EP1049677A1 - Nouveaux derives de sulfamide comme inhibiteurs de la resorption osseuse et comme inhibiteurs de l'adherence cellulaire - Google Patents

Nouveaux derives de sulfamide comme inhibiteurs de la resorption osseuse et comme inhibiteurs de l'adherence cellulaire

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Publication number
EP1049677A1
EP1049677A1 EP99904789A EP99904789A EP1049677A1 EP 1049677 A1 EP1049677 A1 EP 1049677A1 EP 99904789 A EP99904789 A EP 99904789A EP 99904789 A EP99904789 A EP 99904789A EP 1049677 A1 EP1049677 A1 EP 1049677A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
radical
aryl
formula
heteroaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99904789A
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German (de)
English (en)
Inventor
Anuschirwan Peyman
David William Will
Jochen Knolle
Karlheinz Scheunemann
Denis Carniato
Jean-François Gourvest
Thomas Gadek
Robert Mcdowell
Sarah Catherine Bodary
Robert Andrew Cuthbertson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Aventis Deutschland GmbH
Genentech Inc
Original Assignee
Aventis Pharma Deutschland GmbH
Genentech Inc
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Publication date
Application filed by Aventis Pharma Deutschland GmbH, Genentech Inc filed Critical Aventis Pharma Deutschland GmbH
Publication of EP1049677A1 publication Critical patent/EP1049677A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/12—Nitrogen atoms not forming part of a nitro radical
    • C07D239/16—Nitrogen atoms not forming part of a nitro radical acylated on said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Novel sulfonamide derivatives as inhibitors of bone resorption and as inhibitors of cell adhesion
  • the present invention relates to sulfonamide derivatives of the formula I,
  • R 1 , R 2 , R 4 , R 5 and R 6 have the meanings indicated below, their physiologically tolerable salts and their prodrugs.
  • the compounds of the formula I are valuable pharmaceutical active compounds. They are vitronectin receptor antagonists and inhibitors of cell adhesion and inhibit bone resorption by osteoclasts. They are suitable, for example, for the therapy and prophylaxis of diseases which are caused at least partially by an undesired extent of bone resorption, for example of osteoporosis.
  • the invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as pharmaceutical active ingredients, and pharmaceutical preparations comprising them.
  • Bone resorption is based on the destruction of bone matrix by osteoclasts. The majority of bone disorders are based on a disturbed equilibrium between bone formation and bone resorption.
  • Osteoporosis is a disease characterized by low bone mass and enhanced bone fragility resulting in an increased risk of fractures. It results from a deficit in new bone formation versus bone resorption during the ongoing remodelling process.
  • Conventional osteoporosis treatment includes, for example, the administration of bisphosphonates, estrogens, estrogen/progesterone (hormone replacement therapy or HRT), estrogen agonists/antagonists (selective estrogen receptor modulators or SERMs), calcitonin, vitamin D analogues, parathyroid hormone, growth hormone secretagogues, or sodium fluoride (Jardine et al., Annual Reports in Medicinal Chemistry 1996, 31 , 211 ).
  • Activated osteoclasts are polynuclear cells having a diameter of up to 400 ⁇ m, which remove bone matrix. Activated osteoclasts become attached to the surface of the bone matrix and secrete proteolytic enzymes and acids into the so-called "sealing zone", the region between their cell membrane and the bone matrix. The acidic environment and the proteases cause the destruction of the bone.
  • the compounds of the formula I inhibit bone resorption by osteoclasts.
  • Integrins are a superfamily of receptors which include, inter alia, the fibrinogen receptor ⁇ Mb ⁇ 3 on the blood platelets and the vitronectin receptor ⁇ v ⁇ 3 .
  • the vitronectin receptor ⁇ v ⁇ 3 is a membrane glycoprotein which is expressed on the cell surface of a number of cells such as endothelial cells, cells of the vascular smooth musculature, osteoclasts and tumor cells.
  • the vitronectin receptor ⁇ v ⁇ 3 which is expressed on the osteoclast membrane, controls the process of attachment to the bones and bone resorption and thus contributes to osteoporosis.
  • ⁇ v ⁇ 3 in this case binds to bone matrix proteins such as osteopontin, bone sialoprotein and thrombospontin, which contain the tripeptide motif Arg-Gly-Asp (or RGD).
  • vitronectin ⁇ v ⁇ 3 on human cells of the vascular smooth musculature of the aorta stimulates the migration of these cells into the neointima, which finally leads to arteriosclerosis and restenosis after angioplasty (Brown et al., Cardiovascular Res. 1994, 28, 1815).
  • WO-A-94/12181 describes substituted aromatic or nonaromatic ring systems
  • WO-A-94/08577 describes substituted heterocycles as fibrinogen receptor antagonists and inhibitors of platelet aggregation.
  • EP-A-528586 and EP-A- 528587 disclose aminoalkyl-substituted or heterocyclyl-substituted phenylalanine derivatives
  • WO-A-95/32710 discloses aryl derivatives as inhibitors of bone resorption by osteoclasts.
  • WO-A-96/00574 describes benzodiazepines
  • WO-A-96/00730 describes fibrinogen receptor antagonist templates, in particular benzodiazepines which are linked to a nitrogen-bearing 5-membered ring, as vitronectin receptor antagonists.
  • WO-A-98/00395 (DE-A- 19654483) describes vitronectin receptor antagonists derived from a tyrosine scaffold.
  • EP-A-820991 (German patent application 19629816.4) describes cycloalkyl derivatives and European patent application 97122520.6 describes carbamic ester derivatives which are vitronectin receptor antagonists. Further investigations have shown that the sulfonamide derivatives of the formula I are particularly strong inhibitors of the vitronectin receptor and of bone resorption by osteoclasts.
  • the present invention relates to compounds of the formula I,
  • R 1 and R 2 independently of one another are hydrogen or (d-C 6 )-alkyl which is unsubstituted or substituted by R 3 , or in which the radicals R 1 - and R 2 - together are a saturated or unsaturated bivalent (C 2 -C 9 )-alkylene radical, for example the group -(CH 2 ) P -, in which p is 2,
  • R 5 is (C ⁇ -C 20 )-alkyl, (C 3 -C 2 o)-monocycloalkyl, (C 5 -C 2 o)-bicycloalkyl, (C 5 -C 20 )- tricycloalkyl, (C 6 -d 4 )-aryl, (C 5 -C ⁇ 4 )-heteroaryl, (C 6 -C 14 )-aryl-(C ⁇ -C 6 )-alkyl- or (C 5 - C ⁇ 4 )-heteroaryl-(C ⁇ -C 6 )-alkyl-, where the aryl radical, the heteroaryl radical, the alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the tricycloalkyl radical each is unsubstituted or is substituted by one, two or three radicals R 3 and wherein in the alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the
  • R 6 is hydrogen, (d-C 6 )-alkyl-O-CO-, hydroxyl, (d-C 6 )-alkyl-O-CO-O- or nitro; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
  • radicals which can occur several times in the compounds of the formula I can each independently of one another have the meanings indicated, and can in each case be identical or different. Radicals which independently of one another can have a meaning indicated, can in each case be identical or different.
  • alkyl radicals containing from 1 to 20 carbon atoms are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl and eicosyl, the n-isomers of all these radicals, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, isodecyl, 3- methylpentyl, 2,3,4-trimethylhexyl, sec-butyl, tert-butyl, tert-pentyl.
  • a preferred group of alkyl radicals is formed by the radicals methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
  • Unsaturated alkyl radicals are, for example, alkenyl radicals such as vinyl, 1- propenyl, allyl, butenyl, 3-methyl-2-butenyl, or alkynyl radicals such as ethynyl, 1-propynyl or propargyl.
  • alkenylene radicals are vinylene or propenylene
  • examples of alkynylene radicals are ethynylene or propynylene.
  • Alkyl radicals can also be unsaturated when they are substituted.
  • cycloalkyl radicals can be monocyclic, bicyclic or tricyclic, i. e. they can be monocycloalkyl radicals, bicycloalkyl radicals and tricycloalkyl radical, provided they have a suitable number of carbon atoms.
  • Monocycloalkyl radicals are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotetradecyl or cyclooctadecyl which, can also be substituted by, for example, (d-C 4 )-alkyl.
  • substituted cycloalkyl radicals which may be mentioned are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl.
  • Bicycloalkyl radicals and tricycloalkyl radicals can be unsubstituted or substituted in any desired suitable position, for example by one or more oxo groups and/or one or more identical or different (C ⁇ -C )-alkyl groups, for example methyl or isopropyl groups, preferably methyl groups.
  • the free bond 8 via which the bicyclic or the tricyclic radical is bonded can be located in any desired position in the molecule; the radical can thus be bonded via a bridgehead atom or an atom in a bridge.
  • the free bond can also be located in any desired stereochemical position, for example in an exo-position or an endo- position.
  • bicycloalkyl radicals and tricycloalkyl radicals are, camphanyl, bornyl, adamantyl, such as 1-adamantyl and 2-adamantyl, caranyl, epiisobornyl, epibornyl, norbomyl and norpinanyl.
  • Halogen is, for example, fluorine, chlorine, bromine or iodine.
  • Examples of carbocyclic (C 6 -d 4 )-aryl radicals are phenyl, naphthyl, biphenylyl, anthryl or fluorenyl, where 1-naphthyl, 2-naphthyl and phenyl are preferred.
  • aryl radicals in particular phenyl radicals, can be unsubstituted or substituted by one or more radicals, preferably one, two or three identical or different radicals.
  • aryl radicals can be substituted by identical or different radicals from the group consisting of (d-C 8 )-alkyl, in particular (d-C )-alkyl, (d-C 8 )-alkoxy, in particular (d-C 4 )-alkoxy, halogen, such as fluorine, chlorine and bromine, nitro, amino, trifluoromethyl, hydroxyl, methylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl, (C ⁇ -C )- alkoxycarbonyl, phenyl, phenoxy, benzyl and benzyloxy.
  • halogen such as fluorine, chlorine and bromine, nitro, amino, trifluoromethyl, hydroxyl, methylenedioxy, cyano, hydroxycarbonyl, aminocarbon
  • the substituent can be located in the 2- position, the 3-position or the 4-position, the 3- and the 4-position being preferred. If phenyl is disubstituted, the substituents can be in the 2, 3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. Preferably, in disubstituted phenyl radicals, the two substituents are arranged in the 3,4- 9 position, relative to the linkage site. In trisubstituted phenyl radicals, the substituents can be in the 2,3,4-position, 2, 3,5-position, 2,3,6-position, 2,4,5- position, 2,4,6-position or 3,4,5-position.
  • naphthyl radicals and other aryl radicals can be substituted in any desired position, for example a 1-naphthyl radical in the 2-, 3-, 4-, 5-, 6-, 7- and 8-position, a 2-naphthyl radical in the 1-, 3-, 4- 5-, 6-, 7- and 8-position.
  • Beside carbocyclic systems, (C5-C ⁇ 4 )-aryl groups can also be monocyclic or polycyclic, for example bicyclic or tricyclic, aromatic ring systems in which 1, 2, 3, 4 or 5 ring carbon atoms are replaced by heteroatoms, in particular by identical or different heteroatoms from the group consisting of nitrogen, oxygen and sulfur.
  • heterocyclic (C 5 -d 4 )-aryl groups and (C 5 -C ⁇ )-heteroaryl groups are pyridyl like 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrrolyl like 2-pyrrolyl and 3-pyrrolyl, furyl like 2-furyl and 3-furyl, thienyl like 2-thienyl and 3-thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, ⁇ -carbolinyl, or be
  • monocyclic or bicyclic aromatic ring systems having 1, 2 or 3 heteroatoms, in particular 1 or 2 heteroatoms, from the group consisting of N, O and S, which can be unsubstituted or substituted by 1 , 2 or 3 substituents from the group consisting of (d-C 6 )-alkyl, (d-C 6 )-alkoxy, fluorine, chlorine, nitro, amino, trifluoromethyl, hydroxyl, (d-C 4 )-alkoxycarbonyl, phenyl, phenoxy, benzyloxy and benzyl, are preferred.
  • Particularly preferred here are monocyclic or bicyclic aromatic 5-membered to 10-membered ring systems having 1 to 3 heteroatoms, in particular having 1 or 2 heteroatoms, from the group consisting of N, O and S, which can be substituted by 1 to 2 10
  • substituents from the group consisting of (d-C )-alkyl, (C ⁇ -C )-alkoxy, phenyl, phenoxy, benzyl and benzyloxy More particularly preferred are 5-membered or 6-membered monocyclic heteroaryl groups and 9- or 10-membered bicyclic he- teroaryl groups containing 1 or 2, in particular 1 , heteroatom from the group con- sisting of N, O and S which are unsubstituted or substituted as described before.
  • R 1 - and R 2 - together represent a bivalent saturated or unsaturated (C 2 -C 9 )-alkylene radical
  • these two radicals together with the two nitrogen atoms to which they are bonded and the central carbon atom of the guanidino group to which these two nitrogen atoms are bonded, form a monocyclic 1 ,3-diazaheterocycle which is bonded to the nitrogen atom in the group (CH 2 ) 2 -CO-NH via its 2-position.
  • radicals of such 1 ,3- diazaheterocycles which can be substituted as indicated in the (C 2 -Cg)-alkylene radical and also on the guanidino nitrogen atom, are the 2-imidazolyl radical, the 4,5-dihydro-2-imidazolyl radical, the 1 ,4,5,6-tetrahydro-2-pyrimidinyl radical or the 4,5,6,7-tetrahydro-1 H-1,3-diazepin-2-yl radical.
  • a 5-membered to 7- membered ring is fused to a carbon-carbon bond in the (C 2 -C 9 )-alkylene radical, then the two radicals R 1 and R 2 , together with the two nitrogen atoms to which they are bonded and the central carbon atom of the guanidino group to which these two nitrogen atoms are bonded form a bicyclic heterocycle which is bonded to the nitrogen atom in the group (CH 2 ) 2 -CO-NH and which can be substituted as indicated.
  • the fused (or condensed) 5-membered to 7-membered ring can be saturated, mono-unsaturated or di-unsaturated or aromatic.
  • a cyclopentane ring, cyclohexane ring, cyclohexene ring, cyclohexadiene ring, cycloheptane ring or benzene ring can be condensed.
  • the (C 2 -C 8 )-alkylene radical is substituted, they are preferably independently of one another monosubstituted or disubstituted by identical or different radicals R 3 . If alkyl groups representing R 1 and/or R 2 are substituted, they are preferably independently of one another monosubstitued or disubstituted, in particular monosubstituted, by identical or different radicals R 3 .
  • Optically active carbon atoms present in the compounds of the formula I can independently of one another have the R configuration or the S configuration.
  • the compounds of the formula I can be present in the form of pure enantiomers or pure diastereomers or in the form of enantiomer mixtures, for example in the form of racemates, or of diastereomer mixtures.
  • the present invention relates to both pure enantiomers and enantiomer mixtures as well as to pure diastereomers and diastereomer mixtures.
  • the invention comprises mixtures of two or of more than two stereoisomers of the formula I and all ratios of the stereoisomers in the mixtures.
  • the compounds of the formula I can optionally be present as E isomers or Z isomers.
  • the invention relates to both pure E isomers and pure Z isomers and E/Z mixtures in all ratios.
  • Diastereomers, including E/Z isomers can be separated into the individual isomers, for example, by chromatography. Racemates can be separated into the two enantiomers by customary methods, for example, by chromatography on chiral phases or by resolution.
  • Stereochemically unifom compounds of the formula I can also be obtained by employing stereochemically uniform starting materials or by using stereoselective reactions.
  • Physiologically tolerable salts of the compounds of formula I are nontoxic salts that are physiologically acceptable, in particular pharmaceutically utilizable salts. Such salts of compounds of the formula I containing acidic groups, for 12
  • example carboxyl are, for example, alkali metal salts or alkaline earth metal salts such as, for example, sodium salts, potassium salts, magnesium salts and calcium salts, and also salts with physiologically tolerable quaternary ammonium ions and acid addition salts with ammonia and physiologically tolerable organic amines, such as, for example, triethylamine, ethanolamine or tris-(2- hydroxyethyl)amine.
  • alkali metal salts or alkaline earth metal salts such as, for example, sodium salts, potassium salts, magnesium salts and calcium salts
  • physiologically tolerable quaternary ammonium ions and acid addition salts with ammonia and physiologically tolerable organic amines such as, for example, triethylamine, ethanolamine or tris-(2- hydroxyethyl)amine.
  • Compounds of the formula I containing basic groups form acid addition salts, for example with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic acids and sulfonic acids such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid.
  • Compounds of the formula I which contain a basic group and an acidic group for example the guanidino group and a carboxyl group, can be present as zwitterions (betaines), which are likewise included by the present invention.
  • the physiologically tolerable anion Q " which is contained in the compounds of the formula I when R 4 is an alkyl radical which is substituted by a positively charged ammonium group, is, in particular, a monovalent anion or an eqivalent of a polyvalent anion of a nontoxic, physiologically utilizable, in particular also pharmaceutically utilizable, inorganic or organic acid, for example the anion or an anion equivalent of one of the abovementioned acids suitable for the formation of acid addition salts.
  • Q ⁇ can thus be, for example, one of the anions (or an anion equivalent) from the group consisting of chloride, sulfate, phosphate, acetate, citrate, benzoate, maleate, fumarate, tartrate, methanesulfonate and p-toluenesulfonate.
  • Salts of compounds of the formula I can be obtained by customary methods known to those skilled in the art, for example by combining a compound of the formula I with an inorganic or organic acid or base in a solvent or dispersant, or from other salts by cation exchange or anion exchange.
  • the present invention also includes all salts of the compounds of the formula I which, because of low physiologically tolerability, are not directly suitable for use in pharmaceuticals, 13
  • the present invention moreover includes all solvates of compounds of the formula I, for example hydrates or adducts with alcohols, and also derivatives of the compounds of the formula I, for example esters, prodrugs and other physiologically tolerable derivatives, as well as active metabolites of the compounds of the formula I.
  • the invention relates in particular to prodrugs of the compounds of the formula I, which can be converted into compounds of the formula I under physiological conditions.
  • Suitable prodrugs for the compounds of the formula I i. e. chemically modified derivatives of the compounds of the formula I having properties which are improved in a desired manner, are known to those skilled in the art.
  • prodrugs More detailed information relating to prodrugs is found, for example, in Fleisher et al., Advanced Drug Delivery Reviews 19 (1996) 115-130; Design of Prodrugs, H. Bundgaard, Ed., Elsevier, 1985; H. Bundgaard, Drugs of the Future 16 (1991) 443; Saulnier et al., Bioorg. Med. Chem. Lett. 4 (1994) 1985; Safadi et al., Pharmaceutical Res. 10 (1993) 1350 which are all incorporated herein by reference.
  • Suitable prodrugs for the compounds of the formula I are especially ester prodrugs of carboxylic acid groups, in particular of the COOH group which is present when R 4 in the group COOR 4 is hydrogen, for example alkyl esters of this group like (d-C 6 )-alkyl esters or (C 1 -C 4 )-alkyl esters, and also acyl prodrugs and carbamate prodrugs of acylatable nitrogen-containing groups such as amino groups and in particular the guanidino group.
  • the acyl prodrugs or carbamate prodrugs one or more times, for example twice, a hydrogen atom located on a nitrogen atom in these groups is replaced by an acyl group or carbamate group.
  • Suitable acyl groups and carbamate groups for the acyl prodrugs and carbamate prodrugs are, for example, the groups R 10 -CO and R 11 O-CO, in which R 10 is hydrogen, (d-d ⁇ )- alkyl, (C 3 -C ⁇ 4 )-cycloalkyl, (C 3 -C ⁇ 4 )-cycloalkyl-(C ⁇ -C 8 )-alkyl-, (C 5 -d 4 )-aryl, in which 1 to 5 carbon atoms can be replaced by heteroatoms such as N, O or S, or (C 5 - 14
  • the radicals R 1 and R 2 are preferably hydrogen or together are a saturated or unsaturated, in particular a saturated, bivalent (C 2 -C 5 )-alkylene radical, in particular a (C 2 -C )-alkylene radical, especially a (C 2 -C 3 )-alkylene radical, which is unsubstituted or is substituted by one or two identical or different radicals from the group consisting of halogen, (CrC ⁇ )-alkyl, (d-C 6 )-alkoxy, (C 6 -d 4 )-aryl, (C 6 -C ⁇ 4 )-aryl-(C ⁇ -C 6 )-alkyl-, (C 5 -d 4 )- heteroaryl, (C 5 -d 4 )-heteroaryl-(C ⁇ -C 6 )-alkyl-, (C 3 -C ⁇ 2 )-cycloalkyl, (C 3 -C 12 )
  • the radicals R 1 and R 2 are particularly preferably hydrogen or the group -(CH 2 ) P -, in which p is the numbers 2, 3, 4 or 5, preferably the numbers 2, 3 or 4, particularly preferably the numbers 2 or 3, and which is unsubstituted or is substituted by one or two identical or different radicals from the group consisting of halogen, (C ⁇ -C 6 )-alkyl, (d-C 6 )-alkoxy, (C 6 -d )-aryl, (C 6 -C 14 )-aryl-(C ⁇ -C 6 )- alkyl-, (C 5 -C 14 )-heteroaryl, (C 5 -C ⁇ 4 )-heteroaryl-(C ⁇ -C 6 )-alkyl-, (C 3 -d 2 )-cycloalkyl, (C 3 -C ⁇ 2 )-cycloalkyl-(C ⁇ -C6)-alkyl- and oxo
  • radicals R 1 and R 2 together are the group -(CH 2 ) P -, in which p is the numbers 2, 3, 4 or 5, preferably the numbers 2, 3 or 4, particularly preferably the numbers 2 or 3, which preferably is unsubstituted.
  • radicals R 1 - and R 2 - together are the bivalent radical -CH 2 -CH 2 -CH 2 -i. e. R 1 and R 2 together 15
  • R 3 preferably is (C ⁇ -C ⁇ o)-alkyl, (C 3 -C 2 o)-monocycloalkyl, (C 5 -C 2 o)-bicycloalkyl, (C 5 -C 20 )-tricycloalkyl, (d-C 8 )-aikoxy, (C 6 -d 4 )-aryl, (C 5 -d 4 )-heteroaryl, (C 6 -d )- aryl-(C ⁇ -C 4 )-alkyl-, (C 5 -C ⁇ 4 )-heteroaryl-(d-C 4 )-alkyl-, halogen, trifluoromethyl, cyano, oxo, -N((C ⁇ -C 4 )-alkyl) 2 or -NH-CO-(C ⁇ -C 4 )-alkyl.
  • R 3 is (C ⁇ -C 4 )-alkyl, (C 3 -C ⁇ o)-monocycloalkyl, (C 5 -d 2 )-bicycloalkyl, (C5-C 1 2)- tricycloalkyl, (C ⁇ -C 4 )-alkoxy, (C 6 -C ⁇ 4 )-aryl, (C 6 -Ci )-aryl-(d-C )-alkyl-, halogen, trifluoromethyl, cyano, oxo, -N((C ⁇ -C 4 )-alkyl) 2 or -NH-CO-(C ⁇ -C 4 )-alkyl.
  • R 3 is (C ⁇ -C )-alkyl, (C 3 -C 10 )-monocycloalkyl, (C5-C 12 )- bicycloalkyl, (C 5 -C ⁇ 2 )-tricycloalkyl, (C ⁇ -C 4 )-alkoxy, (C 6 -d )-aryl, halogen, trifluoromethyl, cyano, oxo, -N((C ⁇ -C 4 )-alkyl) 2 or -NH-CO-(C ⁇ -C )-alkyl.
  • R 4 is preferably hydrogen or unsubstituted or substituted (C ⁇ -C 6 )-alkyl, particularly preferably hydrogen or (d-C 6 )-alkyl, which is unsubstituted or substituted by a radical from the group consisting of (C ⁇ -C 4 )-alkoxy, (C ⁇ -C 4 )- alkyl-S(O) 2 - and -NR 7 R 7 , where R 7 and R 7 independently of one another are hydrogen or (d-C )-alkyl.
  • R 4 is very particularly preferably hydrogen or unsubstituted or substituted (C ⁇ -C 4 )-alkyl, moreover preferably hydrogen or (d- C 4 )-alkyl which is unsubstituted or substituted as indicated before.
  • R 5 preferably is (C ⁇ -C 2 o)-alkyl, (C 3 -C 20 )-monocycloalkyl, (Cs-C 2 o)-bicycloalkyl, (C 5 -C 2 o)-tricycloalkyl, (C 6 -C ⁇ 4 )-aryl, (C 5 -d )-heteroaryl, (C 6 -C 14 )-aryl-(d-C 6 )- alkyl- or (C 5 -C ⁇ 4 )-heteroaryl-(d-C 6 )-alkyl- where the aryl radical, the heteroaryl radical, the alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the tricycloalkyl radical each is unsubstituted or is substituted by one, two or three identical or different radicals R 3 .
  • R 5 is (d-C ⁇ o)-alkyl, (C 3 - C ⁇ 5 )-monocycloalkyl, (C 5 -C 15 )-bicycloalkyl, (C 5 -C ⁇ 5 )-tricycloalkyl, (C 6 -d 4 )-aryl, (C 5 -C 14 )-heteroaryl, (C 6 -C 14 )-aryl-(d-C 6 )-alkyl- or (C 5 -Ci )-heteroaryl-(d-C 6 )- 16 alkyl-, where the aryl radical, the heteroaryl radical, the alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the tricycloalkyl radical each is unsubstituted or is substituted by one, two or three identical or different radicals R 3 .
  • radicals R 5 is formed by the radicals (C 3 -C 20 )-monocycloalkyl, (C 5 -C 2 o)-bicycloalkyl and (C 5 - C 20 )-tricycloalkyl which can be substituted or otherwise modified as indicated above and which moreover preferred are (C 5 -Ci5)-monocycloalkyl, (C 5 -C 15 )- bicycloalkyl, (C 5 -C ⁇ 5 )-tricycloalkyl.
  • radicals R 5 is formed by the radicals (d-C 2 o)-alkyl, (C 6 -C ⁇ 4 )-aryl, (C 5 -C 14 )-heteroaryl, (C 6 -C 14 )- aryl-(C ⁇ -C 6 )-alkyl- or (C 5 -C 14 )-heteroaryl-(C ⁇ -C 6 )-alkyl-, of which (C 6 -C 14 )-aryl and (C 5 -C ⁇ 4 )-heteroaryl are preferred, which can be substituted or otherwise modified as indicated above.
  • a particularly preferred groups of radicals R 5 is formed by the radicals phenyl and naphthyl, i. e. phenyl, 1-naphthyl and 2-naphthyl, which can be unsubstituted or substituted as indicated above.
  • R 6 is preferably hydrogen or (Ci-CeJ-alkyl-O-CO-, particularly preferably hydrogen or (C ⁇ -C 4 )-alkyl-O-CO- in particular hydrogen.
  • Preferred compounds of the formula I are those compounds in which one or more of the radicals have preferred meanings or have one specific or some specific of their respective denotations, all combinations of such preferred meanings or specific denotations being a subject of the present invention.
  • Particularly preferred compounds of the formula I are those compounds in which R 1 and R 2 are hydrogen or together are a saturated or unsaturated bivalent (C 2 - Cs)-alkylene radical, in particular hydrogen or together the group -(CH 2 ) P -, in which p is the numbers 2, 3, 4 or 5, where the (C 2 -C 5 )-alkylene radical and the group -(CH 2 ) P - are unsubstituted or are substituted by a radical from the group consisting of halogen, (d-C 6 )-alkyl, (d-C 6 )-alkoxy, (C 6 -C 14 )-aryl, (C 6 -C ⁇ 4 )-aryl- (C ⁇ -C 6 )-alkyl-
  • R 3 substituted by R 3 , in particular by one or two radicals R 3 , and which is a carbocyclic ring or heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carbon-carbon bond in the (C 2 -C 5 )-alkylene radical and in the group -(CH 2 ) P -;
  • R 3 is (d-dc -alkyl, (C 3 -C 2 o)-monocycloalkyl, (C 5 -C 20 )-bicycloalkyl, (C 5 -C 20 )- tricycloalkyl, (d-C 8 )-alkoxy, (C 6 -C 1 )-aryl, (C 5 -C 14 )-heteroaryl, (C 6 -C 1 )-aryl-(d-
  • R 4 is hydrogen or (d-C 6 )-alkyl which is unsubstituted or is substituted by a radical from the group consisting of (d-C 4 )-alkoxy, (C ⁇ -C 4 )-alkyl-S(O) 2 - and
  • R 7 and R 7 independently of one another are hydrogen or (C 1 -C 4 )- alkyl
  • R 5 is (C ⁇ -C 20 )-alkyl, (C 3 -C 20 )-monocycloalkyl, (C 5 -C 20 )-bicycloalkyl, (C 5 -C 20 )- tricycloalkyl, (C 6 -C ⁇ 4 )-aryl, (C 5 -C 1 )-heteroaryl, (C 6 -Ci 4 )-aryl-(d-C 6 )-alkyl- or (C 5 - Ci4)-heteroaryl-(C ⁇ -C 6 )-alkyl-, where the aryl radical, the heteroaryl radical, the alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the tricycloalkyl radical each is unsubstituted or is substituted by one, two or three radicals R 3
  • R 6 is hydrogen or (d-C 6 )-alkyl-O-CO-; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
  • Very particularly preferred compounds of the formula I are those compounds in which R 1 and R 2 are hydrogen or together are a saturated or unsaturated bivalent (C 2 - C 4 )-alkylene radical, in particular hydrogen or together the group -(CH 2 ) P - in which p is the numbers 2, 3 or 4, where the (C 2 -C 4 )-alkylene radical and the group -(CH 2 ) P - are unsubstituted or are substituted by a radical from the group consisting of halogen, (d-C 6 )-alkyl, (d-C 6 )-alkoxy, (C 6 -C 14 )-aryl, (C 6 -C ⁇ 4 )-aryl- (C ⁇ -C 6 )-alkyl-, (C 5 -d 4 )-heteroaryl, (C 5 -C 14 )-heteroaryl-(C ⁇ -C 6 )-alkyl- (C 3 -C 12 )- cycloalky
  • R 3 7-membered saturated or unsaturated ring which is unsubstituted or is substituted by R 3 , in particular by one or two radicals R 3 , and which is a carbocyclic ring or heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a carbon-carbon bond in the (C 2 -C 4 )-alkylene radical and in the group -(CH 2 ) P -;
  • R 3 is (C ⁇ -C 4 )-alkyl, (C 3 -do)-monocycloalkyl, (C 5 -C ⁇ 2 )-bicycloalkyl, (C 5 -C 12 )- tricycloalkyl, (d-C 4 )-alkoxy, (C 6 -C 14 )-aryl, (C 6 -C ⁇ )-aryl-(d-C 4 )-alkyl-, halogen, trifluoromethyl, cyano, oxo, -N((C ⁇ -C 4 )-alkyl) 2 or -NH-CO-(d-C 4 )-alkyl;
  • R 4 is hydrogen or (d-C 6 )-alkyl;
  • R 5 is (C ⁇ -C ⁇ o)-alkyl, (C 3 -d 5 )-monocycloalkyl, (C 5 -C ⁇ )-bicycloalkyl, (C 5 -C 15
  • R 6 is hydrogen or (d-C 4 )-alkyl-O-CO-; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
  • R 1 and R 2 are hydrogen or together are a saturated or unsaturated bivalent (C 2 - C 3 )-alkylene radical, in particular hydrogen or together the group -(CH 2 ) P - in which p is the numbers 2 or 3, where the (C 2 -C 3 )-alkylene radical and the group -(CH 2 ) P - are unsubstituted or are substituted by a radical from the group consisting of halogen, (d-C 6 )-alkyl, (d-C 6 )-alkoxy, (C 6 -C ⁇ 4 )-aryl, (C 6 -C ⁇ 4 )-aryl- (d-C 6 )-alkyl-, (C 5 -C 14 )-heteroaryl, (C 5 -C ⁇ 4 )-heteroaryl-(C ⁇ -C 6 )-alkyl-, (C 3 -C 12 )- cycloalkyl, (C 3 -C ⁇ 2 )
  • R 3 is (C ⁇ -C 4 )-alkyl, (C 3 -C 10 )-monocycloaikyl, (C 5 -d 2 )-bicycloalkyl, (C 5 -C 12 )- tricycloalkyl, (C ⁇ -C 4 )-alkoxy, (C 6 -C ⁇ 4 )-aryl, halogen, trifluoromethyl, cyano, oxo, -N((d-C 4 )-alkyl) 2 or -NH-CO-(C ⁇ -C 4 )-alkyl;
  • R 4 is hydrogen or (C ⁇ -Ce)-alkyl;
  • R 5 is (d-do)-alkyl, (C 3 -d 5 )-monocycloalkyl, (C 5 -d 5 )-bicycloalkyl, (C 5 -C 15 )- tricycloalkyl, (C 6 -C ⁇ 4 )-aryl, (C 5 -C ⁇ 4 )-heteroaryl, (C 6 -Ci 4 )-aryl-(C ⁇ -C 6 )-alkyl- or (C 5 - C ⁇ 4 )-heteroaryl-(C ⁇ -C 6 )-alkyl-, where the aryl radical, the heteroaryl radical, the alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the tricycloalkyl radical each is unsubstituted or is substituted by one, two or three radicals R 3
  • R 6 is hydrogen or (d-C 4 )-alkyl-O-CO-; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
  • R 5 is (C 6 -d 4 )- aryl or (C 5 -Ci 4 )-heteroaryl, preferably (C 6 -Ci 4 )-aryl, where the aryl radical and the heteroaryl radical each is unsubstituted or is substituted by one, two or three identical or different radicals R 3 and preferably is unsubstituted or substituted by one or two identical or different radicals R 3 , in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
  • R 5 is a naphthyl radical, such as a 1-naphthyl radical or a 2-naphthyl radical, which is unsubstituted or is substituted by one, two or three radicals R 3 , and which preferably is unsubstituted, such as an unsubstituted 1 -naphthyl radical or an unsubstituted 2-naphthyl radical, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs.
  • R 5 is a naphthyl radical, such as a 1-naphthyl radical or a 2-naphthyl radical, which is unsubstituted or is substituted by one, two or three radicals R 3 , and which preferably is unsubstituted, such as an unsubstituted 1 -naphthyl radical or an unsubstituted 2-naphth
  • Preferred compounds of the formula I are additionally those in which the carbon atom to which the two groups R 4 O-CO- and R 5 -SO 2 -NH- are bonded has the S configuration, in all their stereoisomeric forms and mixtures thereof in all ratios, 20
  • a specific group of compounds of the formula I is formed by compounds in which R 1 and R 2 independently of one another are hydrogen or (d-C 6 )-alkyl which is unsubstituted or substituted by R 3 , or in which the radicals R 1 - and R 2 - together are a saturated or unsaturated bivalent (C 2 -C 9 )-alkylene radical, for example the group -(CH 2 ) P -, in which p is 2, 3, 4, 5, 6, 7, 8 or 9, which is unsubstituted or is substituted by one or more groups from the group consisting of halogen, (C ⁇ C ⁇ )-alkyl, (C ⁇ -C 6 )-alkoxy, (C 6 - C 14 )-aryl, (C 6 -d 4 )-aryl-(Ci-C 6 )-alkyl, (C 5 -C 14 )-heteroaryl, (C 5 -C 14 )-heteroaryl-(d- C 6 )-
  • R 3 is (d-C 8 )-alkyl, (C ⁇ -C 8 )-alkoxy, (C 5 -C ⁇ 4 )-aryl, (C5-d4)-aryl-(C ⁇ -C 4 )-alkyl, (C 5 - C 14 )-heteroaryl, (C 5 -Ci 4 )-heteroaryl-(d-C 4 )-alkyl, halogen, trifluoromethyl, hydroxyl, oxo, nitro, amino, NH-(C ⁇ -C 4 )-alkyl, N-((d-C 4 )-alkyl)2, NH-CO-(d-C 4 )- alkyl, CO-(d-C 4 )-alkyl;
  • R 4 is hydrogen, (d-C 6 )-alkyl-CO-O-(C ⁇ -C 4 )-alkyl or (d-C 6 )-alkyl, which is unsubstituted or is substituted by a radical from the group consisting of hydroxyl, (d-C 4 )-alkoxy, (C ⁇ -C 4 )-alkyl-S(O)2, NR 7 R 7' and N + R 7 R 7 R 7" Q " , where R 7 , R 7' and R 7 independently of one another are hydrogen, (d-C 6 )-alkyl, (C -Ci4)-aryl or (C5-C 14 )-aryl-(C ⁇ -C 6 )-alkyl and Q " is a physiologically tolerable anion, or in which R 4 is one of the radicals 21
  • R 5 is (C ⁇ -C 20 )-alkyl, (C 5 -C2o)- onocycloalkyl, (C 5 -C 2 o)-bicycloalkyl, (C 5 -C 2 o)- tricycloalkyl, (C 6 -C 14 )-aryl, (C 5 -C ⁇ 4 )-heteroaryl, (drd ⁇ -aryHd ⁇ -alkyl or (C 5 - d 4 )-heteroaryl-(C ⁇ -C 6 )-alkyl, where the aryl radical, the heteroaryl radical, the alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the tricycloalkyl radical each is unsubstituted or is substituted by one, two or three radicals R 3 and wherein in the alkyl radical, the monocycloalkyl radical, the
  • the present invention also relates to processes for the preparation of the compounds of the formula I.
  • the compounds can generally be prepared, for example in the course of a convergent synthesis, by linkage of two or more fragments which can be derived retrosynthetically from the formula I.
  • it can generally be advantageous or necessary in the course of the synthesis to introduce functional groups which could lead to undesired reactions or side reactions in the respective synthesis 22 step, in the form of precursors which are later converted into the desired functional groups, or to temporarily block functional groups by a protective group strategy suited to the synthesis problem.
  • Such strategies are well known to one skilled in the art (see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, Wiley, 1991).
  • precursor groups nitro groups and cyano groups may be mentioned which can later be converted by reduction, for example by catalytic hydrogenation, into amino groups and aminomethyl groups, respectively.
  • the compounds of the formula I can be prepared, for example, by linking in a manner known per se a carboxylic acid or carboxylic acid derivative of the formula II
  • R 4 and R 5 are defined as indicated for the formula I, or in which alternatively functional groups are present in the form of precursors which are later converted into the groups present in the compounds of the formula I, or in which functional groups are present in protected form, and in which X is a nucleophilically substitutable leaving group, with a guanidine or guanidine derivative of the formula III 23
  • R 1 , R 2 and R 6 are defined as indicated for the formula I, or alternatively functional groups are present in the form of precursors which are later converted into the groups present in the compounds of the formula I, or functional groups are present in protected form.
  • the group COX in the formula II is preferably the carboxylic acid group COOH or an activated carboxylic acid derivative.
  • X for example, is hydroxyl or halogen, in particular chlorine or bromine, alkoxy, preferably methoxy or ethoxy, aryioxy, for example phenoxy or pentafluorophenoxy, phenylthio, methylthio, 2- pyridylthio or a radical of a nitrogen heterocycle bonded via a nitrogen atom, in particular of an azole, such as, for example, 1-imidazolyl.
  • X can furthermore be, for example, ((d-C )-alkyl)-O-CO-O- or tolylsulfonyloxy and the activated acid derivative can thus be a mixed anhydride.
  • the carboxylic acid is expediently first activated.
  • the activation can be carried out, for example, with dicyclohexylcarbodiimide (DCCI) or with O- ((cyano(ethoxycarbonyl)-methylen)amino)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TOTU; K ⁇ nig et al., Proc. 21st Europ. Peptide Symp. 1990 (Eds. Giralt, Andreu), Escom, Leiden 1991 , p. 143) or other activating reagents customary in peptide chemistry.
  • DCCI dicyclohexylcarbodiimide
  • TOTU O- ((cyano(ethoxycarbonyl)-methylen)amino)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate
  • TOTU K ⁇ nig et al., Proc. 21st Europ. Peptide
  • guanidinium salts can also be employed in the reaction with the compounds of the formula II, from which the free guanidines are then prepared in situ or in a separate step by means of a base.
  • the reaction of an activated carboxylic acid derivative of the formula II 24 with the guanidine (derivative) of the formula III is preferably carried out in a manner known per se in a protic or aprotic polar, but inert, organic solvent.
  • the reactions of compounds of the type COX with salt-free guanidines are advantageously carried out in aprotic inert solvents such as dimethylformamide, tetrahydrofuran, dimethoxyethane or dioxane, if appropriate with addition of a base such as, for example, potassium tert-butoxide or sodium methoxide.
  • a base such as, for example, potassium tert-butoxide or sodium methoxide.
  • water can also be used as a solvent in the reaction of compounds of the formula II with guanidines, for example when using a base such as sodium hdyroxide.
  • reaction is advantageously carried out with addition of an acid scavenger, for example an additional base or in the presence of excess guanidine (derivative), for binding the resulting hydrohalic acid.
  • an acid scavenger for example an additional base or in the presence of excess guanidine (derivative), for binding the resulting hydrohalic acid.
  • the reaction mixture is worked up and, if desired, the reaction product is then purified by the customary processes familiar to those skilled in the art.
  • Protective groups optionally still present in the products obtained from the compounds of the formulae II and III are then removed by standard processes.
  • tert-butyl ester groups are converted into the carboxylic acid groups by treatment with trifluoroacetic acid, benzyl groups are removed by hydrogenation or fluorenylmethoxycarbonyl groups are removed by secondary amines.
  • further reactions are then carried out by standard processes, for example acylat ⁇ on reactions or esterification reactions.
  • a conversion into a physiologically tolerable salt or prodrug can then be carried out by known processes.
  • the carboxybenzaldehyde of the formula IV can be reacted, for example in the presence of pyridine and piperidine, with the malonic acid ester salt of the formula V to give the cinnamic acid derivative of the formula VI which, after hydrogenation, for example in the presence of palladium on carbon, gives the compound of the formula VII.
  • the compound of the formula VII can be condensed with the 2,3-diaminopropionic acid derivative of the formula VIII to give the compound of the formula IX (Scheme 1 ).
  • the condensation can be carried out, for example, in the presence of TOTU or another customary agent for activating carboxylic acids.
  • Y can be the group R 5 -SO 2 - which is present in the final compounds of the formula I according to the invention and which can then remain in the molecule, or Y can be a group which temporarily protects the amino group in the 2-position and which in a later stage is removed to give a free amino group which can then be converted into an R 5 -SO 2 -NH group by standard procedures for the preparation of sulfonamides, for example by reacting the free amine with a sulfonyl chloride of the formula R 5 -SO 2 -CI.
  • An example of a protecting group representing Y is the benzyloxycarbonyl group (Z group) which can be removed by catalytic hydrogenation.
  • Sulfonyl chlorides of the formula R 5 -SO 2 -CI and other sulfonic acid derivatives suitable for introducing the group R 5 -SO 2 are commercially available or can be prepared according to or analogously to procedures described in the literature. Instead of the tert-butyl ester present in the compounds of formula VIII and IX other esters can be 26
  • the compounds of the formula IX are examples of compounds of the formula II in which X is methoxy. These compounds and analogous compounds which are obtained from the synthesis described above and which contain a group that is 27
  • an activated carboxylic acid derivative can be reacted directly with the compounds of the formula III.
  • the compounds obtained in the above synthesis can also first be converted under standard conditions by cleavage of the methyl ester group or another ester group present in the position concerned in the compounds of the formula IX, into the corresponding carboxylic acids which are then reacted with the guanidines of the formula III after in situ activation, for example with TOTU or DCCI, or after conversion into an activated carboxylic acid derivative.
  • this conversion can be carried out, for example, by using thionyl chloride.
  • the compounds of the formula I are valuable pharmaceutical active ingredients which are suitable, for example, for the therapy and prophylaxis of bone disorders, tumor diseases or cardiovascular disorders.
  • the compounds of the formula I and their physiologically tolerable salts and their prodrugs can be administered to animals, preferably to mammals, and in particular to humans as pharmaceuticals for therapy or prophylaxis. They can be administered on their own, or in mixtures with one another or in the form of pharmaceutical 28
  • compositions which permit enteral or parenteral administration and which, as active constituent, contain an efficacious dose of at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs in addition to customary pharmaceutically innocuous carriers and/or additives.
  • the present invention therefore also relates to the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs for use as pharmaceuticals, to the use of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs for the production of pharmaceuticals for the therapy and prophylaxis of the diseases mentioned above or below, for example for the therapy and prophylaxis of bone disorders, and also to the use of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs for the therapy and prophylaxis of these diseases.
  • the present invention furthermore relates to pharmaceutical preparations or pharmaceutical compositions which contain an efficacious dose of at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs in addition to a customary pharmaceutically innocuous carrier.
  • the pharmaceuticals can be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injection solutions or infusion solutions, microcapsules, implants or rods, or percutaneously or topically, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays .
  • compositions according to the invention are prepared in a manner known per se and familiar to one skilled in the art, pharmaceutically 29
  • inert inorganic or organic carriers being used in addition to the compound(s) of the formula I and/or its (their) physiologically tolerable salts and/or its (their) prodrugs.
  • lactose corn starch or derivatives thereof, talc, stearic acid or its salts, etc.
  • Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc.
  • Suitable carriers for the production of solutions for example injection solutions, or of emulsions or syrups are, for example, water, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc.
  • Suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid.
  • the pharmaceutical preparations normally contain approximately 0.5 to 90% by weight of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs.
  • the amount of the active ingredient of the formula I and/or its physiologically tolerable salts and/or its prodrugs in the pharmaceutical preparations normally is 0.2 to 500 mg, preferably 1 to 200 mg.
  • the pharmaceutical preparations can additionally contain additives, such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings or aromatizers, thickeners, diluents, buffer substances, and also solvents or solubilizers or agents for achieving a depot effect, and also salts for altering the osmotic pressure, coating agents or antioxidants.
  • additives such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings or aromatizers, thickeners, diluents, buffer substances, and also solvents or solubilizers or agents for achieving a depot effect, and also salts for altering the osmotic pressure, coating agents or antioxidants.
  • They can also contain two or more compounds of the formula I
  • the compounds of the formula I are antagonists of the vitronectin receptor and inhibitors of cell adhesion. They have, for example, the ability to inhibit the 30
  • the compounds of the formula I can be demonstrated, for example, in an assay in which the inhibition of the binding of vitronectin to cells which contain the vitronectin receptor is determined. Details of such an assay are given below.
  • vitronectin receptor antagonists the compounds of the formula I and their physiologically tolerable salts and their prodrugs are generally suitable for the therapy and prophylaxis of diseases which are based on the interaction between vitronectin receptors and their ligands in cell-cell interaction processes or cell-matrix interaction processes, or which can be influenced by an inhibition of interactions of this type, or for their prevention, alleviation or cure an inhibition of interactions of this type is desired.
  • Such interactions play a part in bone resorption, in angiogenesis or in the proliferation of cells of the vascular smooth musculature.
  • the compounds of the formula I and their physiologically tolerable salts and their prodrugs are therefore suitable, for example, for the alleviation or cure of diseases which are caused at least partially by an undesired extent of bone resorption, angiogenesis or proliferation of cells of the vascular smooth musculature.
  • Bone diseases for whose treatment and prevention the compounds of the formula I according to the invention can be employed are especially osteoporosis, hypercalcemia, osteopenia, for example caused by metastases, dental disorders, hyperparathyroidism, periarticular erosions in rheumatoid arthritis and Paget's disease.
  • the compounds of the formula I can be used for the allevation, avoidance or therapy of bone disorders which are caused by a glucocorticoid, steroid or corticosteroid therapy or by a lack of sex hormone(s). All these disorders are characterized by bone loss, which is based on the inequilibrium between bone formation and bone destruction and which can be favorably influenced by the inhibition of bone resorption by osteoclasts.
  • the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs can also favorably be used as inhibitor of bone resorption, 31
  • osteoporosis for example in the therapy or prophylaxis of osteoporosis, in combination with conventional osteoporosis treatments, for example in combination with bisphosphonates, estrogens, estrogen/progesterone, estrogen agonists/antagonists, calcitonin, vitamin D analogues, parathyroid hormone, growth hormone secretagogues, or sodium fluoride.
  • Administration of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs and of other active ingredients effective in the treatment or prophylaxis of osteoporosis like those listed before can take place simultaneously or sequentially, in any order, and jointly or separately.
  • the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs and one or more other active ingredients like those listed before can together be present in a single pharmaceutical preparation, for example tablets or granules, or can be present in two or more separate pharmaceutical preparations which can be contained in a single package or in two or more separate packages.
  • the use of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs in such a combination therapy or prophylaxis and their use in the production of pharmaceuticals for such a combination therapy or prophylaxis are also subjects of the present invention.
  • the invention furthermore relates to pharmaceutical preparations which comprise efficacious amounts of at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs together with at least one other active ingredient effective in the treatment or prophylaxis of osteoporosis or in the inhibition of bone resorption like those listed before, together with a customary pharmaceutically innocuous carrier.
  • pharmaceutical preparations which comprise efficacious amounts of at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs together with at least one other active ingredient effective in the treatment or prophylaxis of osteoporosis or in the inhibition of bone resorption like those listed before, together with a customary pharmaceutically innocuous carrier.
  • the compounds of the formula I and their physiologically tolerable salts and their prodrugs can be used as inhibitors of tumor growth and tumor metastasis, as antiinflammatories, for the therapy or prophylaxis of cardiovascular disorders such as 32
  • arteriosclerosis or restenosis or for the therapy or prophylaxis of nephropathies or retinopathies, such as, for example, diabetic retinopathy.
  • the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs can also favorably be used in combination with conventional cancer therapy. Examples of conventional cancer therapy are given in Bertino (Editor), Encyclopedia of Cancer, Academic Press, 1997 which is incorporated herein by reference. All the above statements relating to the use of the compounds of formula I in combination with conventional osteoporosis therapy like, for example, possible modes of administration and pharmaceutical combination preparations, correspondingly apply to the use of the compounds of formula I in combination with conventional cancer therapy.
  • the dose can vary within wide limits and, as is customary, is to be suited to the individual conditions in each individual case. It depends, for example, on the compound employed or on the nature and severity of the disease to be treated and on whether an acute or chronic condition is treated or whether prophylaxis is carried out.
  • the daily dose is in general 0.01 to 100 mg/kg, preferably 0.1 to 50 mg/kg, in particular 0.1 to 5 mg/kg, for example 0.3 to 0.5 mg/kg to achieve effective results in an adult weighing about 75 kg (in each case in mg per kg of body weight).
  • the daily dose is in general approximately 0.01 to 100 mg/kg, preferably 0.05 to 10 mg/kg (in each case per kg of body weight).
  • the daily dose can be divided, in particular in the case of the administration of relatively large amounts, into several, for example 2, 3 or 4, part administrations. As usual, depending on individual behavior it may be necessary to deviate upwards or downwards from the daily dose indicated.
  • the active ingredients to be transported are in particular those which can be used for the treatment of the abovementioned diseases.
  • the compounds of the formula I and their salts can furthermore be employed for diagnostic purposes, for example in in vitro diagnoses, and as auxiliaries in biochemical investigations in which blocking of the vitronectin receptor or influencing of cell-cell or cell-matrix interactions is desired. They can furthermore be used as synthesis intermediates for the preparation of other compounds, in particular of other pharmaceutical active ingredients, which are obtainable from the compounds of the formula I, for example by modification or introduction of radicals or functional groups.
  • buffer A H 2 O, 0.1% trifluoroacetic acid (TFA)
  • buffer B acetonitrile (80% v/v)/H 2 O (20 % v/v), 0.1% TFA
  • Step a Reaction with the sulfonyl chloride 0.2 g of (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dimethylformamide and treated with 4 molar equivalents of triethylamine and 2 molar equivalents of the appropriate sulfonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1 ).
  • Step b Formation of the acyl guanidine 43
  • step a The product of step a was dissolved in 1 ml of dimethylformamide and 5 molar equivalents of 2-amino-1 ,4,5,6-tetrahydropyrimidine was added. The reaction mixture was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with dichloromethane/methanol (1/1 ), followed by dichloromethane/methanol/acetic acid/water (85/15/1.5/1.5).
  • Step c Cleavage of the tert-butyl ester
  • step b The product of step b was dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid was added. The solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonitrile/water (1/1 ) and lyophilized.
  • the title compound was synthesized according to general procedure 1 , using 4- tert-butyl-benzenesulfonyl chloride in step a.
  • the title compound was synthesized according to general procedure 1 , using propane-1 -sulfonyl chloride in step a.
  • the title compound was synthesized according to general procedure 1 , using trans-beta-styrenesulfonyl chloride in step a.
  • the title compound was synthesized according to general procedure 1 , using 2-cyano-benzenesulfonyl chloride in step a.
  • the title compound was synthesized according to general procedure 1 , using 10-camphorsulfonyl chloride in step a.
  • the title compound was synthesized according to general procedure 1 , using 4-chloro-benzenesulfonyl chloride in step a.
  • the title compound was synthesized according to general procedure 1 , using 4-methoxy-benzenesulfonyl chloride in step a.
  • the title compound was synthesized according to general procedure 1 , using benzenesulfonyl chloride in step a.
  • the title compound was synthesized according to general procedure 1 , using 2-thiophenesulfonyl chloride in step a.
  • the title compound was synthesized according to general procedure 1 , using 4-biphenylsulfonyl chloride in step a.
  • the title compound was synthesized according to general procedure 1 , using 4-trifluoromethyl-benzenesulfonyl chloride in step a.
  • Step a Reaction with the sulfonyl chloride
  • Step b Formation of the acyl guanidine
  • the product of step a was dissolved in 2 ml of tetrahydrofuran and 1.2 molar equivalents of 2-amino-1 ,4,5,6-tetrahydropyrimidine, 4 molar equivalents of diisopropylethylamine, and 1.1 molar equivalents of O-(7-azabenzotriazol-1 -yl)- 1 ,1 ,3,3-tetramethyluronium hexafluorophosphate were added. The reaction was stirred at room temperature for 20 hours.
  • Step c Cleavage of the tert-butyl ester
  • step b The product of step b was dissolved in 1.5 ml of trifluoroacetic acid/water (95/5). The solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonitrile/water (1/1 ) and lyophilized.
  • the title compound was synthesized according to general procedure 2, using propane-2-sulfonyl chloride in step a.
  • the inhibition of bone resorption by the compounds according to the invention can be determined, for example, with the aid of an osteoclast resorption test ("PIT ASSAY”), for example analogously to WO-A-95/32710 which is incorporated herein by reference.
  • PIT ASSAY osteoclast resorption test
  • the inhibitory action of the compounds according to the invention against the vitronectin receptor ⁇ v ⁇ 3 can be determined, for example, as described below.
  • Human vitronectin is isolated from human plasma and purified by affinity 65 chromatography according to the method of Yatohyo et al., Cell Structure and Function, 1988, 23, 281-292.
  • Cell test 293 cells a human embryonic kidney cell line, which are cotransfected with DNA sequences for the ⁇ intend and ⁇ 3 subunits of the vitronectin receptor ⁇ v ⁇ 3 , are selected for a high rate of expression (> 500,000 ⁇ v ⁇ 3 receptors/cell) according to the FACS method. The selected cells are cultured and sorted again by means of FACS in order to obtain a stable cell line (15 D) with expression rates > 1 ,000,000 copies of ⁇ v ⁇ 3 per cell.
  • a Linbro 96-well tissue culture plate with a flat bottom is coated overnight at 4°C with human vitronectin (0.01 mg/ml, 0.05 ml/well) in phosphate-buffered saline solution (PBS) and then blocked with 0.5% strength BSA (bovine serum albumin).
  • PBS phosphate-buffered saline solution
  • BSA bovine serum albumin

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Abstract

La présente invention concerne des dérivés de sulfamide de la formule (I) dans laquelle R?1, R2, R4, R5 et R6¿ ont les significations indiquées dans les revendications; l'invention concerne également leurs sels physiologiquement tolérables et leurs promédicaments. Les composés de la formule (I) représentent des composés actifs du point de vue pharmaceutique. Ils constituent des antagonistes de récepteur de vitronectine et des inhibiteurs d'adhérence cellulaire et inhibent la résorption osseuse par des ostéoclastes. Ils sont indiqués, par exemple, pour le traitement et la prophylaxie d'affections provoquées au moins en partie par une étendue non voulue d'une résorption osseuse, par exemple de l'ostéoporose. L'invention concerne en outre des procédés de préparation de composés de la formule, leur utilisation, notamment comme ingrédients actifs du point de vue pharmaceutique, ainsi que des préparations pharmaceutiques les contenant.
EP99904789A 1998-01-23 1999-01-16 Nouveaux derives de sulfamide comme inhibiteurs de la resorption osseuse et comme inhibiteurs de l'adherence cellulaire Withdrawn EP1049677A1 (fr)

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US1248998A 1998-01-23 1998-01-23
US12489 1998-01-23
PCT/EP1999/000242 WO1999037621A1 (fr) 1998-01-23 1999-01-16 Nouveaux derives de sulfamide comme inhibiteurs de la resorption osseuse et comme inhibiteurs de l'adherence cellulaire

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JP2002521450A (ja) * 1998-07-29 2002-07-16 メルク エンド カムパニー インコーポレーテッド インテグリン受容体アンタゴニスト
EP1028114A1 (fr) 1999-02-13 2000-08-16 Aventis Pharma Deutschland GmbH Nouveaux dérivés de guanidine et leur utilisation comme inhibiteurs de l'adhésion des cellules
EP1065207A1 (fr) 1999-07-02 2001-01-03 Aventis Pharma Deutschland GmbH Dérivées de la naphthyridine, procédés pour leur preparation, leur utilisation, et compositions pharmaceutique les contenant
EP1065208A1 (fr) * 1999-07-02 2001-01-03 Aventis Pharma Deutschland GmbH Dérivés substitués de la purine inhibiteurs de l'adhésion cellulaire
EP1070707A1 (fr) * 1999-07-21 2001-01-24 Aventis Pharma Deutschland GmbH Dérivés de la 1,4,5,6-tetrahydropyrimidine comme inhibiteurs de la vitronectine
US6849639B2 (en) 1999-12-14 2005-02-01 Amgen Inc. Integrin inhibitors and their methods of use
EP1108721A1 (fr) 1999-12-15 2001-06-20 Aventis Pharma Deutschland GmbH Dérivés de thiénylalanine comme inhibiteurs de l'adhésion cellulaire
AU2207001A (en) * 1999-12-24 2001-07-09 Smithkline Beecham Plc Novel compounds and process
FR2808798A1 (fr) * 2000-05-09 2001-11-16 Hoechst Marion Roussel Inc Nouveaux derives antagonistes du recepteur de la vitronectine
FR2847254B1 (fr) 2002-11-19 2005-01-28 Aventis Pharma Sa Nouveaux derives antagonistes du recepteur de la vitronectine, leur procede de preparation, leur application comme medicaments et les compositions pharmaceutiques les refermant
BRPI0509150B8 (pt) * 2004-03-24 2021-05-25 Jerini Ag compostos para a inibição de angiogênese e uso destes
FR2870541B1 (fr) * 2004-05-18 2006-07-14 Proskelia Sas Derives de pyrimidines antigonistes du recepteur de la vitronectine
GB0412553D0 (en) 2004-06-04 2004-07-07 Univ Aberdeen Therapeutic agents for the treatment of bone conditions
UA87854C2 (en) 2004-06-07 2009-08-25 Мерк Энд Ко., Инк. N-(2-benzyl)-2-phenylbutanamides as androgen receptor modulators
FR2873585B1 (fr) * 2004-07-27 2006-11-17 Aventis Pharma Sa Nouvelles formulations galeniques de principes actifs
GB0705400D0 (en) 2007-03-21 2007-05-02 Univ Aberdeen Therapeutic compounds andm their use
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GB0817207D0 (en) 2008-09-19 2008-10-29 Pimco 2664 Ltd therapeutic apsac compounds and their use
GB201311361D0 (en) 2013-06-26 2013-08-14 Pimco 2664 Ltd Compounds and their therapeutic use
SG11201609050UA (en) 2014-05-30 2016-12-29 Pfizer Carbonitrile derivatives as selective androgen receptor modulators
US10005733B2 (en) 2014-12-17 2018-06-26 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamide and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)-benzenesulfonamide compounds and their therapeutic use
WO2023275715A1 (fr) 2021-06-30 2023-01-05 Pfizer Inc. Métabolites de modulateurs sélectifs du récepteur des androgènes

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JP3895792B2 (ja) * 1995-12-08 2007-03-22 プロスケリア・エス・ア・エス 骨形成促進剤

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ID26219A (id) 2000-12-07
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NO20003765D0 (no) 2000-07-21
AP1269A (en) 2004-04-03
ZA99476B (en) 1999-08-05
EA200000785A1 (ru) 2001-02-26
JP2002501054A (ja) 2002-01-15
YU47200A (sh) 2002-11-15
UA63990C2 (uk) 2004-02-16
WO1999037621A1 (fr) 1999-07-29
NO318795B1 (no) 2005-05-09
CN1177832C (zh) 2004-12-01
KR20010034319A (ko) 2001-04-25
AP2000001863A0 (en) 2000-09-30
AR014456A1 (es) 2001-02-28
CA2318221A1 (fr) 1999-07-29
HUP0100520A1 (hu) 2001-07-30
TR200002160T2 (tr) 2001-07-23

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