CS244149B2 - Method of 9-anthryloxyaminoalkane production - Google Patents

Description

R and R are independently of one another hydrogen, alkyl and 1 to 8 carbon atoms or cycloalkyl β 5 to 7 carbon atoms and.

b is an integer of 2 to 12, and their physiologically acceptable acid addition salts, is characterized in that the elongation of the formula

0 _(CH2 L _and M are integers from 2 to 12, is converted to a compound of, formula I by means of an acyclic or cyclic amine, optionally in the presence of a polar organic solvent, water or jejioh EMSs, the temperature of 60-180 C ^D, free base Compounds of formula (Z) may not be converted by treatment with an acid into a pharmaceutically acceptable acid addition salt, or an acid addition salt of a compound of formula (I) and converted by acid treatment with a base to the corresponding large base; salt with sage.

The compounds of the invention as such or pharmaceutical formulations thereof are suitable for the treatment of inflammation, pain and swelling.

ΟΙΟΪΟ where

U represents a halogen atom, an alkylsulfonyloxyacin or aryleulfonyloxy group and

244.49

The present invention relates to a process for the preparation of 9-anthryloxyaminoalkanes which are an active ingredient of anti-inflammatory and analgesic agents.

An anti-inflammatory and analgesic effect has been demonstrated for compounds representing various structural groups, including, for example, corticosteroids, aspirin and related compounds, arylacetic and arylpropionic acid derivatives, and ranylbutazoh related compounds. However, no representative of any of these classes of compounds has been found ideal.

and

It has now been found that certain 9-anthryloxyeminoalkenes and related compounds have useful anti-inflammatory and analgesic effects.

The present invention relates to new compounds of formula I O (CH ₂₎ ^ ² ®'k

Oíoío] where

12 '

And 8 are independently of each other hydrogen, alkyl of 1 to 8 carbon atoms or cycloalkyl of 5 to 7 carbon atoms, and b is an integer of 2 to 2, and pharmaceutically acceptable acid addition salts and acids thereof.

The present invention also relates to pharmaceutical compositions comprising a compound of formula I and a method of preventing, attenuating or suppressing inflammation associated therewith with compounds of formula 1 or the aforementioned pharmaceutical compositions.

As used herein, the term alkyl means a branched or unbranched saturated hydrocarbon chain containing up to 8 atoms such as methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, n-hexyl, n-heptyl or iooctyl and the like.

Alkoxy refers to the group -OR where R is alkyl as defined herein.

Cycloalkyl means a saturated carbocyclic ring containing from 5 to 7 carbon atoms

Optionally, it indicates that the eventuality or circumstance described below may or may not occur, and that the description includes instances where the eventuality or circumstance occurs and instances where it is. For example, the optionally substituted anthraquinone * may be substituted or it may not be substituted, and the disclosure includes both Meubetitized anthraquinone and anthraquinone that is substituted.

The compounds of the invention herein contain an amine nitrogen on an alkyl side chain where the acid and acid addition salts can be formed. A pharmaceutically acceptable acid addition salt refers to those salts which exhibit biological activity and do not have the properties of the corresponding free bases and which are biologically or otherwise undesirable. Such salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organoacids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid. malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aalieylic acid and the like.

The anthracene ring means the aromatic bonded benzene ring portion of the compounds of the invention.

The numbering system for the anthracene core is given below:

WITH

O (CH ₂ ) _b NR's ²

S2

(AND).

The compounds of the invention are referred to as anthryloxyaminoalkanes. The following are examples of how representative compounds are named:

i 2

The compound of formula I wherein b is 6, and NR R is dimethylamino, is named 1- (9-anthryloxy) -6-dimethylaminohexane.

i 2

The compound of formula I wherein b is 5 and NR R is amino is named 1- (9-anthryloxy) -5-aminopentane.

2

The compound of formula I wherein b is 6 and NR R is ethylamino is named "1- (9-anthryloxy) -6- (2-ethylamino) hexane."

A subgroup of the compounds of this invention are those compounds of formula (ee) which, as -Nr'r ² , contain combinations wherein R 1 and R ² are independently of each other yalo, methyl or ethyl. A preferred embodiment of this subgroup are the compounds of formula I and their pharmaceutically acceptable salts, wherein NR R is amino or dimethylamino. Among them, those compounds in which b is an integer from 2 to 6, in particular 3 and 4, are particularly preferred.

Particularly preferred joau compounds and salts thereof are selected from the group consisting of

1- (9-anthryloxy) -2-aminoethane

1- (9-anthryloxy) -2-dimethylaminoethane,

1- (9-anthryloxy) -3-aminopropane,

- (9-anthryloxy) -3-dimethylaminopropane,

1- (9-anthryloxy) -4-aminobutane,

1- (9-anthryloxy) -4-dimethylaminobutane a

1- (9-anthryloxy) -6-aminohexane.

The compounds of the invention are prepared from the respective / optionally substituted anthronds. Unsubstituted anthrone, as well as a series of substituted anthrons, used as starting materials, are commercially available. Substituted anthrones may also be obtained by well-known synthetic procedures described in the chemical literature. For example, substituted anthrones of formula A (in Scheme I) can be obtained by cyclization of appropriately substituted benzylbenzoic acids by treatment with concentrated sulfuric acid. This method is described in more detail in Chemische Beriehte 27, 2786 (1894). Appropriate substituted benzylbenzoic acids can be prepared in several ways, for example by reducing the corresponding benzoylbenzoic acids using any suitable reducing agent such as zinc in acetic acid or hydrogen in the presence of a catalyst. The corresponding substituted benzoylbenzoic acids are more readily obtained by Prledel-Craft reactions using phthalic anhydrides containing from 0 to 4 substituents (halogen, alkyl or alkoxy) and benzenes and from 0 to 4 similar substituents to produce the expected monosubstituted or polysubstituted benzoylbenzoic acid. The syntheses of these substituted benzoyl, benzoic acids are described in detail in Priedel-Oraft and Related Reactions, edited by O. Olah, Vol. III, Part I, pp. 710-759. Suitable substituted phthalic anhydrides and benzene, used as starting materials, are commercially available yen or are readily prepared by standard procedures well known in the art.

The optionally substituted anthrones of formula (A) can be produced by reducing the corresponding anthraquinones and using, for example, a metal such as tin, zinc or aluminum? and acids such as hydrochloric, acetic or sulfuric acids. Correspondingly substituted anthraquinones are commercially available or can be produced by any of several methods, for example, the methods described by B. H. Rodd in The Chemstry of Carbon Compounds, First Edition, Vol. IIIB, atr. 1 384 and second editions, Vol. III H, atr. 55-71, which also describes the reduction of anthraohinones to the corresponding anthrones. As described in these references, substituted anthraquinones can be obtained by a variety of methods including Diels-Alder reactions of substituted naphthoquinones, oxidation of substituted anthracenes, and cyclization of substituted benzoylbenzoic acids, the synthesis of which is described above. The syntheses of substituted benzoylbensoic acids and the two methods described above for their conversion to substituted anthrones, shown in Scheme I below, are described in more detail in Preparations 1 and 2 below.

Reaction Scheme I

O

(AND)

The alkoxy-substituted anthraquinones and anthrones and e can also be obtained from the corresponding hydroxyanthredinones and hydroxyanthrons by conventional alkylation reactions.

About ·

To produce compounds of the invention from an optionally substituted anthrone (Formula A in Reaction Scheme I), it is first reacted with a compound of Formula B as described in Reaction Scheme II below:

Reaction Boheme II

where b is as defined above,

L is a leaving group such as a halogen or an eulfonate group,

U represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group and a is an integer of 2 to 2.

The process according to the invention is characterized in that it is a compound of the formula

O (CH ₂ ) M where

M is halogen, alkyleulfonyloxy and and is an integer from 2 to 12, converted to a compound of formula I by treatment with an acyclic or cyclic mine, optionally in the presence of a polar organic solvent, water or a salt thereof, at a temperature of up to 180 ° C the base of the compound of formula (I) is converted into a pharmaceutically acceptable acid addition salt by acid treatment, but the acidic salt of the compound of formula (I) is converted to the corresponding free base or acid addition salt of a compound of formula (I) into another pharmaceutically acceptable acid addition salt. salt and acid.

The compound of formula A ae is reacted with aai from 1.0 to 1.3, preferably a and 1.09 with solar equivalents of the compound of formula B in polar and antiparasitic organic solvents such as tetrahydrofuran, formald or, preferably, Η, Μ-diaetbylfornoald. in the presence of one to five solar equivalents of an inorganic base such as sodium hydroxide or preferably about 3 solar equivalents of potassium carbonate. The reaction is carried out at a temperature of 29 to 129 ° C, preferably at 70 ° C, for a period of 2 to 48 hours, and preferably 22 to 26 hours. The resulting product of formula (C aa) is isolated in a conventional manner.

The products of the described reactions aa can be isolated and purified by any suitable eeppenning or purification process, such as filtration, extraction, crystallization, thin-layer or thick-chain eloupo threat analysis, prepaiative low pressure liquid chromatography or a combination of these procedures. Specific illustrations and examples are described in the examples, and other equivalent eeparation or purification procedures may also be used.

Compounds of general formula Cee are then converted to the desired compounds of formula (I) by modification of the side chain by the methods commonly used for the production of amines described by I.T. Harrison and 8. Harrison in Compendlua of Orgmlc Synthetic Meth. 1, pp. 230-270 or R. B. Wagner and K. D. Zook in Synthetic Organic Chemistry. ztr. 693-728, or other standard organic chemistry manuals. Some examples of the nature of the functional group M and the type of reactions required to convert to the group Hr'rr are given in Table 1, but are not exhaustive.

Table 1

Halogen lp reaction

Displacement reference or conditions

Preparation 3 and Examples 1 and 2

Alkyl- or Displacement arylsulfonyloxy group

J. Am. Chem. Soe., 1933, 99, 349, < 7. Chem. Soe., 1999, 694

MH ₂ , NH-alkyl

Alkylaee

Org. Heao., 1949, 9, 301

When H is halogen, alkylsulfonyloxy or arylsulfonylcyclohexyl, compounds of formula I are produced by treating an optionally substituted compound of formula Ce with a compound of formula HMb'r, converting halogen or alkylsulfonyloxy or arylsulfonyloxy to the corresponding nitrogen-containing substituents. To accomplish this, the compound of general formula C is dissolved and reacted with a flow rate of 9 to 29 molar equivalents of the adjacent cyclic or acyclic amine, and preferably an acyclic amine, most preferably Ν, Χ-dimethylamine. This reaction may be carried out in the presence of any polar organic roapoulant, water or its emission, such as mothanol, aqueous ethanol, preferably ethylene glycol, or in the absence of a co-solvent. The reaction is carried out at a temperature of from 60 to 180 ° C, preferably 100 ° C, for about 1 to 8 hours, preferably 3 hours, at a pressure of about 100 to 900 kPa, and preferably at atmospheric pressure.

When the reaction is substantially complete, the product, i.e. the compound of general formula X, is isolated in the usual manner and, if desired, an acceptable salt is converted into the fanatol.

If the Mb'r ² group in the final product has a meaning other than amino, it is salkylated by reaction with an alkyl halophosphate or sulfate in an organic or aqueous organic solvent, as the organic component is a water-miscible solvent such as is methanol or tetrhydrofuran. The reaction is carried out at a temperature of from 25 to 150 [deg.] C. and a pressure of from 100 to 5 kPa. Optionally, the alkylation can be carried out by reacting the starting material with the appropriate aluminum alkoxide and aluminum in a sealed tube from a temperature of from 100 to 350 ° C, preferably at 250 ° C.

All of the compounds of formula (I) may be converted to their editorial salts and acidic salts, as a result of an alkyl amine-terminated amine side chain.

The compounds of formula I in the free base form can be converted into acid addition salts with a stoichiometric excess of a suitable organic or inorganic acid such as phosphoric acid, citric acid, pyruvic acid, hydrochloric acid or sulfuric acid and the like. Usually, the free base is dissolved in a polar organic solvent, such as ethanol or methanol, and acid is added to the solution. The temperature ae is maintained between 0 and 50 ° C. The resulting acid addition salt ee precipitates spontaneously, or ee can be removed from the solution by a polar solvent.

Acid addition salts and acids formed by the compounds of formula (Z) can be converted to the corresponding free base by treatment with an excess of a suitable base such as potassium carbonate or sodium hydroxide, usually in the presence of an aqueous solvent and at a temperature between about 0 and 50 ° C. The free base compound is isolated by conventional methods, such as extraction with an organic solvent.

The salts of the compounds of general formula I may be converted into each other using the advantages of different solubility of salts, volatility or acidity of the acids, or by treatment with an appropriate ion-exchange resin feed. For example, snow can be carried out by reacting a salt of a compound of general formula with a small stoichiometric excess of acid having a lower pK i than the acid component of the starting sele. This conversion is carried out at a temperature between about 0 ° C and the boiling point of the solvent used as the process medium.

The compounds of formula I exhibit suppression of inflammation in mammals in standard laboratory tests. Therefore, the compounds of formula (I), their salts and pharmaceutical compositions containing them can be used to inhibit, prevent or control inflammation in mammals. The anti-inflammatory effect of ee can be determined by the method described by C. N. Pearson in Proc. Soc. Sxp. Biol. Med., 91: 95-101, (1956) uses adjuvant arthritis in rats. This method is described in detail in Example 10 below. The compounds of general formula (I) may also be suitable for the prevention, elimination or control of associated pain in severe conditions of inflammation.

Administration of the active compounds and salts described herein can be accomplished by any medically acceptable route of administration for inflammatory and pain-relieving agents.

Such methods include, but are not limited to, oral, parenteral and other systemic or local routes of administration. Oral or topical administration of the ee, of course, is preferred in the treatment of the disease to be treated. The compounds ee are administered in a therapeutically effective amount to the cell alone or in combination with a suitable pharmaceutically acceptable excipient.

Depending on the intended route of administration, the compounds of the invention may be formulated into any pharmaceutically acceptable dosage form, such as tablets, suppositories, pills, capsules, powders, liquids, suspensions, emulsions, aerosols or the like. Advantageous Means of Administration A single unit dosage form for single administration of precise dosages or sustained-dose sustained dosage forms. A preferred dosage form comprises a pharmaceutically acceptable excipient and an active compound of Formula I, or a pharmaceutically acceptable salt thereof, and may additionally include other therapeutic or pharmaceutical compositions, carriers, excipients, coatings, stabilizers and the like. Depending on the parameters such as method of administration, type of composition and effect of the compound, the pharmaceutical composition of adie contain, and 95% by weight of the active ingredient, the excess being an excipient.

For steam dosage forms, nontoxic solid carriers include, for example, aanitol, lactose,

Starch, magnesium ataarate, sodium aftl saccharin, polyalkylanglycols, talc, esululose, glucose, saeharose and magnesium carbonate of Pharaohil quality are included in the above list. The solid dosage forms of the compounds of the invention are suppositories which contain polypropylene glycol as the carrier. Liquid pharmacologically acceptable dosage forms may, for example, be administered with a solution or auaponso of the active compound of the present invention and, if appropriate, the pharmaceutical agent (s) in the carrier, such as water, saline, aqueous doxtrose, glyoarol, ethanol, and the like to form nobo susps. If desired, the pharmaceutical composition intended for the administration of nftis also comprises other substances such as anacadal or emulsifying agents, buffers to adjust the pH and the like. Typical examples of such compositions are sodium acetate, sorbitan aonolaurut, triathanolaain natriumaeotdt, triathanolanin olaut, and the like. Current methods of making such dosage forms are dreamlike or will be apparent to those skilled in the art, such as Ssaington ' Fharaaooutieal Sciences, Merk Publishing Company, Caston, Penney. The composition, or formulation, to be administered in some instances of its content is such an active compound of the active compound that is effective to alleviate the symptoms of the subject.

For oral administration, a pharmaceutically acceptable nontoxic dosage form may comprise, with normally bound oxo-apantate, such as aanitol, lactose, icrobus, magnesium ataarate, sodium aftl sculpture, naphtha, ealulosa, glucose, saeharose and magnesium carbonate. Such compositions may be in the form of a plant, a suppository, a tablet, a pill, a capsule, a pad, a sustained-release formulation, and the like. Such dosage forms may contain, at 95% effective saliva, and preferably 25 at 70%.

For topical administration, a suitable dosage form consists of the effective annotation of the compound of the general formula X, which is in the form of a pharmaceutically acceptable non-toxic kit and carrier. The suitable rosaose composition comprises 0.1 to 10%, preferably 1 and 2 * active saliva, and most often forms a carrier. The Xa-active drugs in the pharmaceutical compositions suitable for topical application in conjunction with the atolls have been related to the therapeutic effect of the single active drug and the treatment conditions to be treated. Suitable dosage forms for laval poulit! The compounds of the present invention include, but are not limited to, creams, ointments, lotions, oauls and roots.

For example, a suitable topical application of the compounds of this invention will comprise 15 to 45% by weight of a saturated aliphatic alcohol of 16 to 24 carbon atoms such as ethyl alcohol, stearyl alcohol, bansanyl alcohol and the like, and 45 to 85% glycol solvent such as propylene glycol, polyethylene glycol , dipropylene glycol and its salts. In addition, the ointment should contain at least 15% by weight of a plasticizer, for example polyothylonglycol, 1,2,6-hexanediol, aorbltol, glyooral, and the like, at least 15% by weight of a binder, such as saturated aliphatic acids having 16 to 24 carbon atoms, for example stearic acid, of palmitic acid of a Bohonic acid, an aliphatic acid msid, for example oleamide, palattamide, stearamide or behanaaid, or an olefinic oleate of 16 to 24 carbon atoms, for example sorbitol and aaosteard, -polyethylene glycol monoatardate, polypropyleaglycol nobo, and a 20% by weight penetration enhancing agent, such as dimothylaulfoxide on palethyloeetamide.

If the active ingredient administered to you depends on the subject being treated, the severity of the postiloai, the route of administration and the prescribing physician's actions. However, tarapautloky effective doses of the compounds of this invention are in rosaose 1 and 100 mg / kg and don. Thus, a brood of an average weight of 70 kg is 70 g and 7 g sa don nobo, preferably 1.5 g sa day.

The following preparations and examples of alouli are intended to illustrate the invention and are intended in any way to be an extent of the invention as expressed in the present invention.

Claims (6)

Preparation, Method of production 2-ethylanthroA and the present compounds of formula (A) (a) 270 g of aluminum chloride are introduced in portions into Achane with 270 g of phthalic anhydride and 1, 25 µl of ethylbenaene. After 4 hours, ice was poured into Aa and 490 L of concentrated hydrochloric acid was added. Excess ethylbenaene ee is removed by distillation with a water purifier and the resulting roeok is cooled and filtered. 2- (4-ethylbenzoyl) benzoic acid is obtained. b.l) A solution of 2- (4-ethyltoenzoyl) benoic acid in 0.5 A acetic acid and 1.5 A dimethylforaaid containing 4.9 g of 10% palladium on carbon was shaken under an atmosphere and at a pressure of 4.2 kPa for 6 hours. The filter ae potoa is filtered and the filtrate is added to 2000 A of water. A precipitate of 2- (4-ethylbenzyl) benzoic acid was formed. b.2) (Alternative sp & eob reduction :) To the solution 3 g of acid 2- ( 4-ethylbenzoyl) benzoic acid in 50A acetic acid is added, 5 g of tin. Then 5 A hydrochloric acid was added and refluxed for 3 hours, then decanted from the undissolved eln, cooled and diluted with water. A precipitate of 2- (4-ethylbenzyl) benzoic acid is obtained. o) 24 g of 2- (4-ethylbenzyl) benzoic acid at a temperature of 0 [deg.] C. were added to the solution at 200 A with sulfuric acid. After 3 hours, the reaction mixture is poured over water and the product is extracted with ethyl acetate. The extract was washed with aqueous sodium carbonate solution and then dried and evaporated. It attracts 2-ethylanthrone. d) By the method ae of the Priedel-Graft reaction with the addition of substituted phthalic anhydrides and the approved substituted benzenes, as described in paragraphs a) to e) of this preparation, dAS1 produces substituted anthrones of general formula A. Reduction aetode from b.2) ee used when halogenanthrones are produced. Preparation 2 A method of alternative synthesis of halogen-, alkyl- and alkoxyanthrons a) Preparation of 2- and 3-chloroanthrons, 00 g of powdered eln and 70 g of 2-chloroanthraquinone are refluxed in 500 ml of acetic acid, with 30 A of concentrated hydrochloric acid added over 3 hours. The mixture is cooled, the product is filtered off and then chromatographed on silica gel, eluting with benzene and ether. 2-Chloranthron and 3-Chloranthron were obtained. b) In a similar manner, however, if ae the appropriately substituted anthrequinones are authorized, further representative substituted anthrones of general formula A are produced. Preparation 3 Process for the preparation of anthryloxyalkyl chlorides (compounds of general formula 0 in Reaction Scheme II) a) A process for the preparation of 2- (9-anthryloxy) ethyl chloride 6.0 g of 2-chloroethyl p-toluenesulfonate and 5 g of anthrone and 5 g of potassium carbonate in 30 ml of dimethylformamide were added. The reaction mixture was stirred at 70 ° C for 24 hours, then added to ether. The resulting solution was washed with dilute aqueous potassium hydroxide solution, dried over magnesium sulfate and evaporated. A euro product is obtained which is chromatographed on silica gel using hexane / ethyl acetate in a 4: 1 mixture as eluent. 2- (9-anthryloxy) ethyl chloride is obtained. 244) 49 b) In a similar way, svlek sa poulit! Further compounds of general formula C are prepared from the corresponding chain-chloro-chloroalkyl-p-toluenesulfonates. P.example 1 and d 1 A process for the preparation of 1- (9-anthryloxy) -2-diaothylaninoothane and related compounds of formula I a) 5.0 g of 2- (O-anthryloxy) ethyl chloride aa was heated at 90 ° C for 5 hours in 50 µl of ethylonglycol containing 4.0 g of palethylaine per mol. coolers of reported dry ice. Bostok ae potoa cools and adds water. The resulting mixture aa extracts the stearyleate and the extract of the balls and evaporated. The crude product is chromatographed on 100 g of silica gel, eluting with 95: 5: 1 rostokoa methylene chloride, methanol and ammonium hydroxide. mp 132 and 134 ° C. (b) In accordance with the procedure described in paragraph (a) referred to above, svlek sa poulit! of the corresponding 9-anthryloxyalkyl chlorides of the di-chain, the synthesis of which is described in Preparation 3b), as starting materials, the following compounds of formula I are prepared: 1- (9-anthryloxy) -3-dimethylaminopropane, such as phosphate, m.p. 196-200 ° C; 1- (9-anthryloxy) -4-diaothylaninobutane, such as phosphate, m.p. 165-166 ° C, 1- (9-anthryloxy) -6-diaethylaminohexane, as phosphate, m.p. 126 ° C; -8-dimethylaalnooctane, such as phosphate, melting point 100 ° C a 1- (9-anthryloxy) -5-diaathylaainopsntane, such as a succinate, m.p. 115-1.8 ° C. Example 2 Converting a free poem to salt To a ethanol solution of 1.0 g of 1-C9-anthryloxy) -3-diaethylaminopropane and a double sto-ionic excess of 3% phosphoric acid in mothanol was added. Diethyl ether was then added until precipitation was complete. The product was filtered off, washed with ether, air dried