CA2177146C - Heterocyclic benzenesulfonylimine derivatives as inhibitors of il-1 action - Google Patents
Heterocyclic benzenesulfonylimine derivatives as inhibitors of il-1 actionInfo
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- CA2177146C CA2177146C CA002177146A CA2177146A CA2177146C CA 2177146 C CA2177146 C CA 2177146C CA 002177146 A CA002177146 A CA 002177146A CA 2177146 A CA2177146 A CA 2177146A CA 2177146 C CA2177146 C CA 2177146C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4
Abstract
The present invention relates to heterocyclic benzenesulfonylimine derivatives and their use inhibitors of Interleukin-1(IL-1) action. Such inhibitors are useful in the treatment of various disease states as disclosed herein including rheumatoid arthritis, multiple sclerosis. diabetes mellitus, atherosclerosis, septic shock and pulmonary fibrosis.
Description
~ ~ 7 ;7 ~ 4 ~
1-- ,, HETEROCYCLIC BENZENESULFONYLIMINE DERIVATIVES AS INHIBITORS
OF IL-l ACTION
The present invention relates to heterocyclic benzenesulfonylimine derivatives and their use as inhibitors of Interleukin-l (IL-l) action. Such inhibitors are useful in the treatment of various disease states as disclosed herein including rheumatoid arthritis, multiple sclerosis, diabetes mellitus, atherosclerosis, septic shock and pulmonary fibrosis. PCT Application WO-A-9215565 describes compounds which are antagonists of N-methyl-D-aspartate (NMDA).
SUMMARY OF THE INVENTION
The present invention provides a method of inhibiting 25 IL-l action comprising administration of to a patient in need thereof an effective amount of a compound of the formula:
~SO2 Il I Z
/~\ ~
I I Q
A ~
Formula I
1-- ,, HETEROCYCLIC BENZENESULFONYLIMINE DERIVATIVES AS INHIBITORS
OF IL-l ACTION
The present invention relates to heterocyclic benzenesulfonylimine derivatives and their use as inhibitors of Interleukin-l (IL-l) action. Such inhibitors are useful in the treatment of various disease states as disclosed herein including rheumatoid arthritis, multiple sclerosis, diabetes mellitus, atherosclerosis, septic shock and pulmonary fibrosis. PCT Application WO-A-9215565 describes compounds which are antagonists of N-methyl-D-aspartate (NMDA).
SUMMARY OF THE INVENTION
The present invention provides a method of inhibiting 25 IL-l action comprising administration of to a patient in need thereof an effective amount of a compound of the formula:
~SO2 Il I Z
/~\ ~
I I Q
A ~
Formula I
-2- ~ ~ ~7~ ~ ~
wherein A is NH, O, or S;
Ql is -OR or -NRlR2; wherein R, Rl and R2 are each independently hydrogen or C1-C6 alkyl radical of branched, straight chained, or cyclic configuration, wherein in the case of a cyclic configuration is C~-C6 cycloalkyl;
Z is from 1 to 3 substituents chosen independently from the group: halogen, Cl-C4 alkyl, and Cl-C4 alkoxy;
Y is from 1 to 3 substituents chosen independently from the group: Cl-C4 alkyl, C1-C4 alkoxy, and halogen.
Some of the compounds of the present invention are novel heterocyclic benzenesulfonylimine derivatives. These novel compounds are ~seful inhibitors IL-l action. These novel 20 compounds of Formula II are encompassed by the Formula I.
The present invention provides novel heterocyclic benzenesulfonylimine derivatives of the formula:
/ 5~2 ~
Z
/~/'\ ~
~1 Formula II o wherein A is O or S;
A
~ ~ 7 ~ ~ 4 ~
Q2 is -OR3 or -NRlR2; wherein Rl, R2 and R3 are each independently Cl-C6 alkyl radical of branched, straight chained, or cyclic configuration, wherein in the case of a cyclic configuration is C3-C6 cycloalkyli Z is from 1 to 3 substituents chosen independently from the group; halogen, Cl-C4 alkyl, and Cl-C4 alkoxy;
Y is from 1 to 3 substituents chosen independently from the group: C1-C4 alkyl, Cl-C4 alkoxy, and halogen.
These compounds as disclosed herein, are active as inhibitors of IL-l action. The compounds of Formula I
should be considered within the scope of any method, use, or 15 formulation claims.
DETAILED DESCRIPTION OF THE INVENTION
As used in this application:
a) the term "halogen" refers to a fluorine atom , chlorine atom, bromine atom, or iodine atom;
25 b) the terms "Cl-C4 alkyl" refer to a branched or straight chained alkyl radical containing from 1 to 4 carbon atoms, WO95/14670 PCT~S94/12575 ~~
such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc;
c) the term "Cl-C6 alkyl" refer to a cyclic, branched, or 5 straight chained alkyl radical containing from l to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, cyclopentyl, n-hexyl, cyclohexyl, etc;
d) the terms "C1-C4 alkoxy" refer to a straight or branched lO alkoxy group containing from l to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, etc;
e) the term "pharmaceutically acceptable salts thereof"
15 refers to either an acid addition salt or a basic addition salt;
~ he expression "pharmaceutically acceptable acid addi-tion salts" is intended to apply to any non-toxic organic or 20 inorganic acid addition salt of the base compounds represented by Formula I or any of its intermediates.
Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen 25 orthophosphate, and potassium hydrogen sulfate.
Illustrative organic acids which form suitable salts include the mono-, di-, and tricarboxylic acids. Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, 30 tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxy-benzoic, p-toluenesulfonic acid, and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid. Such salts can exist in either a hydrated or 35 substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and which in comparison to - w095/14670 PCT~S94/12S75 their free base forms, generally demonstrate higher melting points.
The expression "pharmaceutically acceptable basic 5 addition salts" is intended to apply to any non-toxic organic or inorganic basic addition salts of the compounds represented by Formula I or any of its intermediates.
Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, 10 potassium, calcium, magnesium, or barium hydroxides;
ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline. Either the mono- or di-basic salts can be formed with those compounds.
As is readily apparent to those skilled in the art, the compounds of Formula I in which A is NH will exist as tautomers. Any reference to the compounds of Formula I or an intermediate thereof should be construed as referring to 20 either tautomer. These tautomers may be depicted as:
~SOz ~ ~50 Y ~ ~ ~ ~ Q
CJ
Examples of compounds encompassed by the present invention include:
35 5,7-Dichloro-4-[4-(fluoro)benzenesulfonylimino]-1,4-dihydro~uinoline-2-carboxylic acid, methyl ester;
WO95/14670 PCT~S94/12S75 5,7-Dichloro-4-[4-(methoxy)benzenesulfonylimino]-1,4-dihydroquinoiline-2-carboxylic acid, methyl ester;
5,7-Dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-5 2-carboxylic acid, methyl ester;
5,7-Dichloro-4-[(4-methyl)benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
10 5,7-Dichloro-4-[(4-chloro)benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
5,7-Dichloro-4-[2-chlorobenzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
5,7-Dichloro-4-[3-chlorobenzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
5,7-Dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-20 2-carboxylic acid, ethyl ester;
5,7-Dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, propyl ester;
25 5,7-Dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, butyl ester;
5,7-Dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid-N-methylamide;
5,7-Dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid-N,N-dimethylamide;
5,7-Dichloro-4-[benzenesulfonylimino]]-4H-chromene-2-35 carboxylic acid, methyl ester;
- WO95/14670 2 1 7 7 1 4 6 pCT~ss4ll2s75 4-[Benzenesulfonylimino]]-4H-thiochromene-2-carboxylic acid, methyl ester;
4-[Benzenesulfonylimino]]-4H-chromene-2-carboxylic acid, 5 methyl ester.
A general synthetic procedure for preparing the compounds of Formula I in which A is NH is set forth in Scheme A. Since, the compounds of Formula II are lO encompassed by the Formula I the general synthetic procedure set out below also allows for the preparation of the compounds of Formula II in which A is NH . In Scheme A, all substituents, unless otherwise indicated, are as previously defined.
Woss/l467o 2 1 7 7 1 4 6 PCT~S9411257~
SCHEME A
5 O ~ O
/~ \~ / \~
0Yk~;~ stepa step b l5 ~ SO2 ~ O
Il I _z 11 \~ step c ~l 20 ~\U/\~/ R y~~~O~R
(Formula I) ~ ~
A is NH
R is -OR optional \ Optional 2 5 step d \step e ~ SO2 ~ \ ~ SO2 Il I Z 11 1 Z
/ \~ \~
N \ ~ ~ OH
(Formula I) G (Formula I) O
A is NH A is NH
R is -NRlR2 R is -OH
95/14670 PcT~S94/1257s In general, in Scheme A, step a, an appropriate acid chloride of structure (l), known analogously in the art [P.
Leeson, European Patent Application No. 0 303 387, published Feb. 15, 1989], is contacted with an appropriate alcohol to 5 give an ester of structure (2).
An appropriate acid chloride of the structure (l) is one in which Y is as desired in the final product of the Formula I. An appropriate alcohol of the structure HOR is one which l0 gives rise to compounds of Formula I in which Ql is -OR as desired in the final product of Formula I or gives rise to a Ql as desired in the final product of Formula I.
For example, an appropriate acid chloride of structure 15 (l) is contacted with an appropriate alcohol. The reaction may be carried out in a suitable solvent, such as tetrahydrofuran, dimethylformamide, or the appropriate alcohol may be used as the solvent. The use of the appropriate alcohol as the solvent is preferred. The 20 reaction is carried out in the presence of a suitable base, such as triethylamine, diisopropylethylamine, sodium carbonate, or sodium bicarbonate. The reaction requires from l to 8 hours. The product is isolated and purified by techniques well known in the art, such as evaporation in 25 vocuo, extraction, chromatography with a suitable organic eluant, and recrystallization to give an ester of structure (2).
In Scheme A, step b, an ester of structure (2) is 30 debenzylated to give a l,4-dihydroquinol-4-one of structure (3).
For example, a compound of structure (2) is contacted with a suitable debenzylating agent, such as trifluoroacetic 35 acid, at a temperature that is sufficient to remove the benzyl group but not degrade the starting material or product. The preferred temperature is 70~C to 80~C when the wogs/14670 2 1 77 1 4S PCT~S94/12575 debenzylating agent is trifluoroacetic acid. The product is isolated and purified by techniques well known in the art, such as evaporation in uacuo, chromatography with a suitable organic eluant, and recrystallization to give a compound of 5 structure (3).
In Scheme A, step c, a l,4-dihydroquinol-4-one of structure (3) is contacted with an appropriate benzenesulfonyl isocyanate to a heterocyclic l0 benzenesulfonylimine of Formula I in which A is NH.
An appropriate benzenesulfonyl isocyanate is one in which Z is as desired in the final product of the Formula I
in which A is NH.
For example, a 1,4-dihydroquinol-4-one of structure (3) is contacted with an from l to 2 molar equivalents of an appropriate benzenesulfonyl isocyanate. The reaction is carried out in a suitable solvent, such as acetonitrile or propionitrile at temperatures of 20~ C to the refluxing 20 temperature of the solvent. The product is isolated and purified by techniques well known in the art, such as evaporation in vacuo, chromatography with a suitable organic eluant, and recrystallization to give a compound of Formula I in which A is NH.
In Scheme A, optional step d, an appropriate compound of Formula I is contacted with an appropriate amine to give a compound of Formula I in which Q1 is -NRlR2 and A is NH.
An appropriate compound of Formula I is one in which Q
is -OR, R is a C1-C6 alkyl, A is NH and Y and Z are as desired in the final product of the Formula I. An appropriate amine of the structure, HNRlR2 gives a compound of Formula I in which Q1 is -NR1R2 as desired in the final product of Formula I in which A is NH.
For example, an appropriate compound of Formula I is contacted with an appropriate amine in a suitable solvent, - WOg5/14670 PCT~S94/12575 such as methanol, ethanol, water, or dioxane. The reaction vessel may be sealed to prevent the escape of volatile amines from the reaction vessel. The reaction is carried out at temperatures from ambient temperature to the refluxing temperature of the solvent. The product is recovered by techniques well known in the art, such as extraction, evaporation in vacuo, chromatography with a suitable organic eluant, and recrystallization.
In Scheme A, optional step e, an appropriate compound of Formula I is hydrolyzed to give a compound of Formula I
in which Ql is -OH and A is NH.
An appropriate compound of Formula I is one in which Ql is -OR, R is a Cl-C6 alkyl, A is NH and Y and Z are as desired in the final product of the Formula I.
For example, an appropriate compound of Formula I is contacted with a suitable base, such as lithium hydroxide or 20 sodium hydroxide. The reaction is carried out in a suitable solvent, such as water, tetrahydrofuran, methanol, water/tetrahydrofuran mixtures, and water/methanol mixtures.
The reactants are typically stirred together for a period of time ranging from 2-24 hours and at a temperature range of 25 from room temperature to reflux. The compound of Formula I
in which Ql is -OH and A is NH is recovered from the reaction zone by acidification followed by filtration and may be purified by recrystallization as is known in the art.
The following examples present typical syntheses as described in Scheme A. These examples are understood to be illustrative only and are not intended to limit the scope of the invention in any way. As used in the following examples, the following terms have the meanings indicated:
35 "g" refers to grams, "mg" refers to milligrams, "mmol"
refers to millimoles, "mL" refers to milliliters, "~C"
refers to degrees Celsius, "Rf" refers to retention "mp"
refers to melting point, "dec" refers to decomposition, "TLC" refers to thin layer chromatography.
5 Scheme A, step a:
5,7-Dichloro-4-benzyloxyquinoline-2-carboxylic acid, ethyl ester Combine 5,7-dichloro-4-benzyloxyquinoline-2-acid chloride (1.83g, Smmol), triethylamine (0.7 mL, 5.0 mmol), 10 and ethanol (0.58 mL, 10 mmol) in tetrahydrofuran (25 mL).
Stir at ambient temperature. After 18 hours evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with dichloromethane to obtain a solid.
Recrystallize the solid from ethyl acetate/hexane to give 15 the title compound as a solid: TLC Rf=0.33 (silica gel, dichloromethane); mp; 146-147~C. Elem. Anal. calculated for ClgHl5Cl2NO3: C, 60.65; H, 4.02; N, 3.72. Found: C, 60.35;
H, 4.17; N, 3.65.
Scheme A, step a:
5,7-Dichloro-4-benzyloxyquinoline-2-carboxylic acid, butyl ester Combine 5,7-dichloro-4-benzyloxyquinoline-2-acid 25 chloride (1.83g, 5mmol), triethylamine (0.7 mL, 5.0 mmol), and butanol (1.04 mL, 10 mmol) in tetrahydrofuran (25 mL).
Stir at ambient temperature. After 18 hours evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with dichloromethane to give a solid.
30 Recrystallize the solid from ethyl acetate/hexane to give the title compound as a solid: TLC Rf=0.50 (silica gel, dichloromethane); mp; 130-132~C. Elem. Anal. calculated for C2lHlgCl2NO3: C, 62.39: H, 4.74; N, 3.46. Found: C, 62.20;
~, 4.83; N, 3.22.
Scheme A, step b:
5,7-Dichloro-quinolin-4-One-2-carboxylic acid, ethyl ester ~095/14670 PCT~ss4/1257s Combine 5,7-dichloro-4-benzyloxyquinoline-2-carboxylic acid, ethyl ester (1.149, 3.0 mmol) and trifluoroacetic acid (60 mL). ~eat in an oil bath at 80~C. After 4 hours evaporate inuacuo. Add hexane and evaporate in vacuo to remove 5 the residual trifluoroacetic acid and give a solid.
Recrystallize the solid from acetonitrile to give the title compound as a solid: TLC Rf=0.33 (silica gel, 2%
acetone/dichloromethane); mp; 256-266~C. Elem. Anal.
calculated for Cl2HlgCl2NO3: C, 50.37; H, 3.17; N, 4.90.
10 Found: C, 50.39; H, 3.31; N, 4.92.
Scheme A, step b:
5,7-Dichloro-quinolin-4-one-2-carboxYlic acid, butyl ester Combine 5,7-dichloro-4-benzyloxyquinoline-2-carboxylic acid, butyl ester (1.35g, 3.3 mmol) and trifluoroacetic acid (65 mL). Heat in an oil bath at 75~C. After 3 hours evaporate invacuo. Add dichloromethane and evaporate in uacuo to remove the residual trifluoroacetic acid to give a 20 residue. Recrystallize the residue from acetonitrile to give the title compound as a solid: mp; 191-193~C.
Scheme A, step c:
25 5,7-Dichloro-4-[benzenesulfonYlimino]-1,4-dihYdroquinoline-2-carboxylic acid, ethyl ester Combine 5,7-dichloro-quinolin-4-one-2-carboxylic acid, ethyl ester (0.59g, 2.1 mmol) and benzenesulfonyl isocyanate (0.56 mL, 4.2 mmol) in acetonitrile (10 mL). Heat to reflux 30 under an inert atmosphere. After 16 hours, quench with methanol (5 mL). Evaporate in uacuo. Chromatograph on silica gel eluting with 2% acetone/dichloromethane. Recrystallize from acetonitrile to give the title compound as a solid: TLC
Rf=0.31 (silica gel, 2% acetone/dichloromethane); mp; 184-35 185~C. Elem. Anal. calculated for ClgHl4C12N2O4S: C, 50.83;H, 3.32; N, 6.59. Found: C, 51.04; H, 3.33; N, 6.56.
WO95/14670 PCT~S94/12575 Scheme A, step c:
5,7-Dichloro-4-tbenzenesulfonylimino]-1,4-dihydroquinoline-5 2-carboxylic acid, butyl ester Combine 5,7-dichloro-quinolin-4-one-2-carboxylic acid, butyl ester (l.OOg, 3.2 mmol) and benzenesulfonyl isocyanate (0.85 mL, 6.3 mmol) in acetonitrile (15 mL). Heat to reflux under an inert atmosphere. After 16 hours, quench with 10 methanol (5 mL). Evaporate in vacuo. Chromatograph on silica gel eluting with 2% acetone/dichloromethane. Recrystallize from ethyl acetate/hexane to give the title compound as a solid: TLC Rf=0.38 (silica gel, 2% acetone/dichloromethane);
mp; 94-95~C. Elem. Anal. calculated for C20Hlôcl2N2o4s: C, 15 52.98; H, 4.00; N, 6.18. Found: C, 53.27; H, 3.95; N, 6.12.
Scheme A, optional step d:
5,7-Dichloro-4-[benzenesulfonYlimino]-1,4-dihydroquinoline-20 2-carboxylic acid-N-methYlamide Combine 5,7-dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (1.0 g, 2.4 mmol) and 40% methylamine in water (25 mL) and dioxane (50 mL). Stopper and stir for 18 hours. Evaporate in uacuo to 25 give a yellow oil. Dissolve the oil in water (15 mL) and add lM hydrochloric acid solution (15 mL). Stir for 15 minutes and then filter to obtain a solid. Rinse the solid with lM hydrochloric acid solution and water. Recrystallize from acetonitrile/water to give the title compound as a 30 solid: mp; 196-197~C. Elem. Anal. calculated for Cl7Hl3Cl2N3O3S-H2O: C, 47.68; H, 3.53; N, 9.81. Found: C, 47.55; H, 3.42; N, 9.78.
A general synthetic procedure for preparing these compounds of Formula I in which A is O or S is set forth in Scheme B. Since, the compounds of Formula II are ~095/14670 2 1 7 7 1 4 6 pCT~S94/12575 encompassed by the Formula I the general synthetic procedure set out below also allows for the preparation of the compounds of Formula II in which A is 0 or S. In Scheme B, all substituents, unless otherwise indicated, are as 5 previously defined.
SCHEME B
O O
,~J~
wherein A is NH, O, or S;
Ql is -OR or -NRlR2; wherein R, Rl and R2 are each independently hydrogen or C1-C6 alkyl radical of branched, straight chained, or cyclic configuration, wherein in the case of a cyclic configuration is C~-C6 cycloalkyl;
Z is from 1 to 3 substituents chosen independently from the group: halogen, Cl-C4 alkyl, and Cl-C4 alkoxy;
Y is from 1 to 3 substituents chosen independently from the group: Cl-C4 alkyl, C1-C4 alkoxy, and halogen.
Some of the compounds of the present invention are novel heterocyclic benzenesulfonylimine derivatives. These novel compounds are ~seful inhibitors IL-l action. These novel 20 compounds of Formula II are encompassed by the Formula I.
The present invention provides novel heterocyclic benzenesulfonylimine derivatives of the formula:
/ 5~2 ~
Z
/~/'\ ~
~1 Formula II o wherein A is O or S;
A
~ ~ 7 ~ ~ 4 ~
Q2 is -OR3 or -NRlR2; wherein Rl, R2 and R3 are each independently Cl-C6 alkyl radical of branched, straight chained, or cyclic configuration, wherein in the case of a cyclic configuration is C3-C6 cycloalkyli Z is from 1 to 3 substituents chosen independently from the group; halogen, Cl-C4 alkyl, and Cl-C4 alkoxy;
Y is from 1 to 3 substituents chosen independently from the group: C1-C4 alkyl, Cl-C4 alkoxy, and halogen.
These compounds as disclosed herein, are active as inhibitors of IL-l action. The compounds of Formula I
should be considered within the scope of any method, use, or 15 formulation claims.
DETAILED DESCRIPTION OF THE INVENTION
As used in this application:
a) the term "halogen" refers to a fluorine atom , chlorine atom, bromine atom, or iodine atom;
25 b) the terms "Cl-C4 alkyl" refer to a branched or straight chained alkyl radical containing from 1 to 4 carbon atoms, WO95/14670 PCT~S94/12575 ~~
such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc;
c) the term "Cl-C6 alkyl" refer to a cyclic, branched, or 5 straight chained alkyl radical containing from l to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, cyclopentyl, n-hexyl, cyclohexyl, etc;
d) the terms "C1-C4 alkoxy" refer to a straight or branched lO alkoxy group containing from l to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, etc;
e) the term "pharmaceutically acceptable salts thereof"
15 refers to either an acid addition salt or a basic addition salt;
~ he expression "pharmaceutically acceptable acid addi-tion salts" is intended to apply to any non-toxic organic or 20 inorganic acid addition salt of the base compounds represented by Formula I or any of its intermediates.
Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen 25 orthophosphate, and potassium hydrogen sulfate.
Illustrative organic acids which form suitable salts include the mono-, di-, and tricarboxylic acids. Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, 30 tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxy-benzoic, p-toluenesulfonic acid, and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid. Such salts can exist in either a hydrated or 35 substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and which in comparison to - w095/14670 PCT~S94/12S75 their free base forms, generally demonstrate higher melting points.
The expression "pharmaceutically acceptable basic 5 addition salts" is intended to apply to any non-toxic organic or inorganic basic addition salts of the compounds represented by Formula I or any of its intermediates.
Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, 10 potassium, calcium, magnesium, or barium hydroxides;
ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline. Either the mono- or di-basic salts can be formed with those compounds.
As is readily apparent to those skilled in the art, the compounds of Formula I in which A is NH will exist as tautomers. Any reference to the compounds of Formula I or an intermediate thereof should be construed as referring to 20 either tautomer. These tautomers may be depicted as:
~SOz ~ ~50 Y ~ ~ ~ ~ Q
CJ
Examples of compounds encompassed by the present invention include:
35 5,7-Dichloro-4-[4-(fluoro)benzenesulfonylimino]-1,4-dihydro~uinoline-2-carboxylic acid, methyl ester;
WO95/14670 PCT~S94/12S75 5,7-Dichloro-4-[4-(methoxy)benzenesulfonylimino]-1,4-dihydroquinoiline-2-carboxylic acid, methyl ester;
5,7-Dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-5 2-carboxylic acid, methyl ester;
5,7-Dichloro-4-[(4-methyl)benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
10 5,7-Dichloro-4-[(4-chloro)benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
5,7-Dichloro-4-[2-chlorobenzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
5,7-Dichloro-4-[3-chlorobenzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
5,7-Dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-20 2-carboxylic acid, ethyl ester;
5,7-Dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, propyl ester;
25 5,7-Dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, butyl ester;
5,7-Dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid-N-methylamide;
5,7-Dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid-N,N-dimethylamide;
5,7-Dichloro-4-[benzenesulfonylimino]]-4H-chromene-2-35 carboxylic acid, methyl ester;
- WO95/14670 2 1 7 7 1 4 6 pCT~ss4ll2s75 4-[Benzenesulfonylimino]]-4H-thiochromene-2-carboxylic acid, methyl ester;
4-[Benzenesulfonylimino]]-4H-chromene-2-carboxylic acid, 5 methyl ester.
A general synthetic procedure for preparing the compounds of Formula I in which A is NH is set forth in Scheme A. Since, the compounds of Formula II are lO encompassed by the Formula I the general synthetic procedure set out below also allows for the preparation of the compounds of Formula II in which A is NH . In Scheme A, all substituents, unless otherwise indicated, are as previously defined.
Woss/l467o 2 1 7 7 1 4 6 PCT~S9411257~
SCHEME A
5 O ~ O
/~ \~ / \~
0Yk~;~ stepa step b l5 ~ SO2 ~ O
Il I _z 11 \~ step c ~l 20 ~\U/\~/ R y~~~O~R
(Formula I) ~ ~
A is NH
R is -OR optional \ Optional 2 5 step d \step e ~ SO2 ~ \ ~ SO2 Il I Z 11 1 Z
/ \~ \~
N \ ~ ~ OH
(Formula I) G (Formula I) O
A is NH A is NH
R is -NRlR2 R is -OH
95/14670 PcT~S94/1257s In general, in Scheme A, step a, an appropriate acid chloride of structure (l), known analogously in the art [P.
Leeson, European Patent Application No. 0 303 387, published Feb. 15, 1989], is contacted with an appropriate alcohol to 5 give an ester of structure (2).
An appropriate acid chloride of the structure (l) is one in which Y is as desired in the final product of the Formula I. An appropriate alcohol of the structure HOR is one which l0 gives rise to compounds of Formula I in which Ql is -OR as desired in the final product of Formula I or gives rise to a Ql as desired in the final product of Formula I.
For example, an appropriate acid chloride of structure 15 (l) is contacted with an appropriate alcohol. The reaction may be carried out in a suitable solvent, such as tetrahydrofuran, dimethylformamide, or the appropriate alcohol may be used as the solvent. The use of the appropriate alcohol as the solvent is preferred. The 20 reaction is carried out in the presence of a suitable base, such as triethylamine, diisopropylethylamine, sodium carbonate, or sodium bicarbonate. The reaction requires from l to 8 hours. The product is isolated and purified by techniques well known in the art, such as evaporation in 25 vocuo, extraction, chromatography with a suitable organic eluant, and recrystallization to give an ester of structure (2).
In Scheme A, step b, an ester of structure (2) is 30 debenzylated to give a l,4-dihydroquinol-4-one of structure (3).
For example, a compound of structure (2) is contacted with a suitable debenzylating agent, such as trifluoroacetic 35 acid, at a temperature that is sufficient to remove the benzyl group but not degrade the starting material or product. The preferred temperature is 70~C to 80~C when the wogs/14670 2 1 77 1 4S PCT~S94/12575 debenzylating agent is trifluoroacetic acid. The product is isolated and purified by techniques well known in the art, such as evaporation in uacuo, chromatography with a suitable organic eluant, and recrystallization to give a compound of 5 structure (3).
In Scheme A, step c, a l,4-dihydroquinol-4-one of structure (3) is contacted with an appropriate benzenesulfonyl isocyanate to a heterocyclic l0 benzenesulfonylimine of Formula I in which A is NH.
An appropriate benzenesulfonyl isocyanate is one in which Z is as desired in the final product of the Formula I
in which A is NH.
For example, a 1,4-dihydroquinol-4-one of structure (3) is contacted with an from l to 2 molar equivalents of an appropriate benzenesulfonyl isocyanate. The reaction is carried out in a suitable solvent, such as acetonitrile or propionitrile at temperatures of 20~ C to the refluxing 20 temperature of the solvent. The product is isolated and purified by techniques well known in the art, such as evaporation in vacuo, chromatography with a suitable organic eluant, and recrystallization to give a compound of Formula I in which A is NH.
In Scheme A, optional step d, an appropriate compound of Formula I is contacted with an appropriate amine to give a compound of Formula I in which Q1 is -NRlR2 and A is NH.
An appropriate compound of Formula I is one in which Q
is -OR, R is a C1-C6 alkyl, A is NH and Y and Z are as desired in the final product of the Formula I. An appropriate amine of the structure, HNRlR2 gives a compound of Formula I in which Q1 is -NR1R2 as desired in the final product of Formula I in which A is NH.
For example, an appropriate compound of Formula I is contacted with an appropriate amine in a suitable solvent, - WOg5/14670 PCT~S94/12575 such as methanol, ethanol, water, or dioxane. The reaction vessel may be sealed to prevent the escape of volatile amines from the reaction vessel. The reaction is carried out at temperatures from ambient temperature to the refluxing temperature of the solvent. The product is recovered by techniques well known in the art, such as extraction, evaporation in vacuo, chromatography with a suitable organic eluant, and recrystallization.
In Scheme A, optional step e, an appropriate compound of Formula I is hydrolyzed to give a compound of Formula I
in which Ql is -OH and A is NH.
An appropriate compound of Formula I is one in which Ql is -OR, R is a Cl-C6 alkyl, A is NH and Y and Z are as desired in the final product of the Formula I.
For example, an appropriate compound of Formula I is contacted with a suitable base, such as lithium hydroxide or 20 sodium hydroxide. The reaction is carried out in a suitable solvent, such as water, tetrahydrofuran, methanol, water/tetrahydrofuran mixtures, and water/methanol mixtures.
The reactants are typically stirred together for a period of time ranging from 2-24 hours and at a temperature range of 25 from room temperature to reflux. The compound of Formula I
in which Ql is -OH and A is NH is recovered from the reaction zone by acidification followed by filtration and may be purified by recrystallization as is known in the art.
The following examples present typical syntheses as described in Scheme A. These examples are understood to be illustrative only and are not intended to limit the scope of the invention in any way. As used in the following examples, the following terms have the meanings indicated:
35 "g" refers to grams, "mg" refers to milligrams, "mmol"
refers to millimoles, "mL" refers to milliliters, "~C"
refers to degrees Celsius, "Rf" refers to retention "mp"
refers to melting point, "dec" refers to decomposition, "TLC" refers to thin layer chromatography.
5 Scheme A, step a:
5,7-Dichloro-4-benzyloxyquinoline-2-carboxylic acid, ethyl ester Combine 5,7-dichloro-4-benzyloxyquinoline-2-acid chloride (1.83g, Smmol), triethylamine (0.7 mL, 5.0 mmol), 10 and ethanol (0.58 mL, 10 mmol) in tetrahydrofuran (25 mL).
Stir at ambient temperature. After 18 hours evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with dichloromethane to obtain a solid.
Recrystallize the solid from ethyl acetate/hexane to give 15 the title compound as a solid: TLC Rf=0.33 (silica gel, dichloromethane); mp; 146-147~C. Elem. Anal. calculated for ClgHl5Cl2NO3: C, 60.65; H, 4.02; N, 3.72. Found: C, 60.35;
H, 4.17; N, 3.65.
Scheme A, step a:
5,7-Dichloro-4-benzyloxyquinoline-2-carboxylic acid, butyl ester Combine 5,7-dichloro-4-benzyloxyquinoline-2-acid 25 chloride (1.83g, 5mmol), triethylamine (0.7 mL, 5.0 mmol), and butanol (1.04 mL, 10 mmol) in tetrahydrofuran (25 mL).
Stir at ambient temperature. After 18 hours evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with dichloromethane to give a solid.
30 Recrystallize the solid from ethyl acetate/hexane to give the title compound as a solid: TLC Rf=0.50 (silica gel, dichloromethane); mp; 130-132~C. Elem. Anal. calculated for C2lHlgCl2NO3: C, 62.39: H, 4.74; N, 3.46. Found: C, 62.20;
~, 4.83; N, 3.22.
Scheme A, step b:
5,7-Dichloro-quinolin-4-One-2-carboxylic acid, ethyl ester ~095/14670 PCT~ss4/1257s Combine 5,7-dichloro-4-benzyloxyquinoline-2-carboxylic acid, ethyl ester (1.149, 3.0 mmol) and trifluoroacetic acid (60 mL). ~eat in an oil bath at 80~C. After 4 hours evaporate inuacuo. Add hexane and evaporate in vacuo to remove 5 the residual trifluoroacetic acid and give a solid.
Recrystallize the solid from acetonitrile to give the title compound as a solid: TLC Rf=0.33 (silica gel, 2%
acetone/dichloromethane); mp; 256-266~C. Elem. Anal.
calculated for Cl2HlgCl2NO3: C, 50.37; H, 3.17; N, 4.90.
10 Found: C, 50.39; H, 3.31; N, 4.92.
Scheme A, step b:
5,7-Dichloro-quinolin-4-one-2-carboxYlic acid, butyl ester Combine 5,7-dichloro-4-benzyloxyquinoline-2-carboxylic acid, butyl ester (1.35g, 3.3 mmol) and trifluoroacetic acid (65 mL). Heat in an oil bath at 75~C. After 3 hours evaporate invacuo. Add dichloromethane and evaporate in uacuo to remove the residual trifluoroacetic acid to give a 20 residue. Recrystallize the residue from acetonitrile to give the title compound as a solid: mp; 191-193~C.
Scheme A, step c:
25 5,7-Dichloro-4-[benzenesulfonYlimino]-1,4-dihYdroquinoline-2-carboxylic acid, ethyl ester Combine 5,7-dichloro-quinolin-4-one-2-carboxylic acid, ethyl ester (0.59g, 2.1 mmol) and benzenesulfonyl isocyanate (0.56 mL, 4.2 mmol) in acetonitrile (10 mL). Heat to reflux 30 under an inert atmosphere. After 16 hours, quench with methanol (5 mL). Evaporate in uacuo. Chromatograph on silica gel eluting with 2% acetone/dichloromethane. Recrystallize from acetonitrile to give the title compound as a solid: TLC
Rf=0.31 (silica gel, 2% acetone/dichloromethane); mp; 184-35 185~C. Elem. Anal. calculated for ClgHl4C12N2O4S: C, 50.83;H, 3.32; N, 6.59. Found: C, 51.04; H, 3.33; N, 6.56.
WO95/14670 PCT~S94/12575 Scheme A, step c:
5,7-Dichloro-4-tbenzenesulfonylimino]-1,4-dihydroquinoline-5 2-carboxylic acid, butyl ester Combine 5,7-dichloro-quinolin-4-one-2-carboxylic acid, butyl ester (l.OOg, 3.2 mmol) and benzenesulfonyl isocyanate (0.85 mL, 6.3 mmol) in acetonitrile (15 mL). Heat to reflux under an inert atmosphere. After 16 hours, quench with 10 methanol (5 mL). Evaporate in vacuo. Chromatograph on silica gel eluting with 2% acetone/dichloromethane. Recrystallize from ethyl acetate/hexane to give the title compound as a solid: TLC Rf=0.38 (silica gel, 2% acetone/dichloromethane);
mp; 94-95~C. Elem. Anal. calculated for C20Hlôcl2N2o4s: C, 15 52.98; H, 4.00; N, 6.18. Found: C, 53.27; H, 3.95; N, 6.12.
Scheme A, optional step d:
5,7-Dichloro-4-[benzenesulfonYlimino]-1,4-dihydroquinoline-20 2-carboxylic acid-N-methYlamide Combine 5,7-dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (1.0 g, 2.4 mmol) and 40% methylamine in water (25 mL) and dioxane (50 mL). Stopper and stir for 18 hours. Evaporate in uacuo to 25 give a yellow oil. Dissolve the oil in water (15 mL) and add lM hydrochloric acid solution (15 mL). Stir for 15 minutes and then filter to obtain a solid. Rinse the solid with lM hydrochloric acid solution and water. Recrystallize from acetonitrile/water to give the title compound as a 30 solid: mp; 196-197~C. Elem. Anal. calculated for Cl7Hl3Cl2N3O3S-H2O: C, 47.68; H, 3.53; N, 9.81. Found: C, 47.55; H, 3.42; N, 9.78.
A general synthetic procedure for preparing these compounds of Formula I in which A is O or S is set forth in Scheme B. Since, the compounds of Formula II are ~095/14670 2 1 7 7 1 4 6 pCT~S94/12575 encompassed by the Formula I the general synthetic procedure set out below also allows for the preparation of the compounds of Formula II in which A is 0 or S. In Scheme B, all substituents, unless otherwise indicated, are as 5 previously defined.
SCHEME B
O O
,~J~
(4) ~ Y ~ A
A is O or S O O
step b ~ ~ z ~ 5~2 ~
y ~ A ~ R1 ' ~ A ~ o ~ R
(Formula I) (Formula I) C
A is O or S ~ A is O or S
Optional step d ~SO2 Il I Z
/~/\ \~
y ~ A
(Formula I) o A is O or S
~ VO95/14670 2 1 7 7 1 4 6 pCT~S94/l2S75 In Scheme B step a, an appropriate acid of structure (4) in which A is O or S, known analogously in the art, [Chromenes, Chromanones, andChromones, edited by G. P. Ellis (John Wiley & Sons 1977)] is contacted with an appropriate alcohol to give an ester of structure (5).
An appropriate acid of structure (4) is one in which A
is O or S and Y is as desired in the final product of the Formula I. An appropriate alcohol of the structure HOR is one which gives rise to compounds of Formula I in which Q
is -OR as desired in the final product of Formula I or gives rise to a Ql as desired in the final product of Formula I.
For example, an acid of structure (4) is contacted with an appropriate alcohol in the presence of an acid, such as sulfuric acid. The appropriate alcohol is used as the solvent. The reaction is carried out at temperatures from ambient temperature to the refluxing temperature of the alcohol. The product is recovered by techniques well known in the art, such as extraction, evaporation invacuo, chromatography with a suitable organic eluant, and recrystallization to give an ester of structure (5).
In Scheme B, step b, a compound of structure (5) is contacted with an appropriate benzenesulfonyl isocyanate to give a heterocyclic benzenesulfonylimine of Formula I in which A is O or S.
An appropriate benzenesulfonyl isocyanate is one is which Z is as desired in the final product of the Formula I
in which A is O or S.
For example, a compound of structure (5) is contacted 35 with an appropriate benzenesulfonyl isocyanate. The reaction is carried out in a suitable solvent, such as acetonitrile or propionitrile at temperatures from ambient temperature to the refluxing temperature of the solvent.
The product is recovered by techniques well known in the art, such as evaporation invacuo, chromatography with a suitable organic eluant, and recrystallization to give a compound of Formula I in which A is O or S.
s In Scheme B, Optional step c, an appropriate compound of Formula I is contacted with an appropriate amine to give a compound of Formula I in which Ql is -NR1R2 and A is O or S.
An appropriate compound of Formula I is one in which Q
is -OR, R is a Cl-C6 alkyl, A is O or S, and Y and Z are as desired in the final product of the Formula I. An appropriate amine of the structure, HNRlRz gives a compound of Formula I in which Ql is -NRlRz as desired in the final product of Formula I in which A is O or S.
For example, an appropriate compound of Formula I is contacted with an appropriate amine in a suitable solvent, such as methanol, ethanol, water, or dioxane. The reaction vessel may be sealed to prevent the escape of volatile amines from the reaction vessel. The reaction is carried out at temperatures from ambient temperature to the refluxing temperature of the solvent. The product is recovered by techniques well known in the art, such as extraction, evaporation invacuo, chromatography with a suitable organic eluant, and recrystallization.
In Scheme B, Optional step d, an appropriate compound of Formula I is hydrolyzed to give a compound of Formula I in which Ql is -OH and A is O or S.
An appropriate compound of Formula I is one in which Ql is -OR, R is a Cl-C6 alkyl, A is O or S, and Y and Z are as desired in the final product of the Formula I.
For example, an appropriate compound of Formula I is contacted with a suitable base, such as lithium hydroxide or sodium hydroxide. The reactants are typically stirred -VO95/14670 PCT~S94/12S75 together for a period of time ranging from 2-24 hours and at a temperature range of from room temperature to reflux.
The acid of Formula I in which A is O or S is recovered from the reaction zone by acidification followed by filtration and may be purified by recrystallization as is known in the art.
The following examples present typical syntheses as described in Scheme B. These examples are understood to be 10 illustrative only and are not intended to limit the scope of the invention in any way. As used in the following examples, the following terms have the meanings indicated:
"g" refers to grams, "mmol" refers to millimoles, "mL"
refers to milliliters, "~C" refers to degrees Celsius, 15 "mp" refers to melting point.
Scheme B, step a:
Chromone-2-carboxylic acid methyl ester Combine chromone-2-carboxylic acid (2.0 g, 10.5 mmol) and methanol (25 mL). Add sulfuric acid (2.5 mL) and heat to reflux. After 2 hours pour the reaction mixture into ice water and filter. Rinse the filter cake with water and a cold dilute aqueous solution of sodium bicarbonate.
25 Chromatograph on silica gel eluting with tetrahydrofuran to give a residue. Recrystallize the residue from methanol to give the title compound as a solid: mp; 120-122~C.
30 Scheme A, step b:
4-[Benzenesulfonylimino]-4H-chromene-2-carboxylic acid, methyl ester Combine chromone-2-carboxylic acid methyl ester (0.341 g, 1.66 mmol) and benzenesulfonyl isocyanate (0.365 g, 1.88 35 mmol) in acetonitrile (5.0 mL) and reflux. After 24 hours, quench the reaction with methanol (1 mL). Concentrate in vacuo and triturate with hexane. Filter to obtain a paste.
Recrystallize the paste from methanol to obtain a solid.
Recrystallize from methanol to give the title compound as a solid: mp; 144-146~C.
Interleukin-l (IL-l) consists of two polypeptides, termed IL-l~ and IL-l~,that belong to a family of cytokines that also includes tumor necrosis factor (TNF~) and IL-6.
These cytokines have overlapping biological properties, including the ability to stimulate T and B lymphocytes and 10 to effect the expression of proteins involved in many immunological and inflammatory responses.
Agents which inhibit IL-l action may do so by several mechanisms including: inhibition of IL-l production by 15 inhibition of the expression, synthesis, or release of IL-l;
antagonism at an IL-l receptor; inhibition of the IL-l induced amplification of IL-l production; or inhibition of IL-l induced production of other cytokines; etc.
It is known, for example, that IL-l is produced by 20 epithelial cells and stimulates fibroblast proliferation and release of proteolytic enzymes (e.g. collagenase) and prostaglandins in inflammatory processes, i.e. rheumatoid arthritis. See Durom, S. K.; Schmidt, J. A.; Oppenheim, J.
J.; Interleukin 1: an Immunological Per~e~live , Ann. Rev. Immunol. 3, 5 263-287 (1985), Otterness, I. G.; Bliven, M. L.; Downs, J.
T.; Natoli, E. J.; Hanson, D. C.; InhibitionofInterleukin- 1 Synthesis by Tenidap: a New Drug forArthritis, Cytokine, 3, 277-283 (1991), and Miyasaka, N.; Sato, K.; Goto, M.; Sasano, M.;
Natsuyma, M.; Inoue, K.; and Nishioks, K., Augmented 30 Interleukin-1 Production and HL,A-DR Expression in the Synouium of Rheumatoid Arthritis Patients, Arthritis and Rheumatism, 31, 480-486 (1988). Thus agents which inhibit IL-l action would be useful in the treatment of rheumatoid arthritis.
35 It has also been shown that IL-l may affect the pathogenesis of atherosclerosis directly, by stimulating smooth muscle cell proliferation or, indirectly, through the - ~oss/14670 2 1 7 7 1 4 6 PCT~S94/12S7S
action of platelet-derived growth factor (PDGF). See Jackson, R. L. and Ku, G., Interleukin-1~, itsRoleinthePathogenesis of Atherosclerosis and Agents that Inhibit its Action, Current Druqs:
Anti-atherosclerotic Aqents, pp 831-B42 (October 1991).
5 In addition, Tenidap, an agent known to block IL-l production, reduces the total level of serum cholesterol, serum LDL cholesterol and serum triglycerides in a mammal having an arthritic condition for which Tenidap is being administered. See U.S. Patent No. 5,122,534 (February 8, 10 1991). Thus agents which inhibit IL-l action may also be useful in the prophylactic treatment of atherosclerosis.
In addition, it has also been postulated that macrophages infiltrating the pancreatic islets may play a 15 role in the destruction of ~-cells and that cytokines, in particular IL-l, released locally from the macrophages may be the toxic molecules causing ~-cell destruction in insulin-dependent diabetes mellitus (IDDM). See Sandler, S., Eizirik, D., Svensson, C., Strandell, E., Welsh, M. and 20 Welsh, N., Biochemical and MolecularAction of Interleukin l on Pancreatic ~-Cells, Autoimmunity, 10, 241-253 (1991). Thus agents which inhibit IL-l action may also be useful in the treatment of diabetes mellitus.
A correlation has also been shown between increased IL-l 25 production and the clinical course of multiple sclerosis (MS). It has been demonstrated that there is a significant increase in IL-la production by cultured blood mononuclear cells for patients with MS, with patients in the active phase of relapsing MS showing the greatest increase in IL-la 30 production. See Matsuda, M., Tsukada, N., Miyagi, K., and Yanagisawa, N., Increased Interleukin-l production by peripheral blood mononuclearcells in patients with multiple sclerosis, Journal of the Neuroloqical Sciences, 102, 100-104 (1991). Thus agents which inhibit IL-l action may also be useful in the 35 treatment of multiple sclerosis.
WO95/14670 PCT~S94/12575 Studies have also shown that IL-l receptor antagonists might be useful for the treatment of incipient or established pulmonary fibrosis. See Piguet, P., Vesin, C., Grau, G., Thompson, R., Interleukin-1 ReceptorAntagonist ~IL-l ra) 5 Prevents or Cures Pulmonary Fibrosis Flicited in Mice By Bleomycin or Silica, Cytokine, 5, 57-61 (1993). Thus agents which inhibit IL-l action may also be useful in the treatment of pulmonary fibrosis.
It has also been suggested that IL-l receptor antagonists may play a role in reducing mortality from septic shock. See Ohlsson, K., Bjork, P., Bergenfeldt, M., Hageman, R., and Thompson, R., Interleukin-l ReceptorAntagonist Re~cesMortalityfromEndotoxinShock, Nature, 348, 550-552 15 (l990). Thus agents which inhibit IL-l action may also be useful in the treatment of septic shock.
The compounds of Formula I inhibit IL-l action. One mechanism for inhibiting IL-l action is to inhibit IL-l production. Inhibition of IL-l production was tested using 20 lipopolysaccharide (LPS) stimulated macrophages. Inhibition of IL-l induced production of cytokines was tested by measuring the inhibition of TNF~ (tumor necrosis factor alpha) synthesis from IL-l stimulated macrophages, The protocols for these test procedures are described below.
.i Endotoxin-Induced Interleukin-l Beta Release by ~uman Macrophaqes 30 Obiective The objective of this test is to determine the inhibitory concentrations for the test compounds against endotoxin-induced interleukin-l beta (IL-l~) release (production) by human peripheral blood monocyte-derived macrophages.
Source The source of the human peripheral blood monocyte-derived macrophages is as follows:
'~095/14670 PCT~S94/12S75 Venous blood is collected from healthy volunteers in 10 mM
sodium citrate (2 mL sterile sodium citrate for 40 mL
blood). Mononuclear cells are isolated with the Leucoprep 5 tubes (Becton Dickenson, product number 2752 or 2751) spun at 1500 g for 15 minutes. Aliquots of 3 x 106 mononuclear cells are added to 24-well tissue culture plates (Corning) in RPMI-1640. After one hour incubation at 37~C, non-adherent cells are gently rinsed off. The adherent cells 10 (macrophages) are given back fresh medium RPMI-1640, 1 mL/well.
Procedure Macrophage monolayer cultures are pretreated with compounds one hour prior to endotoxin (20 ng/mL, Salmonella 15 typhimurium, Re-mutant, from Ribi Immuchem.) stimulation.
Compounds dissolved in 95% ethanol or DMSO would require additional monolayer cultures treated with 10 or 2.5 ~1 95 ethanol or DMSO, respectively. Culture supernatants are collected 24 hours later and are tested for IL-lB using a 20 commercial ELISA kit (Cistron).
AnalysisofResults The IL-lB concentration in the culture supernatant is calculated by a standard curve generated from a series of known concentrations. Potency of compound is 25 reported in IC50 (~M).
Results:
Compound IC60 5,7-Dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester 6~M
35 5,7-Dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, ethyl ester 2~M
WO95/14670 2 1 77 1 46 PCT~S94/12575 5,7-Dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, butyl ester 3~M
5,7-Dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid-N-methylamide 3~M
4-[Benzenesulfonylimino]-4H-chromene-2-carboxylic acid, methyl ester 3~M
Interleukin-l-Beta-Induced Tumor Necrosis Factor Alpha Release by ~uman Macrophaqes Objectiue To determine the inhibitory concentrations for the test compounds against interleukin-l beta (IL-lB)-induced tumor necrosis factor alpha (TNF~) release by human 20 peripheral blood monocyte-derived macrophages. It should be understood that this is a test of the ability of the test compounds to modulate, i.e. inhibit, the activity of IL-lB
by measuring the inhibition of IL-lB induced release of TNF~.
SourceHuman peripheral blood monoc~te-derived macropha~es:
Venous blood is collected form healthy volunteers in 10 mM
sodium citrate (2 mL sterile sodium citrate for 40 mL
30 blood). Mononuclear cells are isolated with the Leucoprep tubes (Becton Dickinson, product number 2752 or 2751) spun at 1500 g for fifteen minutes. Aliquots of 3 x 106 mononuclear cells are added to 24-well tissue culture plates (Corning) in RPMI-1640. After 1 hour incubation at 37~C, 35 non-adherent cells are gently rinsed off. The adherent cells - (macrophages) are given back fresh medium RPMI-1640, 1 mL/well.
'~OgS/14670 PCT~sg4ll2s7s Procedure Macrophage monolayer cultures are pretreated with compounds one hour prior to IL-lB (20 ng/mL, recombinant human IL-lB) stimulation. Compounds dissolved in 95% ethanol 5 or DMSO would require additional monolayer cultures treated with lO or 2.5~1 95~ ethanol or DMSO, respectively. Culture supernatants are collected 24 hours later and are tested for TNF-a using a commercial ELISA kit (Cistron).
10 Analysis of Results The TNF-~ concentration in the culture supernatant is calculated by a standard curve generated from a series of known concentrations. Potency of compound is reported in IC50 (~M).
15 Results:
Com~c! n~l IC50 5,7-Dichloro-4-[benzenesulfonylimino]-20 l,4-dihydroquinoline-2-carboxylic acid, methyl ester 3~M
5,7-Dichloro-4-[benzenesulfonylimino]-l,4-dihydroquinoline-2-carboxylic 25 acid, ethyl ester 3~M
5,7-Dichloro-4-[benzenesulfonylimino]-l,4-dihydroquinoline-2-carboxylic acid, butyl ester 5~M
5,7-dichloro-4-[benzenesulfonylimino]-l,4-dihydroquinoline-2-carboxylic acid-N-methylamide 4~M
4-[Benzenesulfonylimino]-4~-chromene-2-carboxylic acid, methyl ester 2~M
WO95/14670 2 1 7 7 1 4 6 PCT~Sg4/12575 The compounds of the present invention may be administered by a variety of routes. They are effective if administered orally. The compounds may also be administered 5 parenterally (i.e. subcutaneously, intravenously, intramuscularly, intraperitoneally, or intrathecally).
In order to exhibit these therapeutic properties, the compounds need to be administered in a quantity sufficient to inhibit IL-l action. The dosage range at which these compounds exhibit this inhibitory effect can vary widely depending upon the particular disease being treated, the severity of the patient's disease, the patient, the particular compound being administered, the route of administration, and the presence of other underlying disease states within the patient, etc. Typically the compounds exhibit their therapeutic effect at a dosage range of from about O.l mg/kg/day to about 50 mg/kg/day for any of the diseases or conditions listed above.
Pharmaceutical compositions can be manufactured utilizing techniques known in the art. Typically an effective amount of the compound will be admixed with a pharmaceutically acceptable carrier.
For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions, or emulsions. Solid unit dosage forms can be capsules of the 30 ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and cornstarch or they can be sustained release preparations.
In another embodiment, the compounds of Formula I can be 35 tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch, or selatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as ~~~Og5/14670 PCT~S94/~2575 stearic acid or magnesium stearate. Liquid preparations are prepared by dissolving the active ingredient in an aqueous or non-aqueous pharmaceutically acceptable solvent which may also contain suspending agents, sweetening agents, flavoring 5 agents, and preservative agents as are known in the art.
For parenteral administration the compounds may be dissolved in a physiologically acceptable pharmaceutical carrier and administered as either a solution or a lO suspension. Illustrative of suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin. The pharmaceutical carrier may also contain preservatives, buffers, etc., as are known in the 15 art.
As used in this application:
a) the "patient" refers to warm blooded animals such as, for example guinea pigs, mice, rats, cats, rabbits, dogs, monkeys, chimpanzees, and human;
b) the term "treat" refers to the ability of the compounds to either relieve, alleviate, or slow the progression of the patient's disease.
c) the term "an effective amount" refers to an amount which is effective, upon single or multiple dose administration to the patient, in inhibiting IL-l action.
The compounds of this invention can also be administered topically. This can be accomplished by simply preparing a solution of the compound to be administered, preferably using a solvent known to promote transdermal absorption such as ethanol or dimethyl sulfoxide (DMSO) with or without other excipients. Preferably topical administration will be accomplished using a patch either of Woss/14670 2 1 7 7 1 4 S PCT~S94/12S75 the reservoir and porous membrane type or of a solid matrix variety.
Some suitable transdermal devices are described in U.S.
Pat. Nos. 3,742,951; 3,797,494; 3,996,934; and 4,031,894.
These devices generally contain a backing member which defines one of its face surfaces, an active agent permeable adhesive layer defining the other face surface and at least one reservoir containing the active agent interposed between the face surfaces. Alternatively, the active agent may be contained in a plurality of microcapsules distri-buted throughout the permeable adhesive layer. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predeter-mined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane.
In another device for transdermally administering the compounds in accordance with the present invention, the pharmaceutically active compound is contained in a matrix from which it is delivered in the desired gradual, constant and controlled rate. The matrix is permeable to the release of the compound through diffusion or microporous flow. The release is rate controlling. Such a system, which reguires no membrane is described in U.S. Pat. No.
3,921,636. At least two types of release are possible in these systems. Release by diffusion occurs when the matrix is nonporous. The pharmaceutically effective compound dissolves in and diffuses through the matrix itself.
Release by microporous flow occurs when the pharmaceu-tically effective compound is transported through a liquidphase in the pores of the matrix.
- ~095/14670 PCT~S94/1257s While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art.
A is O or S O O
step b ~ ~ z ~ 5~2 ~
y ~ A ~ R1 ' ~ A ~ o ~ R
(Formula I) (Formula I) C
A is O or S ~ A is O or S
Optional step d ~SO2 Il I Z
/~/\ \~
y ~ A
(Formula I) o A is O or S
~ VO95/14670 2 1 7 7 1 4 6 pCT~S94/l2S75 In Scheme B step a, an appropriate acid of structure (4) in which A is O or S, known analogously in the art, [Chromenes, Chromanones, andChromones, edited by G. P. Ellis (John Wiley & Sons 1977)] is contacted with an appropriate alcohol to give an ester of structure (5).
An appropriate acid of structure (4) is one in which A
is O or S and Y is as desired in the final product of the Formula I. An appropriate alcohol of the structure HOR is one which gives rise to compounds of Formula I in which Q
is -OR as desired in the final product of Formula I or gives rise to a Ql as desired in the final product of Formula I.
For example, an acid of structure (4) is contacted with an appropriate alcohol in the presence of an acid, such as sulfuric acid. The appropriate alcohol is used as the solvent. The reaction is carried out at temperatures from ambient temperature to the refluxing temperature of the alcohol. The product is recovered by techniques well known in the art, such as extraction, evaporation invacuo, chromatography with a suitable organic eluant, and recrystallization to give an ester of structure (5).
In Scheme B, step b, a compound of structure (5) is contacted with an appropriate benzenesulfonyl isocyanate to give a heterocyclic benzenesulfonylimine of Formula I in which A is O or S.
An appropriate benzenesulfonyl isocyanate is one is which Z is as desired in the final product of the Formula I
in which A is O or S.
For example, a compound of structure (5) is contacted 35 with an appropriate benzenesulfonyl isocyanate. The reaction is carried out in a suitable solvent, such as acetonitrile or propionitrile at temperatures from ambient temperature to the refluxing temperature of the solvent.
The product is recovered by techniques well known in the art, such as evaporation invacuo, chromatography with a suitable organic eluant, and recrystallization to give a compound of Formula I in which A is O or S.
s In Scheme B, Optional step c, an appropriate compound of Formula I is contacted with an appropriate amine to give a compound of Formula I in which Ql is -NR1R2 and A is O or S.
An appropriate compound of Formula I is one in which Q
is -OR, R is a Cl-C6 alkyl, A is O or S, and Y and Z are as desired in the final product of the Formula I. An appropriate amine of the structure, HNRlRz gives a compound of Formula I in which Ql is -NRlRz as desired in the final product of Formula I in which A is O or S.
For example, an appropriate compound of Formula I is contacted with an appropriate amine in a suitable solvent, such as methanol, ethanol, water, or dioxane. The reaction vessel may be sealed to prevent the escape of volatile amines from the reaction vessel. The reaction is carried out at temperatures from ambient temperature to the refluxing temperature of the solvent. The product is recovered by techniques well known in the art, such as extraction, evaporation invacuo, chromatography with a suitable organic eluant, and recrystallization.
In Scheme B, Optional step d, an appropriate compound of Formula I is hydrolyzed to give a compound of Formula I in which Ql is -OH and A is O or S.
An appropriate compound of Formula I is one in which Ql is -OR, R is a Cl-C6 alkyl, A is O or S, and Y and Z are as desired in the final product of the Formula I.
For example, an appropriate compound of Formula I is contacted with a suitable base, such as lithium hydroxide or sodium hydroxide. The reactants are typically stirred -VO95/14670 PCT~S94/12S75 together for a period of time ranging from 2-24 hours and at a temperature range of from room temperature to reflux.
The acid of Formula I in which A is O or S is recovered from the reaction zone by acidification followed by filtration and may be purified by recrystallization as is known in the art.
The following examples present typical syntheses as described in Scheme B. These examples are understood to be 10 illustrative only and are not intended to limit the scope of the invention in any way. As used in the following examples, the following terms have the meanings indicated:
"g" refers to grams, "mmol" refers to millimoles, "mL"
refers to milliliters, "~C" refers to degrees Celsius, 15 "mp" refers to melting point.
Scheme B, step a:
Chromone-2-carboxylic acid methyl ester Combine chromone-2-carboxylic acid (2.0 g, 10.5 mmol) and methanol (25 mL). Add sulfuric acid (2.5 mL) and heat to reflux. After 2 hours pour the reaction mixture into ice water and filter. Rinse the filter cake with water and a cold dilute aqueous solution of sodium bicarbonate.
25 Chromatograph on silica gel eluting with tetrahydrofuran to give a residue. Recrystallize the residue from methanol to give the title compound as a solid: mp; 120-122~C.
30 Scheme A, step b:
4-[Benzenesulfonylimino]-4H-chromene-2-carboxylic acid, methyl ester Combine chromone-2-carboxylic acid methyl ester (0.341 g, 1.66 mmol) and benzenesulfonyl isocyanate (0.365 g, 1.88 35 mmol) in acetonitrile (5.0 mL) and reflux. After 24 hours, quench the reaction with methanol (1 mL). Concentrate in vacuo and triturate with hexane. Filter to obtain a paste.
Recrystallize the paste from methanol to obtain a solid.
Recrystallize from methanol to give the title compound as a solid: mp; 144-146~C.
Interleukin-l (IL-l) consists of two polypeptides, termed IL-l~ and IL-l~,that belong to a family of cytokines that also includes tumor necrosis factor (TNF~) and IL-6.
These cytokines have overlapping biological properties, including the ability to stimulate T and B lymphocytes and 10 to effect the expression of proteins involved in many immunological and inflammatory responses.
Agents which inhibit IL-l action may do so by several mechanisms including: inhibition of IL-l production by 15 inhibition of the expression, synthesis, or release of IL-l;
antagonism at an IL-l receptor; inhibition of the IL-l induced amplification of IL-l production; or inhibition of IL-l induced production of other cytokines; etc.
It is known, for example, that IL-l is produced by 20 epithelial cells and stimulates fibroblast proliferation and release of proteolytic enzymes (e.g. collagenase) and prostaglandins in inflammatory processes, i.e. rheumatoid arthritis. See Durom, S. K.; Schmidt, J. A.; Oppenheim, J.
J.; Interleukin 1: an Immunological Per~e~live , Ann. Rev. Immunol. 3, 5 263-287 (1985), Otterness, I. G.; Bliven, M. L.; Downs, J.
T.; Natoli, E. J.; Hanson, D. C.; InhibitionofInterleukin- 1 Synthesis by Tenidap: a New Drug forArthritis, Cytokine, 3, 277-283 (1991), and Miyasaka, N.; Sato, K.; Goto, M.; Sasano, M.;
Natsuyma, M.; Inoue, K.; and Nishioks, K., Augmented 30 Interleukin-1 Production and HL,A-DR Expression in the Synouium of Rheumatoid Arthritis Patients, Arthritis and Rheumatism, 31, 480-486 (1988). Thus agents which inhibit IL-l action would be useful in the treatment of rheumatoid arthritis.
35 It has also been shown that IL-l may affect the pathogenesis of atherosclerosis directly, by stimulating smooth muscle cell proliferation or, indirectly, through the - ~oss/14670 2 1 7 7 1 4 6 PCT~S94/12S7S
action of platelet-derived growth factor (PDGF). See Jackson, R. L. and Ku, G., Interleukin-1~, itsRoleinthePathogenesis of Atherosclerosis and Agents that Inhibit its Action, Current Druqs:
Anti-atherosclerotic Aqents, pp 831-B42 (October 1991).
5 In addition, Tenidap, an agent known to block IL-l production, reduces the total level of serum cholesterol, serum LDL cholesterol and serum triglycerides in a mammal having an arthritic condition for which Tenidap is being administered. See U.S. Patent No. 5,122,534 (February 8, 10 1991). Thus agents which inhibit IL-l action may also be useful in the prophylactic treatment of atherosclerosis.
In addition, it has also been postulated that macrophages infiltrating the pancreatic islets may play a 15 role in the destruction of ~-cells and that cytokines, in particular IL-l, released locally from the macrophages may be the toxic molecules causing ~-cell destruction in insulin-dependent diabetes mellitus (IDDM). See Sandler, S., Eizirik, D., Svensson, C., Strandell, E., Welsh, M. and 20 Welsh, N., Biochemical and MolecularAction of Interleukin l on Pancreatic ~-Cells, Autoimmunity, 10, 241-253 (1991). Thus agents which inhibit IL-l action may also be useful in the treatment of diabetes mellitus.
A correlation has also been shown between increased IL-l 25 production and the clinical course of multiple sclerosis (MS). It has been demonstrated that there is a significant increase in IL-la production by cultured blood mononuclear cells for patients with MS, with patients in the active phase of relapsing MS showing the greatest increase in IL-la 30 production. See Matsuda, M., Tsukada, N., Miyagi, K., and Yanagisawa, N., Increased Interleukin-l production by peripheral blood mononuclearcells in patients with multiple sclerosis, Journal of the Neuroloqical Sciences, 102, 100-104 (1991). Thus agents which inhibit IL-l action may also be useful in the 35 treatment of multiple sclerosis.
WO95/14670 PCT~S94/12575 Studies have also shown that IL-l receptor antagonists might be useful for the treatment of incipient or established pulmonary fibrosis. See Piguet, P., Vesin, C., Grau, G., Thompson, R., Interleukin-1 ReceptorAntagonist ~IL-l ra) 5 Prevents or Cures Pulmonary Fibrosis Flicited in Mice By Bleomycin or Silica, Cytokine, 5, 57-61 (1993). Thus agents which inhibit IL-l action may also be useful in the treatment of pulmonary fibrosis.
It has also been suggested that IL-l receptor antagonists may play a role in reducing mortality from septic shock. See Ohlsson, K., Bjork, P., Bergenfeldt, M., Hageman, R., and Thompson, R., Interleukin-l ReceptorAntagonist Re~cesMortalityfromEndotoxinShock, Nature, 348, 550-552 15 (l990). Thus agents which inhibit IL-l action may also be useful in the treatment of septic shock.
The compounds of Formula I inhibit IL-l action. One mechanism for inhibiting IL-l action is to inhibit IL-l production. Inhibition of IL-l production was tested using 20 lipopolysaccharide (LPS) stimulated macrophages. Inhibition of IL-l induced production of cytokines was tested by measuring the inhibition of TNF~ (tumor necrosis factor alpha) synthesis from IL-l stimulated macrophages, The protocols for these test procedures are described below.
.i Endotoxin-Induced Interleukin-l Beta Release by ~uman Macrophaqes 30 Obiective The objective of this test is to determine the inhibitory concentrations for the test compounds against endotoxin-induced interleukin-l beta (IL-l~) release (production) by human peripheral blood monocyte-derived macrophages.
Source The source of the human peripheral blood monocyte-derived macrophages is as follows:
'~095/14670 PCT~S94/12S75 Venous blood is collected from healthy volunteers in 10 mM
sodium citrate (2 mL sterile sodium citrate for 40 mL
blood). Mononuclear cells are isolated with the Leucoprep 5 tubes (Becton Dickenson, product number 2752 or 2751) spun at 1500 g for 15 minutes. Aliquots of 3 x 106 mononuclear cells are added to 24-well tissue culture plates (Corning) in RPMI-1640. After one hour incubation at 37~C, non-adherent cells are gently rinsed off. The adherent cells 10 (macrophages) are given back fresh medium RPMI-1640, 1 mL/well.
Procedure Macrophage monolayer cultures are pretreated with compounds one hour prior to endotoxin (20 ng/mL, Salmonella 15 typhimurium, Re-mutant, from Ribi Immuchem.) stimulation.
Compounds dissolved in 95% ethanol or DMSO would require additional monolayer cultures treated with 10 or 2.5 ~1 95 ethanol or DMSO, respectively. Culture supernatants are collected 24 hours later and are tested for IL-lB using a 20 commercial ELISA kit (Cistron).
AnalysisofResults The IL-lB concentration in the culture supernatant is calculated by a standard curve generated from a series of known concentrations. Potency of compound is 25 reported in IC50 (~M).
Results:
Compound IC60 5,7-Dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester 6~M
35 5,7-Dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, ethyl ester 2~M
WO95/14670 2 1 77 1 46 PCT~S94/12575 5,7-Dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, butyl ester 3~M
5,7-Dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid-N-methylamide 3~M
4-[Benzenesulfonylimino]-4H-chromene-2-carboxylic acid, methyl ester 3~M
Interleukin-l-Beta-Induced Tumor Necrosis Factor Alpha Release by ~uman Macrophaqes Objectiue To determine the inhibitory concentrations for the test compounds against interleukin-l beta (IL-lB)-induced tumor necrosis factor alpha (TNF~) release by human 20 peripheral blood monocyte-derived macrophages. It should be understood that this is a test of the ability of the test compounds to modulate, i.e. inhibit, the activity of IL-lB
by measuring the inhibition of IL-lB induced release of TNF~.
SourceHuman peripheral blood monoc~te-derived macropha~es:
Venous blood is collected form healthy volunteers in 10 mM
sodium citrate (2 mL sterile sodium citrate for 40 mL
30 blood). Mononuclear cells are isolated with the Leucoprep tubes (Becton Dickinson, product number 2752 or 2751) spun at 1500 g for fifteen minutes. Aliquots of 3 x 106 mononuclear cells are added to 24-well tissue culture plates (Corning) in RPMI-1640. After 1 hour incubation at 37~C, 35 non-adherent cells are gently rinsed off. The adherent cells - (macrophages) are given back fresh medium RPMI-1640, 1 mL/well.
'~OgS/14670 PCT~sg4ll2s7s Procedure Macrophage monolayer cultures are pretreated with compounds one hour prior to IL-lB (20 ng/mL, recombinant human IL-lB) stimulation. Compounds dissolved in 95% ethanol 5 or DMSO would require additional monolayer cultures treated with lO or 2.5~1 95~ ethanol or DMSO, respectively. Culture supernatants are collected 24 hours later and are tested for TNF-a using a commercial ELISA kit (Cistron).
10 Analysis of Results The TNF-~ concentration in the culture supernatant is calculated by a standard curve generated from a series of known concentrations. Potency of compound is reported in IC50 (~M).
15 Results:
Com~c! n~l IC50 5,7-Dichloro-4-[benzenesulfonylimino]-20 l,4-dihydroquinoline-2-carboxylic acid, methyl ester 3~M
5,7-Dichloro-4-[benzenesulfonylimino]-l,4-dihydroquinoline-2-carboxylic 25 acid, ethyl ester 3~M
5,7-Dichloro-4-[benzenesulfonylimino]-l,4-dihydroquinoline-2-carboxylic acid, butyl ester 5~M
5,7-dichloro-4-[benzenesulfonylimino]-l,4-dihydroquinoline-2-carboxylic acid-N-methylamide 4~M
4-[Benzenesulfonylimino]-4~-chromene-2-carboxylic acid, methyl ester 2~M
WO95/14670 2 1 7 7 1 4 6 PCT~Sg4/12575 The compounds of the present invention may be administered by a variety of routes. They are effective if administered orally. The compounds may also be administered 5 parenterally (i.e. subcutaneously, intravenously, intramuscularly, intraperitoneally, or intrathecally).
In order to exhibit these therapeutic properties, the compounds need to be administered in a quantity sufficient to inhibit IL-l action. The dosage range at which these compounds exhibit this inhibitory effect can vary widely depending upon the particular disease being treated, the severity of the patient's disease, the patient, the particular compound being administered, the route of administration, and the presence of other underlying disease states within the patient, etc. Typically the compounds exhibit their therapeutic effect at a dosage range of from about O.l mg/kg/day to about 50 mg/kg/day for any of the diseases or conditions listed above.
Pharmaceutical compositions can be manufactured utilizing techniques known in the art. Typically an effective amount of the compound will be admixed with a pharmaceutically acceptable carrier.
For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions, or emulsions. Solid unit dosage forms can be capsules of the 30 ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and cornstarch or they can be sustained release preparations.
In another embodiment, the compounds of Formula I can be 35 tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch, or selatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as ~~~Og5/14670 PCT~S94/~2575 stearic acid or magnesium stearate. Liquid preparations are prepared by dissolving the active ingredient in an aqueous or non-aqueous pharmaceutically acceptable solvent which may also contain suspending agents, sweetening agents, flavoring 5 agents, and preservative agents as are known in the art.
For parenteral administration the compounds may be dissolved in a physiologically acceptable pharmaceutical carrier and administered as either a solution or a lO suspension. Illustrative of suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin. The pharmaceutical carrier may also contain preservatives, buffers, etc., as are known in the 15 art.
As used in this application:
a) the "patient" refers to warm blooded animals such as, for example guinea pigs, mice, rats, cats, rabbits, dogs, monkeys, chimpanzees, and human;
b) the term "treat" refers to the ability of the compounds to either relieve, alleviate, or slow the progression of the patient's disease.
c) the term "an effective amount" refers to an amount which is effective, upon single or multiple dose administration to the patient, in inhibiting IL-l action.
The compounds of this invention can also be administered topically. This can be accomplished by simply preparing a solution of the compound to be administered, preferably using a solvent known to promote transdermal absorption such as ethanol or dimethyl sulfoxide (DMSO) with or without other excipients. Preferably topical administration will be accomplished using a patch either of Woss/14670 2 1 7 7 1 4 S PCT~S94/12S75 the reservoir and porous membrane type or of a solid matrix variety.
Some suitable transdermal devices are described in U.S.
Pat. Nos. 3,742,951; 3,797,494; 3,996,934; and 4,031,894.
These devices generally contain a backing member which defines one of its face surfaces, an active agent permeable adhesive layer defining the other face surface and at least one reservoir containing the active agent interposed between the face surfaces. Alternatively, the active agent may be contained in a plurality of microcapsules distri-buted throughout the permeable adhesive layer. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predeter-mined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane.
In another device for transdermally administering the compounds in accordance with the present invention, the pharmaceutically active compound is contained in a matrix from which it is delivered in the desired gradual, constant and controlled rate. The matrix is permeable to the release of the compound through diffusion or microporous flow. The release is rate controlling. Such a system, which reguires no membrane is described in U.S. Pat. No.
3,921,636. At least two types of release are possible in these systems. Release by diffusion occurs when the matrix is nonporous. The pharmaceutically effective compound dissolves in and diffuses through the matrix itself.
Release by microporous flow occurs when the pharmaceu-tically effective compound is transported through a liquidphase in the pores of the matrix.
- ~095/14670 PCT~S94/1257s While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art.
Claims (12)
1. Use in the manufacture of a medicament for inhibiting IL-1 action of compounds of the structure wherein A is NH, O, or S;
Q1 is -OR or -NR1R2; wherein R, R1 and R2 are each independently hydrogen or C1-C6 alkyl radical of branched, straight chained, or cyclic configuration, wherein in the case of a cyclic configuration is C3-C6 cycloalkyl;
Z is from 1 to 3 substituents chosen independently from the group: halogen, C1-C4 alkyl, and C1-C4 alkoxy;
Y is from 1 to 3 substituents chosen independently from the group: C1-C4 alkyl, C1-C4 alkoxy, and halogen.
Q1 is -OR or -NR1R2; wherein R, R1 and R2 are each independently hydrogen or C1-C6 alkyl radical of branched, straight chained, or cyclic configuration, wherein in the case of a cyclic configuration is C3-C6 cycloalkyl;
Z is from 1 to 3 substituents chosen independently from the group: halogen, C1-C4 alkyl, and C1-C4 alkoxy;
Y is from 1 to 3 substituents chosen independently from the group: C1-C4 alkyl, C1-C4 alkoxy, and halogen.
2. Use according to claim 1 for the treatment of an inflammatory disease.
3. Use according to claim 1 for the treatment of multiple sclerosis.
4. Use according to claim 1 for the treatment of insulin-dependent diabetes mellitus.
5. Use according to claim 1 for the treatment or prevention of atherosclerosis.
6. Use according to claim 1 for the treatment or prevention of septic shock.
7. Use according to claim 1 for the treatment of pulmonary fibrosis.
8. Use according to claim 1 for the treatment of rheumatoid arthritis.
9. A compound of formula wherein A' is O or S;
Q2 is -OR3 or -NR1R2; wherein R1, R2 and R3 are each independently C1-C6 alkyl radical of branched, straight chained, or cyclic configuration, wherein in the case of a cyclic configuration is C3-C6 cycloalkyl;
Z is from 1 to 3 substituents chosen independently from the group: halogen, C1-C4 alkyl, and C1-C4 alkoxy;
Y is from 1 to 3 substituents chosen independently from the group: C1-C4 alkyl, C1-C4 alkoxy, and halogen.
Q2 is -OR3 or -NR1R2; wherein R1, R2 and R3 are each independently C1-C6 alkyl radical of branched, straight chained, or cyclic configuration, wherein in the case of a cyclic configuration is C3-C6 cycloalkyl;
Z is from 1 to 3 substituents chosen independently from the group: halogen, C1-C4 alkyl, and C1-C4 alkoxy;
Y is from 1 to 3 substituents chosen independently from the group: C1-C4 alkyl, C1-C4 alkoxy, and halogen.
10. The compound according to claim 9 which is 4-[benzenesulfonylimino]]-4H-chromene-2-carboxylic acid, methyl ester.
11. The compound according to claim 9 which is 4-[benzenesulfonylimino]]-4H-thiochromene-2-carboxylic acid, methyl ester.
12. A pharmaceutical composition comprising an effective amount of a compound according to claim 9 in admixture with a pharmaceutically acceptable carrier.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US15866193A | 1993-11-29 | 1993-11-29 | |
| US08/158,661 | 1993-11-29 | ||
| PCT/US1994/012575 WO1995014670A1 (en) | 1993-11-29 | 1994-11-03 | Heterocyclic benzenesulfonylimine derivatives as inhibitors of il-1 action |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2177146A1 CA2177146A1 (en) | 1995-06-01 |
| CA2177146C true CA2177146C (en) | 1999-07-06 |
Family
ID=22569128
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002177146A Expired - Fee Related CA2177146C (en) | 1993-11-29 | 1994-11-03 | Heterocyclic benzenesulfonylimine derivatives as inhibitors of il-1 action |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US5668143A (en) |
| EP (1) | EP0731792B1 (en) |
| JP (1) | JP3612073B2 (en) |
| KR (1) | KR100351884B1 (en) |
| CN (1) | CN1045596C (en) |
| AT (1) | ATE176225T1 (en) |
| AU (1) | AU682736B2 (en) |
| CA (1) | CA2177146C (en) |
| DE (1) | DE69416324T2 (en) |
| DK (1) | DK0731792T3 (en) |
| ES (1) | ES2129794T3 (en) |
| FI (1) | FI113368B (en) |
| GR (1) | GR3029485T3 (en) |
| HU (1) | HU222819B1 (en) |
| IL (1) | IL111774A (en) |
| NO (1) | NO306158B1 (en) |
| NZ (1) | NZ276570A (en) |
| TW (1) | TW281671B (en) |
| WO (1) | WO1995014670A1 (en) |
| ZA (1) | ZA949301B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU219565B (en) * | 1993-11-29 | 2001-05-28 | Merrell Pharmaceuticals Inc. | Novel benzenesulfonylimine derivatives as inhibitors of il-1 action and use thereof |
| US7048906B2 (en) | 1995-05-17 | 2006-05-23 | Cedars-Sinai Medical Center | Methods of diagnosing and treating small intestinal bacterial overgrowth (SIBO) and SIBO-related conditions |
| US6861053B1 (en) * | 1999-08-11 | 2005-03-01 | Cedars-Sinai Medical Center | Methods of diagnosing or treating irritable bowel syndrome and other disorders caused by small intestinal bacterial overgrowth |
| US6562629B1 (en) | 1999-08-11 | 2003-05-13 | Cedars-Sinai Medical Center | Method of diagnosing irritable bowel syndrome and other disorders caused by small intestinal bacterial overgrowth by detecting the presence of anti-saccharomyces cerivisiae antibodies (asca) in human serum |
| WO2003001968A2 (en) * | 2001-06-26 | 2003-01-09 | Beth Israel Deaconess Medical Center | Compositions and methods for inhibiting platelet activation and thrombosis |
| KR100687522B1 (en) * | 2005-05-28 | 2007-02-27 | 한국화학연구원 | Therapeutic agent for antiinflammatory disease induced by pge2 activity containing 2,2-dimethyl-3-ester-4-alkoxy-6-alkyl amino benzopyrane derivatives as an effective ingredient |
| EP2771180B1 (en) | 2011-10-28 | 2016-05-04 | Alfred Iseli | Method for manufacturing ultralight cardboard structures having substantial mechanical stability |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3797494A (en) * | 1969-04-01 | 1974-03-19 | Alza Corp | Bandage for the administration of drug by controlled metering through microporous materials |
| US3742951A (en) * | 1971-08-09 | 1973-07-03 | Alza Corp | Bandage for controlled release of vasodilators |
| US3996934A (en) * | 1971-08-09 | 1976-12-14 | Alza Corporation | Medical bandage |
| US3921636A (en) * | 1973-01-15 | 1975-11-25 | Alza Corp | Novel drug delivery device |
| US4031894A (en) * | 1975-12-08 | 1977-06-28 | Alza Corporation | Bandage for transdermally administering scopolamine to prevent nausea |
| GB8719102D0 (en) * | 1987-08-12 | 1987-09-16 | Merck Sharp & Dohme | Therapeutic agents |
| JP3465794B2 (en) * | 1991-02-27 | 2003-11-10 | メレルファーマスーティカルズ インコーポレイテッド | NMDA antagonist |
| JPH05331169A (en) * | 1992-05-26 | 1993-12-14 | Sumitomo Pharmaceut Co Ltd | Benzonaphthaylidine derivative |
-
1994
- 1994-11-03 DK DK95901741T patent/DK0731792T3/en active
- 1994-11-03 EP EP95901741A patent/EP0731792B1/en not_active Expired - Lifetime
- 1994-11-03 KR KR1019960702790A patent/KR100351884B1/en not_active IP Right Cessation
- 1994-11-03 AT AT95901741T patent/ATE176225T1/en not_active IP Right Cessation
- 1994-11-03 CN CN94194303A patent/CN1045596C/en not_active Expired - Fee Related
- 1994-11-03 ES ES95901741T patent/ES2129794T3/en not_active Expired - Lifetime
- 1994-11-03 DE DE69416324T patent/DE69416324T2/en not_active Expired - Lifetime
- 1994-11-03 CA CA002177146A patent/CA2177146C/en not_active Expired - Fee Related
- 1994-11-03 NZ NZ276570A patent/NZ276570A/en unknown
- 1994-11-03 US US08/648,150 patent/US5668143A/en not_active Expired - Lifetime
- 1994-11-03 JP JP51507995A patent/JP3612073B2/en not_active Expired - Fee Related
- 1994-11-03 HU HU9601434A patent/HU222819B1/en not_active IP Right Cessation
- 1994-11-03 AU AU10868/95A patent/AU682736B2/en not_active Ceased
- 1994-11-03 WO PCT/US1994/012575 patent/WO1995014670A1/en active IP Right Grant
- 1994-11-23 ZA ZA949301A patent/ZA949301B/en unknown
- 1994-11-24 TW TW083110934A patent/TW281671B/zh active
- 1994-11-27 IL IL11177494A patent/IL111774A/en not_active IP Right Cessation
-
1996
- 1996-05-28 FI FI962236A patent/FI113368B/en not_active IP Right Cessation
- 1996-05-28 NO NO962156A patent/NO306158B1/en not_active IP Right Cessation
-
1999
- 1999-02-24 GR GR990400582T patent/GR3029485T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU1086895A (en) | 1995-06-13 |
| JPH09506344A (en) | 1997-06-24 |
| TW281671B (en) | 1996-07-21 |
| HUT76272A (en) | 1997-07-28 |
| EP0731792A1 (en) | 1996-09-18 |
| CN1045596C (en) | 1999-10-13 |
| ES2129794T3 (en) | 1999-06-16 |
| FI962236A (en) | 1996-05-28 |
| IL111774A0 (en) | 1995-01-24 |
| DE69416324T2 (en) | 1999-06-10 |
| AU682736B2 (en) | 1997-10-16 |
| DK0731792T3 (en) | 1999-09-13 |
| NO962156L (en) | 1996-05-28 |
| NO306158B1 (en) | 1999-09-27 |
| WO1995014670A1 (en) | 1995-06-01 |
| EP0731792B1 (en) | 1999-01-27 |
| HU222819B1 (en) | 2003-11-28 |
| JP3612073B2 (en) | 2005-01-19 |
| NZ276570A (en) | 2001-02-23 |
| FI113368B (en) | 2004-04-15 |
| KR100351884B1 (en) | 2002-12-31 |
| HU9601434D0 (en) | 1996-07-29 |
| FI962236A0 (en) | 1996-05-28 |
| ATE176225T1 (en) | 1999-02-15 |
| IL111774A (en) | 1999-11-30 |
| US5668143A (en) | 1997-09-16 |
| GR3029485T3 (en) | 1999-05-28 |
| ZA949301B (en) | 1995-08-07 |
| NO962156D0 (en) | 1996-05-28 |
| CA2177146A1 (en) | 1995-06-01 |
| CN1136312A (en) | 1996-11-20 |
| DE69416324D1 (en) | 1999-03-11 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20131105 |
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| MKLA | Lapsed |
Effective date: 20131105 |