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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• • 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
  • 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
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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C255/00—Carboxylic acid nitriles
  • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
  • C07D213/62—Oxygen or sulfur atoms
  • C07D213/63—One oxygen atom
  • C07D213/65—One oxygen atom attached in position 3 or 5
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
  • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

• the present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to serine protease HtrAl inhibitors for the treatment or prophylaxis of HtrAl -mediated ocular diseases, such as wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity and polypoidal choroidal vasculopathy.
• HtrAl -mediated ocular diseases such as wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity and polypoidal choroidal vasculopathy.
• the present invention provides novel compounds of formula (I)
• R is selected from i) Ci-6-alkyl, ii) C 3 - 8 -cycloalkyl substituted with R 24 , R 25 and R 26 , iii) halo-Ci_6-alkyl, iv) heterocycloalkyl-Ci 24 25
• R 2 , R 3 , R 4 , R 6 , R 7 , R 9 , R 10 and R 23 are independently selected from i) H, ii) Ci-6-alkyl, and GB / 30.06.2017 iii) C 3 _g-cycloalkyl;
• R 5 is selected from i) aryl substituted with R 12 , R 13 and R 14 , ii) aryl-Ci-6-alkyl substituted with R 12 , R 13 and R 14 , iii) heteroaryl substituted with R 12 , R 13 and R 14 , and iv) heteroaryl-Ci_ 6 -alkyl substituted with R 12 , R 13 and R 14 ;
• R is selected from i) H, ii) hydroxy, iii) amino-Ci_6-alkyl substituted on the nitrogen atom by one or two substituents selected from H, Ci-6-alkylcarbonyl, Ci-6-alkoxycarbonyl, Ci-6-alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted with R 15 , R 16 and R 17 , iv) aminocarbonyl substituted on the nitrogen atom by one or two substituents selected from H, Ci-6-alkylcarbonyl, Ci-6-alkoxycarbonyl, Ci-6-alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted with R 15 , R 16 and R 17 , v) aminocarbonyl-Ci_6-alkyl substituted on the nitrogen atom by one or two substituents selected from H, Ci-6-
• heterocycloalkyl-C 1-6 -alkyl substituted with R 18 , R 19 and R 20 xx) heterocycloalkyl-C 3-8 -cycloalkyl substituted with R 18 , R 19 and R 20 , xxi) heterocycloalkyl(halo)-C 3 _8-cycloalkyl substituted with R 18 , R 19 and R 20 , xxii) heterocycloalkyl(halo)-Ci_ 6 -alkyl substituted with R 18 , R 19 and R 20 , xxiii) heteroaryl substituted with R 18 , R 19 and R 20 ,
• R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 24 , R 25 and R 26 are independently selected from i) H, ii) cyano, iii) halogen, iv) oxo, v) Ci- 6 -alkyl, vi) amino substituted on the nitrogen atom by two substituents independently selected from H, Ci- 6 -alkyl, Ci- 6 -alkoxycarbonyl, arylcarbonyl and heteroarylcarbonyl,
• Ci- 6 -alkoxycarbonyl independently selected from H, C 1-6 -alkyl, Ci- 6 -alkoxycarbonyl, arylcarbonyl and heteroarylcarbonyl, viii) Ci- 6 -alkyl, ix) halo-Ci_ 6 -alkyl, x) C3-8-cycloalkyl, xi) Ci- 6 -alkoxycarbonyl-Ci_ 6 -alkyl, xii) carboxy-Ci_ 6 -alkyl, xiii) Ci_ 6 -alkoxycarbonyl-Ci_ 6 alkylaminocarbonyl-Ci_ 6 alkyl, xiv) carboxy-Ci- 6 -alkylaminocarbonyl-Ci_ 6 alkyl, xv) Ci- 6 -alkoxy, xvi) halo-Ci_ 6 -alkoxy, xvii) Ci_ 6 -alkoxycarbonyl
• R 21 and 22 are independently selected from i) H, ii) Ci- 6 -alkoxycarbonyl, iii) carboxy-Ci- 6 -alkyl, iv) arylcarbonyl, and v) heteroarylcarbonyl; or pharmaceutically acceptable salts;
• HtrAl serine protease HtrAl
• HtrAl serine protease HtrAl
• the pathophysiological relevance of HtrAl in the progression of the age-related macular degeneration has been firmly established by human genetic studies where a SNP in the HtrAl promoter region results in increased HtrAl transcript and protein levels.
• Age-related macular degeneration is the leading cause of severe irreversible central vision loss and blindness in individuals over 65 years of age in developed countries.
• AMD dry AMD and wet AMD.
• Wet AMD also known as exudative AMD
• Wet AMD is associated with pathologic posterior choroidal neovascularization subsequent to the disruption of the delimiting Bruch's membrane. Tissue edema due to the leakage from the abnormal blood vessels damages the macula and impairs vision, eventually leading to blindness.
• drusen have been reported in the macula of the eye, the cells in the macula die for the progressive accumulation of the drusen, resulting in progressive vision loss.
• Dry AMD is clinically described to occur in three stages: 1) early, 2) intermediate, and 3) advanced dry AMD. Dry AMD can also progress into wet AMD during any stage of the disease. Treatment strategies for wet AMD exists and the current standard of care is Lucentis
• HtrAl is a fundamental factor involved in the pathophysiology and progression in AMD.
• HtrAl protease activity is directed to the cleavage of the fibulins as substrates.
• a direct inhibition of HtrAl protease activity is expected to provide a protection reducing degradation of extracellular matrix proteins, in particular fibulins and fibrionectin, therefore preserving the retina tissue structure.
• the relevance of HtrAl's role in maintenance of the physiological homeostasis of the ECM components is firmly provided by the identification of human loss-of-function mutations causing familial ischemic cerebral small- vessel disease.
• the molecular mechanism underlies in the deficient TGFbeta inhibition by HtrAl resulting in increased signaling levels, which in conjunction with deficient HtrAl -mediated degradation of various extracellular matrix components determine thickening of the intima responsible for the ischemic small-vessels.
• HtrAl Given its fundamental role in regulating intracellular signaling pathways (e.g. TGFbeta) and the regulation of ECM proteins turnover, HtrAl has been involved in several pathologies, as ocular diseases, rheumatoid arthritis, osteoarthritis, Alzheimer's disease, and some types of cancer.
• amino denotes a -NH 2 group.
• amino-Ci_ 6 -alkyl denotes an Ci_ 6 -alkyl group wherein one of the hydrogen atoms of the Ci- 6 -alkyl group has been replaced by an amino group.
• amino-C 1-6 - alkyl groups are aminomethyl, aminoethyl or aminopropyl. Particular examples of amino-Ci- 6 - alkyl is aminomethyl.
• aminocarbonyl denotes a group of the formula -C(0)-R', wherein R' is an amino group.
• aminocarbonyl-Ci_ 6 -alkyl denotes an Ci- 6 -alkyl group wherein one of the hydrogen atoms of the Ci_ 6 -alkyl group has been replaced by an aminocarbonyl group.
• aminocarbonyl-Ci_ 6 -alkyl groups are aminocarbonylmethyl, aminocarbonylethyl or aminocarbonylpropyl
• Ci- 6 -alkoxy denotes a group of the formula -O-R', wherein R' is an Ci- 6 -alkyl group.
• Ci_ 6 -alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, isobutoxy and tert-butoxy. Particular example is methoxy. In the case of R 12 , particular example is methoxy.
• Ci_ 6 -alkoxycarbonyl denotes a group of the formula -C(0)-R', wherein R' is a Ci_ 6 -alkoxy group.
• Ci_ 6 -alkoxycarbonyl is a group wherein R' is tert- butoxy.
• Ci_ 6 -alkoxycarbonyl-Ci_ 6 -alkoxy denotes an Ci- 6 -alkoxy group wherein one of the hydrogen atoms of the Ci- 6 -alkoxy group has been replaced by a Ci- 6 -alkoxycarbonyl group.
• Ci_ 6 -alkoxycarbonyl-Ci_ 6 -alkoxy is a methoxy wherein one of the hydrogen atoms has been replaced by tert-butoxycarbonyl.
• Ci_ 6 -alkoxycarbonyl-Ci_ 6 -alkyl denotes an Ci- 6 -alkyl group wherein one of the hydrogen atoms of the Ci- 6 -alkyl group has been replaced by a Ci- 6 -alkoxycarbonyl group.
• Ci_ 6 -alkoxycarbonyl-Ci_ 6 -alkyl is a methyl wherein one of the hydrogen atoms has been replaced by tert-butoxycarbonyl.
• Ci- 6 alkoxycarbonyl-Ci_ 6 alkylaminocarbonyl-Ci_ 6 alkoxy denotes an Ci- 6 -alkoxy group wherein one of the hydrogen atoms of the Ci- 6 -alkoxy group has been replaced by a Ci_ 6 alkoxycarbonyl-Ci_ 6 alkylaminocarbonyl group.
• Ci_ 6 alkoxycarbonyl-Ci_ 6 alkylaminocarbonyl group Particular example is methoxy wherein one of the hydrogen atoms has been replaced by ter-butoxycarbonylmethylamino.
• Ci_ 6 alkoxycarbonyl-Ci_ 6 alkylaminocarbonyl-Ci_ 6 alkyl denotes an Ci_ 6 -alkyl group wherein one of the hydrogen atoms of the Ci_ 6 -alkyl group has been replaced by a Ci_ 6 alkoxycarbonyl-Ci_ 6 alkylaminocarbonyl group. Particular example is methyl wherein one of the hydrogen atoms has been replaced by ter-butoxycarbonylmethylaminocarbonyl.
• Ci_ 6 alkoxycarbonyl-Ci_ 6 alkylaminocarbonyl denotes a group of the formula -
• R' is a Ci_ 6 alkoxycarbonyl-Ci_ 6 alkylamino group. Particular example is a group wherein R' is ter-butoxycarbonylmethylamino.
• Ci_ 6 -alkoxycarbonyl-Ci_ 6 -alkylamino denotes a group of the formula -NH-R', wherein R' is an Ci_ 6 -alkoxycarbonyl-Ci_ 6 -alkyl group. Particular example is a group wherein R' is ter-butoxycarbonylmethyl.
• Ci_ 6 -alkoxycarbonyl-Ci_ 6 -alkyl denotes an Ci- 6 -alkyl group wherein one of the hydrogen atoms of the Ci- 6 -alkyl group has been replaced by an Ci- 6 -alkoxycarbonyl group. Particular example is a methyl wherein one of the hydrogen atoms of has been replaced by a ter- butoxycarbonyl.
• Ci- 6 -alkyl denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms.
• Ci- 6 -alkyl examples include methyl, ethyl, propyl, isopropyl, n- butyl, iso-butyl, sec-butyl, tert-butyl and pentyl.
• Particular Ci_ 6 -alkyl groups are methyl and isopropyl.
• R particular example is isopropyl.
• aryl denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms.
• aryl group include phenyl and naphthyl. Particular aryl group is phenyl.
• aryl(halo)-Ci_ 6 -alkyl denotes a halo-Ci_ 6 -alkyl group wherein one of the hydrogen atoms of the halo-Ci- 6 -alkyl group has been replaced by an aryl group.
• Particular examples are groups wherein the aryl group is phenyl. Further particular example is phenyl- difluoromethyl.
• aryl-Ci_ 6 -alkyl denotes an -Ci_ 6 -alkyl group wherein one of the hydrogen atoms of the Ci- 6 -alkyl group has been replaced by an aryl group.
• Particular aryl-Ci- 6 -alkyl group is phenyl-Ci- 6 -alkyl.
• Further particular examples of aryl-Ci- 6 -alkyl are phenylmethyl and phenylpropyl.
• aryl-Ci- 6 -alkyl is phenylmethyl.
• aryl-Ci_6- alkoxy denotes an -Ci_6-alkoxy group wherein one of the hydrogen atoms of the -Ci_6-alkoxy group has been replaced by an aryl group.
• Particular examples are groups wherein the aryl group is phenyl.
• Particular aryl-Ci_6- alkoxy group is phenylmethoxy..
• aryloxy denotes a group of the formula -O-R', wherein R' is an aryl group. Particular examples of aryloxy group are groups wherein R' is phenyl.
• aryloxy-Ci_6-alkyl denotes an Ci_6-alkyl group wherein one of the hydrogen atoms of the Ci-6-alkyl group has been replaced by an aryloxy group. Particular examples are groups wherein the aryloxy group is phenoxy. Further particular example of aryloxy-Ci-6-alkyl is phenoxyalkyl. Further particular example is phenoxymethyl.
• aryloxy(halo)-Ci_6-alkyl denotes a halo-Ci_6-alkyl group wherein one of the hydrogen atoms of the halo-Ci-6-alkyl group has been replaced by an aryloxy group. Particular examples are groups wherein the aryloxy group is phenoxy.
• arylcarbonyl denotes a group of the formula -C(0)-R', wherein R' is an aryl group. Particular example is a group wherein R' is phenyl.
• aryl(halo)-C 3 _8-cycloalkyl denotes a halo- C 3 _8-cycloalkyl group wherein one of the hydrogen atoms of the halo- C 3 _8-cycloalkyl group has been replaced by an aryl group.
• Particular examples are groups wherein the aryl group is phenyl. Further particular example is phenyl-difluorocyclopropyl.
• aryl-C 3 _8-cycloalkyl denotes a halo- C 3 _8-cycloalkyl group wherein one of the hydrogen atoms of the C 3 _8-cycloalkyl group has been replaced by an aryl group.
• Particular examples are groups wherein the aryl group is phenyl. Further particular example is
• aryloxy- C 3 _8-cycloalkyl denotes a C 3 _8-cycloalkyl group wherein one of the hydrogen atoms of the C 3 _8-cycloalkyl group has been replaced by an aryloxy group.
• Particular examples are groups wherein the aryloxy group is phenoxy. Further particular example is phenyl-difluorocyclopropyl.
• aryloxy(halo)- C 3 _8-cycloalkyl denotes a halo- C 3 _8-cycloalkyl group wherein one of the hydrogen atoms of the halo- C 3 _8-cycloalkyl group has been replaced by an aryloxy group.
• Particular examples are groups wherein the aryloxy group is phenoxy. Further particular example is phenoxy-difluorocyclopropyl.
• aryloxy-C 3 _g-cycloalkyl denotes a C 3 _g-cycloalkyl group wherein one of the hydrogen atoms of the C 3 _g-cycloalkyl group has been replaced by an aryloxy group.
• Particular examples are groups wherein the aryloxy group is phenoxy. Further particular example is phenoxycyclopropyl.
• bicyclic ring system denotes two rings which are fused to each other via a common single or double bond (annelated bicyclic ring system), via a sequence of three or more common atoms (bridged bicyclic ring system) or via a common single atom (spiro bicyclic ring system).
• Bicyclic ring systems can be saturated, partially unsaturated, unsaturated or aromatic.
• Bicyclic ring systems can comprise heteroatoms selected from N, O and S.
• carboxy-Ci- 6 -alkoxy denotes an Ci- 6 -alkoxy group wherein one of the hydrogen atoms of the Ci- 6 -alkoxy group has been replaced by a carboxy group. Particular example is carboxymethoxy.
• carboxy-Ci_ 6 -alkyl denotes an Ci_ 6 -alkyl group wherein one of the hydrogen atoms of the Ci- 6 -alkyl group has been replaced by a carboxy group. Particular example is carboxymethyl.
• carboxy-Ci_ 6 -alkylaminocarbonyl-Ci_ 6 alkoxy denotes an Ci_ 6 -alkoxy group wherein one of the hydrogen atoms of the Ci_ 6 -alkoxy group has been replaced by a carboxy-Ci_ 6 -alkylaminocarbonyl group. Particular example is carboxymethylaminocarbonylmethoxy.
• carboxy-Ci_ 6 alkylaminocarbonyl-Ci_ 6 alkyl denotes an Ci- 6 -alkyl group wherein one of the hydrogen atoms of the Ci_ 6 -alkyl group has been replaced by a carboxy-Ci_
• 6alkylaminocarbonyl group Particular example is carboxymethylaminocarbonylmethyl.
• carboxy-Ci_ 6 alkylaminocarbonyl group denotes a group of the formula -C(O)- R', wherein R' is a carboxy-Ci_ 6 alkylamino group. Particular example is carboxymethylamino.
• carboxy-Ci_ 6 alkylamino denotes a group of the formula -NH-R', wherein R' a carboxy-Ci_ 6 alkyl group. Particular example is a group wherein R' is carboxymethyl.
• C 3 _8-cycloalkyl denotes a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms.
• Bicyclic means a ring system consisting of two saturated carbocycles having two carbon atoms in common.
• Examples for monocyclic cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl.
• Particular monocyclic cycloalkyl groups are cyclopropyl, cyclobutanyl, cyclopentyl and cyclohexyl. More particular monocyclic cycloalkyl group is cyclopropyl.
• C 3 _g-cycloalkyl(halo)-Ci_6-alkyl denotes a halo-Ci_6-alkyl group wherein one of the hydrogen atoms of the halo-Ci_6-alkyl group has been replaced by an C 3 _g-cycloalkyl group.
• C 3 _8-cycloalkyl-Ci_6-alkyl denotes an -Ci-6-alkyl group wherein one of the hydrogen atoms of the Ci-6-alkyl group has been replaced by an C 3 _8-cycloalkyl group.
• Examples of cycloalkylalkyl include cyclopropylmethyl, cyclopropylethyl, cyclopropylbutyl,
• cyclobutylpropyl 2-cyclopropylbutyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptanylmethyl, bicyclo[4.1.0]heptanylethyl, bicyclo[2.2.2]octanylmethyl and bicyclo[2.2.2]octanylethyl.
• Particular examples of cycloalkylalkyl are cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptanylmethyl, bicyclo[4.1.0]heptanylethyl,
• cycloalkylalkyl is cyclohexylethyl.
• halo-Ci-6-alkoxy denotes an Ci-6-alkoxy group wherein at least one of the hydrogen atoms of the Ci_6-alkoxy group has been replaced by same or different halogen atoms.
• perhaloalkoxy denotes an alkoxy group where all hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms. Examples of haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy,
• haloalkoxy groups is difluoromethoxy.
• halo-Ci-6-alkyl denotes an Ci-6-alkyl group wherein at least one of the hydrogen atoms of the Ci-6-alkyl group has been replaced by the same or different halogen atoms.
• perhaloalkyl denotes an alkyl group where all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl and
• haloalkyl group is trifluoroethyl.
• halo-C 3 _8-cycloalkyl denotes an C 3 _8-cycloalkyl group wherein at least one of the hydrogen atoms of the C 3 _8-cycloalkyl group has been replaced by the same or different halogen atoms.
• halogen and “halo” are used interchangeably herein and denote fluoro, chloro, bromo or iodo. Particular halogen is chloro.
• heteroaryl denotes a monovalent aromatic heterocyclic mono- or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
• heteroaryl group examples include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolin
• heteroaryl groups are pyrazinyl, pyridinyl, pyrimidinyl and thiophenyl.
• substituent R 11 particular heteroaryl groups are pyrazinyl, pyridinyl, pyrimidinyl and thiophenyl, more particularly pyridinyl.
• heteroaryl(halo)-Ci_6-alkyl denotes a halo-Ci_6-alkyl group wherein one of the hydrogen atoms of the halo-Ci-6-alkyl group has been replaced by a heteroaryl group.
• heteroaryl-Ci_6-alkyl denotes an Ci-6-alkyl group wherein one of the hydrogen atoms of the Ci_6-alkyl group has been replaced by a heteroaryl group.
• heteroaryl-Ci_6- alkoxy denotes an Ci_6-alkoxy group wherein one of the hydrogen atoms of the Ci-6-alkoxy group has been replaced by a heteroaryl group.
• heteroaryloxy denotes a group of the formula -O-R', wherein R' is a heteroaryl group.
• heteroaryloxy-Ci_6-alkyl denotes an Ci_6-alkyl group wherein one of the hydrogen atoms of the Ci-6-alkyl group has been replaced by anheteroaryloxy group.
• heteroaryloxy(halo)-Ci_6-alkyl denotes a halo-Ci-6-alkyl group wherein one of the hydrogen atoms of the halo-Ci_6-alkyl group has been replaced by a heteroaryloxy group.
• heteroarylcarbonyl denotes a group of the formula -C(0)-R', wherein R' is a heteroaryl group. Particular heteroarylcarrbonyl is a group wherein R' is pyridinyl.
• heteroaryl(halo)-C 3 _g-cycloalkyl denotes a halo- C 3 _g-cycloalkyl group wherein one of the hydrogen atoms of the halo- C 3 _g-cycloalkyl group has been replaced by a heteroaryl group.
• heteroaryl-C3_8-cycloalkyl denotes a halo- C 3 _8-cycloalkyl group wherein one of the hydrogen atoms of the C 3 _g-cycloalkyl group has been replaced by a heteroaryl group.
• heteroaryloxy- C 3 _g-cycloalkyl denotes a C 3 _g-cycloalkyl group wherein one of the hydrogen atoms of the C 3 _g-cycloalkyl group has been replaced by a heteroaryloxy group.
• heteroaryloxy(halo)- C 3 _g-cycloalkyl denotes a halo- C 3 _g-cycloalkyl group wherein one of the hydrogen atoms of the halo- C 3 _g-cycloalkyl group has been replaced by a heteroaryloxy group.
• heterocycloalkyl denotes a monovalent saturated or partly unsaturated mono- or bicyclic ring system of 4 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
• Bicyclic means consisting of two cycles having two ring atoms in common, i.e. the bridge separating the two rings is either a single bond or a chain of one or two ring atoms.
• Examples for monocyclic saturated heterocycloalkyl are 4,5- dihydro-oxazolyl, oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, l,l-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl.
• bicyclic saturated heterocycloalkyl examples include 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza- bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3-thia-9-aza- bicyclo[3.3.1]nonyl.
• Examples for partly unsaturated heterocycloalkyl are dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl.
• heterocycloalkyl-Ci-6-alkyl denotes an Ci-6-alkyl group wherein one of the hydrogen atoms of the Ci_6-alkyl group has been replaced by a heterocycloalkyl group.
• particular heterocycloalkyl-Ci_6-alkyl is morpholinoethyl.
• heterocycloalkyl-Ci-6- alkoxy denotes an Ci-6-alkoxy group wherein one of the hydrogen atoms of the Ci-6-alkoxy group has been replaced by a heterocycloalkyl group.
• heterocycloalkyl(halo)-Ci_6-alkyl denotes a halo-Ci_6-alkyl group wherein one of the hydrogen atoms of the halo-Ci_6-alkyl group has been replaced by a heterocycloalkyl group.
• heterocycloalkyl(halo)-C 3 _8-cycloalkyl denotes a halo- C 3 _8-cycloalkyl group wherein one of the hydrogen atoms of the halo- C 3 _g-cycloalkyl group has been replaced by a heterocycloalkyl group.
• hydroxy denotes a -OH group.
• phenoxy denotes a group of the formula -O-R', wherein R' is a phenyl.
• pharmaceutically acceptable salts refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable.
• the salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, N-acetylcystein and the like.
• inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
• organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid
• salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like.
• Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as
• Particular pharmaceutically acceptable salts of compounds of formula (I) are the hydrochloride salts, methanesulfonic acid salts and citric acid salts.
• “Pharmaceutically acceptable esters” means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention.
• protecting group denotes a group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry.
• Protecting groups can be removed at the appropriate point.
• Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups.
• Particular protecting groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn) groups.
• Further particular protecting groups are the tert-butoxycarbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc) groups. More particular protecting group is the tert-butoxycarbonyl (Boc) group.
• uM means microMolar and is equivalent to the symbol ⁇ .
• the abbreviation uL means microliter and is equivalent to the symbol ⁇ L ⁇ .
• the abbreviation ug means microgram and is equivalent to the symbol ⁇ g.
• the compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
• the asymmetric carbon atom can be of the "R" or "S" configuration.
• CF 2 - ketone moieties in compounds I exist in part, mainly or totally in form of its hydrate.
• any description of a CF 2 -ketone moiety always describes both ketone and hydrate form.
• an embodiment of the present invention are compounds according to formula (I) as described herein and pharmaceutically acceptable salts or esters thereof, in particular compounds according to formula (I) as described herein and pharmaceutically acceptable salts thereof, more particularly compounds according to formula (I) as described herein.
• R 1 is selected from i) Ci_6-alkyl, and ii) heterocycloalkyl-Ci-6-alkyl substituted with R 24 , R 25 and R 26 ;
• R 2 is Ci-6-alkyl;
• R 3 , R 4 , R 6 , R 7 R 9 and R 10 are H;
• R 5 is selected from i) phenyl substituted with R 12 , R 13 and R 14 , and ii) phenyl-Ci-6-alkyl substituted with R 12 , R 13 and R 14 ,
• R 8 is phenyl substituted with R 15 , R 16 and R 17 ;
• R 11 is selected rom i) phenyl substituted with R 18 , R 19 and R 20 , and ii) pyridinyl substituted with R 18 , R 19 and R 20 ;
• R 12 is selected from i) H, and ii) Ci-6-alkoxy;
• R 13 , R 14 , R 17 and R 20 are H;
• R 15 is selected from i) H, ii) cyano, and iii) halogen;
• R is selected from i) H, and ii) halogen
• R is selected from i) halogen, and ii) cyano;
• R 19 is selected from i) H, ii) cyano, iii) Ci-6-alkyl, and iv) halogen; or pharmaceutically acceptable salts.
• Ci_6-alkyl and ii) heterocycloalkyl-Ci-6-alkyl substituted with R 24 , R 25 and R 26 .
• a furthermore particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 1 is halo-C-i-6-alkyl.
• a furthermore particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 1 is trifluoroethyl.
• Another particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is Ci_6-alkyl. Also a furthermore particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is isopropyl.
• a particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is H.
• a particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 4 is H.
• a particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 6 is H.
• a particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is H.
• a particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 9 is H.
• a particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 10 is H.
• a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 3 , R 4 , R 6 , R 7 R 9 and R 10 are H.
• a particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 5 is selected from
• a more particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 5 is phenyl substituted with one Ci_6-alkoxy.
• a particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 8 is phenyl substituted with R 15 , R 16 and R 17 .
• a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is selected from i) hydroxy, and ii) phenyl substituted with R 15 , R 16 and R 17 .
• a more particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 8 is phenyl substituted with R 15 , R 16 and R 17 .
• Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 11 is selected rom i) phenyl substituted with R 18 , R 19 and R 20 , and ii) pyridinyl substituted with R 18 , R 19 and R 20 .
• a more particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 11 is phenyl substituted with R 18 , R 19 and R 20 .
• Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 12 is selected from i) H, and ii) Ci_6-alkoxy.
• Another particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 12 is Ci_6-alkoxy.
• Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 13 , R 14 , R 17 and R 20 are H.
• R 15 is selected from i) H, ii) cyano, and iii) halogen.
• a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 15 is halogen.
• Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 16 is selected from i) H, and ii) halogen.
• Another particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 16 is H.
• Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 18 is selected from i) halogen, and ii) cyano.
• Another particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 19 is selected from i) cyano, and ii) halogen.
• R 19 is selected from i) cyano, and ii) halogen.
• Particular examples of compounds of formula (I) as described herein are selected from
• the preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those persons skilled in the art. In case a mixture of enantiomers or diastereomers is produced during a reaction, these enantiomers or diastereomers can be separated by methods described herein or known to the man skilled in the art such as, e.g., chromatography on a chiral column or crystallization. The substituents and indices used in the following description of the processes have the significance given herein.
• BOC t-butyloxycarbonyl
• DBU 2,3,4,6,7, 8, 9, 10-octahydro-pyrimido[l,2-a]azepine
• DCE 1,2-dichloroethane
• DCM dichloromethane
• DEAD diethyl-azodicarboxylate
• DIAD diisopropyl-azodicarboxylate
• DCC N,N'-dicyclohexylcarbodiimide
• DMAP 4- dimethylaminopyridine
• DMF N,N-dimethylformamide
• EDCI N-(3-dimethylaminopropyl)- N'-ethylcarbodiimide hydrochloride, eq.
• HATU 0-(7-azabenzotriazol-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate
• HPLC high performance liquid chromatography
• HOBT 1-hydroxybenzo-triazole
• Huenig's base iPr 2
• NEt iV-ethyl diisopropylamine
• LAH lithium aluminum hydride
• PG protecting group
• rt room temperature
• TBAF tetrabutylammonium fluoride
• TBDMS t-butyldimethylsilyl
• TBME t- butyl methyl ether
• TBTU 0-benzotriazol-l-yl-N,N,N',N'-tetramethyl-uronium
• TFA trifluoroacetic acid
• THF trifluoroacetic acid
• Deprotection as above delivers amino-alcohol 9 (scheme 1, step e) which is ready for coupling with acid 10 (for its synthesis, see below), again under standard peptide coupling conditions to furnish penultimate intermediate 11 (scheme 1, step f).
• acid 10 for its synthesis, see below
• penultimate intermediate 11 (scheme 1, step f)
• oxidation e. g., with Dess Martin periodinane, in an inert solvent like DCM or a mixture of DCM and THF as solubilizing agent, generates the final target molecule I.
• R 11 is an optionally substituted alkyl group, it is introduced by classical alkylation with the appropriate halide, preferably an iodide, and a base, e.g., NaH or KOtBu, in a polar aprotic solvent like DMF, acetone, or acetonitrile, as indicated in scheme 3.
• halide preferably an iodide
• base e.g., NaH or KOtBu
• compound 10 in scheme 1 can be prepared as outlinded in scheme 4.
• Aldehyde or ketone 1 is reacted with a suitably protected, e.g., as TBDMS-ether, Wittig- Horner reagent 2 in the presence of a base like KOtBu or NaH in an inert solvent like THF or DMF in a temperature range between -20°C and RT to afford enolether 3 as E/Z-mixture
• a suitably protected e.g., as TBDMS-ether, Wittig- Horner reagent 2 in the presence of a base like KOtBu or NaH in an inert solvent like THF or DMF in a temperature range between -20°C and RT to afford enolether 3 as E/Z-mixture
• step e Standard hydrolysis as above, e. g., with LiOH in a mixture of water, MeOH or EtOH, and THF, in a temperature range of -20°C to RT, generates finally building block 10 (scheme 4, step e).
• step b a chiral catalyst, it is in principle possible to prepare also by this route 4, 5, 6, and 7 as pure enantiomers.
• an embodiment of the present invention is a process to prepare a compound of formula (I) as defined above comprising i) the reaction of a compound of formula (III) with a compound of formula (IV)
• an object of the present invention is a compound according to formula (I) as described herein for use as a therapeutically active substance.
• an object of the present invention is a pharmaceutical composition
• a pharmaceutical composition comprising a compound according to formula (I) as described herein and a therapeutically inert carrier.
• An object of the invention is the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of ocular diseases, in particular HtrAl -mediated ocular diseases, more particularly wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity or polypoidal choroidal vasculopathy.
• the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity or polypoidal choroidal vasculopathy.
• the present invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity and polypoidal choroidal vasculopathy.
• an object of the invention is a method for the treatment or prophylaxis of wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity and polypoidal choroidal vasculopathy, which method comprises administering an effective amount of a compound according to formula (I) as described herein.
• Human HtrAl protein comprising the catalytic and the PDZ domain from amino acid Asp 161 up to Pro480 was expressed in BL21(DE3) cells as an N-terminal fusion protein with a 6xHis-SUMO tag.
• the transformed cells were grown in LB medium at 37°C until the optical density at 600 nm was between 0.6 and 0.8. Then, the temperature was decreased to 18°C and the recombinant protein production induced by adding IPTG to a final concentration of 250 mM. Fermentation was performed over night at 18°C.
• the protein was purified to homogeneity following a four-step procedure. 40 g of cells were suspended in 50 mM HEPES pH 7.8, 250 mM NaCl, 10 mM MgCl 2 , 0.35% CHAPS, 10% glycerol containing 20 tabs per liter of EDTA-free cOmplete Protease Inhibitor (Roche) as well as 30 mg/1 DNAse and Rnase. The cells were broken by a single passage through a homogenizer at 750 bar and then centrifuged at 20'000xg for 30 minutes.
• HtrAl fusion protein was eluted within a linear gradient from 10 to 100% of the same buffer containing 500 mM imidazole.
• HtrAl containing fractions were pooled, concentrated and then applied to a Superdex S200 prep grade (XK26/100 - GE Healthcare) column equilibrated in 50 mM ethanolamine pH 9.6, 500 mM NaCl, 0.35% CHAPS, 10% glycerol, 0.02% sodium azide.
• the pooled fractions from the size exclusion chromatography were blended with SUMO protease (Life Technologies) and incubated ca. 20 hours at RT.
• HtrAl was isolated out of the reaction solution by chromatography on a Superdex S200 prep grade (XK26/100 - GE Healthcare) column equilibrated 50 mM ethanolamine pH 9.6, 500 mM NaCl, 0.35% CHAPS, 10% glycerol, 0.02% sodium azide. Fractions containing active HtrAl were pooled and concentrated. Following the above strategy 150 mg of the HtrAl (catalytical domain/PDZ construct) could be purified. As shown by RP-HPLC and SDS-PAGE, >98% pure protein was obtained.
• Enzyme activity is measured by observing the increase in fluorescence intensity caused by cleavage of a peptide substrate containing a fluorophore, whose emission is quenched in the intact peptide.
• Assay buffer 500 mM Tris pH 8.0, 200 mM NaCl, 0.025% CHAPS, 0.005% BSG Enzyme: human HtrAl Cat-PDZ, final concentration 1 nM
• PCT_Inhibition 100-100* (ARFU com pound-ARFU b i ank )/( ARFU neg ctri-ARFU b i ank ) where neg.
• Ctrl is protease with substrate and DMSO blank is as neg.
• Ctrl without protease compound is as neg.
• the compounds are added to the protease-substrate reaction mix only after 2h incubation, when all the substrate is turned over, to identify auto-fluorescent or absorbing compounds giving false positive hits.
• Example IC50 ( ⁇ ) Example IC50 ( ⁇ )
• Example IC50 ( ⁇ ) Example IC50 ( ⁇ )
• Example IC50 ( ⁇ ) Example IC50 ( ⁇ )
• the compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations).
• the pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays), rectally (e.g. in the form of suppositories) or topical ocularly (e.g. in the form of solutions, ointments, gels or water soluble polymeric inserts).
• the administration can also be effected parenterally, such as intramuscularly, intravenously, or intraocularly (e.g. in the form of sterile injection solutions).
• the compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees, hard gelatin capsules, injection solutions or topical formulations; lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.
• Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
• Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
• Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
• Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
• Suitable adjuvants for topical ocular formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.
• the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
• the dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should it be appropriate.
• the formulation can contain 0.001 to 15% by weight of medicament and the required dose, which can be between 0.1 and 25 mg, can be administered either by single dose per day or per week, or by multiple doses (2 to 4) per day, or by multiple doses per week.
• the required dose which can be between 0.1 and 25 mg
• parenteral application such as intramuscularly, intravenously, or intraocularly, the
• formulation can contain 0.001% to 15% by weight of medicament and the required dose, which can be between 0.01 and 25 mg, can be administered either by single dose per day, per week or per month, or by multiple doses (2 to 4) per day, or by multiple doses per week or per month. It will, however, be clear that the upper or lower limit given herein can be exceeded when this is shown to be indicated.
• step B 3-chloro-5-methylphenol instead of 3,5-dichlorophenol, as white crystals; MS: 323.2 (M-H) " .
• step A (3,4-dichlorophenyl)magnesium bromide instead of (3-chlorophenyl)- magnesium bromide
• step B 3-chlorophenol instead of 3,5-dichlorophenol, as white crystals; MS: 343.1 (M-H) ⁇ .
• step B 5-hydroxybenzene-l,3-dicarbonitrile instead of 3,5-dichlorophenol, as white solid; MS: 325.2 (M-H) ⁇ .
• step B 5-chloropyridin-3-ol instead of 3,5-dichlorophenol, as white foam; MS: 310.2 (M-H) ⁇ .
• step A (3,5-dichlorophenyl)magnesium bromide instead of (3-chlorophenyl)- magnesium bromide
• step B 3-chlorophenol instead of 3,5-dichlorophenol, as yellow semisolid; MS: 343.2 (M-H) ⁇ .
• step A (R)-methyl oxirane-2-carboxylate instead of (S)-methyl oxirane-2- carboxylate and (3,5-dichlorophenyl)magnesium bromide instead of (3-chlorophenyl)- magnesium bromide, respectively, and in step B] 3-chlorophenol instead of 3,5-dichlorophenol, as white solid; MS: 343.2 (M-H) " .
• step B 3-chloro-5-hydroxybenzonitrile instead of 3,5-dichlorophenol, as colorless oil; MS: 334.1 (M-H) ⁇ .
• step A (3-fluorophenyl)magnesium bromide instead of (3-chlorophenyl)- magnesium bromide
• step B 5-hydroxyisophthalonitrile instead of 3,5-dichlorophenol, white solid; MS: 309.1 (M-H) ⁇ .
• step A (3-fluorophenyl)magnesium bromide instead of (3-chlorophenyl)- magnesium bromide, and in step B] 3-hydroxybenzonitrile instead of 3,5-dichlorophenol, as white solid; MS: 284.1 (M-H) ⁇ .
• step A (3-fluorophenyl)magnesium bromide instead of (3-chlorophenyl)- magnesium bromide
• step B 3-chlorophenol instead of 3,5-dichlorophenol, as white solid; MS: 293.1 (M-H) ⁇ .
• a compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet
• a compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule

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• 2017
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