CS200232B2

Process for preparing 4-substituted imidazo 1,2-a-quinoxalines

Abstract

A 1-(2-acylaminophenyl)imidazole of formula: <IMAGE> wherein R2 is hydrogen or a radical bonded to the nitrogen by a carbon to nitrogen linkage and selected from the group consisting of aliphatic, cycloaliphatic, phenyl, substituted phenyl, fused bicyclic aryl, and monocyclic aryl substituted aliphatic groups.

CS200232B2, drawing sheet 1 — Sheet 1 of 168

Term

No projected expiry on record.

7 claims: 1 independent, 6 dependent

1
PŘEDMĚT VYNÁLEZU 1. Způsob výroby 4-substituovaných imidazo [1,2-aJ chínoxalinů obecného vzorce I (I) ve kterém ·
2
2 5 2 X představuje zbytek vzorce -R' nebo -NHR , v nichž Ri představuje alkylovou skupinu s 1 až 17 atomy uhlíku, rozvětvenou isoalkylovou skupinu se 4 až 7 atomy uhlíku, přímou nenasycenou alkenylovou skupinu se 4 až 17 atomy uhlíku, obsahující 1 až 4 dvojné vazby, cykloalkylovou skupinu se 4 až 6 atomy uhlíku, 'trifluormethylovou skupinu, fenoxymethylovou skupinu, alkoxyalkylovou skupinu, v níž jednotlivé alkylové části obsahují vždy 1 až 4 atomy uhlíku, fenylovou skupinu, popřípadě substituovanou jedním až třemi substituenty vybranými ze skupiny zahrnující methylovou skupinu, trifluormethylovou skupinu, terc.butylovou skupinu, fenylovou skupinu, nitroskupinu, kyanoskupinu, atomy halogenů a methoxyskupinu, dále znamená naftylovou skupinu, benzylovou skupinu, alfa-fenylpropylovou skupinu nebo styrylovou skupinu a о R znamená alkylovou skupinu se 3 až 4 atomy uhlíku, cykloalkylovou skupinu se 4 až 6 atomy uhlíku, fenylovou skupinu, popřípadě substituovanou jedním až třemi substituenty vybranými ze skupiny zahrnující alkylová skupiny s 1 až 4 atomy uhlíku, atorný halogenů, alkoxyskupiny s 1 až 4 atomy uhlíku, alkylthioskupiny s 1 až 4 atomy uhlíku, fenoxyskupinu, nitroskupinu, trifluormethylovou skupinu a kyanoskupinu, nebo znamená naftylovou skupinu, vyznačující se tím, že se 1-(2-acylaminofenyl)imidazol obecného vzorce II ve kterém X má shora uvedený význam, cyklizuje působením oxychloridu fosforečného. 2. Způsob podle bodu 1, vyznačující se tím, Že se jako výchozí látka použije sloučenina shora uvedeného obecného vzorce II, ve kterém X^ představuje výše definovaný zbytek r\
3
Způsob podle bodu 1 nebo 2, vyznačující se tím, že se jako výchozí látka po- 2 5 užije sloučenina shora uvedeného obecného vzorce II,.ve kterém X představuje zbytek R znamenající alkylovou skupinu s 1 až 17 atomy uhlíku, rozvětvenou isoalkylovou skupinu se 4 až 7 atomy uhlíku, přímou nenasycenou alkenylovou skupinu se 4 až 17 atomy uhlíku, obsahující 1 až 4 dvojné vazby, trifluormethylovou skupinu, fenoxymethylovou skupinu nebo alkoxyalkylovou skupinu,v níž jednotlivé alkylové části obsahují vždy 1 až 4 atomy uhlíku.
4
Způsob podle bodu 1 nebo 2, vyznačující se tím, Že se jako výchozí látka použije 2 5 sloučenina shora uvedeného obecného vzorce II, ve kterém X představuje zbytek R znamenající alkylovou skupinu obsahující 3 až 6 atomů uhlíku, rozvětvenou isoalkylovou skupinu se 4 až 6 atomy uhlíku nebo alkenylovou skupinu se 4 až 6 atomy uhlíku.
5
Způsob, podle bodu 1 nebo 2, vyznačující se tím, že se jako výchozí látka použije 2 5 sloučenina shora uvedeného obecného vzorce II, ve kterém X představuje zbytek R znamenající fenylovou skupinu substituovanou jedním až třemi substituenty vybranými ze skupiny zahrnující methylovou skupinu, trifluormethylovou skupinu, terč.butylovou skupinu, fenylovou skupinu, nitroskupinu, kyanoskupinu, atomy halogenů a methoxyskupinu.
6
Způsob podle bodu 1, vyznačující se tím, že se jako výchozí látka použije sloučenina shora uvedeného obecného vzorce II, ve kterém představuje zbytek -NHR 2 , kde R^ má význam jako v bodu 1·
7
Způsob podle bodu 1 nebo 6, vyznačující se tím, že se jako výchozí látka použije sloučenina shora uvedeného obecného vzorce II, ve kterém X^ představuje zbytek -NHR 2 , kde

Independent claims7

2,224 paragraphs in 60 sections, as filed

INynález se tyká urwhosetých? substituted ^ imMazoO,2-e3 chinoxalinat azpimpressu jejich production. Furthermore, the invention describes certain 1- (2-acylaminophenyl) -iniidazoles, which are additionally useful as intermediates for the preparation of 4-substituted imidazo [1,2-e] quinoxalines. The above compounds are useful for a number of purposes, which will be described in more detail below. Some of these are useful as immunosuppressants, others are useful as anti-inflammatory agents or exhibit antifungal activity. In addition, some of the compounds exhibit two or all three types of these effects.

The 4-substituted imidazo [1,2-a] quinoxalines within the scope of the invention can be described by the formula (I)

(I) in which

X2 represents a radical of the formula -R5 or -NHR3 *, in which r5 C 1 -C 17 alkyl, branched C 4 -C 7 branched alkyl, C 4 -C 17 straight-chain unsaturated alkenyl, C 4 -C 6 cycloalkyl, trifluoromethyl , a phenoxymethyl group, an alkoxyalkyl group in which each alkyl moiety contains from 1 to 4 carbon atoms, a phenyl group, a pin, optionally substituted with one to three substituents selected from the group consisting of methyl, trifluoromethyl, tert-butyl, phenyl, nitro, cyano, halogen and methoxy, and further represents naphthyl, benzyl, alpha-phenylpropyl or styryl, and

R2 means aalkylC 3 -C 4 carbon atom, cykloalkylovou skupandnu C 4 -C 6 -phenyl; three substituents selected from the group consisting of C 1 -C 4 alkyl, halogen atoms, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, phenoxy, nitro, trifluoromethyl and cyano, or naphthyl.

Do. pharmaceutically acceptable salts thereof.

In accordance with the invention, the compounds of formula (I) above may be prepared by heating the corresponding 1- (2-acylaminophenyl) imidazole to reflux in the presence of a cyclizing effective amount of a cyclizing agent such as polyphosphoric acid or phosphorus oxychloride and the like. during cyclization.

The starting 1- (2-acylaminophenyl) imidazoles which can be used in the process according to the invention can be described by the general formula II

wherein X is as defined above.

The reaction according to the invention can be described by the following reaction scheme:

The reaction according to the above scheme is preferably carried out in the presence of an excess of an amine-type organic solvent. A wide variety of solvents may be used, including pyridine, 2,6-dimethylpyridine, Ν, Ν-dimethylaniline, trimethylamine, N-methylmorpholine and the like. The preferred organic solvent is pyridine.

The amount of phosphorus oxychloride used for the reaction may vary somewhat. Generally, phosphorus oxychloride is used in an amount of about 0.5 mol to about 6 mol, preferably 0.5 mol to 2 mol, for each mol of the compound of formula (II).E

The desired product of formula (I) may be isolated from the reaction mixture by any conventional method. The reaction time depends inter alia on the nature of the reaction components and on the molar amounts of the reaction components used. Generally, the reaction time ranges from about 30 to 20 minutes. , '

The reaction temperature of the process according to the invention also varies depending on the nature of the reaction components, the solvent used and other factors. Usually a temperature corresponding to the boiling point of the reaction mixture at reflux temperature is used, which is at 0 ° Cbinykle pohybuje zhrubaod 95 ° C d195 ° C.

The process for preparing 1- (2-acylaminophenyl) imidazoles (compounds of formula II) depends on the type of compound produced. For example, to prepare compounds of formula III

(III) in which r 'is as defined above, 1- (2-aminophenyl) imidazole is reacted with a halide of the appropriate acid, for example an acid chloride. ·t

This reaction can be described by the following reaction scheme:

in himof R ^ mand withhor as defined above.

The reaction is usually carried out using an equimolar amount of the appropriate acid chloride and in the presence of an excess of solvent (e.g. pyridine) at reflux.

Phenylureylene-type compounds, for example compounds of formula V

wherein R 'is as defined above, are prepared by reacting an aminophenylimidazole with the appropriate isocyanate.

This reaction can be described by the following reaction scheme:

(IV) (V) wherein R is as defined above.

This reaction is preferably carried out in the presence of a solvent at the temperature of the steam bath. A typical solvent used is toluene and the reactants are usually used in equimolar amounts.

The products obtained by the latter two reactions can be isolated by standard methods. techniques known to those skilled in the art.

Preparation of 1- (2-acylaminophenyl) imidazoles ·

The 1- (2-acylaminophenyl) imidazoles of the invention are prepared by the general procedures described above. The following Tables I to IV show for each compound the respective process for its preparation as well as its physicochemical properties. Melting points were determined in a capillary using a Mel-Temp melting point apparatus and are not corrected. Ultraviolet spectra were measured in ethanol on a Beckman UV Acta III or Beckman DBG instrument. 1- (2-aminophenyl) imidazole was prepared according to the procedure described by AF Pozharsky, AM Siminov and LM Sitkin in Chim. Geterot. Soedin., 1916 (1069) [Chem. Absti., 22, 11427 (1970) J.

Except for the notes in Tables I and II, amides are prepared by reacting equimolar amounts of the appropriate acid chloride and 1- (2-aminophenyl) imidazole in the presence of excess pyridine on a steam bath for 45 minutes. The reaction mixture is then added to ice-water with stirring and the crude product is isolated by one of the following methods:

Method A:

When a solid product is obtained, it crystallizes directly from the solvent shown in the table.

Method B

When an oily product is obtained, it is dissolved in as little chloroform as possible and the solution is applied to an alumina column, the amount of alumina being about 20 times the weight of the crude product. The column is eluted with chloroform. After evaporation of the chloroform, the product was crystallized from the solvent indicated in the table.

Method C

If, after stirring in ice-water, a solution is obtained, the azeotropic mixture of pyridine and water is distilled off until a crude product precipitates and is then worked up as described above for Method B.

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The various compounds of the invention exhibit antifungal and anti-yeast activity. For example, it has been found that said compounds are effective against such organisms as Candida albicans (ATCC No. 10,231), Candida tropicalis, Aspergillus niger (ATCC No. 16,404), Trichophyton mentagrophytes (ATCC No. 8,757), and 9'129), Trichophyton rubrum (ATCC Nos. 10,218 and 14,001) and Trichiphyton ajelloi.

The antifungal activity of the compounds of the invention is indicative of their utility against dermatomycoses such as tinea capitis. tinea'favosa, tinea 'berbae, tinea corporis, tinea impricata, - tinea cruris, tinea pedis, tinea manus, tinea unquium and various types of candidiasis such as glositis,' stomatitis, chelitis, pearl, vaginitis and balanitis. '

When used as antifungal drugs, the compounds of the invention combine. usually with a suitable pharmaceutical carrier. These antifungal compositions may take the form of solutions, lotions, creams, ointments, and the like. The antifungal agent of the present invention may be within certain limits, but is typically about 0.5 to 10.0% by weight based on the total weight. composition · ^

The antifungal activity values of a number of compounds within the scope of the invention are shown in Table IX below. - These values were determined by the dilution method on-. agar as described in Chapters 2. and 3 publications Methods in Microbiology, Vol. - 73, editors JR Norris and DW Ribbons, Academic Press, New York, - 1972.

Table IX antifungal activity (concentration in ppm inhibiting growth of different fungi and yeast species)

<td>Compound No.</td><td>C. albicans</td><td>C. , -tropicalis</td><td>AND. Niger</td><td>T. ajelloi</td><td>T. mentagrophytes</td><td>T. rubrum</td>

<td colspan="2"> 200232</td><td rowspan="2">C. tropicalis</td><td colspan="4"> 36</td>

<td>Compound No.</td><td>C. albicans</td><td>AND. Niger</td><td>T. ajelloi</td><td>T. mentagrophytes</td><td>T. rubrum</td>

<td>It was</td><td colspan="3">found that a number of compounds falling within</td><td colspan="3">within the scope of the invention is immunosuppressive</td>

<td>efficiency.</td><td>From tested</td><td>compounds belong</td><td>most k</td><td colspan="3">type 4-substituted imidazofl, 2-a] -</td>

of the quinoxalines corresponding to the above general formula I, but the two compounds belong to the 1- (2-acylaminophenyl) imidazole type corresponding to the above. of the above formula II. In view of this activity, the compounds are suitable for use in the treatment of those diseases which can be favorably influenced by the administration of immunosuppressive agents. These conditions include serum glomerulonephritis. disease, organ transplantation, rheumatoid arthritis, systemic lupus erythematosis, ulcerative colitis, chronic active hepatitis, multiple sclerosis, heterogeneous and homogeneous burns in burns, psoriatic arthritis, urticaria, respiratory allergies, ie asthma and hernia, sclerosis, sclerosis, sclerosis, sclerosis, sclerosis , psoriasis and contact dermatitis (including the response to sumac poison).

The dosage levels for the administration of the immunosuppressive agents of the present invention vary depending on the compound to be administered, but generally roughly corresponds to the dosage used with prior art immunosuppressive agents. In most cases, oral or intravenous administration of the immunopressants of the present invention ranges from about 0.1 mg to 15 mg / kg body weight per day. When using another route of administration, such as depot injections, implants and the like, the dosage may be substantially higher, i.e. up to about 100 mg / kg body weight. in a single injection.

- 200232 ι

The immunosuppressive activity of the compounds of the invention is determined by the mouse haemolysin assay and the delayed hypersensitivity assay. The hemolysin assay described in Methods of Immunology, red, DH Campbell et al., WA Bejnamin, New York 1963, p.1 is used.72 andof 1 * 75, I eatof se zsištuje tissueová odpovéd or creation protilátek. pIn a delayed hypersensitivity test, the effect of the test compound on the ability of the test mouse to produce a cell-mediated immunological response to the Mycobacterium tuberculosis H37Ra antigen is examined. The mouse is sensitized to antigen by subcutaneous administration to the root of the tail. The onset of delayed hypersensitivity can be determined at any time beginning on the sixth day after sensitization, but is usually determined on the ninth. day as follows:.

Purified protein derivative (tuberculin) is injected into the right hind leg of the test animal, while physiological saline is injected into the left hind leg (control). After 24 hours, the volumes of both limbs are measured and the significant increase in right hind limb volume is taken as a measure of the effect on delayed-hypersensitivity.

The results of these experiments are summarized in the following Table X. The expression HL (Εϋ ^ θ) mg / kg, sc expresses the number of milligrams (per kilogram of body weight) of the subcutaneously administered test compound required to reduce antibody efficacy by 50% compared to control experiment. In this case, the lower the level of HL (ED?), The more effective the immunosuppressant.

The DHS (EDgg) mg / kg, sc · value reported in the third column of the table represents the efficacy of the test compound to suppress edema accompanying the cell-mediated immunological response. This value represents the number of milligrams of subcutaneously administered test compound per kilogram of body weight needed to suppress the cell-mediated immunological response edema by 60% compared to the control. Here again, the lower the DHS value (ED50), the more potent the immunosuppressant for the cell-mediated immunological response is.

Table X Compound no.

hb (ED50mg / kg, sc

DHSCED 60 mg / kg, sc

<td>compound no.</td><td>hl (ed50mg / kg, sc</td><td>DHS (ED6qmg / kg, sc</td>

Legend: a value> 50 indicates that more than 50 mg / kg of the test compound is required to reduce the efficacy of tissue antibodies by 50% or to suppress the edema of the cell-mediated immunological response by 60%. Because these values are higher than interesting for clinical practice, no further testing is performed with these compounds.

A number of compounds within the scope of the invention exhibit anti-inflammatory properties of the non-steroidal type. In general, they appear to be the 4-substituted imidazo 1,2- and quinoxalines of the above formula I and the 1- (2-acylaminophenyl) imidazoles of the formula II. Because of this property, the compounds are suitable for use in the treatment of those diseases which are known to be beneficial in the administration of non-steroidal anti-inflammatory drugs. Such conditions include, for example, ichthyosis, psoriasis, alopecia, atypical eczema, and the like.

The dosage levels of the anti-inflammatory compounds of the invention may vary somewhat depending on the compound, the disease being treated and the mode of administration. In general, for topical application, the active ingredient is dispersed in a pharmaceutical carrier suitable for topical application. In these compositions, the active compound content of the invention ranges from about 0.5 to 15.0% by weight, based on the total weight of the composition.

The anti-inflammatory active compounds of the invention may also be administered orally, intravenously, subcutaneously, intramuscularly or intradermally. In these cases, the daily dose of the anti-inflammatory active compound of the invention ranges from 0.5 to 20 mg / kg body weight.

Anti-inflammatory activity · Representative 1 The compounds of the invention are examined by assay. 'edema on the paw of the rat, both when local. administration (see Table XI) and oral administration (see Table XII). For oral administration, the procedure described by CA Winter, EA Risley and GW Nuss, Proc. Soc. Exp. · Biol., Med. 111, 544 (1962), which is performed 4 hours after administration of the test compound. For topical application, tests are performed similarly except that the irritant (carrageenin) and test compound are injected simultaneously at time 0.

The following Tables XI and XII show anti-inflammatory activity values as a percentage of the difference in edema volume or edema compared to the control. These tables also provide, in numerous cases, the results obtained with different doses of one and the same compound.

Table

XI test for rat paw edema when administered topically (injected directly into paw) difference in% versus control dose

Compound No.

117

110

122

140

Table

XII test for rat paw edema when administered orally

<td>compound no.</td><td colspan="2">difference in% versus control dose</td>

<td>Indomethacin</td><td> -65</td>

<td>Phenylbutazone</td><td> -76</td>

<td>Aspirin</td><td> -57</td>

<td>compound</td><td colspan="2">% difference from control</td>

<td>C.</td><td>trying to</td><td>applicationdoses</td>

SUBJECT OF THE INVENTION

Contents60

54 members in 19 offices

This recordMember, by publication datePriority claim9 more offices are in the list below

Priority claims3

Priority claims
Document	Office	Kind	Date
75764077	United States of America	A	1977-01-07
77757640	–	–	–
US19770757640	–	–	–

Members54

Family members, oldest first
Document	Office	Kind
BE862608A	Belgium	A	1978-07-03
IE780037L	Ireland	L	1978-07-07
IE810213L	Ireland	L	1978-07-07
DK4278A	Denmark	A	1978-07-08
FI780023A	Finland	A	1978-07-08
FI780023A7	Finland	A7	1978-07-08
SE7800138L	Sweden	L	1978-07-08
NL7800114A	Netherlands (Kingdom of the)	A	1978-07-11
DE2800480A1	Germany	A1	1978-07-13
JPS5387398A	Japan	A	1978-08-01
FR2376858A1	France	A1	1978-08-04
LU78813A1	Luxembourg	A1	1978-09-18
ZA7827B	South Africa	B	1979-01-31
US4160097A	United States of America	A	1979-07-03
AU3233178A	Australia	A	1979-07-19
US4172947A	United States of America	A	1979-10-30
US4191766A	United States of America	A	1980-03-04
US4191767A	United States of America	A	1980-03-04
US4197403A	United States of America	A	1980-04-08
US4198508A	United States of America	A	1980-04-15
US4200750A	United States of America	A	1980-04-29
CS200232B2This record	Czechoslovakia (until 1993)	B2	1980-08-29
US4225724A	United States of America	A	1980-09-30
US4229452A	United States of America	A	1980-10-21
FR2376858B1	France	B1	1980-10-24
GB1579498A	United Kingdom	A	1980-11-19
GB1579499A	United Kingdom	A	1980-11-19
US4236015A	United States of America	A	1980-11-25
FI821308L	Finland	L	1982-04-14
AU521807B2	Australia	B2	1982-04-29
SE8300945D0	Sweden	D0	1983-02-21
SE8300945L	Sweden	L	1983-02-21
IE46191B1	Ireland	B1	1983-03-23
IE46192B1	Ireland	B1	1983-03-23
CH636102A5	Switzerland	A5	1983-05-13
CA1149385A	Canada	A	1983-07-05
FI64374B	Finland	B	1983-07-29
FI64375B	Finland	B	1983-07-29
FI64374C	Finland	C	1983-11-10
FI64375C	Finland	C	1983-11-10
CH640229A5	Switzerland	A5	1983-12-30
GR73168B	Greece	B	1984-02-14
CA1164877A	Canada	A	1984-04-03
SE436359B	Sweden	B	1984-12-03
JPS61171470A	Japan	A	1986-08-02
JPS6259110B2	Japan	B2	1987-12-09
JPH0130825B2	Japan	B2	1989-06-22
SE460477B	Sweden	B	1989-10-16
DK157024B	Denmark	B	1989-10-30
DK157024C	Denmark	C	1990-04-02
DE2858766C2	Germany	C2	1990-04-05
DE2800480C2	Germany	C2	1990-04-12
YU2178A	Yugoslavia, later Serbia and Montenegro (until 2006)	A	1990-04-30
YU44663B	Yugoslavia, later Serbia and Montenegro (until 2006)	B	1990-12-31

Abstract

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SUBJECT OF THE INVENTION

Priority claims3

Members54

Numbers

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