CA2263846C - Novel pyranoside derivatives - Google Patents
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Abstract
The present invention relates to new pyranoside derivatives of general formula I, processes for preparing them and their use in pharmaceutical compositions.
Description
S017-052.200 New Pyranoside Derivatives The present invention relates to new pyranoside derivatives, processes for preparing them and their use in pharmaceutical compositions. The new pyranoside derivatives correspond to general formula I
NH
(OH)m o / I \ I \ _NHZ
(HOCH2)1 I
\ /
O O / I _O
(HOOC)n wherein I, m and n independently of one another denote an integer chosen from 0, 1, 2, 3 and 4 and I+m+n<_4 - in the form of their racemates, in enantiomerically pure or concentrated form, optionally as pairs of diastereomers and are obtained in the form of free bases or salts, preferably with physiologically acceptable acids.
The compounds according to the invention are potent LTB4-antagonists. In particular the compound of Example 1 is obtained in vivo as a metabolite of an LTB4-antagonistic compound and in the receptor binding test it has a Ki-value of 1.0 nM.
As has been found, the compounds of formula I are characterised by their versatility of use in the therapeutic field. Particular mention should be made of --those applications in which the LT84-receptor-antagonistic properties play a part. Examples include, in particular:
arthritis, asthma, chronic obstructive lung diseases, such as chronic bronchitis, psoriasis, ulcerative colitis, gastropathy or enteropathy induced by nonsteroidal antiinflammatories, cystic fibrosis, Alzheimer's disease, shock, reperiusion damage/ischaemia, atherosclerosis and multiple sclerosis.
The new compounds may also be used to treat diseases or conditions in which the passage of cells from the blood through the vascular endothelium into the tissues is of importance (such as metastasis) or diseases and conditions in which the combination of LTB4 or another molecule (such as 12-HETE) with the LTB4-receptor influences cell proliferation (such as chronic myeloid leukaemia).
The new compounds may also be used in combination with other active substances, e.g. those which are used for the same indications, or for example with antiallergics, secretolytics, f32-adrenergics, inhaled steroids;
antihistamines and/or PAF-antagonists. They may be administered by topical, oral, transdermal, nasal or parenteral route or by inhalation.
The activity ratios may be investigated pharmacologically and biochemically using tests such as those described in WO 93/16036, pp. 15 to 17.
The therapeutic or prophylactic dose depends not only on the potency of the individual compounds and the body weight of the patient but also on the nature and gravity of the illness. For oral administration the dose is between and 500 mg, preferably between 20 and 250 mg. For inhalation the patient is given between about 0,5 and 25 mg, preferably between about 2 and 20 mg of active substance.
Inhalable solutions generally contain between about 0.5 and 5 % of active substance. The new compounds may be administered in conventional preparations, e.g. as plain or coated tablets, capsules, lozenges, powders, granules, solutions, emulsions, syrups, inhalable aerosols, ointments or suppositories.
The Examples which follow show some possible ways of formulating the preparations:
NH
(OH)m o / I \ I \ _NHZ
(HOCH2)1 I
\ /
O O / I _O
(HOOC)n wherein I, m and n independently of one another denote an integer chosen from 0, 1, 2, 3 and 4 and I+m+n<_4 - in the form of their racemates, in enantiomerically pure or concentrated form, optionally as pairs of diastereomers and are obtained in the form of free bases or salts, preferably with physiologically acceptable acids.
The compounds according to the invention are potent LTB4-antagonists. In particular the compound of Example 1 is obtained in vivo as a metabolite of an LTB4-antagonistic compound and in the receptor binding test it has a Ki-value of 1.0 nM.
As has been found, the compounds of formula I are characterised by their versatility of use in the therapeutic field. Particular mention should be made of --those applications in which the LT84-receptor-antagonistic properties play a part. Examples include, in particular:
arthritis, asthma, chronic obstructive lung diseases, such as chronic bronchitis, psoriasis, ulcerative colitis, gastropathy or enteropathy induced by nonsteroidal antiinflammatories, cystic fibrosis, Alzheimer's disease, shock, reperiusion damage/ischaemia, atherosclerosis and multiple sclerosis.
The new compounds may also be used to treat diseases or conditions in which the passage of cells from the blood through the vascular endothelium into the tissues is of importance (such as metastasis) or diseases and conditions in which the combination of LTB4 or another molecule (such as 12-HETE) with the LTB4-receptor influences cell proliferation (such as chronic myeloid leukaemia).
The new compounds may also be used in combination with other active substances, e.g. those which are used for the same indications, or for example with antiallergics, secretolytics, f32-adrenergics, inhaled steroids;
antihistamines and/or PAF-antagonists. They may be administered by topical, oral, transdermal, nasal or parenteral route or by inhalation.
The activity ratios may be investigated pharmacologically and biochemically using tests such as those described in WO 93/16036, pp. 15 to 17.
The therapeutic or prophylactic dose depends not only on the potency of the individual compounds and the body weight of the patient but also on the nature and gravity of the illness. For oral administration the dose is between and 500 mg, preferably between 20 and 250 mg. For inhalation the patient is given between about 0,5 and 25 mg, preferably between about 2 and 20 mg of active substance.
Inhalable solutions generally contain between about 0.5 and 5 % of active substance. The new compounds may be administered in conventional preparations, e.g. as plain or coated tablets, capsules, lozenges, powders, granules, solutions, emulsions, syrups, inhalable aerosols, ointments or suppositories.
The Examples which follow show some possible ways of formulating the preparations:
Formulation examples 1. Tablets Composition:
Active substance according to invention 20 parts by weight Stearic acid 6 parts by weight Glucose 474 parts by weight The ingredients are processed in the usual way to form tablets weighing 500 mg. If desired the content of active substance may be increased or reduced and the quantity of glucose reduced or increased accordingly.
2. Suppositories Composition:
Active substance according to invention 100 parts by weight Lactose, powdered 45 parts by weight Cocoa butter 1555 parts by weight The ingredients are processed in the usual way to form suppositories weighing 1.7 g.
3. Powder for Inhalation _ Micronised active substance powder (compound of formula I; particle size about 0.5 to 7 p.m) is packed into hard gelatin capsules in a quantity of 5 mg, optionally with the addition of micronised lactose. The powder is inhaled from conventional inhalers, e.g. according to DE-A 33 45 722, which is referred to herein.
The compounds according to the invention are prepared by methods which are known ep ~ se from the prior art. Thus, the compounds of general formula I
Active substance according to invention 20 parts by weight Stearic acid 6 parts by weight Glucose 474 parts by weight The ingredients are processed in the usual way to form tablets weighing 500 mg. If desired the content of active substance may be increased or reduced and the quantity of glucose reduced or increased accordingly.
2. Suppositories Composition:
Active substance according to invention 100 parts by weight Lactose, powdered 45 parts by weight Cocoa butter 1555 parts by weight The ingredients are processed in the usual way to form suppositories weighing 1.7 g.
3. Powder for Inhalation _ Micronised active substance powder (compound of formula I; particle size about 0.5 to 7 p.m) is packed into hard gelatin capsules in a quantity of 5 mg, optionally with the addition of micronised lactose. The powder is inhaled from conventional inhalers, e.g. according to DE-A 33 45 722, which is referred to herein.
The compounds according to the invention are prepared by methods which are known ep ~ se from the prior art. Thus, the compounds of general formula I
NH
(OH)m (HOCH2) 1 '~ / I / I I ~ 'NHZ
p ~ ~ p / p ~
I
(HOOC)n wherein I, m and n are as hereinbefore defined, are prepared by reacting 4-[[3-[[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenoxy]methyl]phenyl]methoxy]-benzenecarboximidamide with a glucose derivative of general formula II
(a3)m v -o (~2 ) 1 x (HOOC) n wherein when n>0 the carboxyl group is optionally protected in the form of a C1-4-alkyl ester and the hydroxy groups are protected in the form of acyl groups of an aliphatic or aromatic carboxylic acid and X denotes a leaving group which may be displaced by a phenoxide oxygen, converted from a phenoxide and optionally the ester groups are saponified.
The compounds according to the invention may also be prepared from an optionally protected glucose derivative (II) and the abovementioned phenol using basic heavy metal compounds such as Ag20 or CdC03 in inert solvents such as toluene or dichloromethane. The product is optionally freed of the protecting groups by saponification.
The compounds (I) may also be prepared from derivatives of formula (II) and the abovementioned phenol using Lewis acids such as, for example, BFg, AICIg, ZnCl2, SnCl4, TiCl4, or from alkoxide derivatives of these Lewis acids in inert solvents such as toluene, dichloromethane, etc.
Furthermore, the compounds according to the invention may be prepared from an optionally protected derivative (II) wherein X=OH and the abovementioned phenol using acid catalysts such as e.g. methanesulphonic acid or tetrafluoroboric acid or using Lewis acids such as for example BFg, AICIg, ZnCl2, SnCl4, TiCl4, or from alkoxide derivatives of these Lewis acids in inert solvents such as aliphatic, aromatic, alkylsubstituted aromatics or in a halogenated hydrocarbon - preferably in toluene or in dichloromethane.
C1-4-alkyl in the preparation processes described above generally represents a branched or unbranched hydrocarbon group having 1 to 4 carbon atoms, which may optionally be substituted with one or more halogen atoms -preferably fluorine -, which may be identical to or different from one another.
Examples include the following hydrocarbon groups: methyl, ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl.
The compounds according to the invention may be prepared starting from compounds which are known from the prior art, using infer alia the methods described in the following Examples. Various other embodiments of the processes will become apparent to the skilled person from the description provided. However, it is expressly pointed out that these Examples and the associated description are provided solely for illustration and must not be regarded as limiting the invention.
Examples Example 1 HO O
NH
HO,,. O ~ , ~ NH _ HO _ O \ \ O ~ I O
OH
4-[[3-[[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenoxy]methyl]phenyl]methoxy]-benzenecarboximidamide-O-glucuronide To a solution of 37.8 g of 4-[[3-[[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenoxy]methyl]phenyl]methoxy]-benzenecarboximidamide in 1000 ml dimethoxyethane is added a 30% solution of sodium methoxide in methanol and the mixture is stirred for 10 min. After cooling to -10oC, 32.4 g of methyl acetobromo-a-D-glucuronate are added and the mixture is stirred for 48 h at ambient temperature. After the addition of a solution of 3.5 g of LiOH in 100 ml of water the mixture is stirred for a further 48 h and the solvent is distilled off at ambient temperature in vacuo. The residue is dissolved in 200 ml of eluant H1) and the aqueous phase precipitated is separated off.
The substance is chromatographed using preparative thin-layer plates, isolated after extraction with methanol and crystallised with water. Yield:
(OH)m (HOCH2) 1 '~ / I / I I ~ 'NHZ
p ~ ~ p / p ~
I
(HOOC)n wherein I, m and n are as hereinbefore defined, are prepared by reacting 4-[[3-[[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenoxy]methyl]phenyl]methoxy]-benzenecarboximidamide with a glucose derivative of general formula II
(a3)m v -o (~2 ) 1 x (HOOC) n wherein when n>0 the carboxyl group is optionally protected in the form of a C1-4-alkyl ester and the hydroxy groups are protected in the form of acyl groups of an aliphatic or aromatic carboxylic acid and X denotes a leaving group which may be displaced by a phenoxide oxygen, converted from a phenoxide and optionally the ester groups are saponified.
The compounds according to the invention may also be prepared from an optionally protected glucose derivative (II) and the abovementioned phenol using basic heavy metal compounds such as Ag20 or CdC03 in inert solvents such as toluene or dichloromethane. The product is optionally freed of the protecting groups by saponification.
The compounds (I) may also be prepared from derivatives of formula (II) and the abovementioned phenol using Lewis acids such as, for example, BFg, AICIg, ZnCl2, SnCl4, TiCl4, or from alkoxide derivatives of these Lewis acids in inert solvents such as toluene, dichloromethane, etc.
Furthermore, the compounds according to the invention may be prepared from an optionally protected derivative (II) wherein X=OH and the abovementioned phenol using acid catalysts such as e.g. methanesulphonic acid or tetrafluoroboric acid or using Lewis acids such as for example BFg, AICIg, ZnCl2, SnCl4, TiCl4, or from alkoxide derivatives of these Lewis acids in inert solvents such as aliphatic, aromatic, alkylsubstituted aromatics or in a halogenated hydrocarbon - preferably in toluene or in dichloromethane.
C1-4-alkyl in the preparation processes described above generally represents a branched or unbranched hydrocarbon group having 1 to 4 carbon atoms, which may optionally be substituted with one or more halogen atoms -preferably fluorine -, which may be identical to or different from one another.
Examples include the following hydrocarbon groups: methyl, ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl.
The compounds according to the invention may be prepared starting from compounds which are known from the prior art, using infer alia the methods described in the following Examples. Various other embodiments of the processes will become apparent to the skilled person from the description provided. However, it is expressly pointed out that these Examples and the associated description are provided solely for illustration and must not be regarded as limiting the invention.
Examples Example 1 HO O
NH
HO,,. O ~ , ~ NH _ HO _ O \ \ O ~ I O
OH
4-[[3-[[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenoxy]methyl]phenyl]methoxy]-benzenecarboximidamide-O-glucuronide To a solution of 37.8 g of 4-[[3-[[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenoxy]methyl]phenyl]methoxy]-benzenecarboximidamide in 1000 ml dimethoxyethane is added a 30% solution of sodium methoxide in methanol and the mixture is stirred for 10 min. After cooling to -10oC, 32.4 g of methyl acetobromo-a-D-glucuronate are added and the mixture is stirred for 48 h at ambient temperature. After the addition of a solution of 3.5 g of LiOH in 100 ml of water the mixture is stirred for a further 48 h and the solvent is distilled off at ambient temperature in vacuo. The residue is dissolved in 200 ml of eluant H1) and the aqueous phase precipitated is separated off.
The substance is chromatographed using preparative thin-layer plates, isolated after extraction with methanol and crystallised with water. Yield:
5.3 g (Mp. 205oC (decomp.)).
1 ) 36 parts of n-butanol, 15 parts of formic acid, 15 parts of water, 15 parts of acetone, 5 parts of chloroform are combined, shaken thoroughly, and after 3 days the aqueous phase precipitated is separated off.
Example 2 HO
NH
HO ,,. NH2 -O i i I
HO O \ ~ O ~ O
OH w I
4-[[3-[[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenoxy]methyl]phenyl]methoxy]-benzenecarboximidamide-O-glucose The compound is prepared according to the method of Example 1 from 4-([3-[[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenoxy]methyl]phenyl]methoxy]-benzenecarboximidamide and tetraacetylbromoglucose.
1 ) 36 parts of n-butanol, 15 parts of formic acid, 15 parts of water, 15 parts of acetone, 5 parts of chloroform are combined, shaken thoroughly, and after 3 days the aqueous phase precipitated is separated off.
Example 2 HO
NH
HO ,,. NH2 -O i i I
HO O \ ~ O ~ O
OH w I
4-[[3-[[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenoxy]methyl]phenyl]methoxy]-benzenecarboximidamide-O-glucose The compound is prepared according to the method of Example 1 from 4-([3-[[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenoxy]methyl]phenyl]methoxy]-benzenecarboximidamide and tetraacetylbromoglucose.
Claims (23)
1. A pyranoside derivative of general formula I
wherein l, m and n independently of one another denote an integer chosen from 0, 1, 2, 3 or 4, and 1+m+n<=4 - in the form of a racemate, in enantiomerically pure or concentrated form, optionally as pairs of diastereomers and in each case in the form of a free base or a salt.
wherein l, m and n independently of one another denote an integer chosen from 0, 1, 2, 3 or 4, and 1+m+n<=4 - in the form of a racemate, in enantiomerically pure or concentrated form, optionally as pairs of diastereomers and in each case in the form of a free base or a salt.
2. A pyranoside derivative according to claim 1, wherein the salt is a physiologically acceptable acid addition salt.
3. 4-[[3-[[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenoxy]methyl]phenyl]methoxy]-benzenecarboximidamide-O-glucuronide, or a salt thereof.
4. 4-[[3-[[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenoxy]methyl]phenyl]methoxy]-benzenecarboximidamide-O-glucose, or a salt thereof.
5. A process for preparing a compound of general formula I
wherein l, m and n are defined as in claim 1, wherein 4-[[3-[[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenoxy]methyl]phenyl]methoxy]-benzenecarboximidamide is reacted with a glucose derivative of general formula II
wherein, if n > 0, the carboxyl group may optionally be in the form of a C1-4-alkylester and the hydroxyl groups in the form of acyl groups are protected with an aliphatic or aromatic carboxylic acid and X denotes a leaving group which may be displaced by a phenoxide oxygen, and optionally the ester groups are saponified.
wherein l, m and n are defined as in claim 1, wherein 4-[[3-[[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenoxy]methyl]phenyl]methoxy]-benzenecarboximidamide is reacted with a glucose derivative of general formula II
wherein, if n > 0, the carboxyl group may optionally be in the form of a C1-4-alkylester and the hydroxyl groups in the form of acyl groups are protected with an aliphatic or aromatic carboxylic acid and X denotes a leaving group which may be displaced by a phenoxide oxygen, and optionally the ester groups are saponified.
6. A process according to claim 5, wherein the reaction is carried out in the presence of an acidically reacting catalyst or a Lewis acid.
7. A process according to claim 6, wherein the acidically reacting catalyst is methanesulphonic acid or tetrafluoroboric acid.
8. A process according to claim 6, wherein the Lewis acid is BF3, AlCl3, ZnCl2, SnCl4 or TiCl4 or an alkoxide of these Lewis acids.
9. A process according to claim 5, wherein the reaction is carried out in the presence of a basically reacting transition metal compound.
10. A process according to claim 9, wherein the transition metal compound is Ag2O or CdCO3.
11. A process according to any one of claims 5 to 10, wherein an aliphatic or aromatic hydrocarbon, an alkyl-substituted aromatic or a halogenated hydrocarbon is used as the reaction medium.
12. A process according to claim 11, wherein toluene or dichloromethane is used as solvent.
13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, optionally in the form of a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier or excipient.
14. A pharmaceutical composition according to claim 13 for treating a disease or condition responsive to a substance having LTB4-antagonistic activity.
15. A pharmaceutical composition according to claim 13 or 14 for treating arthritis, asthma, chronic obstructive lung disease, chronic bronchitis, psoriasis, ulcerative colitis, gastropathy or enteropathy induced by nonsteroidal antiinflammatories, cystic fibrosis, Alzheimer's disease, shock, reperfusion damage/ischaemia, atherosclerosis or multiple sclerosis.
16. A compound according any one of claims 1 to 4, or a pharmaceutically acceptable acid addition salt thereof for treating a disease or condition responsive to a substance having LTB4-antagonistic activity.
17. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable acid addition salt thereof for treating arthritis, asthma, chronic obstructive lung disease, chronic bronchitis, psoriasis, ulcerative colitis, gastropathy or enteropathy induced by nonsteroidal antiinflammatories, cystic fibrosis, Alzheimer's disease, shock, reperfusion damage/ischaemia, atherosclerosis or multiple sclerosis.
18. A use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable acid addition salt thereof in preparation of a pharmaceutical composition for treating a disease or condition responsive to a substance having LTB4-antagonistic activity.
19. A use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable acid addition salt thereof in preparation of a pharmaceutical composition for treating arthritis, asthma, chronic obstructive lung disease, chronic bronchitis, psoriasis, ulcerative colitis, gastropathy or enteropathy induced by nonsteroidal antiinflammatories, cystic fibrosis, Alzheimer's disease, shock, reperfusion damage/ischaemia, atherosclerosis or multiple sclerosis.
20. A use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable acid addition salt thereof for treating a disease or condition responsive to a substance having LTB4-antagonistic activity.
21. A use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable acid addition salt thereof for treating arthritis, asthma, chronic obstructive lung disease, chronic bronchitis, psoriasis, ulcerative colitis, gastropathy or enteropathy induced by nonsteroidal antiinflammatories, cystic fibrosis, Alzheimer's disease, shock, reperfusion damage/ischaemia, atherosclerosis or multiple sclerosis.
22. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable acid addition salt thereof in preparing a pharmaceutical composition having an LTB4-antagonistic activity.
23. A use of a compound of general formula I, as defined in claim 1, a stereoisomer thereof or an acid addition salt thereof in preparing a pharmaceutical composition for the therapeutic treatment of arthritis, asthma, chronic obstructive lung disease, chronic bronchitis, psoriasis, ulcerative colitis, gastropathy or enteropathy induced by nonsteroidal antiinflammatories, cystic fibrosis, Alzheimer's disease, shock, reperfusion damage/ischaemia, atherosclerosis or multiple sclerosis.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19637123A DE19637123A1 (en) | 1996-09-12 | 1996-09-12 | New pyranoside derivatives |
| DE19637123.6 | 1996-09-12 | ||
| PCT/EP1997/004948 WO1998011119A1 (en) | 1996-09-12 | 1997-09-10 | Novel pyranoside derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2263846A1 CA2263846A1 (en) | 1998-03-19 |
| CA2263846C true CA2263846C (en) | 2006-11-14 |
Family
ID=7805404
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002263846A Expired - Fee Related CA2263846C (en) | 1996-09-12 | 1997-09-10 | Novel pyranoside derivatives |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0931087B1 (en) |
| JP (1) | JP4215278B2 (en) |
| AR (1) | AR009769A1 (en) |
| AT (1) | ATE215551T1 (en) |
| AU (1) | AU4622597A (en) |
| CA (1) | CA2263846C (en) |
| DE (2) | DE19637123A1 (en) |
| DK (1) | DK0931087T3 (en) |
| ES (1) | ES2174297T3 (en) |
| HR (1) | HRP970487A2 (en) |
| ID (1) | ID18262A (en) |
| PE (1) | PE107398A1 (en) |
| PT (1) | PT931087E (en) |
| WO (1) | WO1998011119A1 (en) |
| YU (1) | YU37597A (en) |
| ZA (1) | ZA978086B (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL141654A0 (en) * | 1998-09-04 | 2002-03-10 | Byk Gulden Lomberg Chem Fab | Pyranose derivatives and pharmaceutical compositions containing the same |
| US6528491B2 (en) | 2000-10-24 | 2003-03-04 | Boehringer Ingelheim Pharma Kg | Pyranoside derivatives |
| DE10052658A1 (en) * | 2000-10-24 | 2002-05-02 | Boehringer Ingelheim Pharma | New pyranoside derivatives |
| JP2004523512A (en) * | 2001-01-16 | 2004-08-05 | ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト | Use of an LTB4 antagonist for the treatment and / or prevention of diseases caused by increased expression of mucin genes |
| JP2005502630A (en) * | 2001-07-14 | 2005-01-27 | ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト | Pharmaceutical preparation containing LTB4 antagonist |
| EP3383389B1 (en) | 2015-11-30 | 2021-04-28 | Merck Sharp & Dohme Corp. | Aryl acylsulfonamides as blt1 antagonists |
| EP3383388B1 (en) | 2015-11-30 | 2021-04-14 | Merck Sharp & Dohme Corp. | Aryl acylsulfonamides as blt1 antagonists |
| US10450309B2 (en) | 2015-11-30 | 2019-10-22 | Merch Sharp & Dohme Corp. | Aryl sulfonamides as BLT1 antagonists |
| US20190382363A1 (en) | 2015-11-30 | 2019-12-19 | Merck Sharp & Dohme Corp. | Aryl sulfonamides as blt1 antagonists |
| JP7373191B2 (en) * | 2017-05-12 | 2023-11-02 | 国立研究開発法人理化学研究所 | Class A GPCR-binding compound variants |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5246965A (en) * | 1991-06-11 | 1993-09-21 | Ciba-Geigy | Arylethers, their manufacture and methods of treatment |
| ES2165122T3 (en) * | 1992-02-05 | 2002-03-01 | Boehringer Ingelheim Pharma | NEW DERIVATIVES OF AMIDINA, ITS PREPARATION AND USE AS MEDICATIONS WITH ANTAGONIST EFFECT OF LTB4. |
| DE19546452A1 (en) * | 1995-12-13 | 1997-06-19 | Boehringer Ingelheim Kg | New phenylamidine derivatives, process for their preparation and their use as medicaments |
-
1996
- 1996-09-12 DE DE19637123A patent/DE19637123A1/en not_active Withdrawn
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1997
- 1997-08-19 PE PE1997000733A patent/PE107398A1/en not_active Application Discontinuation
- 1997-09-09 ZA ZA9708086A patent/ZA978086B/en unknown
- 1997-09-10 JP JP51325298A patent/JP4215278B2/en not_active Expired - Fee Related
- 1997-09-10 EP EP97944867A patent/EP0931087B1/en not_active Expired - Lifetime
- 1997-09-10 ES ES97944867T patent/ES2174297T3/en not_active Expired - Lifetime
- 1997-09-10 DK DK97944867T patent/DK0931087T3/en active
- 1997-09-10 WO PCT/EP1997/004948 patent/WO1998011119A1/en active IP Right Grant
- 1997-09-10 AT AT97944867T patent/ATE215551T1/en not_active IP Right Cessation
- 1997-09-10 CA CA002263846A patent/CA2263846C/en not_active Expired - Fee Related
- 1997-09-10 AU AU46225/97A patent/AU4622597A/en not_active Abandoned
- 1997-09-10 YU YU37597A patent/YU37597A/en unknown
- 1997-09-10 DE DE59706897T patent/DE59706897D1/en not_active Expired - Fee Related
- 1997-09-10 PT PT97944867T patent/PT931087E/en unknown
- 1997-09-11 HR HR19637123.6A patent/HRP970487A2/en not_active Application Discontinuation
- 1997-09-11 ID IDP973152A patent/ID18262A/en unknown
- 1997-09-12 AR ARP970104188A patent/AR009769A1/en unknown
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|---|---|
| DK0931087T3 (en) | 2002-07-01 |
| DE59706897D1 (en) | 2002-05-08 |
| PT931087E (en) | 2002-09-30 |
| CA2263846A1 (en) | 1998-03-19 |
| EP0931087B1 (en) | 2002-04-03 |
| YU37597A (en) | 1999-11-22 |
| WO1998011119A1 (en) | 1998-03-19 |
| JP2001500146A (en) | 2001-01-09 |
| ES2174297T3 (en) | 2002-11-01 |
| DE19637123A1 (en) | 1998-03-19 |
| HRP970487A2 (en) | 1998-08-31 |
| AR009769A1 (en) | 2000-05-03 |
| PE107398A1 (en) | 1999-02-03 |
| ID18262A (en) | 1998-03-19 |
| EP0931087A1 (en) | 1999-07-28 |
| JP4215278B2 (en) | 2009-01-28 |
| AU4622597A (en) | 1998-04-02 |
| ZA978086B (en) | 1998-03-12 |
| ATE215551T1 (en) | 2002-04-15 |
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