CA2425368C - New sulphoxybenzamides - Google Patents
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- CA2425368C CA2425368C CA002425368A CA2425368A CA2425368C CA 2425368 C CA2425368 C CA 2425368C CA 002425368 A CA002425368 A CA 002425368A CA 2425368 A CA2425368 A CA 2425368A CA 2425368 C CA2425368 C CA 2425368C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C305/00—Esters of sulfuric acids
- C07C305/22—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to carbon atoms of six-membered aromatic rings
- C07C305/24—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to carbon atoms of six-membered aromatic rings of non-condensed six-membered aromatic rings
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Abstract
The present invention relates to new sulphoxybenzamides of general formula I, processes for preparing them as well as their use as medicaments.
(see formula I)
(see formula I)
Description
1/1157-ff Boehringer Ingelheim Pharma KG
New sulphoxybenzamides The present invention relates to new sulphoxybenzamides of formula 1, HO O
'S" NR
~ ~ -Z ( A1 Z1 )( AZ Z2 ) NH
" 2 RZ m (I) wherein the groups R1, RZ, R3, A', AZ, Z , Z1, Z2, m and n have the meanings given in the claims and specification, processes for preparing them as well as their use as medicaments, particularly as leukotriene B4 (LTB4) antagonists.
Background to the invention Benzamidine derivatives are known from the prior art as active substances with valuable pharmaceutical properties. Thus, for example, Intern.ational Patent Applications WO
97/21670 and WO 98/11062 disclose inter alia benzamidines which have free hydroxy groups. They contain no references of any kind to benzamidines containing sulphate groups.
The aim of the present invention is to prepare new LTB4 antagonists which, by virtue of their LTB4 antagonistic properties, have many possible uses in the therapeutic field.
Detailed description of the invention Surprisingly, it has been found that benzamidine derivatives containing sulphate groups, of general formula (I) O
O~S" O NR
Q-Z -( AI ZI )m( AZ Z2 )n \ / NH 2 (1) 1/1157-ff Boehringer Ingelheim Pharma KG
New sulphoxybenzamides The present invention relates to new sulphoxybenzamides of formula 1, HO O
'S" NR
~ ~ -Z ( A1 Z1 )( AZ Z2 ) NH
" 2 RZ m (I) wherein the groups R1, RZ, R3, A', AZ, Z , Z1, Z2, m and n have the meanings given in the claims and specification, processes for preparing them as well as their use as medicaments, particularly as leukotriene B4 (LTB4) antagonists.
Background to the invention Benzamidine derivatives are known from the prior art as active substances with valuable pharmaceutical properties. Thus, for example, Intern.ational Patent Applications WO
97/21670 and WO 98/11062 disclose inter alia benzamidines which have free hydroxy groups. They contain no references of any kind to benzamidines containing sulphate groups.
The aim of the present invention is to prepare new LTB4 antagonists which, by virtue of their LTB4 antagonistic properties, have many possible uses in the therapeutic field.
Detailed description of the invention Surprisingly, it has been found that benzamidine derivatives containing sulphate groups, of general formula (I) O
O~S" O NR
Q-Z -( AI ZI )m( AZ Z2 )n \ / NH 2 (1) 1/1157-ff Boehringer Ingelheim Pharma KG
wherein the groups Rl, RZ, R3, A1, A2, Z , Z1, Z2, m and n have the meanings given in the claims and specification, have an LTB4 antagonistic activity and may be used according to the invention for the prevention and treatment of diseases in which LTB4 antagonists may provide a therapeutic benefit.
The invention thus relates to sulphoxybenzamides of general formula I
wherein Z denotes a group selected from the formulae -Xl-(CHZ)r X2- and -CR4R5-, A1 and A 2 independently of one another each denote a 1,4-phenylene- or 1,3-phenylene group optionally substituted by one or more halogen atoms, C1-Cg-alkyl groups, C2-C8-alkenyl groups, C1-C8-haloalkyl groups or C1-C8-alkoxy groups, Z' and Z2 independently of one another each denote a group of formula -X3-(CH2)S X4- or a single bond, R1 denotes hydrogen, hydroxy, -COO-C1-Cg-alkyl or -COO-C1-C4-alkyl-phenyl, whilst in the abovementioned group the phenyl ring in each case may be substituted by CI-C4-alkyl or C1-C4-alkoxy, Rz and R3 independently of one another each denote a hydrogen or halogen atom, or a C1-C8-alkyl, C1-C8-haloalkyl, C1-C8-alkoxy, aryl, aryloxy or aralkyl group, R4 and RS independently of one another each denote hydrogen or C1-C4-alkyl, XI and X2 independently of one another each denote -0, -S, -NH- or a single bond, X3 and X4 independently of one another each denote -0, -S, -NH- or a single bond, m and n independently of one another each denote 0 or 1, and r and s independently of one another denote an integer from 1 to 8, optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, as well as optionally the pharmacologically acceptable salts thereof.
1/1157-ff Boehringer Ingelheim Pharma KG
The invention thus relates to sulphoxybenzamides of general formula I
wherein Z denotes a group selected from the formulae -Xl-(CHZ)r X2- and -CR4R5-, A1 and A 2 independently of one another each denote a 1,4-phenylene- or 1,3-phenylene group optionally substituted by one or more halogen atoms, C1-Cg-alkyl groups, C2-C8-alkenyl groups, C1-C8-haloalkyl groups or C1-C8-alkoxy groups, Z' and Z2 independently of one another each denote a group of formula -X3-(CH2)S X4- or a single bond, R1 denotes hydrogen, hydroxy, -COO-C1-Cg-alkyl or -COO-C1-C4-alkyl-phenyl, whilst in the abovementioned group the phenyl ring in each case may be substituted by CI-C4-alkyl or C1-C4-alkoxy, Rz and R3 independently of one another each denote a hydrogen or halogen atom, or a C1-C8-alkyl, C1-C8-haloalkyl, C1-C8-alkoxy, aryl, aryloxy or aralkyl group, R4 and RS independently of one another each denote hydrogen or C1-C4-alkyl, XI and X2 independently of one another each denote -0, -S, -NH- or a single bond, X3 and X4 independently of one another each denote -0, -S, -NH- or a single bond, m and n independently of one another each denote 0 or 1, and r and s independently of one another denote an integer from 1 to 8, optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, as well as optionally the pharmacologically acceptable salts thereof.
1/1157-ff Boehringer Ingelheim Pharma KG
Preferred compounds are those of formula I wherein Z denotes a group selected from the formulae -X1-(CH2)r X2- and -CR4R5-, A' and A2 independently of one another each denote a 1,4-phenylene or 1,3-phenylene group optionally substituted by a C1-C4-alkyl group or C2-C4-alkenyl group, Z' and Z2 independently of one another each denote a group of formula -X3-(CH2)S X4- or a single bond, Rl denotes hydrogen, R2 and R3 each denote a hydrogen atom, R¾ and R5 independently of one another each denote Cl-C4-alkyl, X1 and X2 independently of one another each denote -0- or a single bond, X3 and X4 independently of one another each denote -0- or a single bond, m and n independently of one another each denote 0 or 1, and r and s independently of one another each denote an integer from I to 3.
Another preferred embodiment comprises the compounds of formula I, wherein Z denotes a group of formula -CR4 RS-, 1/1157-ff Boehringer Ingelheim Pharma KG
Another preferred embodiment comprises the compounds of formula I, wherein Z denotes a group of formula -CR4 RS-, 1/1157-ff Boehringer Ingelheim Pharma KG
AI and A 2 independently of one another each denote a 1,4-phenylene or 1,3-phenylene group optionally substituted by a C1-C4-alkyl group or C2-C4-alkenyl group, and preferably A' denotes 1,4-phenylene and A2 denotes 1,3-phenylene, Z1 and Z2 independently of one another each denote a group of formula -X3-(CH2)s-X4-, and preferably Z1 denotes -O-CH2- and Z2 denotes -CH2-O-R' denotes hydrogen, R2 and R3 each denote a hydrogen atom, R4 and R5 each denote methyl, X3 and X4 independently of one another each denote -0- or a single bond, m and n each denote 1, and s denotes 1.
Also preferred are compounds of formula I wherein Z denotes a group of formula -Xl-(CH2)r X2-, A 2 denotes a 1,4-phenylene group substituted by a C1-C4-alkyl group or C2-C4-alkenyl group, preferably a 1,4-phenylene group substituted by an n-propyl or allyl group, Z2 denotes a single bond, R' denotes hydrogen, R2 and R3 each denote a hydrogen atom, Xt and X2 independently of one another each denote -0-, 1/1157-ff Boehringer Ingelheim Pharma KG
m denotes 0, n denotes 1, and r denotes 2.
Unless specifically stated otherwise, the general definitions are used in the following sense:
Ci-Cg-alkyl and C1-C4-alkyl generally denote a branched or unbranched hydrocarbon group with 1 to 4 or 8 carbon atom(s), which may optionally be substituted by one or more halogen atom(s), preferably fluorine, which may be identical to or different from one another. The following hydrocarbon groups are mentioned as examples:
methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-l-methylpropyl and 1-ethyl-2-methylpropyl. Unless otherwise stated, lower alkyl groups with 1 to 4 carbon atoms are preferred, such as methyl; ethyl, n-propyl, iso-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.
C2-C8-alkenyl and C2-C4-alkenyl generally denote a branched or unbranched unsaturated hydrocarbon group with 2 to 4 or 8 carbon atom(s), which may optionally be substituted by one or more halogen atom(s), preferably fluorine, which may be identical to or different from one another. The following hydrocarbon groups are mentioned as examples:
Vinyl, allyl, prop-1-enyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl.
Unless otherwise stated, lower alkenyl groups with 2 to 4 carbon atoms, such as vinyl or allyl, are preferred.
1/1157-ff Boehringer Ingelheim Pharma KG
Also preferred are compounds of formula I wherein Z denotes a group of formula -Xl-(CH2)r X2-, A 2 denotes a 1,4-phenylene group substituted by a C1-C4-alkyl group or C2-C4-alkenyl group, preferably a 1,4-phenylene group substituted by an n-propyl or allyl group, Z2 denotes a single bond, R' denotes hydrogen, R2 and R3 each denote a hydrogen atom, Xt and X2 independently of one another each denote -0-, 1/1157-ff Boehringer Ingelheim Pharma KG
m denotes 0, n denotes 1, and r denotes 2.
Unless specifically stated otherwise, the general definitions are used in the following sense:
Ci-Cg-alkyl and C1-C4-alkyl generally denote a branched or unbranched hydrocarbon group with 1 to 4 or 8 carbon atom(s), which may optionally be substituted by one or more halogen atom(s), preferably fluorine, which may be identical to or different from one another. The following hydrocarbon groups are mentioned as examples:
methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-l-methylpropyl and 1-ethyl-2-methylpropyl. Unless otherwise stated, lower alkyl groups with 1 to 4 carbon atoms are preferred, such as methyl; ethyl, n-propyl, iso-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.
C2-C8-alkenyl and C2-C4-alkenyl generally denote a branched or unbranched unsaturated hydrocarbon group with 2 to 4 or 8 carbon atom(s), which may optionally be substituted by one or more halogen atom(s), preferably fluorine, which may be identical to or different from one another. The following hydrocarbon groups are mentioned as examples:
Vinyl, allyl, prop-1-enyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl.
Unless otherwise stated, lower alkenyl groups with 2 to 4 carbon atoms, such as vinyl or allyl, are preferred.
1/1157-ff Boehringer Ingelheim Pharma KG
The group -(CH2)r or -(CH2)S- denotes a branched or unbranched double-bonded hydrocarbon bridge with 1 to 8 carbon atoms, which may optionally be substituted by one or more halogen atom(s), preferably fluorine, which may be identical to or different from one another.
Aryl generally denotes an aromatic group with 6 to 10 carbon atoms, preferably phenyl, while the aromatic group may be substituted by one or more lower alkyl group(s), lower alkenyl group(s), trifluoromethyl group(s), cyano group(s), alkoxy group(s), nitro group(s), amino group(s) and/or one or more halogen atom(s), which may be identical or different; the preferred aryl group is an optionally substituted phenyl group, the preferred substituents being halogen - such as fluorine, chlorine or bromine - as well as hydroxyl.
Alkoxy generally denotes a straight-chain or branched hydrocarbon group with 1 to 8 carbon atom(s) bound via an oxygen atom. A lower alkoxy group with 1 to 3 carbon atom(s) is preferred. The methoxy group is particularly preferred.
Aryloxy generally denotes an aromatic group with 6 to 10 carbon atoms bound via an oxygen, preferably phenoxy, whilst the aromatic group may be substituted by one or more lower alkyl group(s), lower alkenyl group(s), trifluoromethyl group(s), cyano group(s), alkoxy group(s), nitro group(s), amino group(s) and/or one or more halogen atom(s), which may be identical or different; the preferred aryl group is an optionally substituted phenyl group, the preferred substituents being halogen - such as fluorine, chlorine or bromine - as well as hydroxyl.
Aralkyl generally denotes a aromatic group with 6 to 10 carbon atoms bound via an alkylene group, preferably phenylalkyl, whilst the aromatic group may be substituted by one or more lower alkyl group(s), lower alkenyl group(s), trifluoromethyl group(s), cyano group(s), alkoxy group(s), nitro group(s), amino group(s) and/or one or more halogen atom(s), which may be identical or different; the preferred aryl group is an optionally substituted phenyl group, the preferred substituents being halogen - such as fluorine, chlorine or bromine -as well as hydroxyl. The alkylene group is generally a double-bonded hydrocarbon bridge with 1 to 8 carbon atoms, preferably 1 to 3 carbon atoms, optionally substituted by one or more halogen atom(s) - preferably fluorine - which may be identical to or different from one another.
1/1157-ff Boehringer Ingelheim Pharma KG
Aryl generally denotes an aromatic group with 6 to 10 carbon atoms, preferably phenyl, while the aromatic group may be substituted by one or more lower alkyl group(s), lower alkenyl group(s), trifluoromethyl group(s), cyano group(s), alkoxy group(s), nitro group(s), amino group(s) and/or one or more halogen atom(s), which may be identical or different; the preferred aryl group is an optionally substituted phenyl group, the preferred substituents being halogen - such as fluorine, chlorine or bromine - as well as hydroxyl.
Alkoxy generally denotes a straight-chain or branched hydrocarbon group with 1 to 8 carbon atom(s) bound via an oxygen atom. A lower alkoxy group with 1 to 3 carbon atom(s) is preferred. The methoxy group is particularly preferred.
Aryloxy generally denotes an aromatic group with 6 to 10 carbon atoms bound via an oxygen, preferably phenoxy, whilst the aromatic group may be substituted by one or more lower alkyl group(s), lower alkenyl group(s), trifluoromethyl group(s), cyano group(s), alkoxy group(s), nitro group(s), amino group(s) and/or one or more halogen atom(s), which may be identical or different; the preferred aryl group is an optionally substituted phenyl group, the preferred substituents being halogen - such as fluorine, chlorine or bromine - as well as hydroxyl.
Aralkyl generally denotes a aromatic group with 6 to 10 carbon atoms bound via an alkylene group, preferably phenylalkyl, whilst the aromatic group may be substituted by one or more lower alkyl group(s), lower alkenyl group(s), trifluoromethyl group(s), cyano group(s), alkoxy group(s), nitro group(s), amino group(s) and/or one or more halogen atom(s), which may be identical or different; the preferred aryl group is an optionally substituted phenyl group, the preferred substituents being halogen - such as fluorine, chlorine or bromine -as well as hydroxyl. The alkylene group is generally a double-bonded hydrocarbon bridge with 1 to 8 carbon atoms, preferably 1 to 3 carbon atoms, optionally substituted by one or more halogen atom(s) - preferably fluorine - which may be identical to or different from one another.
1/1157-ff Boehringer Ingelheim Pharma KG
Most particularly preferred compounds are those of formulae IA and IB, NH
HO NH z O S
O / O~~O
\ I
~IA) \
z HO--O, \ I \ I I/ NH
O O O O
(IB) The compounds IA and IB may be formed in vivo as metabolites of a corresponding LTB4-antagonistic compound with a free hydroxy group and exhibit the following Ki values in the receptor binding test:
Compound Ki [nM]
IA 3.2 IB 40.0 As has been found, the compounds of formula I are characterised by their versatility of use in the therapeutic field. Particular emphasis should be laid on those applications for which the LTB4-receptor-antagonistic properties play a part.
The following should be mentioned in particular: arthritis, asthma, chronic obstructive lung diseases such as chronic bronchitis, psoriasis, ulcerative colitis, gastro- or enteropathy induced by nonsteroidal antiphlogistics, cystic or pulmonary fibrosis, Alzheimer`s disease, shock, reperfusion damage/ischaemia such as stroke or cardiac infarct, atherosclerosis, multiple sclerosis, autoimmune diseases, malignant neoplasia, alveolitis.
1/1157-ff Boehringer Ingelheim Pharma KG
HO NH z O S
O / O~~O
\ I
~IA) \
z HO--O, \ I \ I I/ NH
O O O O
(IB) The compounds IA and IB may be formed in vivo as metabolites of a corresponding LTB4-antagonistic compound with a free hydroxy group and exhibit the following Ki values in the receptor binding test:
Compound Ki [nM]
IA 3.2 IB 40.0 As has been found, the compounds of formula I are characterised by their versatility of use in the therapeutic field. Particular emphasis should be laid on those applications for which the LTB4-receptor-antagonistic properties play a part.
The following should be mentioned in particular: arthritis, asthma, chronic obstructive lung diseases such as chronic bronchitis, psoriasis, ulcerative colitis, gastro- or enteropathy induced by nonsteroidal antiphlogistics, cystic or pulmonary fibrosis, Alzheimer`s disease, shock, reperfusion damage/ischaemia such as stroke or cardiac infarct, atherosclerosis, multiple sclerosis, autoimmune diseases, malignant neoplasia, alveolitis.
1/1157-ff Boehringer Ingelheim Pharma KG
The new compounds may also be used to treat illnesses 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 illnesses and conditions in which the combination of LTB4 or another active substance (such as 12-HETE) with the LTB4 receptor has an influence on cell proliferation (e.g. chronic myeloid leukaemia).
The new compound may also be used in conjunction with other active substances, e.g. those which are used for the same indications, or e.g. with antiallergic agents, secretolytics,132-adrenergics, steroids taken by inhalation, antihistamines, PDE4 inhibitors, peptido-leukotriene antagonists and/or PAF antagonists. They may be administered topically, orally, transdermally, nasally, parenterally or by inhalation.
The activity can be investigated pharmacologically and biochemically using tests as disclosed for example in WO 93/16036, pp. 15 to 17; reference is hereby made to the contents of this publication.
The therapeutic or prophylactic dose depends - apart from the potency of the individual compounds and the patient's body weight - on the nature and gravity of the condition. For oral administration the dosage is between 10 and 500 mg, preferably between 20 and 250 mg.
By inhalation the amount of active substance delivered to the patient is between about 0.5 and 25, preferably between about 2 and 20 mg.
Solutions for inhalation 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, aerosols for inhalation, ointments and suppositories.
The following Examples show some possible ways of formulating the preparations:
1/1157-ff Boehringer Ingelheim Pharma KG
The new compound may also be used in conjunction with other active substances, e.g. those which are used for the same indications, or e.g. with antiallergic agents, secretolytics,132-adrenergics, steroids taken by inhalation, antihistamines, PDE4 inhibitors, peptido-leukotriene antagonists and/or PAF antagonists. They may be administered topically, orally, transdermally, nasally, parenterally or by inhalation.
The activity can be investigated pharmacologically and biochemically using tests as disclosed for example in WO 93/16036, pp. 15 to 17; reference is hereby made to the contents of this publication.
The therapeutic or prophylactic dose depends - apart from the potency of the individual compounds and the patient's body weight - on the nature and gravity of the condition. For oral administration the dosage is between 10 and 500 mg, preferably between 20 and 250 mg.
By inhalation the amount of active substance delivered to the patient is between about 0.5 and 25, preferably between about 2 and 20 mg.
Solutions for inhalation 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, aerosols for inhalation, ointments and suppositories.
The following Examples show some possible ways of formulating the preparations:
1/1157-ff Boehringer Ingelheim Pharma KG
Examples of formulations 1. Tablets Composition:
Active substance according to the 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 active substance content may be increased or reduced and the quantity of glucose reduced or increased accordingly.
2. Suppositories Composition:
Active substance according to the invention 100 parts by weight Powdered lactose 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 powdered active substance (compound of formula I; particle size about 0.5 to 7 m) is packed into hard gelatine capsules in quantities 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, to which reference is hereby made.
The compounds according to the invention compound are prepared using methods known per se from the prior art. Thus, the compounds of general formula I may be prepared by reacting the benzamides of formula II which contain hydroxy groups:
1/1157-ff Boehringer Ingelheim Pharma KG
NR' OH
Z (A1 Z1 )m( AZ Z2 NH Jn \ / 2 (II) which are known, for example, from International Patent Applications WO
97/21670 and WO
98/11062, wherein Z , A1, A2, Z1, Z2 , Rl, R2, R3, m and n are as hereinbefore defined, with a sulphuric acid derivative of formula III, 5 HO3S-X ( III ) wherein X denotes a leaving group which may be substituted by a phenol oxygen, preferably a halogen atom, particularly chlorine, preferably in the presence of a weak base and a metal iodide.
Active substance according to the 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 active substance content may be increased or reduced and the quantity of glucose reduced or increased accordingly.
2. Suppositories Composition:
Active substance according to the invention 100 parts by weight Powdered lactose 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 powdered active substance (compound of formula I; particle size about 0.5 to 7 m) is packed into hard gelatine capsules in quantities 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, to which reference is hereby made.
The compounds according to the invention compound are prepared using methods known per se from the prior art. Thus, the compounds of general formula I may be prepared by reacting the benzamides of formula II which contain hydroxy groups:
1/1157-ff Boehringer Ingelheim Pharma KG
NR' OH
Z (A1 Z1 )m( AZ Z2 NH Jn \ / 2 (II) which are known, for example, from International Patent Applications WO
97/21670 and WO
98/11062, wherein Z , A1, A2, Z1, Z2 , Rl, R2, R3, m and n are as hereinbefore defined, with a sulphuric acid derivative of formula III, 5 HO3S-X ( III ) wherein X denotes a leaving group which may be substituted by a phenol oxygen, preferably a halogen atom, particularly chlorine, preferably in the presence of a weak base and a metal iodide.
10 In a preferred embodiment of the process according to the invention a compound of formula II
or an acid addition salt thereof is reacted with a sulphuric acid derivative of formula III, particularly chlorosulphonic acid, in an inert diluent and in the presence of a base, or in a basic solvent such as, for example, triethylamine or pyridine, and in the presence of catalytic amounts of a metal iodide, preferably an alkali metal iodide, particularly potassium iodide, at a temperature of from - 80 to + 120 C, preferably from -40 to +100 C, particularly from -10 to + 80 C. Under these preferred conditions the reaction is generally complete in 2 to 36 hours, preferably 4 to 18 hours.
The compound according to the invention may be prepared, starting from compounds known from the prior art, using the processes described in the following Examples, inter alia.
Various other embodiments of the process will be apparent to anyone skilled in the art from the present specification. It is specifically pointed out, however, that these Examples and the related description are provided solely as an illustration and are not to be regarded as restricting the invention.
1/1157-ff Boehringer Ingelheim Pharma KG
or an acid addition salt thereof is reacted with a sulphuric acid derivative of formula III, particularly chlorosulphonic acid, in an inert diluent and in the presence of a base, or in a basic solvent such as, for example, triethylamine or pyridine, and in the presence of catalytic amounts of a metal iodide, preferably an alkali metal iodide, particularly potassium iodide, at a temperature of from - 80 to + 120 C, preferably from -40 to +100 C, particularly from -10 to + 80 C. Under these preferred conditions the reaction is generally complete in 2 to 36 hours, preferably 4 to 18 hours.
The compound according to the invention may be prepared, starting from compounds known from the prior art, using the processes described in the following Examples, inter alia.
Various other embodiments of the process will be apparent to anyone skilled in the art from the present specification. It is specifically pointed out, however, that these Examples and the related description are provided solely as an illustration and are not to be regarded as restricting the invention.
1/1157-ff Boehringer Ingelheim Pharma KG
Example 1 Benzenecarboximidamides, 4-[[3-[[4-[1-methyl-l-[4-(sulphoxy)phenyl] ethyl]phenoxy]methyl]phenyl]methoxy] -0 ~ \ NH2 HO---SO O O ~
O
7.54 g of benzenecarboximidamides, [[4-[[3-[[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenoxy]methyl]phenyl]methoxy], monohydrochloride were taken up in 200 ml of pyridine and combined with 4.0 g of chlorosulphonic acid (slowly added at ambient temperature) as well as a trace of potassium iodide. The mixture was stirred for 6 h at 60 C.
1 o Then the reaction mixture was carefully added to water, the precipitate was suction filtered and washed with methanol. Yield: 4.0 g (m.p. 284 C).
Example 2 [1,1'-Biphenyl]-4-carboximidamides, 3'-propyl-4'-[2-[3-(sulphoxy)phenoxy]ethoxy]-NH
HO
O~S/
2.43 g of [1,1'-Biphenyl]-4-carboximidamides, 4'-[2-(3-hydroxyphenoxy)ethoxy]-3'-propyl, monomethanesulphonate, 100 ml of pyridine and 0.1 g of potassium iodide were combined and 1.5 g of chlorosulphonic acid were slowly added dropwise with stirring.
The mixture was stirred for 6 hours at 50-60 C. After cooling the mixture was added to 1 litre of water, the crystals precipitated were suction filtered and recrystallised 2x from dimethylformamide.
1.25 g of white crystals. M.p. > 270 C:
1/1157-ff Boehringer Ingelheim Pharma KG
O
7.54 g of benzenecarboximidamides, [[4-[[3-[[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenoxy]methyl]phenyl]methoxy], monohydrochloride were taken up in 200 ml of pyridine and combined with 4.0 g of chlorosulphonic acid (slowly added at ambient temperature) as well as a trace of potassium iodide. The mixture was stirred for 6 h at 60 C.
1 o Then the reaction mixture was carefully added to water, the precipitate was suction filtered and washed with methanol. Yield: 4.0 g (m.p. 284 C).
Example 2 [1,1'-Biphenyl]-4-carboximidamides, 3'-propyl-4'-[2-[3-(sulphoxy)phenoxy]ethoxy]-NH
HO
O~S/
2.43 g of [1,1'-Biphenyl]-4-carboximidamides, 4'-[2-(3-hydroxyphenoxy)ethoxy]-3'-propyl, monomethanesulphonate, 100 ml of pyridine and 0.1 g of potassium iodide were combined and 1.5 g of chlorosulphonic acid were slowly added dropwise with stirring.
The mixture was stirred for 6 hours at 50-60 C. After cooling the mixture was added to 1 litre of water, the crystals precipitated were suction filtered and recrystallised 2x from dimethylformamide.
1.25 g of white crystals. M.p. > 270 C:
1/1157-ff Boehringer Ingelheim Pharma KG
Examples 3-14 The following compounds NH
:o0 Z
are prepared analogously to Examples 1 and 2 from the corresponding phenols:
Example No. X R 2 R
3 4-HO3SO- H n-C3H7 4 4-HO3SO-phenyl H n-C3H7 5 4-HO3SO- 3-phenyl n-C3H7 6 4-HO3SO- 2-n-C3H7 n-C3H7 7 4-(4-HO3SO-phenoxy)- H n-C3H7 8 4-[1-(4-HO3SO-phenyl)-1-methyl]-ethyl H n-C3H7 9 4-[1-(4-HO3SO-phenyl)-1-methyl]-ethyl 2-n-C3H7 n-C3H7 3-HO3SO- 2-n-C3H7 n-C3H7 11 2-HO3SO- H n-C3H7 12 5-HO3SO- 2-n-C3H7 n-C3H7 13 3-HO3SO- 4-CH3-O- n-C3H7 14 3-HO3SO- H CH2=CH-CH2-
:o0 Z
are prepared analogously to Examples 1 and 2 from the corresponding phenols:
Example No. X R 2 R
3 4-HO3SO- H n-C3H7 4 4-HO3SO-phenyl H n-C3H7 5 4-HO3SO- 3-phenyl n-C3H7 6 4-HO3SO- 2-n-C3H7 n-C3H7 7 4-(4-HO3SO-phenoxy)- H n-C3H7 8 4-[1-(4-HO3SO-phenyl)-1-methyl]-ethyl H n-C3H7 9 4-[1-(4-HO3SO-phenyl)-1-methyl]-ethyl 2-n-C3H7 n-C3H7 3-HO3SO- 2-n-C3H7 n-C3H7 11 2-HO3SO- H n-C3H7 12 5-HO3SO- 2-n-C3H7 n-C3H7 13 3-HO3SO- 4-CH3-O- n-C3H7 14 3-HO3SO- H CH2=CH-CH2-
Claims (14)
1. New sulphoxybenzamides of general formula I
wherein Z0 denotes a group selected from the formulae -X1-(CH2)r-X2- and -CR4R5-, A1 and A2 independently of one another each denote a 1,4-phenylene- or 1,3-phenylene group optionally substituted by one or more halogen atoms, C1-C8-alkyl groups, C2-C8-alkenyl groups, C1-C8-haloalkyl groups or C1-C8-alkoxy groups, Z1 and Z2 independently of one another each denote a group of formula -X3-(CH2)s-X4- or a single bond, R1 denotes hydrogen, hydroxy, -COO-C1-C8-alkyl or -COO-C1-C4-alkyl-phenyl, whilst in the abovementioned group the phenyl ring in each case may be substituted by C1-C4-alkyl or C1-C4-alkoxy, R2 and R3 independently of one another each denote a hydrogen or halogen atom, or a C1-C8-alkyl, C1-C8-haloalkyl, C1-C8-alkoxy, aryl, aryloxy or aralkyl group, R4 and R5 independently of one another each denote hydrogen or C1-C4-alkyl, X1 and X2 independently of one another each denote -O, -S, -NH- or a single bond, X3 and X4 independently of one another each denote -O, -S, -NH- or a single bond, m and n independently of one another each denote 0 or 1, and r and s independently of one another each denote an integer from 1 to 8, optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, as well as optionally the pharmacologically acceptable salts thereof.
wherein Z0 denotes a group selected from the formulae -X1-(CH2)r-X2- and -CR4R5-, A1 and A2 independently of one another each denote a 1,4-phenylene- or 1,3-phenylene group optionally substituted by one or more halogen atoms, C1-C8-alkyl groups, C2-C8-alkenyl groups, C1-C8-haloalkyl groups or C1-C8-alkoxy groups, Z1 and Z2 independently of one another each denote a group of formula -X3-(CH2)s-X4- or a single bond, R1 denotes hydrogen, hydroxy, -COO-C1-C8-alkyl or -COO-C1-C4-alkyl-phenyl, whilst in the abovementioned group the phenyl ring in each case may be substituted by C1-C4-alkyl or C1-C4-alkoxy, R2 and R3 independently of one another each denote a hydrogen or halogen atom, or a C1-C8-alkyl, C1-C8-haloalkyl, C1-C8-alkoxy, aryl, aryloxy or aralkyl group, R4 and R5 independently of one another each denote hydrogen or C1-C4-alkyl, X1 and X2 independently of one another each denote -O, -S, -NH- or a single bond, X3 and X4 independently of one another each denote -O, -S, -NH- or a single bond, m and n independently of one another each denote 0 or 1, and r and s independently of one another each denote an integer from 1 to 8, optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, as well as optionally the pharmacologically acceptable salts thereof.
2. Compounds of formula I according to claim 1, wherein Z0 denotes a group selected from the formulae -X1-(CH2)r-X2- and -CR4R5-, A1 and A2 independently of one another each denote a 1,4-phenylene or 1,3-phenylene group optionally substituted by a C1-C4-alkyl group or C2-C4-alkenyl group, Z1 and Z2 independently of one another each denote a group of formula -X3-(CH2)s-X4- or a single bond, R1 denotes hydrogen, R2 and R3 each denote a hydrogen atom, R4 and R5 independently of one another each denote C1-C4-alkyl, X1 and X2 independently of one another each denote -O- or a single bond, X3 and X4 independently of one another each denote -O- or a single bond, m and n independently of one another each denote 0 or 1, and r and s independently of one another each denote an integer from 1 to 3.
3. Compounds of formula I according to claim 1 or 2, wherein Z0 denotes a group of formula -X1-(CH2)r-X2-, A 2 denotes a 1,4-phenylene group substituted by a C1-C4-alkyl or C2-C4-alkenyl group, Z2 denotes a single bond, R1 denotes hydrogen, R2 and R3 each denote a hydrogen atom, X1 and X2 independently of one another each denote -O-, m denotes 0, n denotes 1, and r denotes 2.
4. Compound of formula IA
5. Compounds of formula I according to claim 1 or 2, wherein Z0 denotes a group of formula -CR4R5-, A1 and A2 independently of one another each denote a 1,4-phenylene or 1,3-phenylene group optionally substituted by a C1-C4-alkyl group, Z1 and Z2 independently of one another each denote a group of formula -X3-(CH2)s-X4-, R denotes hydrogen, R2 and R3 each denote a hydrogen atom, R4 and R5 each denote methyl, X3 and X4 independently of one another each denote -O- or a single bond, m and n each denote 1, and s denotes 1.
6. Compound of formula IB
7. Compounds of formulae I, IA or IB according to one of claims 1 to 6 for use as pharmaceutical compositions.
8. Process for preparing compounds of formulae I, IA or IB according to one of claims 1 to 6, characterised in that a hydroxybenzamidine of formula II
wherein Z0, A1, A2, Z1, Z2, R1, R2, R3, m and n have the meanings given in claims 1 to 6, is reacted with a sulphuric acid derivative of formula III, HO3S-X ( III ) wherein X denotes a leaving group which can be substituted by a phenoxide oxygen.
wherein Z0, A1, A2, Z1, Z2, R1, R2, R3, m and n have the meanings given in claims 1 to 6, is reacted with a sulphuric acid derivative of formula III, HO3S-X ( III ) wherein X denotes a leaving group which can be substituted by a phenoxide oxygen.
9. Process according to claim 7, characterised in that the reaction is carried out in the presence of a weak base and a metal iodide.
10. Pharmaceutical preparation containing a compound according to one of claims 1 to 6 and pharmaceutically acceptable carriers and excipients.
11. Use of compounds according to one of claims 1 to 6 for preparing a medicament.
12. Use of compounds according to claim 10 for preparing a medicament with an antagonistic activity.
13. Use of compounds of general formula I according to one of claims 1 to 6, the stereoisomers thereof as well as the acid addition salts thereof for preparing a medicament for the therapeutic treatment of arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, ulcerative colitis, gastro- or enteropathy induced by nonsteroidal antiphlogistics, cystic or pulmonary fibrosis, Alzheimer's disease, shock, reperfusion damage/ischaemia, atherosclerosis, multiple sclerosis, autoimmune diseases, malignant neoplasia, alveolitis.
14. Method of treating and/or preventing diseases in which LTB4-antagonists develop a therapeutic benefit, by administering a therapeutically effective amount of one or more compounds of general formula I according to one of claims 1 to 6, the stereoisomers thereof or the acid addition salts thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10052333A DE10052333A1 (en) | 2000-10-24 | 2000-10-24 | New sulfooxybenzamides |
| DE10052333.1 | 2000-10-24 | ||
| PCT/EP2001/012127 WO2002034715A1 (en) | 2000-10-24 | 2001-10-19 | Benzamidine derivatives comprising a sulfate group serving as ltb4 antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2425368A1 CA2425368A1 (en) | 2003-04-08 |
| CA2425368C true CA2425368C (en) | 2008-12-09 |
Family
ID=7660637
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002425368A Expired - Fee Related CA2425368C (en) | 2000-10-24 | 2001-10-19 | New sulphoxybenzamides |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1332128A1 (en) |
| JP (1) | JP3917516B2 (en) |
| AU (1) | AU2002210558A1 (en) |
| CA (1) | CA2425368C (en) |
| DE (1) | DE10052333A1 (en) |
| MX (1) | MXPA03003465A (en) |
| PE (1) | PE20020542A1 (en) |
| WO (1) | WO2002034715A1 (en) |
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| US20080206203A1 (en) * | 2004-07-14 | 2008-08-28 | Inflammation Research Center Company Ltd. | Method for Inhibiting Tumor Metastasis |
| DE602005019897D1 (en) * | 2005-07-08 | 2010-04-22 | Leopold Franzens Uni Innsbruck | Use of extracts and ingredients from Leontopodium to increase cholinergic function |
| CN100402494C (en) * | 2005-08-25 | 2008-07-16 | 江苏吴中苏药医药开发有限责任公司 | Myoinositol sulfate aluminium , its preparation method and oral compositions and uses |
| ES2683306T3 (en) | 2011-03-16 | 2018-09-26 | Creative Therapeutics Gmbh | Substituted Diphenyl Derivatives |
| CA3063334A1 (en) | 2017-05-12 | 2019-12-05 | Riken | Modified class a gpcr binding compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU216191B (en) * | 1992-02-05 | 1999-05-28 | Boehringer Ingelheim Kg | Process for preparing novel amidine derivs. pharmaceutical compns. containing them |
| DE19546452A1 (en) * | 1995-12-13 | 1997-06-19 | Boehringer Ingelheim Kg | New phenylamidine derivatives, process for their preparation and their use as medicaments |
| DE19636689A1 (en) * | 1996-09-10 | 1998-03-12 | Boehringer Ingelheim Kg | New benzamidine derivatives |
-
2000
- 2000-10-24 DE DE10052333A patent/DE10052333A1/en not_active Withdrawn
-
2001
- 2001-10-19 AU AU2002210558A patent/AU2002210558A1/en not_active Abandoned
- 2001-10-19 EP EP01978439A patent/EP1332128A1/en not_active Withdrawn
- 2001-10-19 CA CA002425368A patent/CA2425368C/en not_active Expired - Fee Related
- 2001-10-19 MX MXPA03003465A patent/MXPA03003465A/en unknown
- 2001-10-19 JP JP2002537708A patent/JP3917516B2/en not_active Expired - Fee Related
- 2001-10-19 WO PCT/EP2001/012127 patent/WO2002034715A1/en active Application Filing
- 2001-10-22 PE PE2001001045A patent/PE20020542A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU2002210558A1 (en) | 2002-05-06 |
| MXPA03003465A (en) | 2004-12-06 |
| JP2004512322A (en) | 2004-04-22 |
| CA2425368A1 (en) | 2003-04-08 |
| DE10052333A1 (en) | 2002-05-02 |
| PE20020542A1 (en) | 2002-07-16 |
| JP3917516B2 (en) | 2007-05-23 |
| EP1332128A1 (en) | 2003-08-06 |
| WO2002034715A1 (en) | 2002-05-02 |
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