IE58268B1 - Novel Aroylpyrroles, their production and their use in immunologic therapy - Google Patents

Description

This invention relates to novel aroylated derivatives of pyrrole 5 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): wherein: R^ 1s the methyl radical, the phenyl^or a hydrogen; X is hydrogen, a hydroxy or a methylsulphinyl group; Y is a hydrogen or with A1 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 1s a double bond; C 1s hydrogen or with B1 is a double bond; C' is hydrogen, hydroxy or a methyl sul ph inyl group (CH-jSO); with the proviso that X, A, B, and C0 are not simultaneously a hydrogen when together with Y 13 a double bond.

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 aluminium salt, a magnesium salt, an organic base addition salt as for example an alkylamine salt, a dialkylamine salt, an arylalkylamine salt, a tri-lower-alkylamine, a cyclany1amine, 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 methyl sul ph inyl group and/or wherein C' 1s a hydroxy or a methyl sul phinyl 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 IA: C' wherein: X is a methylsulphinyl group and C' is a hydrogen; or X 1s a hydrogen and C* 1s a methylsulphinyl group; A is a hydrogen or a hydroxy; and Rj has the previously-given meanings. 2) The dihydronaphthalSne diols of the general formula Ιθ: wherein: X is a hydroxy and A is a hydroxy; and C’ are both a hydrogen; or 8 and C’ are both a hydroxy and X and A are both a hydrogen; and R| has the above-given definitions. 3) The desalkylated derivatives of the general formula 1^: wherein D is a hydrogen, 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-methylsulfonyl naphthoyl-1) derivative and the (3-hydroxy or 5-hydroxynaphthoyl-l)-pyrrolyl-2-carboxy1ic acids show depending on the doses either immuno-suppressive or iranuno-stlmulating 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 pharaaceutically-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 alkyl celluloses, carboxymethyl celluloses, 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, multi doses flasks, or auto-inject1ble 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 1 500 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: previously described in the French patent 2.405.246 to the same applicant.

They may also be isolated in the biological fluids and particularly from the urine after administration of the said aroylpyrrolyl2-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.

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 OF N-METHYL-4(NAPHTH0YL-l)-PYRR0LYL-2-CARB0XYLIC ACID TAKEN AS REFERENCE COMPOUND Electronic Impact WEIGHT percentage 279 18 - —> molecular peak 262 80 - —> loss of OH or 234 80 - —> loss of COOH 218 10 205 10 190 10 165 20 152 100 — —>+0 Ξ C basic peak COOH 134 127 108 -> naphthyl -> 152 (-C02) EXAMPLE II Comparison between the spectral data of N-methyl-4-(naphthoyl-l)pyrrolyl-2-carboxylic acid (starting material) and 4-(naphthoyl-l)pyrrolyl-2-carboxyl ic acid obtained either synthetically or by extraction from the urine.

MASS SPECTRA OF: TABLE III MEAN PEAKS OBTAINED FROM THE MASS SPECTRA OF THE N-OEMETHYL DERIVATIVE OBTAINED AFTER EXTRACTION 4-( naphthoyl-1) -pyrrolyl-2-carboxylic acid Electronic Impact Chemical Ionization 265 64% - molecular peak 282 19% -molecular ion + NH4+ 246 22% - loss of water (- 19) 279 11% 230 5% - (-35) 266 100% -molecular ion + H+ 10 220 64% - loss of COOH 157 204 4% 190 18% 165 15% 15 155 7% -(οβΓεΞ°+ 138 21% — XNX COOH 1 127 46% Π 20 120 100% 92 26% After treatment with Diazomethane Electronic Impact Chemical Ionization 25 279 25% - molecular peak 297 10% -molecular ion + nh4+ 246 8% (-33) 294 18% - contamination of the 234 5% previous one 220 31% 280 100% - molecular ion + H+ 190 10% 30 175 8% 166 8% 155 13% 153 20% 144 19% 35 127 39% 120 57% 100 100% TABLE IV MEAN PEAKS OBTAINED FROM THE MASS SPECTRA OF SYNTHETIC N-DEMETHYL DERIVATIVE El ectri 4-(naohthovl-1)-pyrrolyl -2-carboxylic acid onic Impact Chemical Ionization NH^ 265 572 - — molecular peak 266 1002 -molecular ion + H+ 246 232 - — loss of water (-19) 246 72-loss of water 230 72 - - (-35) 220 282 - loss of COOH 220 752 - — loss of COOH « 204 52 190 162 165 62 155 32 — -0°^° 138 82 —05C^kcooh H 127 242 — — naphthalene 120 1002 95 282 69 902 After treatment with 01azomethane Chemical Ionization NHg formation of the methyl ester <-280 1002-molecular ion + H+ 246 52 220 222 EXAMPLE II Preparation and identification of N-methyl-(5.6-dihydroxy-5.6dihydronaphthoyl-l)-pyrrolyl-2-carboxyl1c acid.

TABLE V MAIN PEAKS OBTAINED FROM THE MASS SPECTRA OF THE (5.6-DIHYDR0XY-5.6-DIHYDRONAPHTHOYL-1) DERIVATIVE I.e.

N-methyl-(5.6-dihvdroxy-5.β-dihydronaohthoyl -1)pyrrolyl-2carboxylic acid Electronic Impact Chemical ionization NH^ 313 10X- molecular peak 331 62-molecular ion + NH 295 62- loss of water 314 1002 -molecular ion + H+ 285 5X- loss of -28 ? 296 62-loss of water 269 12X- loss of COOH 280 42 - loss of oxygen (?) 250)61 — loss of COOH + Η20 270 82-loss of COOH 251( 214 152 240 3X 154 72 222 62 206 22 184 252 152 30X-0 Ξ co- ^N COOH ch3 115 302 115 302 108 402 58 1002 - basic peak After treatment with Diazomethane Electronic Impact 327 652-Acid + CHj =φ Methyl ester 309 5X-loss of water 299 30X 283 22X 250 20X 240 30X 166 100X-basic peak MASS SPECTRA EXAMPLE III N-methyl-(3.4-dihydroxy-3.4-d1hydronaphthoyl-l)-pyrrolyl-2 carboxylic acid.

TABLE VII MAIN PEAKS OBTAINED FROM THE MASS SPECTRA OF THE N-METHYL- (3.4-0IHYOROXY-3.4-0IHYDR0NAPHTH0YL -1 PYRR0LYL-2-CARB0XYLIC DERIVATIVE Electronic Imoact Chemical Ionization NH3 313 15J-molecular peak 314 322 -molecular ion + H 295 122-loss of water 296 652 — 1oss of water 279 52-loss fff -34 280 82 269 72-loss of COOH 270 242 250 52 252 1002 -basic peak 234 82 15219S_o Ξ c-j— 222 52 ^N^COOH 206 22 ch3 194 82 170 22 152 1002 - 0 = C - COOH 134 ch3 82 131 152 115 302 108 702 103 202 58 402 After treatment with Oi azomethane Electronic Imoact 327 142 -Acid * ch3 - φ» Methyl ester 309 162 loss 250 162 166 1002 152 102 of water EXAMPLE IV N-methyl -4-(3-hydroxy-naphthoy 1-1)-pyrrolyl-2-carboxyl ic acid and N-methyl-4-(5-hydroxynaphthoy1 -1)-pyrrolyl-2-carboxyl 1c acid.

TABLE VIII MAIN PEAKS OBTAINED FROM THE MASS SPECTRA FROM N-METHYL-4-(3-HYDR0XYNAPHTH0YL-l)-PYRROLYL-2CARBOXYLIC ACID OBTAINED BY EXTRACTION Electronic Impact Chemical Ionization No mass higher than 100 296 100% - molecular ion + H+ 252 60%-loss of COOH After treatment with Di azomethane Electronic Impact Chemical Ionization 323 54%- dimethylated derivative 306 6%- loss of 17 292 6%- loss of OCHg 264 63%- loss of COOCHg 195 4% 185 8% 166 100% 134 31% 114 20% 53% 324 100%-dimethyl ated derivative + H+ TABLE IX MAIN PEAKS OBTAINED FROM THE MASS SPECTRA OF N-METHYL-4-(5-HYDROXYNAPHTHOYL-1)-PYRR0LYL-2CARBOXYLIC ACID RECOVERED BY EXTRACTION Electronic Impact 295 1,9%- molecular peak 281 0,4%- loss of CHg 279 1,2%- loss of oxygen 278 0,6%- loss of water 250 2,2%- loss of COOH 234 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% Chemical Ionization After treatment with Diazomethane Electronic Impact 323 16%-dimethyl ated derivative 309 48%-monomethyl ated derivative 292 16% 264 12% 250 50% 180 21% 166 100% Chemical Ionization 324 98%-di methyl ated derivative + H+ 310 100%-monomethyl ated derivative + H+ 280 30% TABLE X 8,29 7,58 7,51 7,33 7,02 6,91 // 3,85 (8) (2) (Α,α) (3,7) (Ρ) (*) (N-Cllj) EXAMPLE V N-methyl-4-(3-methylsulphinylnaphthoyl-1)-pyrrolyl-2-carboxyli c acid and N-methyl-4-(6-methylsulphinylnaphthoyl-1)-pyrrolyl-2-carboxy1ic acid.

TABLE XI MAIN PEAKS OBTAINED FROM THE MASS SPECTRA OF N-METHYL-4-(3-METHYLSULPHINYLNAPHTH0YL-l)-PYRR0LYL2-CARB0XYLIC ACID RECOVERED AFTER EXTRACTION BY HPLC Electronic Impact Chemical Ionization NHg 341 102- molecular peak 359 152- molecular ion + NH.+ 325 412- loss of oxygen 342 1002 - molecular ion + H 297 7%- loss of COOH 326 302 - loss of oxygen 281 382 298 102- loss of COOH 211 112 282 102- (298 - oxygen) 205 72 267 42- (298 - methoxy) 167 262 236 32 152 1002 -0 Ξ :r\ ^N'^COOH 223 205 42 22 129 342 ch3 191 62- (naphthalene + SOCHg) 108 792 152 62 91 362 After treatment with ι Diazomethane Electronic Impact Chemical Ionization NHg 355 122- molecular peak 356 1002 - molecular ion + H+ 340 122- loss of CHg 342 702 - loss of CHg 324 12- loss of oxygen and 340 802 - loss of oxygen 308 12 CHg 326 202 loss of oxygen and 296 12- (peak 340 - COOH) 324 102- CHg loss of two oxygens 282 12 298 102 223 22 294 152- (loss of SOCH- ?) 166 302 282 82 163 22 191 62 113 402 155 202 104 252 83 302 59 1002 α. ο.

TABLE XII ο ο Μ I Ο CZ3 X Ω ο^<η ο. <53. χθ ΟΊ 8,37 8,12 7,78 7,46 6,96 / / 3,87 2,82 8,26 7,73 en (6) (5) (2) (8) (4,7) (α) (β) (Ν—CH_) (S0C11J TABLE XIII E Q. CX Ul o z j: H- u o u Lu o o GO o -J a. X z SP 4» Z u Ή OS >- CM b“ co O« CM O • Ul o Λ 00 n. in Ul OS vj u UJ 4k % ί» o «Ο z o Ul Ul ex 00 z b— Ul 5» b- Lu O b- c in >- > z H· o Ul os r-· Ul b- o a «0 x *·*» o CJ »—4 < 1 os b- -1 cc 2 >- o o z Ul os 1— z ·—· cu in Ul in z z Ul h— -J o >- o Lu z =3 O ►w in z z Cu (X o —J (9 Ul z u t ►- «< in —I g b >- Ul z bo § a h““ a. Ul c o 00 z •H s Ul 1 »-4 IZ) b- m Q. z 3 <9 ►“4 O z υ »-L a -J z 0l *t •3 O TABLE XIV MAIN PEAKS OBTAINED FROM THE MASS SPECTRA OF (6-METHYLSULPHINYLNAPHTH0YL-l)-N-METHYL-PYRR0LYL-2-CARB0XYLIC ACID Electronic Impact 341 7%- molecular peak 359 325 12%- loss of an oxygen 342 281 16%- (peak 325 - 326 loss of COOH) 267 5%- (peak 281 - 298 loss of CH3) 152 95%- N COOH 282 129 50% 267 108 41% 105 100% 223 205 191 152 Chemical Ionization 2%-molecular ion + NH^+ 100%-molecular ion + H+ 7%- {loss of CH3) 6% - (loss of COOH) 6% - (peak 298 - loss of an oxygen) 12% - (peak 298 - loss of och3) 6% 2% % - (naphthalene - S0CH3 ?) 3% After treatment with Diazomethane 355 2% -molecular peak 373 7%- molecular ion + NH^+ 340 3% - (loss of CH3) 356 100%- molecular ion + H+ 162 1% 340 35%- (loss of an oxygen) 132 8% 294 3% (loss of two oxygens) 113 20% 282 3%- (loss of SOCH3 ?) 83 15% 261 2% 71 100% 167 1% 70 95% 155 6% ε Q.

O.

TABLE XV COUPLING SHOWN AFTER SUCCESSIVE IRRADIATIONS AT (8.46), (8.22), AND (8.01 AND SIGNIFICATION OF THE AROMATIC MOIETY OF THE RMN SPECTRUM OF N-METHYL-4-(6-METHYLSULPHINYLNAPHTH0YL-l)-PYRR0LYL-2-CARB0XYLIC ACID coupling neta EXAMPLE VI Study of the compounds of this invention as immuno-suppressive agents.

Azathloprin and N-methyl-4-(naphthoyl-l)-pyrro1y1-2-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 C57BL/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 ug/ml. 2. - N-methyl-4-(naphthoyl-l)-pyrrolyl-2-carboxylic acid Inhibits the formation of rosettes in about the same percentages at concentrations also ranging from 1 to 10 ug/ml. 3. - 4-(naphthoyl-l)-pyrrolyl-2-carboxylic acid has an inhibition action of about the same order than that of the N-methylated derivative. 4. - N-methyl-(5-hydroxylnaphthoyl-l)pyrrolyl-2-carboxylic acid is also an inhibitor to a similar degree and further possesses an immuno-stimulating activity of low doses.

. - N-methyl -4-(5.6 -d ihydroxy-5.6-d ihydronaphthoy1 -1)-pyrrolyl 2-carboxylic acid and N-methyl-4-(3-methylsulphinylnaphthoyll)-pyrrolyl-2-carboxylic acid have an inhibitory action similar to that of N-methyl-4-(naphthoyl-l)-pyrrolyl-2carboxylic acid. 6. - N-methyl-(3-hydroxynaphthoyl-l)-pyrrolyl-2-carboxylic acid has a mixed immuno-stimulating activity at concentrations ranging from 1 to 10 ug/ml.

Conclusively the derivatives of N-methyl-4-(naphthoyl-l)-pyrrolyl2-carboxylic acid in nitro modulates the formation of rosettes at nearly the effective concentrations of Azathioprin.

The N-methyl-(3-hydroxynaphthoyl-l)-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 ug/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 (10)

1.- The naphthoyl derivatives of pyrrolyl-carboxylic acid having the general formula I: wherein: R| is the methyl radical, the phenyl radical or a hydrogen; X is a hydrogen, a hydroxy or a methylsulphinyl group; Y 1s a hydrogen, or together with A' forms a double bond; A is a hydrogen, or a hydroxy; A' is a hydrogen or together with Y forms a double bond; B is a hydrogen or a hydroxy; 8’ is a hydrogen or together with C forms a double bond; C is a hydrogen, or together with B 1 forms a double bond; C' is a hydrogen, a hydroxy or a methylsulphi nyl group; with the proviso that X, A, B, and are not simultaneously a hydrogen when A^ together with Y is a double bond.

2. - The salts of a compound of formula I according to claim 1 with a mineral or organic base.

3. - A compound according to claim 1 having the formula 1^: wherein: has the above-given meanings; X 1s a methylsulphinyl group and C' is a hydrogen; or X 1s a hydrogen and C' is a methylsulphinyl group; and A is a hydrogen or a hydroxy.

4.- A compound according to claim 1 having the formula Ιθ: X wherein: X is a hydroxy and A is a hydroxy; B and C' are both hydrogen; or B and C* are both a hydroxy, X and A both are a hydrogen; and Rj has the above-given definitions. wherein D is a hydrogen, a hydroxy or a methylsulf inyl group.

5. 6 . [ N-methyl-4- ( 3-methyl sulphinylnaphthoyl-1) -pyrrolyl-2 ] 15 carboxylic acid.

6. 7 . [ N-methyl-4- ( 3-hydroxynaphthoyl-1) -pyrrolyl-2 ] -carboxylic acid.

7. 8 . [ N-methyl-4- (5-hydroxynaphthoyl-1) -pyrrolyl-2 ] -carboxylic acid. 20 g. a pharmaceutical composition containing as active ingredient at least one compound according to any of the claims 1 to 8 in conjunction or admixture with an inert non-toxic pharmaceutically acceptable vehicle or carrier.

8. 10. A pharmaceutical composition according to claim 9 wherein the carrier or vehicle is one of those suitable for administration by parenteral, digestive, rectal or topic way of administration.

9. 11. A compound substantially as hereinbefore described with reference to the Examples.

10. 12. A composition substantially as hereinbefore described with reference to the Examples.