath and treated dropwise over several minutes with a solution of 5.72 g of 2- (6,11-dihydro-11-oxodibenz- [b, e] oxepin-2-yl) acetyl chloride in 200 ml. tetrahydro-10 rofuran. The solution was stirred for 24 hours and allowed to equilibrate to room temperature. The resulting cloudy suspension was concentrated to an oil using rotary evaporation and transferred to a separatory funnel. The product was partitioned between 500 mL of methylene chloride and a sufficient amount (500 mL) of 10% HCl to bring the pH of the aqueous phase below 1. The dried (Na 2 SO 4) organic phase was filtered and concentrated to an oil using rotary evaporation. Thin layer analysis showed a mixture which was separated by HPLC to give 3.92 g (40.2%) of pure material. Recrystallization from acetone gave 2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-hydroxy-N- (1-methylethyl) acetamide, m.p.

144 - 145 eC.

Analysis for C19H19NO4:

Calculated: 70.14% C 5.89% H 4.30% N -. Found: 70.14% C 5.88% H 4.24% N

Example 4 2- (6,11-Dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-ethyl-N-hydroxyacetamide

To the flask was added 4.0 g of N-ethylhydroxylamine-30 hydrochloride in 300 ml of dry pyridine. The mixture was stirred to give a solution, cooled in an ice bath and ♦ · treated dropwise over several minutes with a solution of 5.72 g of 2- (6,11-dihydro-11-oxodibenz- [b, e] oxepin-2-yl) acetyl chloride In 200 ml of dry tetrahydrofuran. The solution was stirred for 24 hours, allowing the 24,92483 bath to equilibrate to room temperature. The resulting suspension was concentrated to an oil using rotary evaporation and then transferred to a separatory funnel. The product was partitioned between 500 mL of methylene chloride and a sufficient amount (250 mL) of 10% HCl to bring the pH of the aqueous phase below 1. The organic phase was then washed with 250 mL of water. The dried (Na 2 SO 4) organic phase was filtered and concentrated to an oil using rotary evaporation. Thin layer analysis showed the mixture to be separated by HPLC to give 3.03 g (49%) of pure material. The product was combined with another batch of similarly prepared material which was found to be pure by thin plate analysis. The total amount of combined material was 4.53 g. Recrystallization from acetone gave 2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -15 N-ethyl-N-hydroxyethyl) acetamide, m.p. 119-121 ° C. Analysis for C18H17NO4:

Calculated: 69.44% C 5.50% H 4.50% N

Found: 69.63% C 5.45% H 4.29% N

Example 5 N-Cyclohexyl-2- (6,11-dihydro-11-oxodibenz- [b, e] oxepin-2-yl) -N-hydroxyacetamide

To the flask was added 4.0 g of N-cyclohexylhydroxylamine in 400 ml of dry pyridine. The mixture was stirred to give a solution, cooled in an ice bath and treated dropwise over several minutes with a solution of 4.86 g of 2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl). acetyl chloride in 200 ml of dry tetrahydrofuran. The solution was stirred for 24 hours, allowing the bath to equilibrate to room temperature. The resulting suspension was concentrated to an oil using rotary evaporation and partitioned; 500 ml of methylene chloride and a sufficient amount (250 ml) of 10% HCl to bring the pH of the aqueous phase below 1. The organic phase was then washed with 250 ml of distilled water. The dried (Na 2 SO 4) organic phase was filtered and concentrated to an oil using rotary evaporation. Thin-

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92483 plate analysis showed a mixture which was separated by preparative HPLC to give 3.14 g (51%) of product. Recrystallization from acetone afforded N-cyclohexyl-2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-hydroxy-5-acetylamide, m.p. 130-131 ° C.

Analysis for C22H23NO4:

Calculated: 72.31% C 6.34% H 3.83% N

Found: 72.12% C 6.15% H 3.58% N

Example 6 2- (6,11-Dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-ethyl-N-hydroxyethylamine

To the flask were added 4.48 g of potassium t-butoxide and 3.95 g of N-ethylhydroxylamine hydrochloride in 500 ml of absolute ethanol. The suspension was stirred and the precipitation of ka-15 lumium chloride was noted. To the suspension was added 3.32 g of finely ground 2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) ethanol methanesulfonate and the slurry was allowed to reflux for 4.5 hours. To the product mixture was added 500 mL of water and the solution was concentrated by rotary evaporation to remove ethanol. The resulting suspension was transferred to a separatory funnel and partitioned between a total of 600 mL of methylene chloride and 1,000 mL of water. The dried (Na 2 SO 4) organic phase was filtered and concentrated to an oil using rotary evaporation. Thin layer analysis showed a mixture which was separated using preparative HPLC to give 1.24 g (42%) of 2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-ethyl -N-hydroxyethylamine, m.p. 86 - 88 eC.

Analysis for C18H19NO3:

30 Calculated: 72.71% C 6.44% H 4.71% N Found: 72.45% C 6.40% H 4.57% N

92483 26

Example 7 2- (6,11-Dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-hydroxy-N- (2-methylethyl) ethylamine

14.37 g of potassium t-bu-5 oxide and 13.08 g of N-isopropylhydroxylamine hydrochloride in 1500 ml of absolute ethanol were added to the flask with stirring. The suspension was stirred and the precipitation of potassium chloride was noted. To the suspension was added 10.62 g of finely ground 2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) ethanol-10 methanesulfonate, and the slurry was allowed to reflux for 24 hours. To the product mixture was added 500 mL of water and the solution was concentrated by rotary evaporation to remove ethanol. The resulting suspension was transferred to a separatory funnel and partitioned between a total of 500 mL of methylene chloride and 1,000 mL of water. The dried (Na 2 SO 4) organic phase was filtered and concentrated to an oil using rotary evaporation. Thin layer analysis showed the mixture to be separated using preparative HPLC to give 3.20 g (32%) of pure material. Recrystallization from acetonitrile afforded 2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-hydroxy-N- (2-methylethyl) ethylamine, m.p. 121-124 ° C. Analysis for C19H21NO3:

Calculated: 73.29% C 6.80% H 4.50% N

Found: 73.55% C 6.52% H 4.67% N

Example 8 2- (6,11-Dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-hydroxy-N-methylpropanamide

To the flask was added a solution of a few drops of dimethylformamide and 50.0 g of 2- (6,11-dihydro-11-ox-30-dibenzo [b, e] oxepin-2-yl) propionic acid in methylene chloride, and the solution was cooled. . To the cold solution was added dropwise over 13 minutes 13.14 ml of thionyl chloride. Occasionally, the solution was heated on a steam bath until all gas evolution ceased, and the solution was stirred for 24 hours. The solution was concentrated to an oil in vacuo to remove solvents and any unreacted thionyl chloride to give 45.4 g (84%) of pure acid chloride.

A stirred solution of 16.6 g of N-methylhydro-5-hydroxylamine hydrochloride in 400 ml of dry pyridine was cooled and treated dropwise over several minutes with a solution of 15.7 g of 2- (6,11-dihydro-11-oxodibenz [ b, e] oxepin-2-yl) propionyl chloride in 500 ml of tetrahydrofuran. The solution was allowed to equilibrate to room temperature with constant stirring. Thin layer analysis (silica gel, 30% hexane in ethyl acetate) showed the reaction to be complete after 5 hours. The pyridine and tetrahydrofuran were removed in vacuo and the resulting mixture was partitioned between a total of 700 mL of methylene chloride and 2000 mL of 10% HCl (pH <1 of the aqueous layers). The organic phase was washed with 500 ml of water. The dried (Na 2 SO 4) organic phase was concentrated in vacuo to an oil. Thin plate analysis showed a mixture which was separated by preparative HPLC to give 10.58 g (68%) of product, 2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl). ) -N-hydroxy-N-methylpropanamide as a viscous oil.

Analysis for C18H17NO4:

Calculated: 69.44% C 5.50% H 4.50% N

Found: 69.12% C 5.72% H 4.06% N

Example 9 4 - {[2- (Methoxycarbonyl) phenyl) methoxy} benzene-propionic acid ethyl ester

To a dry flask under an inert atmosphere were added 97.0 g of 3- (4-hydroxyphenyl) propionic acid, 207 g of potassium carbonate and 1.0 g (cat.) Of sodium iodide in 600 ml. 2-butanone. The suspension was rapidly rinsed with several vacuum / N2 cycles. To the stirred suspension was added dropwise over 30 minutes a solution of 114.5 g of methyl 2- (bromomethyl) benzoate in 1000 ml of 2-butanone. The resulting white suspension was refluxed for 24 hours, cooled and allowed to stir at room temperature for one hour. The solids were removed by vacuum filtration and washed in a funnel. The solution was concentrated to an oil in vacuo. the oil was partitioned between a total of 500 any methylene chloride and 500 any 10% NaOH (pH of aqueous layers> 11) and washed with 800 mL of water. The dried (Na 2 SO 4) organic layer was concentrated to an oil in vacuo. Thin layer analysis showed a mixture which was separated by preparative HPLC to give 109.95 g (64%) of pure 4 - {[2- (methoxycarbonyl) phenyl) methoxy} benzenepropionic acid ethyl ester as an oil.

Analysis for C20H2205t Calculated; 70.16% C 6.47% H 15 Obtained! 70.17% C 6.53% H Example 10 2- (6,11-Dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-ethyl-N-hydroxypropanamide

A solution of a few tips of dimethylformamide and 50.0 g of 2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) propionic acid in 500 ml of methylene chloride was added to the flask and the solution was cooled. To the cooled solution was added dropwise over 13 minutes 13.14 ml of thionyl chloride. Occasionally, the solution was heated: · with a steam bath until all gas evolution ceased, and then the solution was stirred for 24 hours. The solution was concentrated to an oil in vacuo to remove solvents and any unreacted thionyl chloride to give 45.4 g (84%) of pure acid chloride.

A stirred solution of 10.14 g of N-ethylhydroxylamine hydrochloride in 350 ml of dry pyridine was cooled and treated dropwise over several minutes with a solution of 8.0 g of 2- (6,11-dihydro-11-oxodibenz [ b, e] oxepin-2-yl) propionyl chloride in 35,400 ml of tetrahydrofuran. The solution was

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92483 29 to room temperature overnight (16 hours) with constant stirring. The reaction was quenched with 500 mL of water and the mixture was concentrated in vacuo to remove solvents. The product mixture was partitioned between a total of 500 mL of methylene chloride and 5 in 1000 mL of 10% HCl (pH of aqueous layers <1). The organic phase was washed with 500 ml of water, dried (Na 2 SO 4) and concentrated in vacuo to an oil. Thin layer analysis showed the mixture to be separated twice by preparative HPLC to give 2.65 g (30%) of 2- (6,11-dihydro-10,11-oxodibenz [b, e] oxepin-2-yl) -N-ethyl -N-hydroxypropanamide as an oil.

Analysis for C19H19NO4:

Calculated: 70.14% C 5.89% H 4.30% N

Found: 69.64% C 6.02% H 4.11% N

Example 11 3- (6,11-Dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-hydroxy-N-methylpropanamide

The stirred solution of 12.58 g of N-methylhydroxylamine hydrochloride in 300 ml of dry pyridine-20 was cooled, degassed by several vacuum / N2 cycles and the solution was treated for several minutes with a solution containing 9.06 g of 3- (6,11-Dihydro-11-oxodibenz [b, e] oxepin-2-yl) propanyl chloride in 200 ml of dry tetrahydrofuran. The solution was allowed to equilibrate to room temperature overnight. The reaction was quenched with 200 mL of water, the mixture was concentrated in vacuo to remove solvents, and partitioned between a total of 200 mL of methylene chloride and 200 mL of 10% HCl (pH of the resulting aqueous layer was <1). The organic phase was washed with 500 ml of water, dried (Na 2 SO 4) and concentrated in vacuo to an oil. Thin layer analysis showed a mixture which was separated by HPLC eluting with 50% methylene chloride in tetrahydrofuran to give 5.3 g of material. This material was re-separated by HPLC under similar conditions using acetonitrile as eluent to give 3.423 g (39%) of 3- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -. N-hydroxy-N-methylpropanamide as an oil.

Analysis for C 18 H 19 NO 3:

Calculated: 69.44% C 5.50% H 4.50% N 5 Found: 69.24% C 5.62% H 4.50% N

Example 12 3- (6,11-Dihydro-11-oxodibenz [b, e] oxepin-2-yl) -propionyl

A few drops of N, N-dimethyl-10-formamide and 35.25 g of 3- (6,11-dihydro-11-oxodibenz [b, e] -oxepin-2-yl) propanoic acid in 500 ml of dry methylene chloride were added to the flask. . The cooled, stirred suspension was treated dropwise over several minutes with 11.0 mL of thionyl chloride. Occasionally, the suspension was heated on a steam-15 bath until all gas evolution ceased. The resulting solution was then allowed to reflux for 15 minutes and stand at room temperature under a nitrogen atmosphere overnight. The solution was concentrated to an oil in vacuo. The oil was dissolved in 500 mL of methylene chloride and re-treated with 11.0 mL of thionyl chloride. The solution was allowed to reflux for three hours and then concentrated again to an oil in vacuo. The oil still contained a significant amount of crystalline impurity, which was filtered off with hexane / ether solution after trituration. The supernatant was concentrated in vacuo to an oil which solidified overnight on standing in the refrigerator. The purified solids were recrystallized from three portions of cyclohexane to give 25.03 g (67%) of 3- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) propanyl chloride, m.p.

30 69 - 72 "C.

Analysis for C17H13C103:

Calculated: 67.89% C 4.36% H

Found: 68.05% C 4.61% H

li 3i 92485

Example 13 3- (6,11-Dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-hydroxy-N- (1-methylethyl) propanamide

The stirred solution containing 11.58 g of N-isopropyl-5-hydroxylamine hydrochloride in 300 ml of dry pyridine was cooled, degassed by several vacuum / N2 cycles and the solution was treated dropwise over several minutes with a solution containing 7.54 g. g of 3- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) propan-10-yl chloride in 200 ml of dry tetrahydrofuran. The solution was allowed to equilibrate to room temperature overnight. The reaction was quenched with 200 mL of water, concentrated in vacuo to remove solvents, and partitioned between a total of 300 mL of methylene chloride and 400 mL of 10% chloro-15 hydrochloric acid (pH of the resulting aqueous phase was <1). The organic phase was washed with 500 ml of water, dried (Na 2 SO 4) and concentrated in vacuo to an oil. Thin layer analysis showed a mixture which was separated by HPLC to give 3.78 g of an oil which crystallized on standing overnight at room temperature. The purified solids were recrystallized from acetone / cyclohexane to give 2.50 g (29.4%) of 3- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N -hydroxy-N- (1-methylethyl) propanamide, m.p.

117.5-118 ° C.

Analysis for C20H21NO4:

Calculated: 70.78% C 6.24% H 4.13% N

Found: 70.97% C 6.30% H 4.14% N

Example 14 3- (6,11-Dihydro-11-oxodibenz [b, e] oxepin-2-yl) -30 N-ethyl-N-hydroxypropanamide

The stirred solution of 8.98 g of N-ethylhydroxylamine hydrochloride in 300 ml of dry pyridine was cooled, degassed by several vacuum / N2 cycles and the solution was treated dropwise over several minutes with a solution of 9.00 g of 3 - (6,11-dihydro-92485 32 11-oxodibenz [b, e] oxepin-2-yl) propanyl chloride in 200 ml of dry tetrahydrofuran. The solution was allowed to equilibrate to room temperature overnight. The reaction was quenched with 200 mL of water, concentrated in vacuo to remove solvents, and partitioned between a total of 250 mL of methylene chloride and 600 mL of 10% hydrochloric acid (the pH of the resulting aqueous phase was <1). The organic phase was washed with 500 mL of water, dried (Na 2 SO 4) and concentrated in vacuo to an oil, the oil was triturated with 25% hexane / ethyl acetate to give 6.11 g of solids which were recrystallized from hexane / ethyl acetate. to give 4.56 g (46.8%) of 3- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-ethyl-N-hydroxypropanamide, m.p. 120 ° C.

Analysis for C19H19NO4:

Calculated: 70.14% C 5.89% H 4.30% N

Found: 69.97% C 5.85% H 4.27% N

Example 15 3- (6,11-Dihydro-11-oxodibenz [b, e] oxepin-2-yl) -20 N-cyclohexyl-N-hydroxypropanamide

The stirred solution containing 20.5 g of N-cyclohexylhydroxylamine hydrochloride in 300 ml of dry pyridine was cooled, degassed by several vacuum / N2 cycles and the solution was treated dropwise over several minutes with a degassed solution. and containing 13.50 g of 3- (6,11-dihydro-11-oxodibenz- [b, e] oxepin-2-yl) propanyl chloride in 300 ml of dry tetrahydrofuran. The resulting solution was allowed to equilibrate to room temperature overnight. The reaction was quenched with 200 mL of water, stirred for an additional 15 minutes, and concentrated in vacuo to remove solvents. The resulting suspension was partitioned between a total of 300 ml of methylene chloride and 300 ml of 10% hydrochloric acid (the pH of the aqueous phase obtained was <1). The organic phase was washed with 500 mL of 35 water, dried (Na 2 SO 4) and concentrated in vacuo.

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92485 33 into oil. The oil was triturated to an amorphous solid with 25% hexane in ethyl acetate to give 5.26 g (31%) of 3- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N -cyclohexyl-N-hydroxypropanamide, m.p.

5,146-147 ° C.

Analysis for C23H25NO4;

Calculated: 72.80% C 6.64% H 3.69% N

Found: 72.77% C 6.65% H 3.69% N

Example 16 2 - {[4- (3-Hydroxypropyl) phenoxy) methyl] benzoic acid

A stirred solution of 127.1 g of potassium hydroxide in 500 ml of 95% ethanol was treated portionwise over several minutes with 59.4 g of 2 - {[4- (3-hydroxypropyl) phenoxy) with methyl} benzoic acid methyl ester. The resulting mixture was allowed to reflux overnight with constant stirring. The product solution was poured into 900 ml of water and the solution was acidified to a pH below 2 with about 200 ml of concentrated hydrochloric acid. The resulting suspension was transferred to a separatory funnel and partitioned between a total of 1,000 mL of ethyl acetate. The primary aqueous phase was discarded and the organic phase was washed with several 500 ml portions of water until the pH of the final aqueous phase was neutral. The dried (Na 2 SO 4) organic phase was concentrated in vacuo to a solid which was recrystallized from ethanol / water to give 49.13 g (87%) of 2 - {[4- (3-hydroxypropyl) phenoxy) methyl} benzoic acid, mp.

139-140 ° C.

Analysis for C17H1804:

Calculated: 71.31% C 6.34% H Found: 71.42% C 6.27% H

34 92483

Example 17 2 - {[4- (3-Hydroxy-propyl) -phenoxy) -methyl} -benzoic acid methyl ester

A degassed stirred suspension of 57.9 g of 3- (4-hydroxyphenyl) propanol, 157 g of potassium carbonate and a catalytic amount of potassium iodide in 500 ml of 2-butanone was treated dropwise over several minutes with a solution containing 87.6 g of methyl 2- (bromomethyl) benzoate in 10,500 ml of 2-butanone. The resulting mixture was allowed to reflux for 24 hours, after which the resulting suspension was stirred at room temperature for another six hours. The solids were removed by filtration and the product solution was concentrated to an oil in vacuo. The oil was partitioned between a total of 15,500 mL of methylene chloride and 1,500 mL of 10% aqueous sodium hydroxide. The pH of the final aqueous phase was> 12. The organic phase was washed with 500 ml of water, dried (Na 2 SO 4) and concentrated in vacuo to an oil. Thin layer analysis showed the mixture to be separated by HPLC. Poor initial separation afforded a mixture which was separated using 60% hexane in ethyl acetate as eluent to give 68.71 g (60%) of 2 - {[4- (3-hydroxypropyl) -phenoxy) methyl} benzoic acid methyl ester as an oil which solidified. to an amorphous substance when standing at room temperature, m.p. 50.5-52 ° C.

Analysis for C18H20O4:

Calculated: 71.98% C 6.71% H

Found: 72.04% C 6.61% H

Example 18 3- (6,11-Dihydro-11-oxodibenz [b, e] oxepin-2-yl) propyl trifluoroacetate

A stirred solution of 46.71 g of 2 - {[4- (3-hydroxypropyl) phenoxy) methyl} benzoic acid in 500 ml of dry methylene chloride was treated dropwise over several 35 minutes with 82.70 g of trifluoroacetic anhydride.

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35 92483 ridies. The resulting mixture was allowed to reflux for 4 hours, after which it was cooled to ambient temperature and treated with 200 ml of water. The biphasic mixture was acidified with 200 mL of 10% aqueous hydrochloric acid, transferred to a separatory funnel and the aqueous phase was discarded. The organic phase was divided into two 200 mL portions of 5% aqueous sodium bicarbonate until the pH of the final aqueous phase was> 8. The organic phase was washed with 500 ml of water, dried (Na 2 SO 4) and concentrated in vacuo to an oil which solidified on standing at room temperature. A 5.5 g portion of this material was recrystallized from 2,2,4-trimethylpentane (i-octane) to give 3- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2- yl) propyl trifluoroacetate, m.p. 40.5-41 ° C.

Analysis for C19H15F304:

Calculated: 62.64% C 4.15% H

Found: 62.84% C 4.18% H

Example 19 3- (6,11-Dihydro-11-oxodibenz [b, e] oxepin-2-yl) -20 propanol

A degassed stirred solution of 54.03 g of 3- (6,11-dihydro-11-oxodibenz [b, e] -oxepin-2-yl) propyl trifluoroacetate in 300 ml of acetone was treated over 250 minutes with 250 ml of acetone. ml: 11a '. 25% aqueous hydrochloric acid. The resulting solution was allowed to reflux for 24 hours, cooled to room temperature and then concentrated in vacuo to remove acetone. The biphasic mixture was partitioned between a total of 1000 mL of methylene chloride and 1500 mL of 5% aqueous sodium bicarbonate until the final aqueous phase: pH was> 8. The organic phase was washed with 500 ml of water, dried (Na 2 SO 4) and concentrated in vacuo to an oil. Thin layer analysis showed a mixture which was separated by HPLC (silica gel, eluting with 50% ethyl acetate in hexane-35) to give 35.77 g (90.2%) of pure 3- (6.11-3692483 dihydro-11). -oksodibents [b, e] oxepin-2-yl) propanoliaöljy-Na.

Analysis for C17H1403:

Calculated: 76.10% C 6.01% H 5 Found: 76.17% C 6.13% H

Example 20 3- (6,11-Dihydro-11-oxodibenz [s, b, e] oxepin-2-yl) -N-hydroxy-N-methyl-1-propylamine

A stirred, degassed solution of 32.0 g of 3- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) propanol in 500 ml of filter-dried pyridine was treated. dropwise over several minutes at 0 ° C 41.27 g of methanesulfonyl chloride. The resulting solution was allowed to equilibrate to room temperature overnight. The resulting solution was partitioned between a total of 1,300 mL of methylene chloride and 2,750 mL of 10% aqueous hydrochloric acid. The pH of the final aqueous phase was <1. The organic phase was washed with 950 ml of water and dried over saturated aqueous sodium chloride solution. The dried (Na 2 SO 4) 20 organic phase was filtered over MgSO 4 and concentrated in vacuo to a viscous oil. The total yield of pure product was 26.03 g (63%) of 3- (6,11-dihydro-11-oxo-dibenz [b, e] oxepin-2-yl) propanol methanesulfonate.

To a stirred solution of 13.06 g of N-methylhydroxylamine hydrochloride in 250 ml of absolute ethanol was added 17.48 g of potassium t-butoxide. To the resulting suspension was added 9.0 g of 3- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) propanol methanesulfonate. The resulting product suspension was allowed to reflux for 24 hours, after which it was cooled to room temperature.

The suspension was filtered to remove potassium chloride and the mother liquor was then treated with 200 mL of water and concentrated to remove ethanol. The resulting mixture was partitioned between a total of 450 mL of methylene chloride and 250 mL of water.

The organic phase was washed with 250 mL of saturated sodium chloride solution, dried (NaSO 4), filtered and concentrated in vacuo to a viscous oil which solidified on trituration with 10 mL of ethyl acetate in three drops of hexane in a refrigerator. Tin analysis of the solids showed a mixture which was separated by HPLC (silica gel). The purified oil solidified on standing to give 4.03 g (52%) of 3- (6,11-dihydro-11-oxo-dibenz [b, e] oxepin-2-yl) -N-hydroxy-N-methyl -1-propylamine, m.p. 113-114.5 eC.

Analysis for C18H19NO3:

Calculated: 72.71% C 6.44% H 4.71% N

Found: 72.67% C 6.36% H 4.70% N

Example 21 4- (4,10-Dihydro-10-oxotheno [3,2-c] [1] benzoxepin-15-yl) butanol methanesulfonate A cooled, stirred solution containing 9.5 g of 4- (4, 10-dihydro-10-oxothieno [3,2-c] [1] benzoxepin-8-yl) butanol in 200 ml by filtration of dried pyridine, treated with 3.80 g of methanesulfonyl chloride and the addition funnel was rinsed with a few milliliters methylene chloride. The stirred solution was allowed to equilibrate to room temperature overnight with the bath in place. The resulting solution was poured into 750 ml of water and allowed to stand for 15 minutes. The solids were collected by filtration at 25 and dried in vacuo at 42 ° C. Concentration of the mother liquor afforded an additional solid which was combined with the first crop and dried to give a total of 9.09 g (75%) of crude product. A 2.0 g portion of the product was recrystallized from hexane / ethyl acetate to give 1.3 g (49%) of 4- (4,10-dihydro-10-oxo-; thieno [3,2-c] [1] benzoxepin-8-yl) butanol methanesulfonate, m.p. 97-98 ° C.

Analysis for C 17 H 18 O 5 S 2 Calculated: 55.72% C 4.95% H 17.50% S 35 Found: 56.28% C 5.03% H 17.12% S

C. Γ'ι rs - · 38

Example 22 4- (4,10-Dihydro-10-oxothieno [3,2-c] [1] benzoxepin-8-yl) -N-hydroxy-N-methyl-1-butylamine

To a stirred solution of 4.77 g of N-methyl-5-hydroxylamine hydrochloride in 100 ml of absolute ethanol was added 6.38 g of potassium t-butoxide. To the resulting suspension were added 6.98 g of 4- (4,10-dihydro-10-oxothieno [3,2-c] [1] benzoxepin-8-yl) butanol methanesulfonate and an additional 150 mL of absolute ethanol. Suspension 10 was allowed to reflux for 24 hours, after which it was cooled to room temperature. The suspension was filtered to remove potassium chloride and the filter cake was washed with absolute ethanol. The resulting solution was concentrated in vacuo to a waxy solid. The solid was dissolved in 300 mL of methylene chloride and partitioned between 200 any water.

The organic phase was dried over 200 mL of saturated aqueous sodium chloride, collected, dried (Na 2 SO 4) again, filtered and concentrated in vacuo to an oil. The oil solidified on standing and was resuspended in isopropanol to give 3.09 g (51%) of 4- (4,10-dihydro-10-oxothieno [3,2-c] [1] benzoxepin-8-yl). -N-hydroxy-N-methyl-1-butylamine, m.p. 107-108 ° C.

Analysis for C 17 H 19 NO 3 S '25 Calculated: 64.33% C 6.03% H 4.41% N Found: 64.31% C 6.04% H 4.30% N

Example 23 2- (6,11-Dihydro-11-oxodibenz [b, e] oxepin-2-yl) -acetaldoxime 2- (6,11-Dihydro-11-oxodibenz [b, e] oxepin-2-yl) ) - acetyl chloride (15.00 g) in 150 ml of dry diglyme was stirred at -78 ° C under nitrogen as lithium tri-t-butoxyaluminum hydride (104.6 ml of a 0.5 mol / l solution in diglyme) was slowly added dropwise within one hour. The reaction mixture was stirred for ten minutes at -78 ° C,

II

After 92483, the reaction was quenched by the slow dropwise addition of 3 mL of glacial acetic acid. After the reaction mixture was warmed to room temperature, 50 ml of pyridine and two equivalents of hydroxylamine hydrochloride (7.27 g) were added and the slurry was stirred at 50 ° C for two hours. The solvent was evaporated under high vacuum and the residue was taken up in chloroform and 1 mol / L HCl. The layers were separated and the aqueous phase was extracted with chloroform. The combined organic phases were dried (MgSO 4), filtered and evaporated. The residue was purified by flash chromatography (silica di; hexane / EtOAc 5: 2) and recrystallized from ethyl acetate / hexane to give 2- (6,11-dihydro-11-oxodibenz [b, e] oxepine). 2-yl) acetaldoxime as crystals, m.p. 132-134 ° C.

Analysis for C 16 H 13 NO 3

Calculated: 71.90% C 4.90% H 5.24% N

Found: 71.75% C 4.64% H 5.20% N

Example 24 N- [2- (6,11-Dihydro-11-oxodibenz [b, e] oxepin-2-20 yl) methyl] -N-hydroxyacetylacetamide

A solution of 2- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) -N-hydroxymethylamine (5.85 g), triethylamine (6.96 g) and 100 ml of dry di chloromethane, was stirred at 0 ° C under nitrogen when acetyl chloride (3.96 g) was added dropwise. The reaction mixture was stirred at 0 ° C for one hour, then poured into 100 mL of 2 M HCl. The layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried (Na 2 SO 4), filtered and evaporated. The residue was purified by flash chromatography (silica; hexane / EtOAc 2: 1) and re-precipitated from ether / hexane to give N- [2- (6,11-dihydro-11-oxodibenz [b, e] oxepine). 2-yl) methyl] -N-hydroxyacetylacetamide as crystals, m.p. 107-35 109 ° C.

.0 92483

Calculated: 67.25% C 5.05% H 4.13% N

Found: 67.12% C 4.88% H 4.09% N

Example 25 N- [2- (6,11-Dihydro-11-oxodibenz [b, e] oxepin-2-5-yl) methyl] -N-hydroxyacetamide N- [2- (6,11-dihydro-11-oxodibenz) [b, e] oxepin-2-yl) methyl] -N-hydroxyacetylacetamide (2.40 g) in 120 ml of isopropanol was stirred at ambient temperature when 7.0 equivalents of lithium hydroxy-10 dimonohydrate (2.08 g) were added in 50 ml. water was added. The reaction mixture was stirred for one hour and the isopropanol was evaporated. The residue was partitioned between 2M HCl and ether. The layers were separated and the aqueous phase was further extracted with ether. The combined organic phases were dried (Na 2 SO 4), filtered and evaporated. The residue was purified by flash chromatography (silica; ethyl acetate / hexane 2: 1) and recrystallized from ethyl acetate / hexane to give 1.1 g (52%) of N- [2- (6,11-). dihydro-11-oxodibenz [b, e] oxepin-2-yl) methyl] -N-hydroxyacetamide, m.p. 129-130 ° C.

Analysis for C 17 H 15 NO 4 Calculated: 68.68% C 5.09% H 4.71% N

Found: 68.56% C 5.16% H 4.64% N

Claims (1)

Q 0 A 0 7 41. t- 'r Ο ό Oxodibenzoxepine derivatives of the formula Ia 5 Y / (lower alkylene) -c * H-OH 10 in which X together with the carbon atoms to which it is attached forms a benzene ring. 15 Oxodibenzoxepinders with the formula Ia ° H y (from 9 alkyl) -C * N-oh (Ia) CO *? .25 color X columns with a color atom, in the case of a bundle, bildar en bensenring.