FI74460B - FOERFARANDE FOER FRAMSTAELLNING AV ANTIINFLAMMATORISKT OCH ANTIMIKROBISKT EFFECTIVA 3H-NAFT / 1,2-D / IMIDAZOLER. - Google Patents

Description

TTiS ^ TI ANNOUNCEMENT _. .

• would! [β] ΠΟ UTLÄGGNINGSSKRIFT 744 60 (51) Kv.lkVlntCI. "C 07 D 235/02, Α05 / 0Α

SUOMI FINLAND

(FI) (21) Patent application-Patentansökning 801778 (22) Application date - Ansökningsdag 03 · 06.80

National Board of Patents and Registration (23) Start date - Giitighetsdag 03.06.80

Patent- och registerstyrelsen (41) Made public - Biivit offentiig oA. 12.81 (44) Date of presentation and publication. - 30.10.87

Ansökan utlagd och utl.skriften publicerad (86) Kv. application - Int. ansökan (32) (33) (31) Privilege claimed - Begärd priority (71) Gruppo Lepetit SpA, Via G. Murat 23, Milan, I or ia-1 or ien (IT) (72) Emilio Toja, Milan, Amedeo Omodei -Sale, Voghera (Pavia),

Domenica Selva, Milan, I ta 1 ia-I ta 1 ien (IT) (7 * 0 Munsterhielm Ky Kb (5 * 0 Method for the preparation of anti-inflammatory and antimicrobially effective 3 H-naphth / 1,2-d / imidazoles) This invention relates to a process for the preparation of novel 3H-naphtho [1,2-d] imidazole sol derivatives of the following general formula (I): The present invention relates to a process for the preparation of novel 3H-naphtho [1,2-d] imidazole sol derivatives of the following general formula (I).

N --- - A

\ 1 K

Jossaν · i '> R 2 wherein R is (C 1-8) alkyl or (C 3-7) cycloalkyl and R 1 and R 2? represent, independently of one another, hydrogen, halogen or (C 1-4) alkoxy and the symbol A represents pyridyl, furanyl, pyrrolyl or thienyl which are optionally substituted (C 1 -C 4) alkyl groups, or A represents a phenyl radical which is optionally substituted 1-3 groups independently selected from halogen, (C 1-4) alkyl, (C 1-4) alkoxy, hydroxy, benzyloxy, (C 2-4) alkanoyloxy, carboxymethoxy, [carbo (C 1-4) a 1 coke i] methoxy, methyl-2,74460 -enedioxy, amino, mono- or di- () -alkylamino, (C2-4) alkanoylamino or benzoylamino, provided that when R represents a methyl group and and R are both hydrogen, A cannot be a 2-hydroxyphenyl group, and further provided that when R is simultaneously ethyl, one of R1 and R2 is hydrogen and the other is a methoxy group, A cannot be a 4-dimethylaminophenyl group; and for the preparation of salts of these compounds with pharmaceutically acceptable acids.

The novel compounds of formula I have anti-inflammatory, analgesic, antipyretic and antimicrobial properties.

The compounds which are excluded from this invention under the conditions set out above are known from DE Patent 1 1 37 625, which discloses a number of thiazole, oxazole and imidazole derivatives having photoconductive properties which can be suitably used for electrophotographic reproduction.

A compound of formula (I) wherein R is methyl, R 1 and R 2 are hydrogen and A represents a nitro-substituted phenyl group is known from J.W. Lown and M.H. From an article by Akhtor published in Can. J. Chem. 4_9, (1971) 1610, in which the authors discuss the mechanisms involved in the reaction of 1-nitroso-2-naphthylamine with 3-aroyl aziridines.

In addition, other naphthoimidazoles substituted at the 2-position with alkyl groups are disclosed in U.S. Patent 3,046,166, which states that these compounds may be conveniently used to produce printing plates.

As used herein, the term "alkyl" and the alkyl moiety of other disclosed radicals containing an () alkyl moiety means a straight or branched alkyl radical having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl. style, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl, while "(C 1-6) alkyl" means a straight or branched alkyl radical containing up to 6 carbon atoms, such as the above, pentyl, 1-ethylpropyl , 1-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, 4-methylpentyl, 1,3-dimethylbutyl , 3,3-dimethylbutyl and the like The term "(7) cycloalkyl" means cycloalkyl radicals having 3 to 7 carbon atoms which are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. ) al coke "means a straight or branched chain coke radical and having up to 4 carbon atoms which are 3,74460 are methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy.

Halogen means, by term and in part, mainly chlorine, bromine and fluorine.

A most preferred group of compounds are those compounds of formula (I) wherein R is (C 1-6) alkyl, R 1 and R 2 are both hydrogen and the symbol A represents a phenyl radical optionally substituted by 1-3 groups which are, independently of one another , (C 1) alkyl, () alkoxy, amino, mono- and di- (C 1-4) alkylamino; and salts thereof with pharmaceutically acceptable acids.

Acid addition salts are obtained by treating the compounds of formula (I) above with pharmaceutically acceptable acids. Suitable acids for the formation of therapeutically acceptable salts include, for example, hydrogen halides, sulfuric and phosphoric acids, nitric and perchloric acids; aliphatic, α1-cyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as other monetary, acetic, propionic, succinic, glycolic, milk, malic, tartaric, lemon, ascorbic, maleic -, hydroxymaleic, pyruvic acid; phenylacetic, benzoic, para-aminobenzoic, anthranilic, para-hydroxybenzoic, salicylic, para-aminosalicylic or embonic acid, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic acid; halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic acids or sulfanilic acid.

These or other salts of the novel compounds can also be used to purify the obtained compounds, converting the obtained compounds into salts, isolating the latter and liberating the free compound therefrom.

Since the new compounds in the free form and in the form of their salts are very similar, it is to be understood in the above and in the following that the free compounds also mean the corresponding salts.

A general process for the preparation of the novel compounds comprises naphthalenediamine of formula (II) 74460 4 R .. NH2

1 I NHR

® ° f - R2

wherein R, R 1 and R 2 are as defined above, condensation with an appropriately selected aldehyde of formula ACHO, wherein A is as defined above, to give the intermediate imidazoline, which is subsequently oxidized to the final product of formula (I). The above reaction is better described in the following Scheme A

nh0 r

R, 2 IIN-rA

Jl NHR Ri I I

^ ^ condensation 4 '\

/ With ACHO f \ | R

- »LJ1 J

4 II -¾0

2 d III

oxidation step

rl N _z ..... i "· A

-h2 v i r <- i where square brackets mean that the intermediate compound inside the square brackets can still be used without prior separation.

A wide range of conditions can be used for the compensation between naphthalenediamine and aldehyde; however, fairly good results have been obtained by adding an equimolar dose or a slight excess of aldehyde to a solution of a compound of formula (II) in an inert, high boiling organic solvent such as xylene, toluene or cymene and then boiling the resulting reaction mixture in a Dean-Stark apparatus under an inert atmosphere.

The oxidation step shown in the above scheme as a simple dehydrogenation may be carried out in the presence of a mild oxidizing agent such as manganese dioxide or copper acetate, or a more suitable dehydrating agent which is a metal or metal oxide commonly used and referred to as a "hydrogenation catalyst" such as e.g. , platinum, ruthenium, rhodium, platinum dioxide, either in powder form or adsorbed on an activated carbon or asbestos carrier or Raney nickel. The reaction products obtained are recovered by the usual methods of filtering the hot solution and evaporating the solvent under reduced pressure. The purification of the crude material thus obtained is carried out simply by crystallization or using chromatographic methods.

The naphthalenediamine derivatives of formula (II) used as starting materials are generally new and can be prepared in various ways; e.g., in J. Org. Ghem. 3Z (22), 3566 (1972) discloses the synthesis of N'-isopropyl-naphthalene-1,2-diamine by a) nitrating 3-naphthaleneamine to 1-nitro-2-naphthaleneamine, b) amino group exchanged for a chlorine atom, c) aminated with isopropylamine and finally d) the nitro group is reduced to an amino.

In addition, other methods can be compiled from the literature, taking into account the specific reactivity of the naphthalene substrate.

The process we have generally used for the preparation of naphthalenediamine derivatives used as starting materials comprises an N-substituted 1-nitroso-2-naphthaleneamine of formula (IV)

WELL

Ηη I NHR

WAJ

r2 wherein R, R1 and R2 are as defined above, reduction with hydrogen gas in the presence of a hydrogenation catalyst. Various hydrogenation catalysts can be used in the conversion to diamine 6 74460, and generally the same metals and metal oxides are preferably used as in the oxidation step of Scheme A, i. palladium, platinum, ruthenium, rhodium, platinum dioxide, either in powder form or adsorbed on a base and substance, and Raney nickel. The reaction conditions can also vary widely, since all the above-mentioned catalysts are active and are preferably used at room temperature and atmospheric pressure, but they can also be used up to atmospheric pressure. Solvents suitable for use in this reaction include lower aliphatic alcohols such as methanol and ethanol and aromatic hydrocarbons such as benzene, toluene, xylene and cymene.

Alternatively, the reduction of the N-substituted 1-nitroso-2-naphthaleneamine derivative can also be carried out using metals such as tin, zinc or aluminum as the reducing agent in an acidic medium according to well known methods.

The nitroso compounds used as starting materials have been synthesized according to the method of S.T. Morgan and F.P. Evans in J. Chem. Soc. 115, 11 * + 0 (1919), by carrying out an acid-catalyzed rearrangement of the atoms of 2- (N-nitroso-N-substituted) naphthylamine or, preferably, by reacting the primary amines with 1-nitroso-2-naphthol according to the method, by EW Malmberg and C.S. Hamilton in J.Am. Chem. Soc. 20, 2bl5 (19W.

The above process for the preparation of naphthalenediamines of formula (II) as starting materials from the corresponding N-substituted 1-nitroso-2-naphthaleneamines is particularly valuable for a number of reasons. Firstly, the reduction reaction does not require vigorous conditions but, on the contrary, takes place rapidly at room temperature and atmospheric pressure, secondly, the reaction conditions themselves, solvents and starting nitroso compounds are particularly safe from an industrial point of view; thirdly, the naphthalenediamines thus obtained do not necessarily have to be separated from the reaction mixture With ACHO can be carried out without doing anything to the reaction mixture containing the hydrogenated compound of formula (II) before the addition of the aldehyde ACHO. In this case, if the separation of naphthalenediamines is not necessary, the reduction of the N-substituted 1-nitroso-2-naphthaleneamine is also carried out in an inert high-boiling organic solvent. In addition, since the catalyzed reduction that takes place on the surface of the catalyst is a reversible process, the same catalysts used for the reduction of nitrosonaphthaleneamines can be used appropriately in the absence of hydrogen in the dehydrogenation process.

The reaction between a naphthalenediamine of formula (II) and an acid derivative, which may be an acyl chloride, anhydride or ester, constitutes another suitable method for preparing the naphthoimidazoles of this invention. In particular, naphthalenediamine is contacted with a compound of formula ACOX, wherein A is as defined above and X may be - a chlorine atom, - a group -OR 4, where R 1 may be the same radical -COA or trifluoroacetyl, ethoxycarbonyl or alkylsulfonyl- part, or - a group -QR ^, where R ^ is a methyl or ethyl radical.

This two-step reaction involves the formation of mono-acylated naphthalenediamine, which is the required intermediate according to Scheme B below:

CHART B

v R2 Π condensation with ACOX Ψ o Ν = Ί-A R NH2 * 2

R1 K I

ring Vv / 'V /' f A

/ 1 ^ - V l J H

R / R2 V

8 74460

In the first step, which leads to intermediate mono-acylated compounds, it was found that high yields can be obtained by dissolving an equimolar mixture of a naphthalenenediamine of formula (II) and an acid derivative of formula ACOX in an anhydrous, inert, organic solvent which is a lower α 1 -iphatic, halogenated hydrocarbon or aromatic hydrocarbon in the presence of a tertiary organic nitrogen base which binds the inorganic or organic acid formed during the reaction.

Finally, the conversion of the mono-acylated intermediate to the desired final product by removal of water is accomplished by refluxing in an inert, organic solvent, optionally in the presence of an acid catalyst such as sulfuric or p-toluenesulfonic acid. The finishing and purification of the final naphthoimidazoles are carried out by the same conventional methods already described in the previous method. In addition, some of the compounds of formula (I) may also be obtained by chemical conversion of other compounds of the same formula (I) prepared according to one of the above reaction schemes. For example, compounds in which A is phenyl substituted with (R 2) alkoxy 11α, benzyloxy, (N, N, N'-cyanoyloxy), carbomethoxy11a or N-carbo (C 1-4) alkoxy] methoxy11a are conveniently prepared by subjecting the corresponding hydroxyphenyl derivatives to react with suitable substances, such as (C 1-4 alkyl or benzyl halides, tosylates or mesylates, (C 2-4) alkanoyl halides or anhydrides, haloacetic acid or its (C 1-4) alkyl esters, Again, compounds in which A is an aminophenyl group can be readily A suitable method for obtaining monoalkylaminophenyl compounds in the highest yields involves the removal of the corresponding acylamino derivative amide of the amide nitrogen atom and the addition of a sodium derivative, and then substitution with an alkyl derivative.

As mentioned above, some of the novel compounds of formula I are active as anti-inflammatory, mildly analgesic and antipyretic agents. In addition, some of them have a fairly good antibiotic activity, especially against fungi. These biological activities are associated with low toxicity because the mean LD50 values per os in mice are generally higher than 500 mg / kg. Toxicity was determined according to Lichtfield and Wilcoxon, Journ. Pharm. Expt. Ther., ^ 6.99 (19 ^ 9).

Anti-inflammatory activity was detected by many test methods; one method evaluated the ability of the compounds of the invention to reduce edema induced in the rat paw by injection of a carrageenan compound, the test was performed by the method of C.A. Winter et al. in Proc. Soc. Exntl. Biol. Meu.

111. (1962).

The second method examined the change in the weight of granuloma formed on test Hauelle inoculated subcutaneously in rats by test compounds according to the method of Meier et al. in Experimentia 6. E69 (1950).

In yet another method, a few compounds were tested in an adjuvant-induced arthritis experiment in rats. This test, performed as B.B. Newbould has presented in Bri. Journ. Pharmacol., 21, 127 (1963), is absolutely relevant because adjuvant arthritis is one of the best pharmacological aids by which a pharmacologist can evaluate the possible anti-inflammatory activity of compounds due to the fact that this experimental model of chronic inflammation resembles most closely the conditions of arthritis such as rheumatism in human pathology (see Pearson CM, Arthritis and Allied conditions, page 119, Lea and Febiger Pub. 1967 and Pearson CM, J. Chronic Diseases, lj6, 863 (1963) ·

The compounds were administered to rats at various doses, generally corresponding to about one-twentieth or one-twenty-fifth, one-tenth, and one-fifth (highest dose) of the corresponding toxic doses given at LD50 values. However, although the LD50 values of the test compounds are higher than 1000 mg / kg, the maximum dose they are administered is generally no more than 200 mg / kg. These doses are quite far from the toxic dose. In fact, in the carrageenan-induced Edema test used as a preliminary screening test, the test compounds were first dosed at the highest doses corresponding, as mentioned above, to one-fifth of the LD50 value or 200 mg / kg if the LD50 value is higher than 10,74460 1000 rag / kg. Compounds with significant anti-inflammatory activity were observed, i. those with a percentage reduction in induced edema of about * f0 or more were further tested at lower doses followed by a granuloma pellet test. The results obtained from these tests are shown in Table I below.

Es 74460 11

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G -H P rH • H CÖ O cö CO 0

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EH I GM UNO O UNO O UNOO UNOO UNO o

G ^ rH CM H CM H CM rH t-H HOI

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AND i — I i — I i — I i — I i — I

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p P

and φ> h G

12 o o

P-P

SS 74460

-P -H

i-s i — I * H Φ p, d φ

gj C J- 00 ro lr \ r — H

S * H I t OJ I I m Iiro I I J- I I I rO

O rH O cö rH CÖ d 3 d -p to d d Φ O w d <D d d d ή

Ό rH • H «I

O cö m 3 d -p ό d d Φ (MvOJ- VfNO-d- OC ^ t> r OJUncQ pHVTnOCö • H m ro J- lr \ roirwo OJ roj- ro J * Λ roj-, + lr \ d o

H d O d P-H Φ P

φ d -h

tJJ CÖ * rH

<ö a p d Φ -H d Φ -d cö ό d

Ui: o -h en tn o o ooo ooo ooo ooo oooo

d bO C \ JUAO CMITSO OJlfNO löNOO OJUnOO

d rH rH i — I rH OJ i — I 0 * J

<4 \ ω e en O O O O o o o o o o o

0 lr \ Xrs irs O O

Von i — I rH

3 Aa • H O en S Φ: cö Φ -p -p tn J- On ro cm 00 en -h H H OJ ro ro • h Ui Ö d Si Φ> h a 74460 13

The compounds of Examples 6, 19 and 32 that gave the best results in the carrageenan-induced edema test and the granuloma pellet test were then tested in the adjuvant arthritis test at doses corresponding to 1/5 of their LD50 or 200 mg / kg if LD q was higher than 1000. In this test, the efficacy of the compounds was measured as their ability to reduce hindpaw volume in rats. The results obtained are summarized in Table II below:

TABLE II

Compound pre- Dose mg / kg from hindpaw volume percent sign No rats p.o. physical reduction control list 6 200 33 19 100 U-2 32 200 53 These advantageous properties have also been combined with the considerable analgesic and antipyretic properties found by the methods of Randall et al. in Arch. Int. Pharmacodyn. 111. * + 09 (1957) and Buller et al. in J. Pharm. Pharmacol. j), 128 (1957) · In addition, it has been found that the novel naphthoimidazoles of the present invention have a very low exogenous activity which is several times lower than other known and therapeutically used anti-inflammatory agents. The exogenous effect was determined according to the method of Thuillier et al. in Chim. Ther. 51 (1968).

In addition, as already stated, some of the compounds of the invention have considerable antimicrobial activity mainly against fungi, such as various Trichophyton species, for example Trichophyton mentagrophytes, Trichophyton Schoenleinii and Trichophyton version-color. In particular, the compounds of Examples 6, 11, 13, 15, 16, 17 and 18 inhibit the growth of these microorganisms in vitro at concentrations ranging from about 3 to about 25 ml.

14 74460

For anti-inf Lamina tori s use, the compounds of formula I may be administered in a variety of ways. However, they are preferably administered orally and rectally, parenteral administration may also be used. For oral administration, the compounds are combined into pharmaceutical dosage forms, such as tablets. capsules, elixirs, solutions and the like. The tablets may contain, in addition to the therapeutic ingredient, common additives such as inert diluents, e.g., starch, lactose, kaolin, calcium phosphate, mannitol, and the like; binders, e.g. gelatin, starch, sugars, gums, carboxymethylcellulose, polyvinylpyrrolidone and the like; lubricants such as talc, magnesium stearate, stearic acid and the like; and commonly used disintegrants, colors, sweeteners and flavors. Coated or hard-shell capsules may also be prepared, which may contain the same excipients as described above for tablets. Liquid preparations such as elixirs and solutions are prepared by dissolving the active ingredient in an aqueous or non-aqueous pharmaceutically acceptable solvent and may also contain suspended sweetening, flavoring and preservative agents.

For rectal administration, the compounds are prepared as suppositories in which the active ingredient is mixed with conventional carriers such as cocoa butter, wax, whale fat or polyoxyethylene glycols and their derivatives.

The dosage range is about 0.05 to 10.0 g per day, preferably administered in divided doses. Thus, a pharmaceutical preparation for anti-inflammatory use contains from about 50 to 1000 mg of a compound of formula I as active ingredient together with a pharmaceutically acceptable carrier.

For antimicrobial use, the compounds are combined with topical preparations such as ointments, ointments, powders and the like in a concentration of 0.1 to 10%, which are applied once or several times a day as needed. Ointments and creams are prepared by combining the active ingredient with an ointment base, such as an oily base made from vegetable and animal fats, a hydrocarbon base made from petrolatum and wax, or, preferably, a polyethylene glycol ointment base.

Powders are prepared by mixing a very finely divided powder of the active ingredient with a chemically inert carrier.

15 74460

The following examples illustrate the process of the invention and detail some of the compounds of general formula (I).

Example 1 3-Methyl-2-phenyl-3H-naphtho [1,2-d] imidazole 11.35 g of benzoyl chloride (0.08 mol) dissolved in 50 ml of methylene chloride are added to a solution of 13.57 g of N1-methylnaphthalene. -1,2-diamine (0.083 mol) and 11.3 ml of triethylamine (0.08 mol) in 100 ml of methylene chloride, and the resulting reaction mixture is allowed to stand at room temperature for about an hour. It is then heated at reflux for 16 hours, cooled to room temperature and filtered with bleach. The filtrate is diluted with 200 ml of methylene chloride, washed twice with water, once with 5% sodium bicarbonate and then with water until the neutral phase of the aqueous phase is neutral. The methylene chloride solution, which is dried over sodium sulfate, is concentrated to dryness to give a residue which is dissolved in 300 ml of benzene and then poured into a 500 ml flask equipped with a Dean-Stark apparatus. 0.18 g of p-toluenesulfonic acid is gradually added to this solution which has been heated to reflux. After 3 hours, the reaction mixture is cooled to room temperature and filtered. The filtrate is washed with water, dried over sodium sulfate and then concentrated to dryness to give 13.1 g of the title compound. Mp 127-128 ° C (from ethanol).

Example 2 2- (k-Chlorophenyl) -3-methyl-3H-naphtho [1,2-d] imidazole

The title compound is prepared essentially according to the method of the example above using 3-chlorobenzoyl chloride (13.15 g) instead of benzoyl chloride. Yield 16.37 g of pure product. Jul.p. 152-153 ° C (from ethanol).

Example 3 2- (3-Methoxyphenyl) -3-methyl-3H-naphtho [1,2-d] imidazole This compound was prepared according to the method of Example 1 using 3-nitroxybenzoyl chloride (13.75 g) instead of benzoyl chloride. Yield 12.57 g. Mp 138-139 ° C (from ethanol).

Example 3 3-Methyl-2- (3-pyridyl) -3H-naphtho [1,2-d] imidazole

The title compound is prepared according to the procedure described in Example 1 using isonicotinoyl chloride hydrochloride (1.3.25 g) instead of benzoyl chloride. Yield 5.72 g of pure compound. 3ul.o.

158-159 ° O (from ethanol).

16, <74460

Example 5 3-Methyl-2- (N-ethoxyphenyl) -3H-naphtho [1,2-d] imidazole A solution of 11.16 g (0.06 mol) of 2-methylamino-1-nitrosonaphthalene in 800 ml of toluene is hydrogenated. at room temperature and atmospheric pressure in the presence of 3 g of palladium-on-carbon catalyst. After 1 hour, the theoretical amount of hydrogen has been consumed, 9 ml (0.06 mol) of N-ethoxybenzaldehyde are added and the reaction mixture obtained is heated at reflux under an inert atmosphere for 2 hours. The water formed during the reaction is distilled off as a binary azeotrope with toluene and separated on a Dean-Stark apparatus. An additional 1.5 6 $ 5 palladium on carbon is then added and refluxed for an additional two hours. The hot solution is filtered, after which the filtrate is concentrated to dryness in vacuo to give a residue which is purified by crystallization from ethyl acetate. Yield 1 * +, 5 g (80%). Mp 138-139 ° C.

Examples 6 to 21

The following compounds are prepared by working according to the procedure described in the previous example, hydrogenating the starting N-methyl-1-nitrosonaphthaleneamine, condensing the obtained diamino compound with an appropriately selected aldehyde, and then dehydrating the imidazoline derivative thus formed.

6) 2- (N-methoxyphenyl) -3-methyl-3H-naphtho [1,2-d] imidazole, m.p. 132-13 ° + (from ethyl acetate) 7) 2- (3-chlorophenyl) -3-methyl-3H-naphtho [1,2-c] imidazole, m.p. 137-1.39 ° C (from ethyl acetate) 8) 3-methyl-2- (2-pyridyl) -3H-naphtho [1,2-d] imidazole hydrochloride, m.p. 231 ° C (dec.) (From ethyl acetate) 9) 3-methyl-2- (6-methyl-2-pyridyl) -3H-naphthoyl, β-c-imidazole hydrochloride, m.p. 262 ° C (dec.) (From ethanol) 10) 3-methyl-2- (3-pyridyl) -3H-naphtho [1,2-d] imidazole hydrochloride, m.p. 2-5 ° C (dec.) (From methanol) 11) 2- (2-furanyl) -3-methyl-3H-naphtho [1,2-d] imidazole hydrochloride, m.p. 2.3 DEG C. (dec.) (From isopropanol) 12) 3-methyl-2- (1H-pyrrol-2-yl) -3H-naphtho [1,2-d] imidazole, m.p. 283 ° O (from dioxane) 13) 3-methyl-2- (2-thienyl) -3H-naphtho [1,2-d] imidazole, m.p. 166-168 ° C (from ethyl acetate) 74460 17] Λ) N, N-dimethyl-1- (3-methyl-3H-naphtho] 1,2-dimidazol-2-yl) Benzeneamine, m.p. 136-138 ° C (from benzene) 15) 3-methyl-2-Q + - (1-methylethoxy) phenyl] -3H-naphtho] 1,2-d] imidazole, m.p. 1 H -1M-5 ° C (from ethyl ether) 16) 3-methyl-2- (4-methylphenyl) -3H-naphtho] 1,2-d] imidazole? mp 135-136 ° C (from diisopropyl ether) 17) N, N-diethyl (3-methyl-3H-naphtho [1,2-d] imidazol-2-yl) benzeneamine, m.p. 16-162 ° C (from ethyl acetate) 18) 2- (1,3-Benzodioxol-5-yl) -3-methyl-1H-naphtho [1,2-d] imidate sol, m.p. 200-201 ° C (from acetone) 19) * + - (3-methyl-3H-naphtho] 1,2-d] imidazol-2-yl) -2, N, N-trimethylbenzenamine, m.p. 11-18 ° C (from methyl tert-butyl ether)

-I

20) 3-methyl-2- (3-methyl-N-methoxyphenyl) -3H-naphtho-2-d] imidazole, m.p. 10 + - 105 ° C (from diisopropyl ether) 21) N -]] + - (3-methyl-3H-naphtho] 1,2-d] imidazol-2-yl) phenyl] acetamide, m.p. 271-272 ° C (from ethanol).

Example 22 1 + - (3-Methyl-3H-naphtho] -1,2-imidazol-2-yl) -benzeneamine The title compound is prepared by acid hydrolysis of the corresponding monoacetyl derivative. In particular, a solution of 5.7 g of the compound of Example 21 in 75 ml of 5% HCl is heated at reflux for about 1 hour under a stream of nitrogen. The solution is then treated with activated carbon and filtered under vacuum. The filtrate is basified by treatment with concentrated ammonium hydroxide, then cooled and the solid which precipitates is collected by filtration. Mp 250-252 ° C.

Example 23 N-methyl-1 + - (3-methyl-3H-naphtho] -1,2-imidazol-2-yl) -benzeneamine 5 g of n- [2- (3-methyl-3H-naphtho)] (2-d] Imidazol-2-yl) -phenyl] -acetamide prepared as described in Example 21 is dissolved in 80 ml of anhydrous dimethylformamide and added to the resulting solution cooled to 0-5 ° G. 0.69 g of $ 55 Naii gradually. After 1 hour, when the evolution of hydrogen gas ceases, 1 ml of methyl iodide dissolved in 20 ml of dimethylformamide is added dropwise and the reaction mixture is allowed to reach room temperature. The solution is then poured into 1 liter of water and stirred for about 20 18 74460 minutes; the precipitate which precipitates is collected by filtration and dried in vacuo to give * +, 53 g of a mixture of two products, one of which corresponds to the deacetylated product. This mixture is dissolved in 300 ml of methyl alcohol and 200 ml of 10% NaOH and boiled under reflux for 6 hours; then the methanol is distilled off at atmospheric pressure and the reaction mixture is cooled and diluted with water. The precipitate that forms is collected by filtration and crystallized from benzene to give 3.6 g of the title product, melting at 225-227 ° G.

Example 2 * + * + - (3-methyl-3H-naphtho [1,2-d] imidazol-2-yl) phenol This compound was prepared according to the procedure set forth in Example 5 using α-hydroxybenzaldehyde * + - ethoxybenzaldehyde. instead of -d. Melting point> 300 ° C (from acetic acid).

Example 25 3-Methyl-2- [1- (phenylmethoxy) phenyl] -3H-naphtho [1,2-d] imidazole 2.1 + 7 g of the * + - (3-methyl-3H-naphthoyl) obtained in the previous example (d-imidazol-2-yl) phenol, 3.79 g of benzyl chloride, 3.11 g of tributylbenzylammonium chloride, 150 ml of methylene chloride and 15 ml of 1N NaOH are poured into a 500 ml flask and the mixture is stirred vigorously at room temperature for about 6 hours. . After this time, the organic layer is separated, washed with $ 5 NaOH and water and dried over magnesium sulfate. Evaporation of the solvent gives a crude residue which is purified by column chromatography (cyclohexane: ethyl acetate 7: 3) to give 2.21 g (69%) of the title compound. Mp 1 + 8-1 + 9 ° C (from ethanol).

Example 26 * + - (3-Methyl-3H-naphtho-2-d- [imidazol-2-yl) phenol acetate

A solution of 5.0 g (0.02 moles) of the compound of Example 2 * + in 100 ml of anhydrous pyridine and 20 ml of acetic anhydride is heated at 60 ° C for three hours with stirring. The solvent is then boiled off and the residue obtained is dissolved in toluene. After evaporation, the residue is crystallized from ethanol to give 5.0 g of the title compound (87%). Mp 175-177 ° C.

Example 27 b- (3-Methyl-3H-naphtho [1,2-d] imidazol-2-yl) phenol propanoate This compound is prepared according to the procedure described in the example above using propionic anhydride instead of acetic anhydride. Yield 83%. Mp L65-L66 ° C.

19 Q 74460

Example 28 2- (2-Methoxyphenyl) -3-methyl-3H-naphtho [1,2-d] imidazole The title compound is prepared essentially according to the procedure described in Example 5 using 2-methoxybenzaldehyde instead of N-ethoxybenzaldehyde. Yield 82%. Mp 132-133 ° C.

Example 29 b- (3-Methyl-3H-naphtho-1,2-d] imidazol-2-yl) -phenoxy] -acetic acid ethyl ester 60 ml (0.06 mol) of 1N NaOH are added dropwise, over a period of two hours, to a vigorously stirred solution. containing 8.22 g (0.03 mol) of the compound of Example 2b, 0.35 g (0.03 mol) of benzyltributylammonium chloride and 10.0 ml (0.09 mol) of ethyl bromoacetate in 300 ml of methylene chloride . The reaction mixture is further stirred for two hours. 10.3 ml of ethyl bromoacetate and 60 ml of 1N NaOH are then added over a period of two hours with stirring. Stirring is continued for a further two hours and the addition of ethyl bromoacetate and NaOH is repeated under the same conditions. The unreacted starting material is recovered from the solid by filtration and purified by crystallization from dimethylformamide (3.95 g), while the organic layer is separated from the filtrate, washed with water and dried over HgSO 4. The solvent is then evaporated off and the residue is dissolved in 50 ml of isopropanol and diluted with diethyl ether to precipitate the catalyst used in the reaction, which is filtered off. Evaporation of the solvent gives 8.6 g of crude product, which is purified by column chromatography using cyclohexane containing increasing amounts of ethyl acetate up to 8: 2 as the elution system. Yield + 5%. Mp 103 “10 * + · ο0 (isopropanol).

Example 30 [+ (3-Methyl-3H-naphth, 2-d] imidazol-2-yl) -phenoxy] -acetic acid 3.99 g (0.011 mol) of the compound of the previous example, 20 ml of 10% NaOH and * + 0 ml of methanol is heated to reflux for about 30 minutes. The methanol is then boiled off, the mixture is cooled to 5 ° C and the pH is adjusted to 5 by adding glacial acetic acid. The solid which precipitates is collected by filtration and crystallized from ethanol. Yield 53% · M.p. 227 ° C.

Example 31 (3-Methyl-3H-naphthyl-1,2-dimethylzol-2-yl) -N, N, 2,6-tetramethyl-benzeneamine

The title compound is prepared essentially as described in Example k using 3,5-dimethyl-N-dimethylamino-20,74460-benzaldehyde instead of 2-ethoxybenzaldehyde. Purification of the crude product is carried out by triturating the residue with petroleum ether, filtering it and crystallizing the product obtained first from cyclohexane and then from ethanol / water. Yield * + 0 m.p. 136-137 ° C.

Example 32 3- (1-Methylethyl) -2- (N-methoxyphenyl) -3H-naphthyl-1,2-dimidazole In a 500 ml multi-necked flask equipped with a mechanical stirrer and a Dean-otark apparatus, heat the solution. with p 2 g (0.01 mol) of N- (1-methylethyl) naphthalenediamine (known from J. Org. Chem. 3Z (22), 3566 (1972)), 1.36 g (0.01 mol) of k —Methoxybenzaldehyde and 300 ml of toluene, at reflux temperature and under an argon atmosphere for 3 hours. 2 g of 5% nal-lithium on carbon are then added and the reaction mixture is heated at reflux for a further three hours. The catalyst is filtered off, the filtrate is evaporated to a small volume to give 2.86 g of crude product which is collected by filtration and purified by crystallization from ethyl acetate. The mother liquors, which are evaporated to dryness, give a further 1.7 g of product, which is chromatographed on a column of silica gel, eluting with benzene: ethyl acetate 95: 5. Overall, the yield is 57% -Sul.p. 162-163 ° C.

The title compound is also prepared according to the procedure described in Example 5, starting from N-isopropyl-1-nitroso-2-naphthaleneamine instead of N-methyl-1-nitroso-2-naphthaleneamine and using α-methoxybenzaldehyde instead of N-ethoxybenzaldehyde. Yield 60%. Mp 162-163 ° C (from ethyl acetate).

The starting N-isopropyl-1-nitroso-2-naphthaleneamine is prepared by reacting 1-nitroso-2-naphthol with isopropylamine according to the method described in J. Am. Chem. Soc. £ 0.2 * + 15 (19 ^ 8).

Example 33 3-Butyl-2- (N-methoxyphenyl) -3H-naphtho-1,2-dimidazole

The title compound is prepared essentially according to the procedure described in Example 5 starting from 2-butylamino-1-nitrosonaphthalene instead of 2-methylamino-1-nitrosonaphthalene and using N-methoxybenzaldehyde instead of U-ethoxybenzaldehyde. Yield 53% ·

Mp 99.5 to 100.5 ° C.

Example 3 * + 8-Methoxy-2- ('4-methoxyphenyl) -3-methyl-3H-naphtho [L, P-d] imidazole hydrochloride 74460 21

The title compound, such as the free base, is prepared essentially according to the procedure described in Example rj using 7-n-ethoxy-2-methylamino-1-nitrosonaphthalene instead of 2-methylamino-1-nitrosonaphthalene and U-methoxybenzaldehyde instead of N-ethoxybenzaldehyde. Addition of HCl to the diethyl ether solution of the free base precipitates the corresponding hydrochloride. Yield ä-0%. Mp 26 5 ° C dec. (Methanol). Example 35 7-Methoxy-2- (1H-methoxyphenyl) -3-methyl-3H-naphtho [2,2-d] imidazole hydrochloride

The title compound is prepared essentially according to the procedure described in the previous example starting from 6-methoxy-2-methylamino-1-nitrosonaphthalene instead of 7-methoxy-2-methylamino-1-nitrosonaphthalene. Yield $ 35. Mp Five ° C (methanol).

The starting 6-methoxy-2-methylamino-1-nitrosonaphthalene is prepared by adding 3.75 6 6-methoxy-1-nitroso-2-naphthol to a solution of 9.5 ml of $ 35 CH- .NHp In 15 ml of water cooled to about 10 ° C, the reaction mixture is heated in VO C for a few minutes and finally the precipitated solid is collected by cooling to room temperature.

Example 36 6-Chloro-7-methoxy-2- (methoxyphenyl) -3-methyl-TE-naphthyl, 10-dJ-imidazole

The title compound is prepared essentially according to the procedure described in Example f, starting from 5-chloro-6-methoxy-2-methylamino-1-nitrosonaphthalene instead of 2-methylamino-1-nitrosonaphthalene and using N-methoxybenzaldehyde instead of 1 + ethoxybenzaldehyde. Yield ^ 3%. Mp 2a-7-2a-80C (from ethanol).

The starting 5-chloro-6-methoxy-2-methylamino-1-nitrosonaphthalene is prepared by reacting methylamine with 1-chloro-6-methoxy-1-nitroso-2-naphthol according to the procedure described in the example above. in the second part. The latter compound, in turn, is prepared by nitration of 5-chloro-6-methoxy-2-naphthol obtained from (5-chloro-6-methoxy-2-naphthalonyl) -ethanone, which is a commercial product.

Example 37 3-Cyclohexyl-2- (* + - methoxyphenyl) -3H-naphth [1,2-d] midazole hydrochloride

The title compound is prepared essentially according to the procedure set forth in Example V + using 2-cyclohexylamine-1-nitrosonaphthalene instead of 7-methoxy-2-methylamino-1-nitrosonaphthalene.

22

Yield 76%. Sul. mp 238 ° C ha j. 74460 The starting 2-cyclohexylamine-1-nitrosonaphthalene was prepared by reacting 1-nitroso-2-naphthol with cyclohexylamine according to the procedure set forth in the second part of Example 35.

Example 38 3-Ethyl-2- (4-methoxyphenyl) -3H-naphtho, 2-dimidazole

The title compound is prepared according to the procedure described in Example 5 starting from 2-ethylamino-1-nitrosonaphthalene instead of 2-methylamino-1-nitrosonaphthalene and adding 4-methoxybenzaldehyde instead of 4-ethoxybenzaldehyde. Yield 81%. Mp 144-146 ° C (from ethyl acetate).

The starting 2-ethylamino-1-nitrosonaphthalene is prepared by reacting 1-nitroso-2-naphthol with ethylamine according to the procedure described in the second part of Example 35.

Claims (6)

23 PATENT CLAIMS 744 60 A process for the preparation of anti-infamatorially and antimicrobially effective 3 H-naphth, 2-d] imidazoles of formula (I) N = -.— AR, _ 1 N] <γνγ sr ai r2 ^^ wherein R is ( C 1-6 alkyl or (C 3-6) cycloalkyl and R 1 and R 7. independently of one another, hydrogen, halogen or (C 1-4) alkoxy and the symbol A represents pyridyl, furanyl, pyrrolyl or thienyl which are optionally substituted by (C 1-4) alkyl groups, or A represents a phenyl radical which is optionally substituted by substituted with 1 to 3 groups independently selected from halogen, (C 1-4 alkyl, (C 1-4) 1 coke, hydroxy, benzyloxy, (C 2-4) alkanoyloxy, carboxymethoxy, 1 [carbo (C 1-4) alkoxy] methoxy, methylenedioxy , amino, mono- or di (C 1-4) alkylamino, (C 2-4) alkanoylamino or benzoylamino, provided that when R represents methyl and and R 2 are both hydrogen, A cannot represent a 2-hydroxyphenyl group and further provided that that when R is simultaneously one of R 1 and R 2 is hydrogen and the other is methoxy, A cannot represent a 4-dimethylaminophenyl group, and for the preparation of these pharmaceutically acceptable salts, characterized in that a) N-substituted naphthalene-1,2-diamine of formula (II) wherein R, R 1 and R 2 are as defined above are condensed with an appropriately selected aldehyde of formula ACHO wherein A has the same meaning as above to give the corresponding imidazoline derivative 24 of formula (III) 74460 HN-i-A VAA IR (III) wherein R 1, R 2 and A have the same meaning as above, which in turn is converted to the final one of formula (I) b) N-substituted 1-nitroso-2-naphthalene amine derivative of formula (IV) with NO R 1 | NHR I || (IV) r 2 wherein R, R 1 and R 2 have the same meaning as above, is reduced to the corresponding N-substituted naphthalene-1,2-diamine of formula (II) above with hydrogen in the presence of a hydrogenation catalyst, and The compound of formula (II) is treated as in a) above to give a compound of formula (I), or c) the N-substituted naphthalene-1,2-diamine of formula (II) above is condensed with an acid derivative of formula is ACX, wherein A is the same as above and X is a chlorine-O 0 atom, a group -ORg in which R1 is the same radical -CA, a trifluoroacetyl, ethoxycarbonyl or alkylsulfonyl moiety, or a group -OR2, wherein R 1 is methyl or ethyl to form the corresponding monoacylated compound of formula (V) is NH 74460 25 RV \ ^ V "-CA Q Ί Ti 8 (V) wherein R, R 1, R 2 and A are as defined for above, which compound in turn is cyclized to give the final compound of formula (I), and for which process is further characterized in that in steps a), b) and c) (i), when a compound of formula (I) is obtained in which A is hydroxyphenyl radical, it can be converted into the corresponding compound of formula (I) wherein A is phenyl substituted with (C 1-4) alkoxy, benzyloxy11a, (C 2-4) alkanoyloxy 1a, carboxymethoxy or 1H-carbo (C 1-4) alkoxy] methoxy by reacting with suitable substances such as (C 1-4) alkyl or benzyl halides, tosylates or mesylates, () alkanoyl halides or anhydrides, α-haloacetic acid and its (C 1-4) alkyl esters, and (ii) when the formula ( A compound of formula (I) wherein A is phenyl substituted with a 1-canoylamino or benzoylamino group may be converted by acid hydrolysis to the corresponding compound of formula (I) wherein A is phenyl substituted with amino or may be converted to the corresponding compound of formula (I) (I) wherein A is phenyl which is subs substituted with mono- (C 1-4) alkylamino groups, by reaction with alkyl halides followed by alkaline hydrolysis, and · '. if desired, the resulting compound is converted into a pharmaceutically acceptable acid addition salt thereof. Process for the preparation of 2- (4-methoxyphenyl) -3- (1-methylethyl) -3H-naphth 1,2-dimidazole according to Claim 1, characterized in that N- (1-methyl) is used as starting material -ethyl) -naphthalenediamine and 4-methoxybenzaldehyde. Process for the preparation of 2- (4-methoxyphenyl) -3-methyl-3H-naphtho [1,2-d] imidazole according to Claim 1, characterized in that N-methyl is used as starting material -naphthalene-1,2-diamine and 4-methoxybenzaldehyde. Process for the preparation of 4- (3-methyl-3H-naphth, 2-dimethylazol-2-yl) -2, N, N-trimethylbenzeneamine according to Claim t, characterized in that the starting materials used are N-methylnaphthalene, t-2-diamine and 3-methyl-4- (N, N-dimethylamino) benzaldehyde. A process for the preparation of an anti-inflammatory and anti-microbial effect of 3 H-naphtha, 2-d] [imidazole derivative with the formula (I) N-1-A '' £ X7 " alkyl or () cycloalkyl and R 2 and R 2 are optionally substituted with halogen or (C 1 -C 4) alkoxy and symbols A is pyridyl, furanyl, pyrrolyl or thienyl, even if substituted with substituents ( C 1-4 alkyl, or A is a phenyl group, optionally substituted with 1-3 groups, optionally substituted with halogen, (C 1-4) alkyl, (C 1-4) alkoxy, hydroxy, benzyl- I "* + Y 1 "'oxy, (C 2-4) al canoyloxy, carboxymethoxy, β-carbo (C 1-4) alkoxymethoxy, methylenedioxy, amino, mono- or di (alkylamino), (C 2-4) alkanoylamino or benzoylamino no; under den förutsättningen , wherein R is methyl and R 2 and R 2 are hydrogen, A is the same as the 2-hydroxyphenyl group and the same conditions as the same, R is ethyl, but not R 1 and R 2 are used. den andra är a methoxy group; The same is preferred for the preparation of a pharmaceutically acceptable salt, which is described above, in which a) N-substituted naphthalene-1,2-diamine with formula (II) 74460 27 R "h2 nhr I / J. I (II) i vilken R, R1 and R2 is a solid which is condensed with a lamp to give an aldehyde with the formula ACHO, and which is used in the form of an imidazoline derivative with the formula (III) *. H '| N ~ AV / N v (111) I ii ^ RX · ^ R2 i are selected from R, R ^, R ^ och A and a single deck are present, each of which is then converted to a solution having the formula (I) in which - oxidation media or dehydration media, b) N-substituted 1-nitroso-2-naphthaleneamine derivatives of formula (IV) NO V JL NHR V \ A / ^ k (IV) - · and R, R, and R9 are selected from the group consisting of •, '2 In this case, the N-substituted naphthalene-1,2-diamine is treated with anhydrous formula (II) with the aid of a hydrogen and a catalytic catalyst and a compound of formula (I). I) a compound according to (a) overnight for a compound of formula (I), or c) an N-substituted naphthalene-1,2-diamine with an anhydrous formula (II) 74460 28 condenser with a displacement of formula ACX , i vilken A beteck- II 0 nar decamma som ovan och X X en en chloro, en grupp -ORg, i vilken R- är den samma radicalen -CA, en trifluoroacetyl-, ethoxycarbo- J II 0 nyl- or alkylsulfonyldel, eller the group -0R4> is selected from the group consisting of methyl or ethyl, for which the mono- and acyl derivatives of formula (V) nh2 r2 are selected from the group consisting of R, R1, R1 and A, each of which is cyclized to the above in the case of formulation (I); varvid förfarandet ytterligare kännetecknas av, att under a) b) och c) (i) dl det erhälles en förening med formula (I), i vilken A är en '... hydroxifenyl radi kai, kan den överföres account motsvarande förening' ' In formula (I), the phenyl is substituted with phenyl (C 1-4) alkoxy, benzyloxy, (C24) alkanoyloxy, carboxymethoxy or [carbo (_4) -ai coxy] methoxy, the genome being reacted with a warming agent (C (C4-4) -alkyl- or benzylhalogen, tosylater or mesylater, (C2-4) alkanoylhalogen or ell-anhydrider, and o (-halogenated) and (C 1-4) allyl esters; I), in which A is phenyl substituted with a amino acid or a benzoylamino group, the genome of which is hydrolysed by the addition of a compound of formula (I), and in which A is phenyl substituted by amino, or in the form of an ester in which a compound of formula (I) is selected from the group consisting of mono- (C 1-4) substituents of the same genome and the reaction The alkyl halide may be subjected to alkaline hydrolysis, and, in particular, may be treated as a pharmaceutical product.