Novel aroylpyrroles, their production and their use in immunologic therapy

Abstract

This invention relates to novel aroylated derivatives of pyrrole. More particularly it provides the novel naphthoyl derivatives of pyrrolyl-2-carboxylic acid having the general formula I: ##STR1## wherein: R.sub.1 is a lower alkyl radical, a phenyl radical or a hydrogen;X is a hydrogen, a hydroxy or a methylsulphinyl group;Y is a hydrogen or together with A' a double bond;A is a hydrogen or a hydroxy;A' is a hydrogen or together with Y a double bond;B is a hydrogen or a hydroxy;B' is a hydrogen or together with C a double bond;C is a hydrogen or together with B' a double bond;C' is a hydrogen, a hydroxy or a methylsulphinyl group; with the proviso that X, Y, A, A', B, B', C and C' are not simultaneously a hydrogen.The compounds according to this invention, may exist in the free acid form or as a salt.They found a use in human or veterinary medicine in the form of pharmaceutical compositions for preventing or treating the immunological diseases.

Description

PRIOR ART

The prior Art may best illustrated by the following references:

French Pat. No. 2.405.246 U.S. patent application Ser. No. 738,043, now U.S. Pat. No. 4,617,315.

PREFERRED EMBODIMENTS

This invention relates to novel aroylated derivatives of pyrrole. More particularly it relates to 4-aroylpyrrolyl-2-carboxylic acid.

This invention specifically provides novel naphthoyl derivatives of pyrrolyl-carboxylic acid having the general formula (I): ##STR2## wherein: R.sub.1 is a lower alkyl radical, a phenyl or a hydrogen;

X is hydrogen, a hydroxy or a methylsulphinyl group; Y is a hydrogen or with A' is a double bond; A is hydrogen or hydroxy; A' is hydrogen or together with Y is a double bond; B is hydrogen or hydroxy; B' is hydrogen or with C is a double bond; C is hydrogen or with B' is a double bond; C' is hydrogen, hydroxy or a methylsulphinyl group (CH.sub.3 SO); with the proviso that X, Y, A, A', B, B', C and C' are not simultaneously a hydrogen.

These compounds may be in the form of a free acid or in the form of an addition salt thereof as for example an alkali metal salt, an earth alkaline metal salt, an iron salt, an aluminum salt, a magnesium salt, an organic base addition salts as for example an alkylamine salt, a dialkylamine salt, an arylalkylamine salt, a tri-lower-alkylamine, a cyclanylamine, a basic amino-acid salt, an amino-alkanol salt, a cyclic base salt such as dihydropyridine, lutidine or collidine salt.

The compounds of general formula I in which X is a hydroxy or a methylsulphinyl group and/or wherein C' is a hydroxy or a methylsulphinyl group and C is a hydrogen have from 1 to 3 asymetric centers. They may therefore exist in the form of various diastereo-isomers which may be isolated by means of chemical, physical or enzymatic methods. The resulting diastereo-isomeric forms may be further be resolved into their optical isomers.

The diastereo-isomeric forms and the optical isomers thereof are part of this invention.

Depending on the meanings of the various substituents three distinct subgroups, equally interesting, may be evidenced:

(1) The 4-naphtoyl derivatives having the general formula I.sub.A : ##STR3## wherein: X is a methylsulphinyl group and C' is a hydrogen; or X is a hydrogen and C' is a methylsulphinyl group; A is a hydrogen or a hydroxy; and R.sub.1 has the previously-given meanings. (2) The dihydronaphthalene diols of the general formula I.sub.B : ##STR4## wherein: X is a hydroxy and A is a hydroxy; B and C' are both a hydrogen; or B and C' are both a hydroxy and X and A are both a hydrogen; and R.sub.1 has the above-given definitions. (3) The desalkylated derivatives of the general formula I.sub.C : ##STR5## wherein the naphthyl ring may further include a hydroxy or a methylsulphinyl substituent.

In each of these structures the naphthyl ring is bound to the carbonyl through the carbon-1 or the carbon-2.

The compounds of formula I and their base addition salts with a mineral or organic base are endowed with interesting pharmacological properties. They more particularly show immunological properties and precisely immuno-suppressive properties. Moreover some compounds and namely the (3-methylsulfonylnaphthoyl-1) derivative and the (3-hydroxy or 5-hydroxynaphthoyl-1)-pyrrolyl-2-carboxylic acids show depending on the doses either immuno-suppressive or immuno-stimulating properties.

Due to their low toxicity, they may found a use in human or veterinary therapy and more particularly as a medicine for the immunological disturbances.

As immuno-suppressive drugs they found a use in human or veterinary medicine as a treatment of auto-immune diseases such as erythematons lupus, rheumatoidal polyarthritis, insulino-dependant diabetes of the young, myopathias, and some renal diseases. They also are suitable for preventing or avoiding the phenomena of rejection after implantation of grafts or graft of tissues.

As an immuno-stimulating drug they found a use in human or veterinary medicine for the treatment of chronic diseases such as bronchitis or for the increase of phenomena of healing of the wounds.

For these purposes they are dispensed in the form of pharmaceutical compositions having as active ingredient at least a compound of general formula I or a mineral or organic base addition salt in conjunction or admixture with an inert non-toxic pharmaceutically-compatible vehicle or carrier.

The excipient or the vehicle are one of those suitable for administration through parenteral, digestive, rectal or topic routes of administration. It may be particularly cited the aqueous or saline solutions, the starches, the celluloses, the alkylcelluloses, carboxymethylcelluloses, carboxymethyl starches, earth alkaline metal phosphates or carbonates, magnesium phosphate, cacao butter or polyethyleneglycol stearates.

The pharmaceutical compositions according to this invention are manufactured in the form of uncoated or coated tablets, dragees, pills, capsules, soft capsules, drinkable solutions or suspensions, injectible solutions divided into ampuls, multidoses flasks, or auto-injectible syringes, suppositories, rectal capsules, creams or pressurized sprays for percumous applications.

The efficient dosology may vary within a broad range depending of the way of administration, the weight or age of the patient and on the therapeutic aim. As a general rule the unit dosology ranges from 25 to 1 1500 mg per unit dosage and the daily dosage range from 25 to 2 000 mg in the adult.

The pharmaceutical compositions according to this invention are prepared on an industrial scale according to the methods conventionally utilized in the pharmacotechny.

The compounds of general formula I and the base addition salts thereof are prepared by the known methods of the organic chemistry starting from aroylpyrrolyl-2-carboxylic acids of the general formula II: ##STR6## previously described in the French Pat. No. 2,405,246.

They may also be isolated in the biological fluids and particularly from the urine after administration of the said aroylpyrrolyl-2-carboxylic acids to animals and extraction using the usual physical methods.

The compounds of formula I after purification are defined by means of the most performing analytical date such as mass spectra.

BRIEF DESCRIPTION OF THE DRAWINGS

The mass spectra of certain compounds within the scope of the present invention are illustrated in the figures as follows:

FIG. I shows the mass spectra of:

a. N-methyl-4-(naphthoyl-1)-pyrrolyl-2-carboxylic acid. b. N-(naphthoyl-1)-pyrrolyl-2-carboxylic acid by synthesis. c. 4-(naphthoyl-1)-pyrrolyl-2-carboxylic acid obtained by biological extraction.

FIG. II shows the mass spectra of:

a. N-methyl-(5,6-dihydroxy-5,6-dihydronaphthoyl-1)pyrrolyl-2-carboxylic acid b. N-methyl-(3.4-dihydroxy-3.4-dihydronaphthoyl-1pyrrolyl-2-carboxylic acid.

FIG. III shows the mass spectra of:

a. N-methyl-4-(3-hydroxy-naphthoyl-1)-pyrrolyl-2-carboxylic acid obtained by extraction. b. N-methyl-4-(5-hydroxynaphthoyl-1)-pyrrolyl-2-carboxylic acid recovered by extraction.

FIG. IV shows the mass spectra of:

a. N-methyl-4-(3-methylsulphinylnaphthoyl-1)-pyrrolyl-2-carboxylic acid. b. N-methyl-4-(6-methylsulphinylnaphthoyl-1)-pyrrolyl-2-carboxylic acid.

FIG. V shows the coupling after successive irradiations at (8.46), (8.22), (8.01) ppm and interpretation of the aromatic moiety of the NMR spectrum of the (3-methylsulphinylnaphthoyl-1) derivative recovered by HPLC.

FIG. IV shows the coupling after successive irradiations at (8.46), (8.22), and (8.01) ppm and signification of the aromatic moiety of the RMN spectrum of N-methyl-4-(6-methylsulphinylnaphthoyl-1)-pyrrolyl-2-carboxylic acid.

The following examples are merely intended to illustrate the invention. They do not limit it in any manner.

EXAMPLE I

TABLE I______________________________________MAIN PEAKS OBTAINED FROM MASS SPECTRA OFNMETHYL-4(NAPHTHOYL-1)-PYRROLYL-2-CARBOXYLIC ACID TAKENAS REFERENCE COMPOUNDElectronicImpactWEIGHT percentage______________________________________ 279 ##STR7## 262 ##STR8## 234 ##STR9##218 10205 10190 10165 20 152 ##STR10##134 12 127 ##STR11## 108 ##STR12## 58 90______________________________________ TABLE II__________________________________________________________________________MEAN PEAKS OBTAINED FROM THE MASS SPECTRA OF THENDEMETHYL DERIVATIVE OBTAINED AFTER EXTRACTIONElectronic Impact Chemical Ionization__________________________________________________________________________4-(naphthoyl-1)-pyrrolyl-2-carboxylic acid265 64% - molecular peak 282 19% - molecular ion + NH.sub.4.sup.+246 22% - loss of water (-19) 279 11%230 5% - (-35) 266 100% - molecular ion + H.sup.+220 64% - loss of COOH 157204 4%190 18%165 15%155 ##STR13##138 ##STR14##127 46%120 100%After treatment with Diazomethane279 25% - molecular peak 297 10% - molecular ion + NH.sub.4.sup.+246 8% (-33) 294 18% - contamination of the234 5% previous one220 31% 280 100% - molecular ion + H.sup.+190 10%175 8%166 8%155 13%153 20%144 19%127 39%120 57%100 100%__________________________________________________________________________ TABLE III__________________________________________________________________________MEAN PEAKS OBTAINED FROM THE MASS SPECTRA OFSYNTHETIC NDEMETHYL DERIVATIVE4-(naphthoyl-1)-pyrrolyl-2-carboxylic acidElectronic Impact Chemical Ionization NH.sub.3__________________________________________________________________________265 57% molecular peak 266 100% molecular ion + H.sup.+246 23% loss of water (-19) 246 7% loss of water230 7% (-35) 220 28% loss of COOH220 75% loss of COOH204 5%190 16%165 6%155 3% ##STR15##138 8% ##STR16##127 24% naphthalene120 100% 95 28% 69 90%After treatment with Diazomethane ##STR17## 280 100% molecular ion + H.sup.+ 246 5% 220 22%__________________________________________________________________________

EXAMPLE II

Preparation and identification of N-methyl-4-(5.6-dihydroxy-5.6-dihydronaphthoyl-1)-pyrrolyl-2-carboxylic acid.

TABLE IV__________________________________________________________________________MAIN PEAKS OBTAINED FROM THE MASS SPECTRA OF THE(5.6-DIHYDROXY-5.6-DIHYDRONAPHTHOYL-1) DERIVATIVEi.e.Nmethyl-4-(5.6-dihydroxy-5.6-dihydronaphthoyl-1)pyrrolyl-2-carboxylic acidElectronic Impact Chemical ionization NH.sub.3__________________________________________________________________________313 10% molecular peak 331 6% molecular ion + NH.sub.4.sup.+295 6% loss of water 314 100% molecular ion + H.sup.+285 5% loss of -28 ? 296 6% loss of water269 12% loss of COOH 280 4% loss of oxygen (?)250 6% loss of COOH + H.sub.2 O 270 8% loss of COOH251 214 15%240 3% 154 7%222 6%206 2%184 25%152 30% ##STR18##115 30%115 30%108 40% 58 100% basic peakAfter treatment with Diazomethane327 65% Acid + CH.sub.3 = Methylester309 5% loss of water299 30%283 22%250 20%240 30%166 100% basic peak__________________________________________________________________________

EXAMPLE III

N-methyl-4-(3.4-dihydroxy-3.4-dihydronaphthoyl-1)-pyrrolyl-2-carboxylic acid.

TABLE V__________________________________________________________________________MAIN PEAKS OBTAINED FROM THE MASS SPECTRA OF THENMETHYL-4-(3.4-DIHYDROXY-3.4-DIHYDRONAPHTHOYL-1PYRROLYL-2-CARBOXYLIC DERIVATIVEElectronic Impact Chemical Ionization NH.sub.3__________________________________________________________________________313 15% molecular peak 314 32% molecular ion + H295 12% loss of water 296 65% loss of water279 5% loss of -34 280 8%269 7% loss of COOH 270 24%250 5% 252 100% basic peak234222206194170 8%5%2%8%2% 152 19% ##STR19##152 100% ##STR20##134 8%131 15%115 30%108 70%103 20% 58 40%After treatment with Diazomethane327 14% Acid + CH.sub.3Methylester309 16% loss of water250 16%166 100%152 10%__________________________________________________________________________

EXAMPLE IV

N-methyl-4-(3-hydroxy-naphthoyl-1)-pyrrolyl-2-carboxylic acid and N-methyl-4-(5-hydroxynaphthoyl-1)-pyrrolyl-2-carboxylic acid.

TABLE VI______________________________________MAIN PEAKS OBTAINED FROM THE MASS SPECTRAFROM N--METHYL-4-(3-HYDROXYNAPHTHOYL-1)-PYRROLYL-2-CARBOXYLIC ACIDOBTAINED BY EXTRACTIONElectronic Impact Chemical Ionization______________________________________No mass higher than 100 296 100%-molecular ion + H.sup.+ 252 60%-loss of COOHAfter treatment with Diazomethane323 54%-dimethylated 324 100%-dimethylated derivative derivative + H.sup.+306 6%-loss of 17292 6%-loss of OCH.sub.3264 63%-loss of COOCH.sub.3195 4%185 8%166 100%134 31%114 20%99 53%______________________________________ TABLE VII______________________________________MAIN PEAKS OBTAINED FROM THE MASS SPECTRAOF N--METHYL-4-(5-HYDROXYNAPHTHOYL-1)-PYRROLYL-2-CARBOXYLIC ACID RECOVEREDBY EXTRACTIONElectronic Impact Chemical Ionization______________________________________295 1,9%-molecular peak281 0,4%-loss of CH.sub.3279 1,2%-loss of oxygen278 0,6%-loss of water250 2,2%-loss of COOH234 0,8%-(compound 250 loss of oxygen)220 2,0%211 4,0%180 1,2%172 3,4%166 1,9%152 4,0%122 21%105 31%99 30%91 23%86 24%84 46%77 26%58 100%After treatment with Diazomethane23 16%-dimethylated 324 98%-dimethylated derivative derivative + H.sup.+309 48%-monomethylated 310 100%-monomethylated derivative derivative + H.sup.+292 16% 280 30% ?264 12%250 50%180 21%166 100%______________________________________

EXAMPLE V

N-methyl-4-(3-methylsulphinylnaphthoyl-1)-pyrrolyl-2-carboxylic acid and N-methyl-4-(6-methylsulphinylnaphthoyl-1)-pyrrolyl-2-carboxylic acid.

TABLE VIII__________________________________________________________________________MAIN PEAKS OBTAINED FROM THE MASS SPECTRA OFNMETHYL-4-(3-METHYLSULPHINYLNAPHTHOYL-1)-PYRROLYL-2-CARBOXYLICACID RECOVERED AFTER EXTRACTION BY HPLCElectronic Impact Chemical Ionization NH.sub.3__________________________________________________________________________341 10% molecular peak 359 15% molecular ion + NH.sub.4.sup.+325 41% loss of oxygen 342 100% molecular ion + H.sup.+297 7% loss of COOH 326 30% loss of oxygen281 38% 298 10% loss of COOH211 11% 282 10% (298 - oxygen)205 7% 267 4% (298 - methoxy)167 26% 236 3%152 100% ##STR21## 223205191152 4%2%6%6% (naphthalene 30 SOCH.sub.3)129 34%108 79% 91 36%After treatment with Diazomethane355 12% molecular peak 356 100% molecular ion + H.sup.+340 12% loss of CH.sub.3 342 70% loss of CH.sub.3324 1% loss of oxygen and CH.sub.3 340 80% loss of oxygen308 1% 326 20% loss of oxygen and CH.sub.3296 1% (peak 340 - COOH) 324 10% loss of two oxygens282 1% 298 10%223 2% 294 15% (loss of SOCH.sub.3 ?)166 30% 282 8%163 2% 191 6%113 40% 155 20%104 25% 83 30% 59 100%__________________________________________________________________________ TABLE IX__________________________________________________________________________MAIN PEAKS OBTAINED FROM THE MASS SPECTRA OF(6-METHYLSULPHINYLNAPHTHOYL-1)-NMETHYL-PYRROLYL-2-CARBOXYLIC ACIDElectronic Impact Chemical Ionization__________________________________________________________________________341 7% molecular peak 359 2% molecular ions + NH.sub.4.sup.+325 12% loss of an oxygen 342 100% molecular ion + H.sup.+281 16% (peak 325 - loss of COOH) 326 7% (loss of CH.sub.3)267 5% (peak 281 - loss of CH.sub.3) 298 6% (loss of COOH)152 95% ##STR22## 282 6% (peak 298 - loss of an oxygen)129 50% 267 12% (peak 298 - loss of OCH.sub.3)108 41% 223 6%105 100% 205 2% 191 5% (naphthalene - SOCH.sub.3 ?) 152 3%After treatment with Diazomethane355 2% molecular peak 373 7% molecular ion + NH.sub.4.sup.+340 3% (loss of CH.sub.3) 356 100% molecular ion + H.sup.+162 1% 340 35% (loss of an oxygen)132 8% 294 3% (loss of two oxygens)113 20% 282 3% (loss of SOCH.sub.3 ?) 83 15% 261 2% 71 100% 167 1% 70 95% 155 6%__________________________________________________________________________

EXAMPLE VI

Study of the compounds of this invention as immuno-suppressive agents

Azathioprin and N-methyl-4-(naphthoyl-1)-pyrrolyl-2-carboxylic acid have been selected as reference products.

(A) Action of the compounds according to this invention "in vitro" in the test of Rosettes

This study has been carried out on blood red cells of sheep contacted with spleen cells of mice of the strain C.sub.57 BL/6J. The modulation of the appearance of rosettes by the compounds according to this invention in comparison with that produced by Azathioprin, has given the following results.

1. Azathioprin inhibits the formation of rosettes at concentrations ranging from 1 to 10 .mu.g/ml. 2. N-methyl-4-(naphthoyl-1)-pyrrolyl-2-carboxylic acid inhibits the formation of rosettes in about the same percentages at concentrations also ranging from 1 to 10 .mu.g/ml. 3. 4-(naphthoyl-1)-pyrrolyl-2-carboxylic acid has an inhibition action of about the same order than that of the N-methylated derivative. 4. N-methyl-4-(5-hydroxylnaphthoyl-1)pyrrolyl-2-carboxylic acid is also an inhibitor to a similar degree and further possesses an immuno-stimulating activity of low doses. 5. N-methyl-4-(5.6-dihydroxy-5.6-dihydronaphthoyl-1)-pyrrolyl-2-carboxylic acid and N-methyl-4-(3-methylsulphinylnaphthoyl-1)-pyrrolyl-2-carboxylic acid have an inhibitory action similar to that of N-methyl-4-(naphthoyl-1)-pyrrolyl-2-carboxylic acid. 6. N-methyl-4-(3-hydroxynaphthoyl-1)-pyrrolyl-2-carboxylic acid has a mixed immuno-stimulating activity at concentrations ranging from 1 to 10 .mu.g/ml.

Conclusively the derivatives of N-methyl-4-(naphthoyl-1)-pyrrolyl-2-carboxylic acid in nitro modulates the formation of rosettes at nearly the effective concentrations of Azathioprin. The N-methyl-4-(3-hydroxynaphthoyl-1)-pyrrolyl-2-carboxylic derivative further shows the particular property to stimulate the formation of rosettes.

(B) Study of the activity of the compounds according to this invention in the test of lymphoblastic conversion

In the test of lymphoblastic conversion these compounds show an antimitotic activity at doses ranging from 5 to 50 .mu.g/ml. For some compounds such as the 3-methylsulphinyl- and the N-demethyl derivative, it may be noticed a stimulating activity at low doses as well as opposite Concanavalin A as opposite LPS (Lipopolysaccharids of Escherichia Coli). The evidencing of an immuno-stimulating activity for some of the compounds according to this invention may open the way to another therapeutic field.

Claims

1. The naphthoyl derivatives of pyrrolyl-carboxylic acid selected from the group consisting of:

(a) an acid derivative of the formula ##STR23## wherein: X is hydrogen, hydroxy or methylsulphinyl

Y is hydrogen, or together with A' forms a double bond;

A is hydrogen, or hydroxy;

A' is hydrogen or together with Y forms a double bond;

B is hydrogen or hydroxy;

B' is hydrogen or together with C forms a double bond;

C is hydrogen, or together with B' forms a double bond;

C' is hydrogen, hydroxy or methylsulphinyl with the proviso that at least one member of the group X, A, B, and

C' is other than hydrogen and one member only of the group X, and C' is methylsulfinyl or hydroxy; and

(b) the base addition of salts thereof with a therapeutically compatible mineral or organic base.

2. A compound according to claim 1 having the formula 1.sub.A : ##STR24## wherein X is methylsulphinyl group and C' is hydrogen;

or X is hydrogen and C' is methylsulphinyl and

A is hydrogen or hydroxy.

3. A compound according to claim 1 selected from the group consisting of:

(a) 5-6 dihydrodiols of the formula ##STR25## (b) and the 3,4 dihydrodiols of the formula ##STR26##

4. A compound according to claim 1 namely N-methyl-4-(3,4-dihydroxy-3,4,-dihydronaphthoyl-1)-pyrrolyl-2-carboxylic acid.

5. A compound according to claim 1 namely N-methyl-4-(5,6-dihydroxy-5,6-dihydronaphthoyl-1)-pyrrolyl-2-carboxylic acid.

6. A compound of claim 1 namely N-methyl-4-(6-methylsulfinyl naphtholyl-1)-pyrrolyl-2-carboxylic acid.

7. A compound of claim 1 namely N-methyl-4-(3-methylsulfinyl naphtholyl-1)-pyrrolyl-2-carboxylic acid.