WO2006117316A1 - Composes de promedicaments mutuels utilises comme agents anti-inflammatoires a activite gastro-intestinale protectrice - Google Patents

Composes de promedicaments mutuels utilises comme agents anti-inflammatoires a activite gastro-intestinale protectrice Download PDF

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Publication number
WO2006117316A1
WO2006117316A1 PCT/EP2006/061856 EP2006061856W WO2006117316A1 WO 2006117316 A1 WO2006117316 A1 WO 2006117316A1 EP 2006061856 W EP2006061856 W EP 2006061856W WO 2006117316 A1 WO2006117316 A1 WO 2006117316A1
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WIPO (PCT)
Prior art keywords
dimethyl
hydroxy
phenyl
acid
inn
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PCT/EP2006/061856
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English (en)
Inventor
Christof Brehm
Thomas Klein
Wilm Buhr
Maria Vittoria Chiesa
Andreas Palmer
Peter Jan Zimmermann
Wolfgang-Alexander Simon
Stefan Postius
Wolfgang Kromer
Gerhard Grundler
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Nycomed Gmbh
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Priority to CA002605900A priority Critical patent/CA2605900A1/fr
Priority to AU2006243255A priority patent/AU2006243255A1/en
Priority to EP06763060A priority patent/EP1877410A1/fr
Publication of WO2006117316A1 publication Critical patent/WO2006117316A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • the invention relates to novel compounds, which are used in the pharmaceutical industry as active compounds for the production of medicaments, to medicaments comprising these compounds and to the use of these compounds for the treatment and/or prophylaxis of diseases.
  • Non-steroidal anti-inflammatory drugs are a class of compounds which are widely used inter alia for the treatment of inflammation, pain and fever.
  • NSAID ' s can cause unwanted side effects, inter alia on the gastrointestinal system, such as for example gastrointestinal ulcers, which is a major limitation to the use of NSAID ' s.
  • Reversible proton pump inhibitors also named as potassium competitive acid blockers (P-CABs) or acid pump antagonists (APA ' s)
  • P-CABs potassium competitive acid blockers
  • APA ' s acid pump antagonists
  • Compounds of different chemical classes such as for example imidazopyridine, benzimidazole, quinazoline or pyrrolopyridazine derivatives are known in the art to act as P-CAB ' s.
  • P-CABs which can be used inter alia in the prevention or treatment of gastrointestinal disorders are known from a variety of prior art documents such as, for example, from the international applications WO 91/17164, WO 93/08190, WO 92/06979, WO 98/42707, WO 98/54188, WO 00/17200, WO 00/26217, WO 00/63211 , WO 01/72754, WO 01/72756, WO 01/72755, WO 01/72757, WO 02/34749, WO 03/014120, WO 03/016310, WO 03/014123, WO 03/068774, WO 03/091253, WO 04/046144, WO 04/074289, WO 04/054984, WO 04/087701 , WO 99/55705, WO 99/55706, WO 00/11000, WO 02/20523, WO 02/069968, WO 03/018582,
  • the compounds mentioned in the patent applications cited above are said to have advantageous gas- tro-protective action against certain medicaments (such as, for example, those medicaments mentioned below in the description of this invention, especially antiinflammtraes and antirheumatics, and/or, in particular, those medicaments which cause erosive changes and/or lesions in the gastrointestinal system) and/or are well useful and effective in the prevention or treatment of gastrointestinal disorders associated with certain medicaments indicated below and/or are particularly useful and effective in prevention or treatment of gastrointestinal diseases caused by certain medicaments selected from the group consisting of NSAIDs (non-steroidal antiinflammatory drugs), COX-2 (cyclooxygenase 2) inhibitors, NO-NSAIDs (nitric oxide releasing NSAID), bisphosphonates and corticosteroids.
  • NSAIDs non-steroidal antiinflammatory drugs
  • COX-2 cyclooxygenase 2
  • NO-NSAIDs nitric oxide releasing NSAID
  • bisphosphonates corticosteroids
  • compositions comprising as a first active ingredient an acid pump antagonist which is a tricyclic imidazo[1 ,2-a]- pyridine compound and a second active ingredient which is selected from the group consisting of NSAIDs, COX-2-inhibitors, NO-NSAIDs, bisphosphonates and corticosteroids.
  • the compounds according to the present invention exhibit antipyretic, analgesic, antiphlogistic and/or anti-inflammatory properties as well as gastric acid secretion inhibiting and therefore gastro and intestinal protective properties.
  • the invention relates to compounds of the formula I
  • A is the residue derived from a corresponding carboxylic acid of the formula Na
  • hydroxy compound of the formula III is a compound from the class of potassium competitive acid blockers and is selected from one of the following compounds (7R,8R,9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2- h][1 ,7]naphthyridine,
  • 2,3-Dimethyl-1 -furfuryl-7-(2-hydroxymethylbenzyloxy)-pyrrolo[2,3-d]pyridazin X is either a bond or a linker
  • Y is a radical
  • R1 is hydrogen or 1 -4C-alkyl, or X, Y and z together form a bond, and the salts of these compounds.
  • Some combinations of X, Y and z may be unfavourable as yielding one or more very labile bonds which are cleaved easily or spontaneously and therefore rendering the resulting compounds of the formula I less useful for application in medicaments.
  • some combinations wherein X is a bond may be unfavourable, for example if a bond is formed between two heteroatoms. The person skilled in the art is able to identify such unfavourable combinations due to his expert knowledge. Such an unfavourable combination is, for instance, when
  • Y is the radical
  • Possible salts of compounds of the formula I - depending on substitution - are especially all acid addition salts. Particular mention may be made of the pharmacologically tolerable salts of the inorganic and organic acids customarily used in pharmacy. Those suitable are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)- benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where the acids are used in salt preparation - depending on whether a mono-
  • Pharmacologically intolerable salts which can initially be obtained, for example, as process products in the production of the compounds according to the invention on the industrial scale, are converted into the pharmacologically tolerable salts by processes known to the person skilled in the art.
  • the compounds of the formula I may have, depending on the residues A and B, and depending on the nature of X, Y and z, one or more centers of chirality in the skeleton.
  • the invention thus provides all feasible stereoisomers in any mixing ratio, including the pure stereoisomers, which are a preferred subject matter of the invention.
  • the invention therefore also comprises all solvates and in particular all hydrates of the compounds of the formula I, and also all solvates and in particular all hydrates of the salts of the compounds of the formula I.
  • the compounds of the formula I according to the invention are prodrugs and become pharmaceutically active if, under physiological conditions in the human or animal body, cleavage of these compounds of the formula I with concomitant release of the compounds of the formula Ma and/or the compounds of the formula III occurs.
  • the cleavage can occur hydrolytically, for example under the influence of certain pH conditions, for example in an acidic environment, or under the influence of suitable enzymes present in the human or animal body, such as for example esterases.
  • this compound of the formula IV As the compound of the formula IV, or related compounds, are released after complete hydrolytical cleavage in an equimolar ratio when compared to the compound of the formula Il and the compound of the formula III, this compound of the formula IV has to be a non-toxic compound when applied in doses according to the present invention.
  • Suitable linkers X which can be used for the present invention are known to the person skilled in the art or can be identified by a person skilled in the art due to his expert knowledge. If a linker is to be used according to the present invention, the person skilled in the art will take several considerations into account, such as for example the following: the linker should form two stable covalent bonds to both residues A and B in compounds of the formula I, which are resistant to cleavage under normal physiological conditions in the human and animal body encountered by the administered compound on its way to the target site, the linker should not confer such a steric hindrance on cleavage, that the pharmaceutically active compounds can not be released from the compounds of the formula I, different linkers may be required for different combinations of compounds of the formula Il and of the formula III, different linkers may be required if different diseases or conditions are to be treated with compounds of the formula I, different linkers will regulate the release of the compounds of the formula Il and of the formula III by facilitating or delaying the cleavage from compounds of the formula I, the compound
  • the linker X is a divalent radical.
  • the linker X is a linear or branched, saturated or unsaturated hydrocarbon chain, optionally forming one or more (e.g. 1 , 2 or 3) hydrocarbon cycles of 3 to 7 ring members, whereby the hydrocar- bon chain has 1 to 21 carbon atoms, wherein one or more (e.g. 1 , 2, 3 or 4) of the carbon atoms with its two substituents is optionally replaced by oxygen (-0-), and wherein the chain is optionally substituted on carbon with one or more (e.g.
  • X is a linker of the formula -(CH 2 ) n -(O) m -(CH 2 ) p -(O) q -(CH 2 ) r , wherein n is an integer from 1 to 7, m is either 0 or 1 , p is an integer from 0 to 7, q is either 0 or 1 and r is an integer from 0 to 7, wherein, optionally, one or more of the hydrogen atoms in the -CH 2 - radicals is substituted by a fluoro, 1 -4C-alkyl or fluoro-1 -4C-alkyl radical, with the proviso that p is not 0 if m is 1 , and r is not 0 if q is 1.
  • X is a linker of the formula -(CH 2 ) n -, wherein n is an integer from 1 to 7.
  • X is a linker of the formula -(CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 2 - or -(CH 2 ) 2 -O-CH 2 -.
  • 1 -4C-Alkyl represents straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl radical.
  • Fluoro-1 -4C-alkyl represents one of the aforementioned 1 -4C-alkyl radicals, which is substituted by one or more fluorine atoms.
  • An example which may be mentioned is the trifluoromethyl radical.
  • 1 -4C-Alkoxy represents radicals, which in addition to the oxygen atom contain a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy radical.
  • 1 -4C-Alkoxy-1 -4C-alkyl represents one of the aforementioned 1 -4C-alkyl radicals, which is substituted by one of the aforementioned 1 -4C-alkoxy radicals. Examples which may be mentioned are the meth- oxymethyl, the methoxyethyl radical and the butoxyethyl radical.
  • 3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred.
  • 3-7C-Cycloalkyl-1 -4C-alkyl represents one of the aforementioned 1 -4C-alkyl radicals, which is substituted by one of the aforementioned 3-7C-cycloalkyl radicals. Examples which may be mentioned are the cyclopropylmethyl, the cyclohexylmethyl and the cyclohexylethyl radical.
  • 1 -4C-Alkylcarbonyl represents a radical, which in addition to the carbonyl group contains one of the aforementioned 1 -4C-alkyl radicals.
  • An example which may be mentioned is the acetyl radical.
  • 1 -4C-Alkylcarbonyloxy represents a 1 -4C-alkylcarbonyl group which is bonded to an oxygen atom.
  • An example which may be mentioned is the acetoxy radical (CH 3 CO-O-).
  • 1 -4C-Alkoxycarbonyl represents a carbonyl group, to which one of the aforementioned 1 -4C-alkoxy radicals is bonded. Examples which may be mentioned are the methoxycarbonyl (CH 3 O-C(O)-) and the ethoxycarbonyl radical (CH 3 CH 2 O-C(O)-) .
  • Halogen within the meaning of the invention is bromo, chloro and fluoro.
  • Aryl is is a mono- or bicyclic aromatic residue, which is selected from phenyl or naphthyl optionally substituted by one, two or three identical or different substituents from the group consisting of 1 -4C- alkyl, 1 -4C-alkoxy, carboxyl, 1 -4C-alkoxycarbonyl, halogen, fluoro-1 -4C-alkyl, nitro, trifluoromethoxy, hydroxyl and cyano.
  • Heteroaryl is a mono- or bicyclic aromatic residue, which is selected from pyrrolyl, pyrazolyl, imidazolyl, 1 ,2,3-triazolyl, indolyl, benzimidazolyl, furanyl (furyl), benzofuranyl (benzofuryl), thiophenyl (thienyl), benzothiophenyl (benzothienyl), thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl and isoquinolinyl optionally substituted by one, two or three identical or different substituents from the group consisting of 1 -4C-alkyl, 1 -4C-alkoxy, carboxyl, 1 -4C-alkoxycarbonyl, halogen, fluoro-1 -4C-alkyl, nitro, trifluoromethoxy, hydroxyl and cyano.
  • the compound of the formula Na with antipyretic, analgesic, antiphlogistic and/or anti-inflammatory properties preferably is a compound belonging to the class of NSAID's (non-steroidal antiinflammatory drugs).
  • NSAID according to the present invention is to be understood to comprise compounds which inhibit one or more of the cyclooxygenase isomers C0X1 (cyclooxygenase 1 ), C0X2 (cyclooxygenase 2) or COX 3 (cyclooxygenase 3).
  • the residue A in compounds of the formula I is derived from carboxylic acids of the formula Na with antipyretic, analgesic, antiphlogistic and/or anti-inflammatory properties, which compounds of the for- mula Na can belong to different chemical classes of NSAID ' s. These different chemical classes of NSAID ' s are known to a person skilled in the art. Therefore any compound of formula Na with antipyretic, analgesic, antiphlogistic and/or anti-inflammatory properties can be used according to the present invention.
  • Classes of NSAID ' s which can be used according to the present invention include, but are not limited to, inter alia aryl or heteroaryl acetic acid derivatives, aryl or heteroaryl propionic acid derivatives, aryl or heteroaryl butyric acid derivatives, aryl or heteroaryl carboxylic acid derivatives, aminoaryl or ami- noheteroaryl carboxylic acid derivatives, anthranilic acid derivatives and salicylic acid derivatives.
  • These classes of NSAID ' s are known to a person skilled in the art.
  • Exemplary NSAID ' s of the formula Na within the meaning of the present invention are for example those NAIDS ' s listed in the following List A1 a: glycolic acid [o-(2,6-dichloroanilino)phenyl]acetate(ester) [INN: ACECLOFENAC]; i - ⁇ -chlorobenzoyO- ⁇ -methoxy ⁇ -methyl-I H-indole-S-acetic acid carboxymethyl ester [INN:
  • N-(2-carboxyphenyl)-4-chloroanthranilic acid [INN: LOBENZARIT], 3-(p-chlorophenyl)-1 -phenylpyrazole-4-acetic acid [INN: LONAZOLAC], 2-[4-(2-oxocyclopentan-1 -ylmethyl)phenyl]-propionate [INN: LOXOPROFEN], 2-[2-(2-chloro-6-fluorophenylamino)-5-methylphenyl]acetic acid [INN: LUMIRACOXIB], N-(2,6-dichloro-m-tolyl)anthranilic acid [INN: MECLOFENAMIC ACID] N-(2,3-xylyl)anthranilic acid [INN: MEFENAMIC ACID], 5-aminosalicylic acid [INN: MESALAZINE], 3,4-bis(4-methoxyphenyl)-5-isoxazoleacetic acid [
  • 2-thiophenecarboxylic acid, ester with salicylic acid [INN: TENOSAL], alpha-(5-benzoyl-2-thienyl)propionic acid [INN: TIAPROFENIC ACID],
  • NSAIDs according to the present invention which are to be emphasized are: ACETYL- SALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ELTENAC, ETODOLAC, FENOPROFEN, FLURBIPROFEN, ESFLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, LUMIRACOXIB, MEFENAMIC ACID, NAPROXEN, OXAPROZIN, SALICYLIC ACID, SULINDAC, TIAPROFENIC ACID and TOLMETIN, as well as the pharmaceutically acceptable derivatives of these compounds.
  • exemplary NSAIDs which are to be emphasized are: ACETYLSALICYLIC ACID, DICLOFENAC, DIFLUNISAL, ELTENAC, ETODOLAC, FENOPROFEN, FLURBIPROFEN, ESFLURBIPROFEN, IBUPROFEN, INDOMETHACIN, KETOPROFEN, LUMIRACOXIB, MEFENAMIC ACID, NAPROXEN, OXAPROZIN, SALICYLIC ACID, SULINDAC, TIAPROFENIC ACID and TOLMETIN, as well as the pharmaceutically acceptable derivatives of these compounds.
  • Preferred exemplary NSAIDs according to the present invention which are selected from the above- defined group of exemplary NSAIDs, are, DICLOFENAC, ELTENAC, FLURBIPROFEN, ESFLURBIPROFEN, IBUPROFEN, INDOMETACIN, LUMIRACOXIB and NAPROXEN, SALICYLIC ACID as well as the pharmaceutically acceptable derivatives of these compounds.
  • preferred exemplary NSAIDs according to the present invention are DICLOFENAC, ELTENAC, FLURBIPROFEN, ESFLURBIPROFEN, IBUPROFEN, I N DOM ETACI N, LUMIRACOXIB and NAPROXEN, SALICYLIC ACID as well as the pharmaceutically acceptable derivatives of these compounds.
  • preferred exemplary NSAIDs are DICLOFENAC, ELTENAC, FLURBIPROFEN, ESFLURBIPROFEN ,SALICYLIC ACID, NAPROXEN and INDOMETACIN, as well as the pharmaceutically acceptable derivatives of these compounds.
  • preferred exemplary NSAIDs according to the present invention are those NSAIDs which were used in the examples of the present invention, as well as the pharmaceutically acceptable derivatives of these compounds.
  • the residue A which is derived from a compound of the formula Ma according to the present invention is to be understood as to be the residue A which is attached to the carboxylic acid functionality of the compound of the formula Ma.
  • the residue A and the resulting compound of the formula I which are derived from DICLOFENAC are shown in scheme A1. If the carboxylic acid of the formula Ma comprises more than one carboxylic acid functionality and if the residues A which are attached to functional groups are of a different chemical structure, all the different residues A can be used according to the present invention. This case is shown by way of example in scheme A for CARBOCISTEINE.
  • Second residue A derived Second Compound of the Formula I from Carbocisteine wherein A is derived from Carbocisteine
  • the hydroxy compound of the formula III is a compound from the class of potassium competitive acid blockers (P-CAB ' s) which binds reversibly to the H+/K+-ATPase and thus inhibits gastric acid secretion.
  • P-CAB ' s potassium competitive acid blockers
  • Compounds of different chemical classes, such as for example imidazopyridine, benzimidazole, quinazoline or pyrrolopyridazine derivatives are known in the art to act as P-CAB ' s, for example from those patent applications mentioned in the known technical background, without being limited to these patent applications or to the chemical classes mentioned in these patent applications.
  • the residue B in compounds of the formula I is derived from hydroxyl compounds of the formula III which is a compound from the class of potassium competitive acid blockers, which compounds of the formula III can belong to different chemical classes of P-CAB ' s. These different chemical classes of P- CAB ' s are known to a person skilled in the art.
  • Exemplary P-CAB ' s of the formula III within the meaning of the present invention are, in a further embodiment (embodiment 2) according to the present invention, all those P-CAB ' s listed in the following lists B1 , B2 or B3.
  • FIG. 2 Another special embodiment of the invention (embodiment 2) relates to compounds of the formula I, wherein B is the residue derived from a hydroxy compound of the formula III which are disclosed in the International Patent Applications WO 98/42707, WO 98/54188, WO 00/17200, WO 00/26217, WO 00/63211 , WO 01/72754, WO 01/72756, WO 0172755, WO 0172757, WO 0234749, WO 03014120, WO 03014123, WO 03016310, WO 03/068774, WO 03091253, WO 04/054984, WO 04/087701 , WO 04/046144, WO 04/054984, WO 91/17164, WO 93/08190 and WO 92/06979.
  • the exemplary compounds described in these patent applications are a preferred embodiment of embodiment 2.
  • preferred exemplary P-CABs according to embodiment 2 are those P- CABs which were used in the examples of the present invention, as well as the pharmaceutically acceptable derivatives of these compounds.
  • the residue B which is derived from a corresponding hydroxy compound of the formula III according to the present invention is to be understood as to be the residue B which is attached to the hydroxyl functionality of the compound of the formula III.
  • the residue B and the resulting compound of the formula I which are derived from SORAPRAZAN are shown in scheme B. If the hydroxy compound of the formula III comprises more than one hydroxyl functionality, and if the residues B which are attached to these hydroxyl functionalities are of a different chemical structure, all the different residues B can be used according to the present invention.
  • Soraprazan Residue B derived Compound of the Formula I wherein from Soraprazan B is derived from Soraprazan
  • the invention particularly relates to compounds of the formula I
  • A is the residue derived from a corresponding carboxylic acid of the formula Ma
  • carboxylic acid of the formula Ma is a compound with antipyretic, analgesic, antiphlogistic and/or anti-inflammatory properties
  • B is the residue derived from an exemplary hydroxy compound listed in list B1 ,
  • X is either a bond or a linker
  • Y is a radical
  • carbonyl group is attached to A, is a bond, -0-, -CHR1 - or -NR1 -, wherein R1 is hydrogen or 1 -4C-alkyl, or X, Y and z together form a bond, and the salts of these compounds.
  • the invention particularly also relates to compounds of the formula I
  • A is the residue derived from a corresponding carboxylic acid of the formula Ma
  • a ⁇ O ⁇ H Ha which carboxylic acid of the formula Ma is a compound with antipyretic, analgesic, antiphlogistic and/or anti-inflammatory properties,
  • B is the residue derived from a exemplary hydroxy compound listed in list B2,
  • X is either a bond or a linker
  • Y is a radical
  • R1 is hydrogen or 1 -4C-alkyl, or X, Y and z together form a bond, and the salts of these compounds.
  • the invention particularly also relates to compounds of the formula I
  • A is the residue derived from a corresponding carboxylic acid of the formula Ma
  • carboxylic acid of the formula Ma is a compound with antipyretic, analgesic, antiphlogistic and/or anti-inflammatory properties
  • X is either a bond or a linker
  • Y is a radical
  • R1 is hydrogen or 1 -4C-alkyl, or X, Y and z together form a bond, and the salts of these compounds.
  • a further aspect of the invention relates to compounds of the formula 1 , wherein
  • A is the residue derived from an exemplary carboxylic acid listed in list A1 a,
  • B is the residue derived from an exemplary hydroxy compound listed in list B1 ,
  • X is either a bond or a linker
  • Y and z are as defined in the outset, and the salts of these compounds.
  • a further aspect of the invention relates to compounds of the formula 1 , wherein
  • A is the residue derived from an exemplary carboxylic acid listed in list A1 a,
  • B is the residue derived from an exemplary hydroxy compound listed in list B1 ,
  • X is as defined in embodiment Oa
  • Y and z are as defined in the outset, and the salts of these compounds.
  • a further aspect of the invention relates to compounds of the formula 1 , wherein
  • A is the residue derived from an exemplary carboxylic acid listed in list A1 a,
  • B is the residue derived from an exemplary hydroxy compound listed in list B1 ,
  • Y and z are as defined in in the outset, and the salts of these compounds.
  • a further aspect of the invention relates to compounds of the formula 1 , wherein
  • A is the residue derived from an exemplary carboxylic acid listed in list A1 a
  • B is the residue derived from an exemplary hydroxy compound listed in list B1
  • X is as defined in embodiment Oc
  • Y and z are as defined in in the outset, and the salts of these compounds.
  • a further aspect of the invention relates to compounds of the formula 1 , wherein
  • A is the residue derived from an exemplary carboxylic acid listed in list A1 a,
  • B is the residue derived from an exemplary hydroxy compound listed in list B2,
  • X is a bond or a linker
  • Y and z are as defined in the outset, and the salts of these compounds.
  • a further aspect of the invention relates to compounds of the formula 1 , wherein
  • A is the residue derived from an exemplary carboxylic acid listed in list A1 a,
  • B is the residue derived from an exemplary hydroxy compound listed in list B2,
  • X is as defined in embodiment Oa
  • Y and z are as defined in the outset, and the salts of these compounds.
  • a further aspect of the invention relates to compounds of the formula 1 , wherein
  • A is the residue derived from an exemplary carboxylic acid listed in list A1 a,
  • B is the residue derived from an exemplary hydroxy compound listed in list B2,
  • Y and z are as defined in the outset, and the salts of these compounds.
  • a further aspect of the invention relates to compounds of the formula 1 , wherein
  • A is the residue derived from an exemplary carboxylic acid listed in list A1 a,
  • B is the residue derived from an exemplary hydroxy compound listed in list B2,
  • X is as defined in embodiment Oc
  • Y and z are as defined in in the outset, and the salts of these compounds.
  • a further aspect of the invention relates to compounds of the formula 1 , wherein A is the residue derived from an exemplary carboxylic acid listed in list A1 a, B is the residue derived from an exemplary hydroxy compound listed in list B3, X is a bond or a linker,
  • Y and z are as defined in the outset, and the salts of these compounds.
  • a further aspect of the invention relates to compounds of the formula 1 , wherein
  • A is the residue derived from an exemplary carboxylic acid listed in list A1 a,
  • B is the residue derived from an exemplary hydroxy compound listed in list B3,
  • X is as defined in embodiment Oa
  • Y and z are as defined in the outset, and the salts of these compounds.
  • a further aspect of the invention relates to compounds of the formula 1 , wherein
  • A is the residue derived from a exemplary carboxylic acid listed in list A1 a,
  • B is the residue derived from an exemplary hydroxy compound listed in list B3,
  • Y and z are as defined in the outset, and the salts of these compounds.
  • a further aspect of the invention relates to compounds of the formula 1 , wherein
  • A is the residue derived from an exemplary carboxylic acid listed in list A1 a,
  • B is the residue derived from an exemplary hydroxy compound listed in list B3,
  • X is as defined in embodiment Oc
  • Y and z are as defined in in the outset, and the salts of these compounds.
  • A is the residue derived from one of the following carboxylic acids:
  • INDOMETACIN B is the residue derived from one of the following hydroxy compounds: (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10- tetrahydroimidazo[1 ,2-h][1 ,7]naphthyridine (SORAPRAZAN),
  • X is a linker of the formula -(CH 2 ) n -(O) m -(CH 2 ) p -(O) q -(CH 2 ) r , wherein n is an integer from 1 to 7, m is either 0 or 1 , p is an integer from 0 to 7, q is either 0 or 1 and r is an integer from 0 to 7, wherein, optionally, one or more of the hydrogen atoms in the -CH 2 - radicals is substituted by a fluoro, 1 -4C-alkyl or fluoro-1 -4C-alkyl radical, with the proviso that p is not 0 if
  • A is the residue derived from one of the following carboxylic acids:
  • NAPROXEN or INDOMETACIN B is the residue derived from one of the following hydroxy compounds:
  • X is a linker of the formula -(CH 2 ) n -, wherein n is an integer from 1 to 7, or a linker of the formula
  • A is the residue derived from one of the following carboxylic acids:
  • X is a linker of the formula -(CH 2 ) n -, wherein n is an integer from 1 to 7
  • Y is a radical
  • the compounds according to the invention can be synthesized from corresponding starting compounds, for example according to the reaction schemes given below.
  • the synthesis is carried out in a manner known to the expert, for example as described in more detail in the following examples.
  • the starting compounds are known (for example from the patents or patent applications mentioned above) or they can be prepared in an analogous manner to the known compounds.
  • the compounds according to the invention can be prepared, for example, according to the following reaction schemes.
  • the compounds of the general formula I, wherein X, Y and z together form a bond can be obtained for example by reacting a carboxylic acid of the formula Ma with a hydroxyl compound of the formula III (as shown in scheme 1 ).
  • the esterification can be performed using coupling technologies known per se (for example using acid activating agents like N,N-carbonyldiimidazole or dicyclohexylcarbodiimide in the presence of a base like, for example, 4-(N,N-dimethylamino)pyridine).
  • the linker -Y-X-Z-C(O)-O- can be coupled in a first step either with the compound of the formula Na or with the hydroxyl compound of the formula III by reaction with a linker precursor.
  • the intermediate where either the compound of the formula Ma or the compound of the formula III is attached to the linker -Y-X- Z-C(O)-O- can be coupled by methods known to the expert to the final compounds of the formula I.
  • the linker precursor is a compound of the general formula Lp1
  • G1 a is a group which reacts with the carboxylic acid functionality in compounds of the formula Ma or an activated carboxylic acid analogue thereof, for example a carboxylic acid chloride
  • G2 is a group which reacts with the hydroxyl functionality in compounds of the formula III.
  • Suitable groups G1 a and G2 are, depending on the coupling partner, radicals like for example halogen radicals or hydroxyl groups.
  • the coupling reactions of the linker precursor with the compounds of the formula Na and III again can be performed using coupling technologies known per se to a person skilled in the art, for example those mentioned above for esterification reactions when X, Y and z together form a bond.
  • reaction schemes are shown by way of example in the following scheme 2, where the linker precursor is in an exemplary manner first reacted with the P-CAB of the formula III and the resulting intermediate is then coupled with the NSAID of the formula Ma, respectively.
  • Alternative reaction sequences may be necessary to obtain certain compounds of the formula I.
  • the person skilled in the art is able to identify with his expert knowledge the most favourable scheme of synthesis for each individual compound according to the invention.
  • Suitable protecting groups for these purposes are known to a person skilled in the art, for example from T.W. Greene, P. G. M. Wuts "Protective groups in organic Synthesis", 3 rd edition, J. Wiley & Sons, New York, 1999. The person skilled in the art is able to identify suitable protecting groups for the purposes according to the invention.
  • the isolation and purification of the substances according to the invention are carried out in a manner known per se, for example by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on suitable support material.
  • Salts are obtained by dissolving the free compounds of the formula I in suitable solvent, e.g. in a chlorinated hydrocarbon, such as dichloromethane or chloroform, or a low-molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid, or to which the desired acid is then added.
  • the salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by alkalization or by acidification into the free compounds of the formula I, from which salts can in turn be prepared. In this manner, pharmacologically non-tolerable salts can be converted into pharmacologically tolerable salts.
  • N,N-Carbonyldiimidazole (0.66 g, 4.08 mmol) is added in portions to the solution of [2-(2,6- dichlorophenylamino)-phenyl] acetic acid (1.20 g, 4.08 mmol) in dichloromethane (15 ml) at room temperature. After stirring at reflux for one hour (7S,8fl,9fl)-8-hydroxy-2,3-dimethyl-7-(2-methoxyethoxy)- 9-phenyl-7,8,9,10-tetrahydro-imidazo-[1 ,2-h][1 ,7]naphthyridin (1.00 g, 2.73 mmol) is added.
  • reaction mixture is refluxed for 5 h, poured onto water, and extracted three times with dichloromethane.
  • the collected organic phases are washed with water, dried (MgSO 4 ), and the solvent is removed in vacuo.
  • the oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 4:1 ). 0.16 g of the title compound are obtained.
  • N,N,N',N'-Tetramethyl-O-(benzotriazol-1 -yl)uranium tetrafluoroborate (TBTU) (1.05 g, 3.26 mmol) is added in portions to the suspension of [2-(2,6-dichlorophenylamino)-phenyl] acetic acid (0.89 g, 2.99 mmol) in tetrahydrofuran (10 ml) at room temperature.
  • the oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 9:1 ) and crystallized from isopropanol. 0.21 g of the title compound of melting point 100-123 °C are obtained.
  • N,N,N',N'-Tetramethyl-O-(benzotriazol-1 -yl)uranium tetrafluoroborate (0.53 g, 1.64 mmol) is added in portions to the solution of [4-(2,6-dichlorophenylamino)-thiophen-3-yl] acetic acid (0.45 g, 1.49 mmol) in dichloromethan (10 ml) at room temperature.
  • the oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 4:1 ) and precipitated as salt of oxalic acid from isopropanol. 0.18 g of the title compound of melting point 177-179 °C (isopropanol) are obtained.
  • N,N-Carbonyldiimidazole (0.88 g, 5.44 mmol) is added in portions to the solution of 2-acetoxy benzoic acid (0.98 g, 5.44 mmol) in dichloromethane (15 ml) at room temperature. After stirring at reflux for one hour (7R,8R,9R)-8-hydroxy-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imidazo- [1 ,2-h][1 ,7]naphthyridin (1 .00 g, 2.73 mmol) is added.
  • reaction mixture is refluxed for 6 h, poured onto water, neutralized by adding a saturated NaHCO 3 solution (pH 8), and extracted three times with dichloromethane.
  • the collected organic phases are washed with water, dried (MgSO 4 ), and the solvent is removed in vacuo.
  • the oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 20:1 ) and crystallized from isopropanol. 0.33 g of the title compound are obtained.
  • N,N,N',N'-Tetramethyl-O-(benzotriazol-1 -yl)uranium tetrafluoroborate (1.09 g, 3.40 mmol) is added in portions to the suspension of [2-(2,6-dichlorophenylamino)-phenyl] acetic acid (0.92 g, 3.11 mmol) in tetrahydrofuran (10 ml) at room temperature.
  • the oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 9:1 ) and precipitated as salt of oxalic acid from isopropanol. 0.18 g of the title compound of melting point 139-149 °C are obtained.
  • the oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 9:1 ) and crystallized from isopropanol. 0.84 g of the title compound of melting point 73-81 °C (isopropanol) are obtained.
  • N,N-Carbonyldiimidazole (0.92 g, 5.66 mmol) is added in portions to the solution of 2-acetoxy benzoic acid (1.02 g, 5.66 mmol) in dichloromethane (15 ml) at room temperature. After stirring at reflux for one hour (7R,8R,9R)-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7,8,9,10-tetrahydro-imidazo-[1 ,2- h][1 ,7]naphthyridin (1.00 g, 2.83 mmol) is added. The reaction mixture is refluxed for 6 h, poured onto water, and extracted three times with dichloromethane.
  • N,N,N',N'-Tetramethyl-O-(benzotriazol-1 -yl)uranium tetrafluoroborate (TBTU) (1.78 g, 5.50 mmol) is added in portions to the suspension of [2-(2,6-dichlorophenylamino)-phenyl] acetic acid (1.50 g, 5.00 mmol) in tetrahydrofuran (30 ml) at room temperature.
  • N,N,N',N'-Tetramethyl-O-(benzotriazol-1 -yl)uranium tetrafluoroborate (0.37 g, 1.15 mmol) is added in portions to the solution of [4-(2,6-dichlorophenylamino)-thiophen-3-yl] acetic acid (0.29 g, 0.96 mmol) in dichloromethane (10 ml) at room temperature.
  • the oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 9:1 ) and precipitated as salt of oxalic acid from isopropanol. 0.1 O g of the title compound of melting point 158-160 °C (isopropanol) are obtained.
  • the resulting suspension is stirred at room temperature for 1 h, the precipitate is filtered off, and the filtrate is concentrated.
  • the resulting residue is dissolved in a mixture of ethyl acetate and water, the layers are separated, and the aqueous phase is extracted three times with ethyl acetate.
  • the organic layer is washed with brine, dried (MgSO 4 ), and the solvent is removed in vacuo.
  • the oily residue is purified twice by column chromatography using silica gel (eluent: toluene/dioxane 4:1 and 9:1 , respectively) and lyophilized from dioxane/water. 0.44 g of the title compound are obtained.
  • [1 ,7]naphthyridin-8-yl ester (0.80 g, 1.70 mmol) in tetrahydrofuran (20 ml) at room temperature.
  • the solution is cooled to 0 °C and the solution of toluene sulfonyl chloride (0.49 g, 2.50 mmol) in tetrahydrofuran (7 ml) is added slowly over a period of 1 h via a syringe pump.
  • the resulting suspension is stirred at 0 °C for 10 min, the precipitate is filtered off, and the filtrate is concentrated.
  • the resulting residue is dissolved in a mixture of ethyl acetate and water, the layers are separated, and the aqueous phase is extracted twice with ethyl acetate. The combined organic layers are dried (MgSO 4 ) and the solvent is removed in vacuo. The oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane 5:1 ) and lyophilized from dioxane/water. 0.90 g of the title compound are obtained.
  • the oily residue is purified twice by column chromatography using silica gel (eluent: toluene/dioxane 20:1 ) and lyophilized from dioxane/water. 0.3g of the title compound are obtained.
  • [1 ,7]naphthyridin-8-yl ester (0.60 g, 1.28 mmol) in tetrahydrofuran (15 ml) at room temperature.
  • the solution is cooled to 0 °C and the solution of toluene sulfonyl chloride (0.37 g, 1 .90 mmol) in tetrahydrofuran (6 ml) is added slowly over a period of 15 min.
  • the resulting suspension is stirred at 0 °C for 30 min, the precipitate is filtered off, and the filtrate is concentrated.
  • the resulting residue is dissolved in a mixture of dichloromethane and water, the layers are separated, and the aqueous phase is extracted twice with dichloromethane.
  • the oily residue is purified by column chromatography using silica gel (eluent: tolu- ene/dioxane/methanol 20:2:1 ) and lyophilized from dioxane/water. 0.56 g of the title compound are obtained.
  • the oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane/methanol 40:4:1 ) and and crystallized from ethyl acetate/diisopropylether. 0.30 g of the title compound are obtained.
  • the oily residue is purified by column chromatography using silica gel (eluent: toluene/dioxane/methanol 40:4:1 ) and crystallized from ethyl acetate/diisopropylether. 0.31 g of the title compound are obtained.
  • the excellent gastric protective action and the gastric acid secretion-inhibiting action of the compounds according to the invention can be demonstrated in investigations on animal experimental models.
  • the compounds according to the invention show an excellent profile concerning especially antiinflammatorical, antiphlogistic and analgetic effects, what can be demonstrated in investigations on in vitro models.
  • the substances to be tested were administered intraduodenally in a 2.5 ml/kg liquid volume 60 min after the start of the continuous pentagastrin infusion.
  • the body temperature of the animals was kept at a constant 37.8-38°C by infrared irradiation and heat pads (automatic, stepless control by means of a rectal temperature sensor).
  • the compounds according to the invention have miscellaneous valuable pharmacological properties which make them commercially utilizable.
  • their excellent properties as non-steroidal anti-inflammatory drugs (NSAID ' s) and as potassium competitive acid blockers (P-CAB ' s) allow them to be used in veterinary and/or, particularly, in human medicine as active principles for preventing and/or treating of, for example, inflammation, pain (both chronic and acute), fever, cancer and other cyclooxygenase mediated disorders, for facilitating wound healing and for gastro and intestinal protection, for decreasing or reversing renal or other toxicity (e.g. kidney toxicity) and for providing of medicaments of improved tolerance at the renal level, the cardiovascular level, the level of the central nervous or autonomous system or, in particular, at the gastrointestinal or respiratory level.
  • NSAID ' s non-steroidal anti-inflammatory drugs
  • P-CAB ' s potassium competitive acid blockers
  • cyclooxygenase-1 COX-1
  • COX-2 cyclooxygenase-2
  • COX-3 cyclooxygenase-3
  • a target for inhibition which is to be emphasized with regard to favourable antiinflammatory effects, represents the cyclooxygenase-1 and the cyclooxygenase-2.
  • the compounds according to the invention demonstrate potent inhibition of the cyclooxygenase 1 and/or cyclooxygenase-2 and in parallel demonstrate potent and reversible inhibition of the H/K-ATPase. Therefore the commonly observed side effects of NSAIDs mainly on the gastrointestinal levels are minimized and the compounds are superior to conventional unselective or selective NSAID ' s. Inter alia due to their excellent gastric acid secretion inhibiting and gastro and intestinal protective properties, the compounds according to the invention show also beneficial tolerance and/or an advantageous and desired therapeutic profile.
  • the compounds according to the present invention are characterized by a particularly advantageous kinetic profile, such as for example prolonged half life, associated with the release of the compounds of the formula Na or Mb and III from the compounds of the formula I.
  • a further advantage of the compounds of the formula I is associated with a better compliance of the patients because no co-medication has to take place as compared to standard combination therapies.
  • the compounds according to the present invention can be used to provide agents, which feature, as a whole, inhibition of cyclooxygenase-1 and cyclooxygenase-2 with little selectivity for either isoform but without or with reduced adverse effects commonly associated with the inhibition of the cyclooxygenase-1.
  • the compounds according to the invention can be used as agents, which show - in comparison to the NSAID ' s from which they are derived - further improved properties.
  • the compounds according to the invention can be used, for example as analgesics in the treatment of pain, including but not limited to headaches, migraines, postoperative pain, dental pain, muscular pain and pain resulting from cancer, as antipyretics in the treatment of fever, including but not limited to rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains, strains, myositis, neuralgia and synovitis, or as an anti-inflammatory in the treatment of arthritis, including but not limited to rheumatoid arthritis, degenerative joint disease (osteoarthritis), spondylarthritis, gouty arthritis, systemic lupus erythematosus and juvenile arthritis.
  • analgesics in the treatment of pain including
  • the compounds according to the invention exhibit a marked inhibition of gastric acid secretion and an excellent gastric and intestinal protective action in warm-blooded animals, in particular humans.
  • Gastric and intestinal protection in this connection is understood as meaning the prevention and treatment of gastrointestinal diseases, in particular of gastrointestinal inflammatory diseases and lesions (such as, for example, gastric ulcer, peptic ulcer, including peptic ulcer bleeding, duodenal ulcer, gastritis, hyperacidic or medicament-related functional dyspepsia), which can be caused, for example, by microorganisms (e.g. Helicobacter pylori), bacterial toxins, chemicals (e.g. ethanol), gastric acid or stress situations or in particular by the NSAID which are released from the compounds of the formula I under physiological conditions.
  • gastroesophageal reflux disease GGID
  • a further subject of the invention are therefore the compounds according to the invention for use in the treatment and/or prophylaxis of the abovementioned diseases.
  • the invention likewise includes the use of the compounds according to the invention for the production of medicaments which are employed for the treatment and/or prophylaxis of the abovementioned diseases.
  • the invention furthermore includes the use of the compounds according to the invention for the treatment and/or prophylaxis of the abovementioned diseases.
  • a further subject of the invention are medicaments which comprise one or more compounds of the formula I and/or their pharmacologically acceptable salts.
  • the medicaments are prepared by processes which are known per se and familiar to the person skilled in the art.
  • suitable pharmaceu- tical auxiliaries or excipients in the form of tablets, coated tablets, capsules, suppositories, patches (e.g. as TTS), emulsions, suspensions or solutions, the active compound content advantageously
  • auxiliaries and excipients which are suitable for the desired pharmaceutical formulations are known to the person skilled in the art on the basis of his/her expert knowledge.
  • solvents for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (e.g. cyclodextrins).
  • the active compounds can be administered orally, parenterally or percutaneously.
  • the dosage of the compound of the formula I largely depends on the specific combination of the compound of the formula Ma and of the compound of the formula III. In general, it is desired to use a dose of the compound of the formula I, which results in a release in the human or animal body of an effective doses of both the compound of the formula Na and the compound of the formula III.
  • the compounds of the formula I according to the present invention can be administered in doses of up to 10-times more or less than the optimal dose of a the compound of the formula Na or the compound of the formula III if administered alone.
  • the daily dose of the compounds of the formula I can be administered, in the form of several, preferably 1 to 4, individual doses to achieve the desired results.
  • a parenteral treatment similar or (in particular in the case of the intravenous administration of the active compounds), as a rule, lower doses as compared to oral administration can be used.
  • the establishment of the optimal dose and manner of administration of the active compounds necessary in each case and for each combination of compounds of the formula Ma and compounds of the formula III can easily be carried out by any person skilled in the art on the basis of his/her expert knowledge.
  • the compounds and compositions of the present invention may also be used in a fixed or free combination together with other suitable substances for co-therapies and/or prophylaxis of the abovemen- tioned illnesses.
  • Said suitable substances comprise for example - without being restricted to - opioids and other analgesics, inducible nitric oxide synthase inhibitors, steroids, nonsteroidal antiinflamma-tory drugs (NSAID), cyclooxygenase-2 (COX-2) inhibitors, 5-lipoxygenase (5-LO) inhibitors, leukotriene B4 (LTB4) receptor antagonists, leukotriene A4 (LT A4) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) inhibitors, H2 antagonists, antineoplastic agents, antiplatelet agents, antitussives, decongestants, diuretics, sedating or non-sedating anti-histamins, Helicobacter pylor
  • omeprazole lansoprazole, rabeprazole and pantoprazole are particularly mentioned
  • iso- prostane inhibitors and, optionally, at least one compound that donates, transfers or releases nitric oxide, or elevates levels of endogenous endothelium-derived relaxing factor (EDRF) or nitric oxide, or is a substrate for nitric oxide synthase.
  • EDRF endogenous endothelium-derived relaxing factor
  • the compounds can be administered separately, sequentially or simultaneously.

Abstract

L'invention concerne des composés représentés par la formule I dans laquelle les substituants et les symboles ont les significations indiquées dans la description. Lesdits composés sont des promédicaments, et présentent dans le corps humain et/ou animal une activité antipyrétique, analgésique, antiphlogistique et/ou anti-inflammatoire ainsi qu'une inhibition de la sécrétion d'acide gastrique et donc une activité gastro-intestinale protectrice.
PCT/EP2006/061856 2005-04-29 2006-04-26 Composes de promedicaments mutuels utilises comme agents anti-inflammatoires a activite gastro-intestinale protectrice WO2006117316A1 (fr)

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AU2006243255A AU2006243255A1 (en) 2005-04-29 2006-04-26 Mutual prodrug compounds for use us antiinflammatory agents with gastrointestinal protective activity
EP06763060A EP1877410A1 (fr) 2005-04-29 2006-04-26 Composes de promedicaments mutuels utilises comme agents anti-inflammatoires a activite gastro-intestinale protectrice

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WO2008061671A2 (fr) * 2006-11-24 2008-05-29 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Utilisation d'un acide indazoleméthoxyalcanoïque dans la préparation d'une composition pharmaceutique
WO2009037705A2 (fr) * 2007-09-20 2009-03-26 Ramot At Tel Aviv University Ltd. Méthodes et compositions utiles pour le traitement du cancer et de l'inflammation
WO2011004882A1 (fr) 2009-07-09 2011-01-13 ラクオリア創薬株式会社 Antagoniste de la pompe à acide destiné au traitement de maladies associées à un transit gastro-intestinal anormal
WO2011041870A1 (fr) * 2009-10-07 2011-04-14 Nitrogenix Inc. Anti-inflammatoires non stéroïdiens coadministrés avec des composés d'esters d'acides aminés d'oxyde nitrique comme prophylaxie chez les patients hypertendus
US8278357B2 (en) 2002-10-21 2012-10-02 Ramot At Tel-Aviv University Ltd. Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators
US8765815B2 (en) 2007-09-20 2014-07-01 Ramot At Tel-Aviv University Ltd. N-phenyl anthranilic acid derivatives and uses thereof

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Cited By (14)

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Publication number Priority date Publication date Assignee Title
US8278357B2 (en) 2002-10-21 2012-10-02 Ramot At Tel-Aviv University Ltd. Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators
US8618169B2 (en) 2002-10-21 2013-12-31 Ramot At Tel-Aviv University Ltd. Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators
EP2409698A1 (fr) * 2006-11-24 2012-01-25 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.p.A. Utilisation d'un acide indazoleméthoxyalcanoïque pour la préparation d'une composition pharmaceutique
WO2008061671A2 (fr) * 2006-11-24 2008-05-29 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Utilisation d'un acide indazoleméthoxyalcanoïque dans la préparation d'une composition pharmaceutique
US8198310B2 (en) 2006-11-24 2012-06-12 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F.S.P.A. Use of an indazolemethoxyalkanoic acid for reducing triglyceride, cholesterol and glucose levels
EA016885B1 (ru) * 2006-11-24 2012-08-30 Ацьенде Кимике Рьюните Анджелини Франческо A.K.P.A.Ф. С.П.А. Применение индазолметоксиалкановой кислоты для лечения заболевания, связанного с уровнями триглицерида, холестерина и/или глюкозы и способ лечения указанных заболеваний
AU2007323351B2 (en) * 2006-11-24 2013-05-02 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Use of an indazolemethoxyalkanoic acid for reducing triglyceride, cholesterol and glucose levels
WO2008061671A3 (fr) * 2006-11-24 2008-11-27 Acraf Utilisation d'un acide indazoleméthoxyalcanoïque dans la préparation d'une composition pharmaceutique
WO2009037705A3 (fr) * 2007-09-20 2009-07-09 Univ Ramot Méthodes et compositions utiles pour le traitement du cancer et de l'inflammation
WO2009037705A2 (fr) * 2007-09-20 2009-03-26 Ramot At Tel Aviv University Ltd. Méthodes et compositions utiles pour le traitement du cancer et de l'inflammation
US8765815B2 (en) 2007-09-20 2014-07-01 Ramot At Tel-Aviv University Ltd. N-phenyl anthranilic acid derivatives and uses thereof
US9403756B2 (en) 2007-09-20 2016-08-02 Ramot At Tel-Aviv University Ltd. N-phenyl anthranilic acid derivatives and uses thereof
WO2011004882A1 (fr) 2009-07-09 2011-01-13 ラクオリア創薬株式会社 Antagoniste de la pompe à acide destiné au traitement de maladies associées à un transit gastro-intestinal anormal
WO2011041870A1 (fr) * 2009-10-07 2011-04-14 Nitrogenix Inc. Anti-inflammatoires non stéroïdiens coadministrés avec des composés d'esters d'acides aminés d'oxyde nitrique comme prophylaxie chez les patients hypertendus

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